v.2, n.2, abr./jun. 2012ISSN 2236-1960

Editorial

1

Copyright © 2012 Autopsy and Case Reports – This is an Open Access article distributed of terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any médium provided article is properly cited.

a Hospital Universitário - Universidade de São Paulo - São Paulo/SP – Brazil.

Autopsy and Case Reports 2012; 2(2): 1-3

1

Sharing experience through case reports

Fernando Peixoto Ferraz de Camposa

Campos FPF. Sharing experience through case reports [editorial]. Autopsy Case Rep [Internet]. 2012;2(2):1-3. http://dx.doi.org/10.4322/acr.2012.010

Even before the time of Hippocrates, case reports have provided rich resources for teaching and research in medicine,1,2 despite the disparaging attention given by the scientific community to these reports in comparison with other types of publications. Not only have clinicians been learning from their more experienced peers, but also from their own work with their individual patients for a very long time. Accurate recounting of clinical experience continues to be essential to the progress of medicine, even in the modern era of evidence-based medicine, where, in the pinnacle of this hierarchy, are found the randomized clinical trials, systematic reviews and meta-analysis.3,4,5

Shunned by some, adored by others, case reports are sometimes regarded by researchers and physicians as anecdotal descriptions, underestimating their value and importance. However, few of them know that the Greek word for anecdote (anekdota) means “unpublished;” and according to the Oxford Dictionary one of the meanings is the narrative of an interesting or striking incident or event case.2

Nathan (1967) pointed out several case reports that have become famous and important in the history of medicine, as the case of Phineas Gage, the man who had a four-foot iron bar blown through his frontal lobes and whose immortal remains are now in the Harvard Museum. The importance of this “striking incident or event” was not grasped at the time. Had it been realized that one could interfere with large masses of the cerebral hemispheres without killing the patient, and that great damage to the frontal lobes need cause no obvious intellectual

defect, neurosurgery might have been conceived 40 years earlier. The frontal lobes were believed to be the seat of all intellectual activities, and their relation to personality was not known at the time, although Phineas Gage showed some astounding changes in this respect.2

At the turn of the last century, Sir William Osler, author of many scientific observations, ever encouraged other physicians to record and publish the unusual.1,6,7

In 1981, a case report published in the American Journal of Dermatopathology was the first published account of what is now called AIDS.8 Another recent and prominent example of the usefulness of case reports in clinical medicine was the publication of a case series during the outbreak of Shiga-toxin producing Escherichia coli, a type of enterohemorrhagic E. coli, in Germany in mid-2011.9,10

Case reports can describe important scientific observations that are missed or undetectable in clinical trials; provide insightful information that expands our knowledge and spawns new research; and provide information that strays from the classical textbook and leads to better and safer patient care.11

Notwithstanding the plurality of evidence and benefits that case reports bring to the scientific community, it appears that there is a lack of enthusiasm by the novice doctors to devote part of their time to produce and share their knowledge. We believe that even the most experienced doctors show

2

Autopsy and Case Reports 2012; 2(2): 1-3 Campos FPF.

needs to be overcome. Many doctors would like to engage in great scientific projects, for which they are not properly qualified or trained. Frustrated with the inability to develop them, they forget they could focus on more achievable publications.

Case reports are also important educational tools to both authors and readers. These reports often serve as a clinician’s first experience with scholarly writing and provide an important training ground in manuscript preparation and publication.9

Every medical student, resident, or novice doctor, should be encouraged and guided toward scientific production, which should include publications such as case reports, review, and research articles. This represents a unique opportunity to gain experience in scientific writing and learn from their clinical mentors. Medical schools and related educational institutions should require their teachers to encourage and guide the beginners in this manner.

Autopsy and Case Reports is an electronic medical journal that shares the same opinion, encouraging the medical community to publish clinical case reports, autopsy case reports, and surgical pathology case reports.

REFERENCES

1. McCarthy LH, Reilly KEH. How to write a case report. Fam Med. 2000;32:190-5. PMid:10726220.

2. Nathan PW. When is an anecdote? Lancet. 1967;2:607. http://dx.doi.org/10.1016/S0140-6736(67)907544

3. Jenicek M. Clinical case reporting in evidence-based medicine. 2nd ed. London: Arnold; 2001.

4. Kidd M, Hubbard C. Introducing Journal of Medical Case Reports. J Med Case Reports. 2007;1:1. PMid:17411446 PMCid:1839763. http://dx.doi.org/10.1186/1752-1947-1-1

5. Yitschaky O, Yitschaky M, Zadik Y. Case report on trial: Do you, Doctor, swear to tell the truth, the hole truth and nothing but the truth? J Med Case Reports. 2011;5:179. PMid:21569508 PMCid:3113995. http://dx.doi.org/10.1186/1752-1947-5-179

6. Coccia CT, Ausman JI. Is a case report an anecdote? In defense of personal observations in medicine. Surg Neurol. 1987;28:111-3. http://dx.doi.org/10.1016/0090-3019(87)90082-6

little interest or initiative to engage in this activity. Likewise, some renowned periodicals, with a high impact index, do not drive the same emphasis to publish case reports and their acceptance process takes many twists and turns until the paper fits their requirements. Journals that do publish case reports are very demanding on several criteria, especially that of uniqueness. Novelty is a criterion commonly cited by authors and editors when validating the importance of a case report. However, a truly unique case is a rare event in clinical practice, and by focusing solely on novelty, many novice authors de-emphasize the educational value of their reports.9

Cases that increase the awareness of an unusual condition, describe a rare presentation of a common condition, or identify innovative treatment and diagnostic strategies are valuable additions to the medical literature whether they are novel or not.9,12 Nathan pointed out that although an observation may be uncommon, unless it is reported, the frequency of its occurrence cannot be tabulated.2

A case report can thus be defined and judged by the importance, clarity, and practicality of its educational message.7 When one case has been reported, other doctors become aware of the complication and look out for it; thus, the frequency of the complication can eventually be assessed. Sometimes we think that something we have observed or learned from a patient is unique, whereas, in fact, it is uncommon but not unique.

Case reports can serve several purposes: they offer their readers a recognition pattern to identify similar rare cases in their own practices; they alert readers to new and rare adverse reactions to drugs; and they highlight innovations in medical management, dilemmas in medical ethics, and progress in medical education.9 Given the broad range of topics that can be legitimately highlighted in a case report, there may be many instances during one’s medical career when it may be appropriate to write a case report.

When reporting clinical cases, the author faces some barriers. Some consider the greatest to be lack of time in the doctor’s life, followed by the unfamiliarity with the publication process. Indeed, this process requires time, will and determination. The main obstacle for publication is the intimidation caused by the physician’s self-assessment of his incapacity for this task, followed by ignorance of the demands of the process. Moreover, the inertia

3

Sharing experience through case reports Autopsy and Case Reports 2012; 2(2): 1-3

7. Chelvarajah R, Bycroft J. Writing and publishing case reports: the road to success. Acta Neurochir (Wien). 2004;146:313-6 PMid:15015057. http://dx.doi.org/10.1007/s00701-003-0203-2

8. Gottlieb GJ, Rogoz A, Vogel JV, et al. A preliminary communication on extensively disseminated Kaposi’s sarcoma in a young homosexual man. Am J Dermatopathol. 1981;3:111-4. PMid:7270808. http://dx.doi.org/10.1097/00000372-198100320-00002

9. Carleton HA, Webb ML. The case report in context [editorial]. Yale J Biol Med. 2012;85:93-6. PMid:22461747 PMCid:3313543.

Correspondence: Fernando Peixoto Ferraz de Campos Scientific Editor Autopsy and Case Reports Assistant Physician of Internal Medicine Division Hospital Universitário - Universidade de São Paulo, São Paulo/SP - Brazil E-mail: ffcampos@usp.br

10. Frank C, Werber D, Cramer JP, et al. Epidemic profile of Shiga-toxin-producing Escherichia coli O104:H4 outbreak in Germany. N Engl J Med. 2011;365:1771-80. PMid:21696328. http://dx.doi.org/10.1056/NEJMoa1106483

11. Cohen H. How to write a patient case report. Am J Health-Syst Pharm. 2006; 63:1888-92. PMid:16990637. http://dx.doi.org/10.2146/ajhp060182

12. Vandenbroucke JP. Case reports in an evidence-based world. J R Soc Med. 1999;92:159-63. PMid:10450190 PMCid:1297135.

Article Artigo

5

Copyright © 2012 Autopsy and Case Reports – This is an Open Access article distributed of terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any médium provided article is properly cited.

a Institut of Heart - Faculdade de Medicina - Universidade de São Paulo, São Paulo/SP - Brazil.

b Diagnostic Imaging Service - Hospital Universitário - Universidade de São Paulo, São Paulo/SP - Brazil. c Department of Radiology - Faculdade de Medicina - Universidade de São Paulo, São Paulo/SP - Brazil.

Autopsy and Case Reports 2012; 2(2): 5-10

5

Using the Graf method of ultrasound examination to classify hip dysplasia in neonates

Bruno de Castro Paixão Jacobinoa, Mariana Domingues Galvãoa, Adriano Ferreira da Silvab, Cláudio Campi de Castrob,c

Jacobino BCP, Galvão MD, Silva AF, Castro CC. Using the Graf method of ultrasound examination to classify hip dysplasia in neonates. Autopsy Case Rep [Internet]. 2012;2(2):5-10. http://dx.doi.org/10.4322/acr.2012.018

ABSTRACT

Developmental dysplasia of the hip (DDH) is one of the most common congenital orthopedic anomalies. Ultrasound examination employing the Graf method is used to diagnose DDH. We conducted a retrospective cross-sectional study of 222 neonatal patients (140 females and 82 males) submitted to ultrasound examination of the right and left hips between January of 2009 and May of 2011. The mean age was 5.0 days. The patients were grouped by laterality, mean alpha (α) and beta (β) angles (in degrees), and hip type (as determined by the Graf classification). The data collected were statistically correlated. Mean α angle values were higher in males than in females, as well as being higher for right hips than for left hips (p < 0.001). In contrast, mean β angle values were lower in males than in females, as well as being lower for right hips than for left hips (p < 0.001). Type Ia hips (i.e., mature hips) predominated in both genders and on both sides, having been found in 82.32% of the examinations of males and in 71.09% of those of females. The right hip was classified as type Ia in 78.38% of the examinations, and the left hip was classified as type Ia in 72.07%. Type IIa hips (i.e., immature hips) were found in 12.8% of the examinations of males and in 20% of those of females. The right hip was classified as type IIa in 13.96% of the examinations, and the left hip was classified as type IIa in 20.72%. The remaining hip types were less common. We emphasize the importance of ultrasound as a standard method of screening for DDH.

Keywords: Hip Dislocation; Ultrasonography; Congenital Abnormalities; Infant; Newborn.

INTRODUCTION

The term congenital dislocation of the hip has traditionally been used in order to describe infant hip abnormalities that can progress to dislocation. Developmental dysplasia of the hip (DDH) is currently the preferred term and denotes the same range of hip problems but also includes hips that

have not been classified as dislocated but are poorly developed, as well as hips that are determined to be abnormal after the neonatal period.1

Although the new term has been adopted by the American Academy of Pediatrics, the American Academy of Orthopedic Surgeons, and the Pediatric Orthopedic

6

Autopsy and Case Reports 2012; 2(2): 5-10 Jacobino BCP, Galvão MD, Silva AF, Castro CC.

femoral head moving over the posterior rim of the acetabulum and relocating in the cavity.1-4

The Barlow test is a maneuver in which the examiner attempts to dislocate the unstable hip. The thighs of the patient are held at a right angle to the trunk, in an adduction position; the knee of the child will exert force in a vertical direction to the hip, in an effort to dislocate the femoral head from within the acetabulum. The examiner looks for laxity in the hip being examined, a sign that may or may not be accompanied by a “clunk”. The top of the femur is held between the index and middle fingers and over the greater trochanter, and the thumb is placed on the groin. The femoral head can be levered into and out of the joint, confirming the instability of the hip.1-4

Since the publication of an early study conducted by Graf,5 ultrasound of the hip has gained wide acceptance as the primary method of screening for, diagnosing, and monitoring the treatment of DDH in infants. At facilities in Brazil, the static ultrasound examination introduced by Graf in 1980 and the dynamic ultrasound examination recommended by Harcke et al. in 1985 continue to be the most widely used methods.1,2 In addition to being fast and completely innocuous, ultrasound examination requires no contrast agents nor anesthesia.2 For static ultrasound examination, the patient is placed in the lateral decubitus position with the hips slightly flexed, adducted, and medially rotated (Figure 1), and a coronal sonogram is obtained with a high-resolution (5- to 10 MHz) linear transducer.4

In the Graf method, the hip is evaluated by measuring two angles formed by three lines drawn

Society of North America, it has yet to be universally employed.1

In 1927, Hey-Groves defined DDH as a disease that is silent, painless, and difficult to diagnose, and that inevitably has disastrous consequences if it is not treated in a timely manner.1

In cases of subluxation of the hip, the femoral head is displaced from its normal anatomical position but still maintains some contact with the acetabular cavity. In cases of hip dislocation, there is no contact between the femoral head and the acetabular cavity. An unstable hip is the one reduced in the acetabulum but can be provoked to subluxate or dislocate.2

The incidence of DDH is variable and depends on many factors, including geographic region of birth/genetics; for instance, the incidence of DDH is higher among Italians and those of Italian descent (including those who emigrate to other geographic regions).3 It has been estimated that approximately 1 in every 1,000 neonates is born with hip dislocation, and that approximately 10 in every 1,000 neonates are born with hip subluxation (unstable hip).3

The neonatal risk factors for DDH include being female; being White; having a primiparous young mother; having been a breech presentation; having suffered from oligohydramnios; having a family history of DDH; being above average in terms of weight and length; and having foot or spinal column deformities.3,4 One of the most common congenital orthopedic anomalies, DDH can lead to changes of a disabling nature, hence the need for early diagnosis and treatment (on the first day of life, if possible).2

Regarding the clinical diagnosis of DDH, there is no consensus in the literature regarding the best DDH evaluation protocol. The Ortolani and Barlow tests are the standard techniques for the detection of hip instability in neonates.1-4 The efficacy of those tests is variable, due to the experience of the examining doctor.4 In order to perform theses maneuvers, the hips of the infant are flexed to 90°, the thumbs of the examiner are placed on the medial proximal thigh, and the fingers are placed over the greater trochanter. In the Ortolani test, the contralateral hip is held still while the thigh being tested is abducted and gently pulled anteriorly. The sensation of instability in a positive Ortolani test is the palpable and sometimes audible “clunk” of the

Figure 1 – Patient positioning for ultrasound examination of the hip. The patient is placed in the lateral decubitus position with the hips slightly flexed, adducted, and medially rotated.

7

Using the Graf method of ultrasound examination to classify hip dysplasia in neonates Autopsy and Case Reports 2012; 2(2): 5-10

• Type Ia and Ib hips are mature hips;

• Type IIa hips are immature hips;

• Type IIb and IIc hips are dysplastic hips;

• Type IIIa and IIIb hips are subluxated; and

• Type IV hips are dislocated.

The treatment of DDH depends on the age of the child4:

• Children aged ≤6 months are placed in a Pavlik harness, which maintains the hips flexed and abducted;

• Children aged 6-18 months undergo closed reduction and spica casting; and

• Children aged >18 months undergo open reduction and spica casting.

The objective of this article was to draw a profile of the incidence of the various Graf hip types on the basis of the ultrasound examinations, as well as to correlate that incidence with age; gender; laterality; the α and β angles; and the Graf classification.

from three landmarks, namely the lateral edge of the acetabulum, the bottom of the acetabulum, and the acetabular labrum. These three lines are: the bony roof line, the baseline, and the cartilage roof line measured at the acetabular labrum (Figure 2). After these lines have been drawn, the bony roof angle (known as the alpha [α] angle) and the cartilage roof angle (known as the beta [β] angle) are determined (Figure 3).2-4

The Graf classification is shown in Table 1. The α and β angle values are correlated with a scale of severity4:

Figure 2 – Infant hip joint components as seen on ultrasound examination.

Figure 3 – A - Measurement of the bony roof angle (α angle); B - Measurement of the cartilage roof angle (β angle).

8

Autopsy and Case Reports 2012; 2(2): 5-10 Jacobino BCP, Galvão MD, Silva AF, Castro CC.

the left (Figure 4), whereas the mean β angles were 51.2 ± 6.13° for the right hip and 52.03 ± 5.97° for the left (Figure 5).

In the male patients, the mean α angles were 63.1 ± 3.77° for the right hip and 62.5 ± 4.07° for the left (Figure 4), whereas the mean β angles were 50.1 ± 4.90° for the right hip and 51.5 ± 6.87° for the left (Figure 5).

As shown in Table 2, type Ia hips predominated in both genders and on both sides, the right hip having been classified as type Ia in 174 examinations (78.38%) and the left hip having been classified as type Ia in 160 (72.07%). As shown in Table 3, type Ia hips were found in 135 (82.32%) of the examinations of male patients and in 199 (71.09%) of the examinations of female patients.

Type IIa hip was the second most common hip type, having been found in 21 (12.8%) of the examinations of male patients and in 56 (20%) of the examinations of female patients. As shown in Tables 2 and 3, the right hip was classified as type IIa in 31 examinations (13.96%), compared with 46 examinations (20.72%) for the left hip. The remaining hip types were less common (Tables 2 and 3). None of the patients under study presented with type IV hips.

METHODS

We conducted a qualitative, retrospective cross-sectional study by reviewing the medical records of 222 children who were born at or admitted to the University of São Paulo University Hospital and who underwent ultrasound examination of the right and left hips (initial examination) in the Department of Diagnostic Imaging between January of 2009 and May of 2011. The patients were stratified by gender, as well as by age (<1 month of age; 1-3 months of age; and >3 months of age).

We collected the mean values of the α and β angles (in degrees), as well as the hip types, i.e., Ia, Ib, IIa, IIb, IIc, IId, IIIa, IIIb, and IV, as determined by the Graf classification. The data collected were statistically correlated by the paired t-test, Pearson's correlation test, and the nonparametric Mann-Whitney test.

RESULTS

Of the 222 patients evaluated, 140 were female and 82 were male. The mean age was 5.0 days. In the female patients, the mean α angles were 60.7 ± 4.96° for the right hip and 60.2 ± 4.58° for

Table 1 – Classification of developmental dysplasia of the hip according to Graf and modified by Sernik & Cerri4

TypeBony roof

PromontoriumCartilaginous roof

Ageα angle β angle

I

Good

Angular or slightly rounded

Extends to a greater distance

AnyIa (β ≤ 55°)

≥60°Extends to a greater distance

Ib (β > 55°)

IIa+ Adequateα between 50-59° Rounded Covers the femoral head 0-12 weeks

IIa- Deficientα between 50-59° Rounded Covers the femoral head 6-12 weeks

IIb Deficientα between 50-59° Rounded Covers the femoral head >12 weeks

IIc Highly deficientα between 43-49° Rounded to flat Covers the femoral head β ≤ 77° Any

IId Highly deficient43-49° Rounded to flat Dislocated β > 77° Any

IIIa Poor α < 43° FlatShifted superiorly and normal echogenicity

Any

IIIb Poor α < 43° Flat Shifted superiorly and hyperechoic Any

IV Poor α < 43° Flat Shifted inferiorly Any

9

Using the Graf method of ultrasound examination to classify hip dysplasia in neonates Autopsy and Case Reports 2012; 2(2): 5-10

(12.5%) were suspected of having DDH; of those, 28 (9.7%) were suspected of having type IIa hips and 8 (2.7%) were suspected of having type IIb hips.

In the present study, α angle values were found to be higher in the male patients (p < 0.001, as assessed by Pearson's correlation coefficient), a finding that is consistent with those reported in the literature. Sernik & Cerri4 reported that the presence of relaxin (a hormone produced by the ovaries during pregnancy) constitutes a predisposing factor for DDH, given that the hormone can cause capsular and ligamentous laxity, especially in female fetuses. In the present study, there were no statistically significant correlations between gender and mean β angles.

Regarding laterality, α angle values were higher for the right hip, whereas β angle values were lower (p < 0.001, as assessed by Pearson's correlation test). However, there were no statistically significant differences between sides in terms of the numbers of Graf’s classification hips. Sernik & Cerri4 reported that the incidence of DDH is up to 3 times as high in the left hip as it is in the right because the spinal column of the fetus is generally to the left of the mother in fetuses in cephalic presentation, which leads to limited abduction of the left hip.

One of the criticisms leveled at ultrasound is that it is operator-dependent and the interpretation of the same image by different examiners can lead to different approaches. Interobserver and intraobserver reliability has been widely studied, especially in terms of the Graf classification. According to Theis8, intraobserver reliability is good, whereas interobserver is only moderate.

Figure 4 – Mean α angles by gender.

Figure 5 – Mean β angles by gender. (NS, not significant).

Table 3 – Distribution of hip types (as determined by the Graf classification) by gender

Graf hip type

Gender

Male Female

(n) (%) (n) (%)

Ia 135 82.32 199 71.07

Ib 6 3.66 17 6.07

IIc 21 12.80 56 20.00

IIb 1 0.61 3 1.07

IIc 1 0.61 3 1.07

IIIa 0 0.00 2 0.71

IIIb 0 0.00 0 0.00

TOTAL 164 100.00 280 100.00

Table 2 – Distribution of hip types (as determined by the Graf classification) by laterality

Graf hip type

Right Right Left Left

(n) (%) (n) (%)

Ia 174 78.38 160 72.07

Ib 12 5.41 11 4.95

IIa 31 13.96 46 20.72

IIb 2 0.90 2 0.90

IIc 2 0.90 1 0.45

IIIa 1 0.45 1 0.45

IIIb 0 0 1 0.45

Total 222 100 222 100

DISCUSSION

The analysis of the data collected revealed a predominance of type Ia hips (regardless of gender) in our study sample, a finding that is consistent with those reported in the literature. Baronciani et al.6 examined 3,509 patients and found type Ia right and left hips in 50.1%; type IIa hips in 44.8%; type IIc hips or type IId hips in 4.5%; and type III or IV hips in 0.6%. Gharedaghi et al.7 performed ultrasound examination of 288 neonates and found that 36

10

Autopsy and Case Reports 2012; 2(2): 5-10 Jacobino BCP, Galvão MD, Silva AF, Castro CC.

REFERENCES

1. French L, Dietz FR. Screening for developmental dysplasia of the hip. Am Fam Physician. 1999;60(1):187-8.

2. Milani C, Ishida A, Laredo Filho J, Kuwajima SS, Dodashi ET. Diagnóstico e tratamento da displasia do desenvolvimento do quadril. Diagn Tratamento. 2002;7(2):29-34. Portuguese.

3. Guarniero R. Displasia do desenvolvimento do quadril: uma atualização. Rev Bras Ortop. 2010;45(2):116-21. Portuguese. http://dx.doi.org/10.1590/S0102-36162010000200002

4. Sernik R, Ascencio JEB. Quadril. In: Cerri GG, Sernik R. Ultrassonografia do sistema musculoesquelético: correlação com ressonância magnética. Rio de Janeiro: Revinter; 2009. p. 259-315. Portuguese.

5. Graf R. The diagnosis of congenital hi-joint dislocation by the ultrasonic compound treatment. Arch Orthop Trauma Surg. 1980;97(2):117-33. http://dx.doi.org/10.1007/BF00450934

6. Baronciani D, Atti G, Andiloro F, et al. Screening for developmental dysplasia of the hip: from theory to practice. Pediatrics. 1997;99(2):e5. PMid:9099762. http://dx.doi.org/10.1542/peds.99.2.e5

7. Gharedaghi M, Mohammadzadeh A, Zandi B. Comparison of clinical and sonographic prevalence of developmental dysplasia of the hip. Acta Med Iran. 2011;49(1):25-7. PMid:21425067.

8. Theis JC, Vane A. The role of ultrasound in developmental dysplasia of the hip. Indian J Orthop 2003;37(4):215-22.

9. Dias JJ, Thomas IH, Lamont AC, Mody BS, Thompson JR. The reliability of ultrasonographic assessment of neonatal hips. J Bone Joint Surg Br. 1993;75(3):479-82. PMid:8496227.

10. Cheng JCY, Chang YL, Hui PW, Metreweli C. Ultrasonographic hips morphometry in infants. J Pediatr Orthop. 1994;14(1):24-8. PMid:8113366. http://dx.doi.org/10.1097/01241398-199401000-00006

Dias et al.9 showed that α and β angle measurements are reasonably reproducible, while Cheng et al.10 found that the α angle was the most reliable measurement.9

In fact, in the literature, there is still no gold standard method for the evaluation of the infant hip. Because of its ease of use, ultrasound is the method that is most widely used for that purpose. However, to increase diagnostic accuracy, ultrasound findings should be correlated with clinical data.

CONCLUSION

Most of the ultrasound examinations reviewed in the present study revealed the presence of type I hips (i.e., mature hips). A diagnosis of DDH was found to be most common in females and in the left hip, which is in agreement with data in the literature. We emphasize the importance of performing ultrasound examination employing the Graf method, which represents the standard method of screening for DDH in neonates and infants, despite the low incidence of ultrasound examinations showing signs of positivity for DDH. Data in the literature indicate that all neonates should undergo ultrasound examination as part of the screening for DDH. Unfortunatelly, not all hospitals are yet equipped to adopt this systematic approach. In order to evaluate the largest possible number of cases, ultrasound of the hip is currently performed in all neonates with risk factors for DDH and with clinical findings suggestive of such. Further prospective studies should compare the results of static ultrasound examination with those of dynamic ultrasound examination, especially in patients in whom static ultrasound examination is normal despite a high suspicion or a confirmed diagnosis of DDH (i.e., those already under treatment).

Conflict of interest: None

Submitted on: 16th January 2012 Accept on: 15th March 2012

Correspondence: Serviço de Iconologia Av. Prof. Lineu Prestes, 2565 – Cidade Universitária - São Paulo/SP – Brazil CEP: 05508-000 – Phone: +55 (11) 3091-9301 E-mail: adrimedsilva@uol.com.br

Article / Autopsy Case Report Artigo / Relato de Caso de Autópsia

11

Copyright © 2012 Autopsy and Case Reports – This is an Open Access article distributed of terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any médium provided article is properly cited.

a Department of Internal Medicine - Hospital Universitário - Universidade de São Paulo, São Paulo/SP - Brazil. b Anatomic Pathology Service - Hospital Universitário - Universidade de São Paulo, São Paulo/SP - Brazil. c Department of Pathology - Faculdade de Medicina - Universidade de São Paulo, São Paulo/SP - Brazil.

Autopsy and Case Reports 2012; 2(2): 11-20

11

Hemophagocytic lymphohistiocytosis of indeterminate cause: a fatal adult case

Fernando Peixoto Ferraz de Camposa, Patrícia Picciarelli de Limab, Fabiana Roberto Limab, Angélica Braz Simõesb, Elizabeth In Myung Kima,

Luciana Andréa Avena Smeilia, Maria Claudia Nogueira Zerbinic

Campos FPF, Lima PP, Lima FR et al. Hemophagocytic lymphohistiocytosis of indeterminate cause: a fatal adult case. Autopsy Case Rep [Internet]. 2012;2(2):11-20. http://dx.doi.org/10.4322/acr.2012.011

ABSTRACT

Hemophagocytic lymphohistiocytosis (HLH) is an uncommon life-threatening disorder characterized by wide spread non-neoplastic proliferation and inappropriate activation of mature macrophages resulting in hypercytokinemia. This uncontrollable and ineffective systemic immune response causes fever, hepatosplenomegaly, cytopenias and subsequently multiorgan failure. The authors report a case of a 41-year-old male patient with a 30-day history of weight loss, fever, icterus, hepatomegaly, and cytopenias. The diagnostic workup disclosed hypertriglyceridemia, hypofibrinogenemia, and elevated ferritin. Bone marrow examination and clinical course raised the suspicion of HLH and treatment was started with high-dose corticosteroids and immune globulin. The patient underwent multi-organ failure and expired after 58 days of hospitalization. The autopsy finding included massive bone marrow infiltration by non-neoplastic histiocytes, many of them showing hemophagocytosis, which immunohistochemical study revealed diffuse CD68-positive histiocytes, which were negative for S100 protein. Hemophagocytosis was also observed in the lungs, lymph nodes and liver. The immediate cause of death was attributed to a massive intestinal bleeding due to extensive ischemic necrosis at the duodenum/jejunal transition area.

Keywords: Hemophagocytic syndrome; Hemophagocytic lymphohistiocytosis; Macrophage activation; Autopsy.

CASE REPORT

A 41-year-old male patient sought medical attention complaining of daily high-grade fever accompanied by night sweats and 20 kg of weight loss during the last month. He reported that he was experiencing anorexia, asthenia, and progressive lower-limb weakness and recently noted jaundice. His past medical history included hypertension.

He used to drink a lot of alcohol in the past, still smokes and was taking captopril regularly. Physical examination upon admission showed an apparently healthy man, febrile, slightly dehydrated, and icteric. His blood pressure = 120 / 75 mmHg, pulse rate = 106 beats per minute, respiratory rate = 18 respiratory movements per minute, axillary

12

Autopsy and Case Reports 2012; 2(2): 11-20 Campos FPF, Lima PP, Lima FR, et al.

requiring vasopressors and mechanical ventilation. Supportive care involved frequent red cell, platelets, and plasma transfusions. The revision of the bone marrow aspirate hemophagocytosis was detected, which raised the possibility of a diagnosis of hemophagocytic lymphohistiocytosis (HLH). High-dose methylprednisolone (1 g/day for 3 days) was started in conjunction with gamma globulin therapy 30 g/day for 5 days as well as broad-spectrum antibiotics. A slight clinical improvement was observed. On day 25 of hospitalization, the patient underwent a splenectomy and liver biopsy. The procedures were undertaken to confirm the diagnosis as well as to definitively exclude the diagnostic possibility of lymphoid malignancy.

The splenic pathologic examination revealed massive infiltration of the splenic sinusoids by plump phagocytic histiocytes, associated with 95% of ischemic necrosis of the splenic parenchyma and atrophy of the residual white pulp (Figure 1). The liver biopsy revealed Kupffer cell hyperplasia as well as hemophagocytosis.

Cyclosporine could not be started once the patient developed septicemia. The patient died on day 58 of hospitalization. An autopsy was performed.

AUTOPSY

Among the autopsy findings, histopathological examination revealed massive bone marrow infiltration by non-neoplastic histiocytes, many of them showing hemophagocytosis (the presence of red blood cells, granulocytes and their precursors,

body temperature = 38 °C, body mass index = 21.6. Peripheral lymph node enlargement was not detected. Thorax examination showed the presence of a mild systolic murmur in the mitral valve area, and the lung examination was normal. Abdominal examination showed a palpable liver 1 cm below the right costal margin, as well as painful splenomegaly 5 cm below the left costal margin. The remainder of the physical examination was unremarkable.

Initial laboratory workup is shown in Table 1 and Table 2 summarizes the etiologic investigation.

The upper gastrointestinal endoscopy disclosed an enanthematic pangastritis. Echocardiography was normal. Abdominal ultrasonography showed a splenomegaly with hypoechoic areas within the splenic parenchyma, confirmed by the abdominal computed tomography.

The bone marrow aspiration showed hypercellularity at the expense of the granulocytic series, confirmed on the bone marrow biopsy, which also showed hyperplasia of the megakaryocytic series. On this biopsy, the presence a micro granuloma was also depicted. The Ziehl-Neelsen, Grocott and PAS staining failed to show the presence of acid-fast bacilli and fungi. The bone marrow immunophenotyping did not detect any evidence of lymphoma.

During hospitalization, the patient remained febrile, presented worsening hepatic function, and renal failure demanding hemodialysis. Clinical status was complicated even more with respiratory failure related to presumed pulmonary infection

Table 1 – Initial laboratory examination work up

Exam Result RV Exam Result RV

Hemoglobin 14.8 12.3-15.3 g/dL AST 443 10-31 U/L

Hematocrit 43.7 36.0-45.0% ALT 404 9-36 U/L

Leukocytes 4.78 4.4-11.3.10³/mm3 Alkaline phosphatase 719 10-100 U/L

Rods 0 1-5% γGT 368 2-30 U/L

Segmented 55 46-75% Total bilirubin 9.6 0.3-1.2 mg/dL

Eosinophil 0 1-4% LDH 1274 120-246 U/L

Basophil 2 0-2.5% INR 1.69 1

Lymphocyte 31 18-40% Fibrinogen 67 175-400 mg/dL

Monocyte 12 2-9% Triglycerides 617 <150 mg/dL

Platelet 91.7 150-400.10³/mm3 Ferritin >16500 22-322 ng/mL

ALT = alanine aminotransferase; AST = aspartate aminotransferase; γGT = gamma-glutamyl transferase; INR = international normalization ratio; LDH = lactate dehydrogenase; RV = reference value.

13

Hemophagocytic lymphohistiocytosis of indeterminate cause: a fatal adult case Autopsy and Case Reports 2012; 2(2): 11-20

was positive in small clusters of B-lymphocytes and rare in interstitial lymphocytes; CD3, CD2, and CD5 were positive in interstitial small T-lymphocytes. No other malignancy was present. The histological and immunohistochemical findings observed in the bone marrow were similar to the previous bone marrow biopsy performed during hospitalization.

Hemophagocytosis was also observed in the lungs where the histiocytes were detected in the alveolar lumen (Figure 3). The lymph nodes exhibited hemophagocytosis associated with lymphoid depletion (Figure 4).

The examination of the liver also showed the diffuse presence of hemophagocytic histiocytes throughout the hepatic sinusoids (Figure 5). Extensive areas of ischemic centrilobular necrosis, probably related to the septic shock, were also observed.

The examination of the remaining organs revealed pathological changes associated with

platelet debris as well as lymphocytes encompassed into the cytoplasm of the activated histiocytes) (Figure 2). The immunohistochemical study revealed diffuse CD68-positive histiocytes, which were negative for S100 protein. Other markers were used to evaluate the hematopoietic series and to rule out the presence of lymphomatous infiltration. CD20

Table 2 – Serologic investigation

Exam Result

Anti-HIV Negative

Anti-CMV (IgG and IgM) Negative

Syphilis (VDRL and TPHA) Negative

Anti EBV IgG+/IgM–

Hepatitis B Negative

Anti-HCV Negative

Toxoplasmosis IgG+/IgM–

Anti-S. mansoni (IgM) Negative

Rheumatoid Factor <15 UI/mL

ANF (Hep 2) Negative

Figure 1 – Photomicrography of the spleen. A - Ischemic necrosis of the splenic parenchyma and atrophy of the residual white pulp (HE, 100X); B - Massive infiltration of the splenic sinusoids by phagocytic histiocytes (arrow, with a hematologic precursor cell inside the cytoplasm) (HE 400X); C - Immunohistochemical reaction reveals the CD68 positive histiocytes (Immunoperoxidase for CD 68).

Figure 2 – Photomicrography of the bone marrow. A - Panoramic view of bone marrow shows hypercellularity (HE 100X); B - Massive bone marrow infiltration by non-neoplastic histiocytes, many of them showing hemophagocytosis (HE, 400X); C - Immunohistochemical reaction reveals the CD68 positive histiocytes (Immunoperoxidase for CD 68).

14

Autopsy and Case Reports 2012; 2(2): 11-20 Campos FPF, Lima PP, Lima FR, et al.

infarction, and hemorrhage of the adrenal gland cortex, foci of ischemic necrosis of pancreatic acini, ischemic pituitary infarct, and skin ulcerations.

DISCUSSION

The term hemophagocytosis describes the pathologic finding of activated macrophages, engulfing erythrocytes, leukocytes, platelets, and their precursor cells. This phenomenon is an important finding in patients with hemophagocytic syndrome (HS), also known as hemophagocytic lymphohistiocytosis (HLH). This rare and frequently fatal disorder is characterized by unregulated

Figure 3 – Photomicrography of the lung. A - The alveolar lumen shows many histiocytes. (HE, 200X); B - Hemophagocytosis (arrow) (HE, 1000X).

Figure 4 – Photomicrography of the lymph nodes. A - Lymphoid depletion. (HE, 200X); B - Histiocytes in the lymph node sinuses show hemophagocytosis (arrows) (HE, 400X).

infection and septic shock. The lungs were congested; the right lung weighted 639.0 g (reference value RV = 450.0 g) and the left lung weighted 432.0 g (RV = 375.0 g). Microscopically, intra-alveolar edema and massive congestion were present, as well as hemophagocytic histiocytes into the alveolar lumen. Ischemic injuries were found in many organs, very likely due to the septic shock. The duodenum/jejunal transition area showed extensive mucosal injury and diffuse bleeding, with a large amount (estimated at 500 g) of clots in the small intestine lumen. Its microscopic examination showed ischemic necrosis of the mucosa exhibiting massive intestinal bleeding, which was interpreted as the immediate cause of death (Figure 6). The autopsy also revealed acute renal tubular necrosis,

15

Hemophagocytic lymphohistiocytosis of indeterminate cause: a fatal adult case Autopsy and Case Reports 2012; 2(2): 11-20

proliferative syndrome, in which the HLH may develop.3 In FHLH, the onset of the disease occurs in 70-80% of cases below 1 year of age, although several late-onset cases have been reported.4,5 The acquired, or secondary HLH was first described by Risdall in 1979 and occurs in all age groups.6 The leading triggering agents in secondary HLH are viruses of the herpes group, especially Epstein-Barr virus (EBV) and cytomegalovirus (CMV). Other examples include varicella zoster virus,7 human herpesvirus (HHV)-6,8 and HHV-8,9 HIV,10 Rubella,11 adenovirus,12 parvovirus,8 hepatitis B virus,13 and avian influenza.14 The latter is a particularly potent stimulus for hemophagocytic reactions in Asia, probably associated with the high mortality observed in that infection. Other microbial pathogens include Mycobacterium tuberculosis,15 Serratia marcenses,16 Burkholderia cepacia,17 and fungal infections such as candidiasis,18 aspergillosis,19 and histoplasmosis.20 The identification of an infectious organism does not necessarily discriminate between the genetic and acquired form of HLH, since most episodes in genetic HLH may also be triggered by infections.21

Acquired HLH has also been reported, mostly in adults, in association with malignant diseases especially lymphomas, lymphoma-associated hemophagocytic syndrome (LAHS). In Japan, the EBV genome was detected in more than 80% of patients with T/NK cell lymphoma.22 The EBV-infected T/NK cells seem to play a major role in the development of LAHS, as well as in EBV-associated HLH without lymphoma.23 The HLH that occurs in association with autoimmune diseases is called macrophage-activation syndrome (MAS) and is

activation of the immune system, resulting in a systemic inflammatory response syndrome (SIRS).1 Although rare, increased awareness of these conditions has led to more frequent diagnoses.

HLH occurs in all age groups and is classified in two major forms: genetic or primary, and acquired or secondary. Farquhar and Claireux from the University of Edinburgh are credited with the first description of genetic HLH in 1952, which they named after “familial hemophagocytic reticulosis.”2 This genetic or primary HLH is inherited in an autosomal recessive or x-linked manner and is divided into a) familial HLH (FHLH) in which the clinical syndrome of HLH is the only manifestation; and b) the immune deficiencies like Chédiak-Higashi syndrome, Griscelli syndrome, and x-linked

Figure 5 – Photomicrography of the liver. A - Diffuse presence of hemophagocytic histiocytes throughout the hepatic sinusoids (HE, 400X); B - Detail (HE, 1000X).

Figure 6 – Duodenum/jejunal transition. A - Gross examination reveal extensive mucosal injury with diffuse bleeding, with large amount of clots into the small intestine lumen; B - Photomicrography of the small intestine showing ischemic necrosis of the mucosa (HE, 200X).

16

Autopsy and Case Reports 2012; 2(2): 11-20 Campos FPF, Lima PP, Lima FR, et al.

diagnosis of the case presented here. This disorder was previously called true Histiocytic Lymphoma or Malignant Histiocytosis, but as they were subsequently shown to be lymphomas, generally of T-cell origin, these terms were no longer used. In contrast to HLH, patients with HS present tumoral skin lesions (solitary or multiple), bone lytic lesions and primary tumors in the central nervous system. On the other hand, HLH is characterized by diffuse, rather than localized, histiocytic infiltration. The histopathology of HS shows lymph node involvement by malignant cells similar to histiocytes and the visceral organ involvement may exhibit a sinusal pattern. Hemophagocytosis is seldom seen in the tumor cells, which show large pleomorphic nuclei and variable mitotic activity26.

The incidence of HLH in adults is unknown. The disorder is believed to be underdiagnosed, and most reported studies are related to children. In the case of the primary autosomal recessive form, also known as familial hemophagocytic lymphohistiocytosis (FHL), the incidence is estimated at 1:50,000 live born children.29

The supposed pathophysiology of HLH is an uncontrolled stimulation of histiocytes (macrophages and dendritic cells), natural killer (NK) cells, cytotoxic T lymphocytes (CTLs) leading to persistent hypercytokinemia and systemic inflammatory response syndrome (SIRS).25 In patients with hemophagocytic syndrome, splenic macrophages appear to be activated, as evidenced by increased expression of major histocompatibility complex Class I (MHC-I) and MHC-II molecules, as well as the macrophage colony-stimulating factor receptor.30 Once triggered by an infectious agent, histiocytes (macrophages and dendritic cells), NK cells, and CTLs are activated and mutually stimulate each other. NK cells and CTLs kill their targets through cytolytic vesicles containing perforin and granzyme. The cytolytic vesicles are formed in the killer cells, fuse with the plasma membrane and release their content in the immunological synapse, which is formed upon contact between the killer and the target cells.31 This sequence of events ends with the killing of the offending agent, removal of the antigen, and termination of the immune response. Deficient cytotoxic activity impairs the elimination of cellular targets, expressing antigens and the down-regulation of the immune response as well. This process may be compromised by defects caused by mutations and will be responsible for the inherited or primary HLH.

now considered a special form of HLH occurring in patients with juvenile rheumatoid arthritis, systemic erythematous lupus, Behcet’s syndrome and other entities. The MAS has many characteristic features of HLH, but cytopenias may be less severe, cardiac impairment appears to be more common and coagulopathy more pronounced.24,25 In the case reported here, the laboratory workup failed to point out a triggering etiological agent, and the autopsy failed to reveal evidence of a lymphoma.

The differential diagnosis of non-neoplastic proliferation of histiocytes, regarding histopathological features, includes (Table 3).

Sinus histiocytosis with massive lymphadenopathy (SHML), also known as Rosai-Dorfman Disease deserves special attention in the differential diagnosis of this case. This disorder is characterized by massive bilateral enlargement of cervical lymph nodes, which show, in the histological examination, sinuses expansion by large histiocytes, lymphocytes and plasma cells. The histiocytes show intracytoplasmic vacuoles with the presence of lymphocytes and plasma cells, a process called emperipolesis, as well as erythrophagocytosis.26 Unlike the HLH, however, the histiocytes in the SHML express S-100, what was negative in the present case, permitting the exclusion of this diagnostic possibility. HLH, mainly in the familial form, occurring in early life, can mimic SHML. The pathologic features of the HLH are characterized by lymphoid depletion and massive sinusoidal infiltration by histiocytes. Contrasting with SHML, hemophagocytic syndromes present as a disseminated disease of aggressive clinical course 26, occasionally seen in the SHML27.

The Histiocytic Sarcoma (HS), a malignant proliferation of cells with morphologic and immunophenotypic features of mature tissue histiocytes28 could be consider in the differential

Table 3 – Non-neoplastic histiocytic proliferations26

(1) Reactive sinus histiocytosis

(2) Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman)

(3) Hemophagocytic syndromes:3.a - Familial hemophagocytic lymphohistiocytosis

3.b - Secondary hemophagocytic syndromes

(4) Storage disorders4.a - Niemann-Pick disease

4.b - Gaucher’s disease4.c - Tangier disease

17

Hemophagocytic lymphohistiocytosis of indeterminate cause: a fatal adult case Autopsy and Case Reports 2012; 2(2): 11-20

The symptoms of HLH can be explained by high concentrations of cytokines and organ infiltration by activated lymphocytes and histiocytes.30 Ongoing hypercytokinemia is a reflection of the failure of natural immune down-regulation due to defective NK and CTL function.25 Fever is induced by interleukin-1 (IL-1) and IL-6, and pancytopenia is rather the consequence of high levels of TNF-α and interferon γ, than of hemophagocytosis. TNF-α inhibits lipoprotein lipase leading to elevated triglycerides. Activated macrophages not only secrete ferritin but also plasminogen activators, which results in high plasmin levels and hyper fibrinolysis, hepatosplenomegaly, increased liver enzymes and bilirubin.3 The Histiocyte Society created diagnostic guidelines in 1991, based on common clinical, laboratory, and histopathological findings. This guideline was revised keeping the five criteria of the 1991 guidelines but introducing three additional criteria. The diagnostic criteria for HLH are summarized in Table 4.

A recent review undertaken in a pediatric hospital concerning elevated ferritin results showed that ferritin levels greater than 10,000 mcg/dL were 90% sensitive and 96% specific for HLH diagnosis.35 Although hemophagocytosis in biopsy specimens is the hallmark of HLH, the absence of this finding should not hinder the physician from starting treatment if other diagnostic criteria are met. It is not uncommon to require more than one biopsy specimen to demonstrate this microscopic evidence. On the other hand, the mere presence of hemophagocytosis in the reticuloendothelial system is not implied in the diagnosis, once it also occurs in other disorders.1,21 Some valuable diagnostic and disease markers are: increased concentrations of IL-2 receptor (sCD25) and decreased NK cell function, b-2 microglobulin,31 macrophage inflammatory protein-1a (MIP-1a)36 and CD163.37

In the diagnostic work up for infectious agent, searching for EBV, CMV, herpes simplex virus, adenovirus, parvovirus B19, and others are recommended. The patient should be screened for underlying immune deficiency, autoimmune diseases, and malignancies.

Since HLH masquerades as a normal infection, the diagnosis is frequently challenging. Time may then be lost with extensive workup for an infectious disease and consequently prolonged antibiotic therapy. Ferritin, fibrinogen, and triglycerides are not routinely determined in patients with fever, and the absence of hemophagocytosis,

Currently, nine genetic disorders have been described as related to the diagnosis of HLH in children; many familial cases still await molecular definition.25 Abnormalities in the function (but rarely in the quantity) of NK cells have been observed in patients with all forms of HLH.25 Sustained immune activation with persistent high cytokine levels will be responsible for the clinical picture of HLH. Studies of cytokine levels in blood and tissues have indicated persistently elevated circulating levels of multiple proinflammatory cytokines during symptomatic disease.25 It is not fully clear how apparently immunocompetent patients develop dysfunction of NK cells and CTLs following triggering events, such as viral infections. In the case of EBV infection, it is believed that instead of affecting B-lymphocytes, as usual, the virus infects NK-T cells, stimulating their proliferation with subsequent production of proinflammatory cytokines, particularly tumor necrosis factor-α (TNF-α) and interferon-γ, through the stimulation by EBV latent-membrane-protein 1 (LMP-1). This hypercytokinemia stimulates macrophages leading to the HLH. EBV infection has also been implicated in the pathogenesis of LAHS—the latter being a continuum of the natural progression of T-cell infection with EBV. Some patients diagnosed with EBV-associated HLH who survived have been observed to progress to T-cell lymphoma. Latent-membrane-protein 1 is believed to protect the EBV-infected T cells against the TNF-α-induced apoptosis. These cells are thought to survive and can later cause a relapse of the disease.1 Chromosome analysis of EBV-infected T-cells in patients with HLH showed clonality early in the course of the disease, accounting for further progression to lymphoma.32 Viruses may interfere with CTL function by specific proteins; high levels of cytokines may have the same effect. The high prevalence of EBV-associated HLH in Asia also suggests a genetic basis. In patients with lymphomas, secretion of cytokines by the malignant cells is a possible explanation.3

The clinical and laboratory findings of HLH consist in prolonged fever, hepatosplenomegaly, and cytopenias, and less frequently, lymphadenopathy, rash, icterus, and neurological symptoms, many of them observed in the patient reported here. Characteristic laboratory alterations include high levels of triglycerides, ferritin, liver enzymes, bilirubin, lactate dehydrogenase, and low fibrinogen due to endothelial activation/coagulopathy, as observed in our patient.24,25 A hallmark of HLH, no matter if in genetic or acquired form, is the impaired or absent function of NK and cytotoxic-T cells. The number of NK cells may be normal or decreased.33

18

Autopsy and Case Reports 2012; 2(2): 11-20 Campos FPF, Lima PP, Lima FR, et al.

the splenectomy showed benefit and considered the splenectomy as a diagnostic aiding tool for HLH.40

HLH is still overlooked since the clinical symptoms are similar to infections found in immune competent patients. Hemophagocytosis does not have to be present in the initial diagnostic workup. Patients with prolonged fever, unresponsive to antibiotics, accompanied by pronounced hepatosplenomegaly and cytopenias should be highly considered in the differential diagnosis of HLH. Due to the severity of the disease, clinical suspicion has to be followed by exhaustive search for the precise diagnosis and early institution of therapy.

REFERENCES

1. Okabe T, Shah G, Mendoza V, Hirani A, Barani M, Marik P. What intensivists need to know about hemophagocytic syndrome: an underrecognized cause of death in adult intensive care units. J Intensive Care Med. 2012;27:58-64. PMid:21257627. http://dx.doi.org/10.1177/0885066610393462

2. Farquhar JW, Claireaux AE. Familial haemophagocytic reticulosis. Arch Dis Child. 1952;27:519-25. PMid:13008468 PMCid:1988563. http://dx.doi.org/10.1136/adc.27.136.519

3. Janka GE. Hemophagocytic Syndromes. Blood Rev. 2007;21:245-5. PMid:17590250. http://dx.doi.org/10.1016/j.blre.2007.05.001

in the early stage of the disease, is often the reason why the diagnosis is unwarranted.3

Because HLH can be rapidly fatal without specific intervention, treatment should be started when a clinical suspicion exists, even when the results of diagnostic studies are still pending.25 High dose corticosteroids, which are cytotoxic for lymphocytes and inhibit expression of cytokines and differentiation of dendritic cells, are indicated for the treatment of HLH. Immunoglobulin has been used mainly in the treatment of adults. They act by cytokine and pathogen-specific antibodies. Cyclosporine A, which affects T-lymphocyte activation and macrophage function, has proved to be effective for maintaining remission in genetic HLH.38 Etoposide is another option for HLH treatment. The HLH-2004 protocol was designed for patients with or without evidence of familial or genetic disease regardless of the presence of suspected or documented viral infections. In this protocol, patients under the age of 18 years at the onset of treatment who fulfill the diagnostic criteria are advised to receive dexamethasone, etoposide and cyclosporine A in an initial therapy scheme for eight weeks.34

The therapeutic effect of the splenectomy has not been extensively reported. Imashuku et al. reported five cases in which splenectomy was part of the treatment; three patients died after the procedure.39 Zang et al. reported a case in which

Table 4 – Revised diagnostic guidelines for HLH34

The diagnosis HLH can be established if one of either 1 or 2 below is fulfilled

(1) A molecular diagnosis consistent with HLH

(2) Diagnostic criteria for HLH fulfilled (5 out of the 8 criteria below)

(A) Initial diagnostic criteria (to be evaluated in all patients with HLH)

Fever

Splenomegaly

Cytopenias (affecting 2 of 3 lineages in the peripheral blood): Hemoglobin <9 g/dL (in infants <4 weeks: hemoglobin <10g/dL),

Platelets <10,000/mm3, Neutrophils <1,000/ mm3

Hypertriglyceridemia and/or hypofibrinogenemia: Fasting triglycerides ≥265 mg/dl, Fibrinogen <150 mg/dL

Hemophagocytosis in bone marrow or spleen or lymph nodes

No evidence of malignancy

(B) New diagnostic criteria

Low or absent NK-cell activity (according to local laboratory reference)

Ferritin >500 mg/L

Soluble CD25 (i.e. soluble IL-2 receptor) ≥2,400 U/mL

19

Hemophagocytic lymphohistiocytosis of indeterminate cause: a fatal adult case Autopsy and Case Reports 2012; 2(2): 11-20

16. Edner J, Rudd E, Zheng C, et al. Severe bacteria-associated hemophagocytic lymphohistiocytosis in an extremely premature infant. Acta Paediatr. 2007;96:1703-6. PMid:17888050. http://dx.doi.org/10.1111/j.1651-2227.2007.00505.x

17. Hisano M, Sugawara K, Tatsuzawa O, Kitagawa M, Murashima A, Yamaguchi K. Bacteria-associated haemophagocytic syndrome and septic pulmonary embolism caused by Burkholderia cepacia complex in a woman with chronic granulomatous disease. J Med Microbiol. 2007;56:702-5. PMid:17446299. http://dx.doi.org/10.1099/jmm.0.47071-0

18. Bhatia S, Bauer F, Bilgrami AS. Candidiasis-associated hemophagocytic lymphohistiocytosis in a patient infected with human immunodeficiency virus. Clin Infect Dis. 2003;37:e161-6. PMid:14614689. http://dx.doi.org/10.1086/379615

19. Delcroix G, Vanstraelen G, Hustinx R, et al. Aspergillus pericarditis with cardiac tamponade and haemophagocytic syndrome: a non-classical case of immunodeficiency. Rev Med Liege. 2006;61:713-8. PMid:17209504.

20. Sanchez A, Celaya AK, Victorio A. Histoplasmosis-associated hemophagocytic syndrome: a case report. AIDS Read. 2007;17:496-9. PMid:17990371.

21. Henter JI, Ehrnst A, Andersson J, Elinder G. Familial hemophagocytic lymphohistiocytosis and viral infections. Acta Paediatr. 1993;82:369-72. PMid:8391350. http://dx.doi.org/10.1111/j.1651-2227.1993.tb12699.x

22. Takahashi N, Chubachi A, Miura I, Nakamura S, Miura AB. Lymphoma-associated hemophagocytic syndrome in Japan. Rinsho Ketsueki. 1999;40:542-9. PMid:10483136.

23. Quintanilla-Martinez L, Kumar S, Fend F, et al. Fulminant EBV (+) T-cell lymphoproliferative disorder following acute/chronic EBV infection: a distinct clinicopathologic syndrome. Blood. 2000;96:443-51. PMid:10887104.

24. Janka G. Familial and acquired hemophagocytic lymphohistiocytosis. Eur J Pediatr. 2007;166:95-109. PMid:17151879. http://dx.doi.org/10.1007/s00431-006-0258-1

25. Filipovich AH. Hemophagocytic lymphohistiocytosis and other hemophagocytic disorders. Immunol Allergy Clin North Am. 2008;28:293-313. PMid:18424334. http://dx.doi.org/10.1016/j.iac.2008.01.010

26. Rezk SA. Nonneoplastic histiocytic proliferations of lymph nodes and bone marrow. In: Jaffe ES, Vardiman J, Campo E, Arber DA, Harris NL, editors. Hematopathology. Saunders; 2010. p. 801.

27. Foucar E, Rosai J, Dorfman RF: Sinus histiocytosis with massive lymphadenopathy. An analysis of 14 deaths occurring in a patient registry. Cancer. 1984;54:1834. http://dx.doi.org/10.1002/1097-0142(19841101)54:9<1834::AID-CNCR2820540911>3.0.CO;2-F

4. Allen M, De Fusco C, Legrand F, et al. Familial hemophagocytic lymphohistiocytosis: how late can the onset be? Haematologica. 2001;86:499-503. PMid:11410413.

5. Clementi R, Emmi L, Maccario R, et al. Adult onset and atypical presentation of hemophagocytic lymphohistiocytosis in siblings carrying PRF1 mutations. Blood. 2002;100:2266-7. PMid:12229880. http://dx.doi.org/10.1182/blood-2002-04-1030

6. Risdall RJ, McKenna RW, Nesbit ME, et al. Virus-associated hemophagocytic syndrome: a benign histiocytic proliferation distinct from malignant histiocytosis. Cancer. 1979; 44:993-1002. http://dx.doi.org/10.1002/1097-0142(197909)44:3<993::AID-CNCR2820440329>3.0.CO;2-5

7. Astigarraga I, Prats JM, Navajus A. Near fatal cerebellar swelling in familial hemophagocytic lymphohistiocytosis. Pediatr Neurol. 2004;30(5):361-4. PMid:15165642. http://dx.doi.org/10.1016/j.pediatrneurol.2003.11.013

8. Hoang MP, Dawson DB, Rogers ZR. Polymerase chain reaction amplification of archival material for Epstein-Barr virus, cytomegalovirus, human herpesvirus 6, and parvovirus B19 in children with bone marrow hemophagocytosis. Hum Pathol. 1998;29:1074-7. http://dx.doi.org/10.1016/S0046-8177(98)90416-6

9. Re A, Tacchetti F, Borlenghi E. Fatal hemophagocytic syndrome related to active human herpesvirus-8/Kaposi sarcoma-associated herpesvirus infection in human immunodeficiency virus-negative, non-transplant patients without related malignancies. Eur J Haematol. 2007;78:361-4. PMid:17331129. http://dx.doi.org/10.1111/j.1600-0609.2007.00828.x

10. Pantanowitz L,DezubeBJ.Editorial comment: hemophagocytic syndrome-an HIV-associated quagmire. AIDS Read. 2007;17:500-2. PMid:17990372.

11. Takenaka H, Kishimoto S, Ichikawa R. Virus-associated haemophagocytic syndrome caused by rubella in an adult. Br J Dermatol. 1998;139: 877-80. PMid:9892958. http://dx.doi.org/10.1046/j.1365-2133.1998.02517.x

12. Rouphael NG, Talati NJ, Vaughan C. Infections associated with haemophagocytic syndrome. Lancet Infect Dis. 2007;7:814-22. http://dx.doi.org/10.1016/S1473-3099(07)70290-6

13. Aleem A, Al Amoudi S, Al-Moshhadani S, Siddiqui N. Haemophagocytic syndrome associated with hepatitis-B virus infection responding to etoposide. Clin Lab Haematol. 2005;27:395-8. PMid:16307542. http://dx.doi.org/10.1111/j.1365-2257.2005.00728.x

14. Carter MJ. A rationale for using steroids in the treatment of severe cases of H5N1 avian influenza. J Med Microbiol. 2007;56:875-83. PMid:17577050. http://dx.doi.org/10.1099/jmm.0.47124-0

15. Brastianos PK, Swanson JW, Torbenson M, et al. Tuberculosis-associated haemophagocytic syndrome. Lancet Infect Dis. 2006;6:447-54. http://dx.doi.org/10.1016/S1473-3099(06)70524-2

20

Autopsy and Case Reports 2012; 2(2): 11-20 Campos FPF, Lima PP, Lima FR, et al.

34. Henter JI, Horne AC, Aricó M, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48:124-31. http://dx.doi.org/10.1002/pbc.21039

35. Allen CE, Yu X, Kozinetz CA, McClain KL. Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistyocitosis. Pediatr Blood Cancer. 2008;50:1227-35. http://dx.doi.org/10.1002/pbc.21423

36. Teruya-Feldstein J, Setsuda J, Yao X, et al. MIP-1alpha expression in tissues from patients with hemophagocytic syndrome. Lab Invest. 1999; 79:1583-90. PMid:10616208.

37. Emmenegger U, Schaer DJ, Larroche C, Neftel KA. Haemophagocytic syndromes in adults: current concepts and challenges ahead. Swiss Med Wkly. 2005;135:299-314. PMid:16034684.

38. Loechelt BJ, Egeler M, Filipovich AH, Jyonouchi H, Shapiro RS. Immunosuppression: preliminary results of alternative maintenance therapy for familial hemophagocytic lymphohistocytosis (FHL). Med Pediatr Oncol. 1994;22:325-8. PMid:8127256. http://dx.doi.org/10.1002/mpo.2950220505

39. Imashuku S, Obayashi M, Hosoi G, et al. Splenectomy in haemophagocytic lymphohystiocytosis: report of histological changes with CD19+ B-cell depletion and therapeutic results. Br J Haematol. 2000;108:505-10. PMid:10759706. http://dx.doi.org/10.1046/j.1365-2141.2000.01904.x

40. Zhang LJ, Zhang SJ, Xu J, et al. Splenectomy for an adult patient with refractory secondary hemophagocytic lymphohystiocytosis. Biomed Pharmacother. 2011;65:432-5. http://dx.doi.org/10.1016/j.biopha.2011.04.008

28. Swedlow SH, Campo E, Harris NL, et al editors. WHO classification of tumours of haematopoietic and lymphoid tissues. 4th ed. Lyon: IARC; 2008.

29. Henter JI, Elinder G, Soder O, Ost A. Incidence in Sweden and clinical features of familial hemophagocytic lymphohistiocytosis. Acta Paediatr Scand. 1991;80:428-35. http://dx.doi.org/10.1111/j.1651-2227.1991.tb11878.x

30. Kereveur A, McIlroy D, Santi D, et al. Up-regulation of adhesion and MHC molecules on splenic monocyte/macrophages in adult hemophagocytic syndrome. Br J Haematol. 1999;104:871-7. PMid:10192453. http://dx.doi.org/10.1046/j.1365-2141.1999.01247.x

31. Stinchcombe J, Bossi G, Griffiths GM. Linking albinism and immunity: the secrets of secretory lysosomes. Science. 2004;305:55-9. PMid:15232098. http://dx.doi.org/10.1126/science.1095291

32. Chuang HC, Lay JD, Chuang SE, Hsieh WC, Chang Y, Su IJ. Epstein-Barr virus (EBV) latent membrane protein-1 down regulates tumor necrosis factor-alpha (TNF-alpha) receptor-1 and confers resistance to TNF-alpha-induced apoptosis in T cells: implication for the progression to T-cell lymphoma in EBV-associated hemophagocytic syndrome. Am J Pathol. 2007;170:1607-1617. PMid:17456766 PMCid:1854955. http://dx.doi.org/10.2353/ajpath.2007.061026

33. Schneider EM, Lorenz I, Muller-Rosenberger M, Steinbach G, Kron M, Janka-Schaub GE. Hemophagocytic lymphohistiocytosis is associated with deficiencies of cellular cytolysis but normal expression of transcripts relevant to killer-cell- induced apoptosis. Blood. 2002;100:2891-8. PMid:12351400. http://dx.doi.org/10.1182/blood-2001-12-0260

Conflict of interest: None

Submitted on: 7th May 2012 Accept on: 6th June 2012

Correspondence: Divisão de Clínica Médica Av. Prof. Lineu Prestes, 2565 – Cidade Universitária - São Paulo/SP – Brazil CEP: 05508-000 – Phone: +55 (11) 3091-9200 E-mail: ffcampos@usp.br

Article / Clinical Case Reports Artigo / Relato de Caso Clínico

21

Copyright © 2012 Autopsy and Case Reports – This is an Open Access article distributed of terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any médium provided article is properly cited.

a Department of Dentistry - Hospital Universitário - Universidade de São Paulo, São Paulo/SP - Brazil. b Department of Surgery, Prosthesis and Maxillofacial Trauma - Faculdade de Odontologia - Universidade de São Paulo, São Paulo/SP - Brazil.

Autopsy and Case Reports 2012; 2(2): 21-23

21

Bilateral lingual lipoma: a case report

Edson Martins de Oliveira Juniora, Carlos Augusto Ferreira Alvesa, Adalmir Gonzaga Santos-Queiroza, Fernando Melhem Eliasa,b, Antônio Carlos de Camposa,b

Oliveira Junior EM, Alves CAF, Santos-Queiroz AG, Elias FM, Campos AC. Bilateral lingual lipoma: a case report. Autopsy Case Rep [Internet]. 2012;2(2):21-23. http://dx.doi.org/10.4322/acr.2012.012

ABSTRACT

Lipoma of the tongue is an uncommon benign tumor, being even more rare when there are multiple lesions. Lipoma accounts for 1-5% of all oral neoplasms. Lipoma occurs predominantly in males over the age of forty, although, in rare cases, children can be affected. Here, we report an unusual case of a female patient with bilateral lingual lipomas that were treated through surgical excision.

Keywords: Lipoma; Tongue; Surgical procedures, operative.

INTRODUCTION

A lipoma is a benign, slow-growing, asymptomatic tumor of mesenchymal origin; lipomas consist of adipose tissue and can be sessile or pedunculated, as well as single or lobulated, typically surrounded by a fibrous capsule.1,2 Although the etiology of lipoma remains unclear, causal factors include endocrine changes, trauma, and genetic makeup.3

Although lipoma of the oral cavity is uncommon, lipomas of the head and neck account for 15-20% of all head and neck neoplasms.4

Lipomas and 1-5% of all neoplasms of the oral cavity.2

The diagnosis of lipoma is predominantly based on clinical findings, histopathological findings being conclusive in all cases. Imaging tests can be useful, especially when lipomas are located in the deeper fascia of the neck or face. Histologically, lipomas consist of well-differentiated adipose tissue surrounded by a connective tissue capsule.5 Here, we report a case of bilateral lipoma of the lateral borders of the tongue treated with surgical excision.

CASE REPORT

An 85-year-old female patient sought medical attention complaining of a “lump” in her tongue. The patient reported that the lump had been present for approximately 5 years. Oral examination revealed

painless, endophytic nodules in the right and left lateral borders of the tongue. The lesion on the right was 1.0 cm in diameter, compared with 1.8 cm for the lesion on the left , in their longest axis. Both were

22

Autopsy and Case Reports 2012; 2(2): 21-23 Oliveira Junior EM, Alves CAF, Santos-Queiroz AG, Elias FM, Campos AC.

soft, yellowish lesions with well-defined borders and no ulcerations (Figure 1).

A presumptive diagnosis of lipoma was made, and the patient underwent surgical excision under local anesthesia. Macroscopic examination revealed yellowish nodules with a lobular surface (Figure 2). Microscopic examination revealed the presence of mature adipose tissue interspersed with bands of dense connective tissue, confirming the diagnosis of lipoma.

In the case reported here, the histological features of the lipomas (i.e., predominance of simple lipomas), their clinical features (asymptomatic, encapsulated, round, yellowish/mucosa-like in color, smooth, and without ulceration), their anatomical location (the dorsum of the tongue), and their presentation (bilateral) were consistent with those reported in the literature, although the age and gender of the patient (an 85-year-old female) were not. At this writing, 2 years after the surgical excision of the lipomas, there were no signs of recurrence.

DISCUSSION

Lipomas rarely affect the oral cavity, accounting for only approximately 5% of all intraoral neoplasms. The etiology of lipoma has yet to be definitively established but includes endocrine changes, hereditary factors, local trauma, and infection.6 Histologically, lipomas are indistinguishable from normal adipose tissue.5

Although some studies have reported that males are more often affected,2,7 others have reported that lipomas are more common in females.8,9 Individuals in the 30-70 year age bracket are the most affected, lipomas being rare in those under 20 years of age.2,10 Regarding the intraoral commitment, the buccal mucosa, the vestibular fornix, the floor of the mouth, the tongue, the inner surface of the lips, the alveolar ridge, the palate, and the salivary glands, are the most commonly affected sites.10

Lipomas can be double (bilateral) or, in rare cases, multiple. Multiple lipomas are generally related to lipomatosis, neurofibromatosis type 1 (formerly known as von Recklinghausen’s disease), Gardner syndrome, and adiposis dolorosa (also known as Dercum’s disease).

The differential diagnosis of lipoma includes epidermoid cysts, lymphoepithelial cysts, ranulas, pleomorphic adenomas, and mucoepidermoid carcinomas.11 In suspected cases of deep-seated lipoma, computed tomography can assist in ruling out vascular lesions and in identifying important anatomical structures that are adjacent to the lesions.12

The histopathological features of lipomas are typical: they consist of well-differentiated adipose tissue surrounded by a connective tissue capsule. Although morphologically indistinguishable from normal fat cells, tumor cells are metabolically more active. The fibrous capsule may sometimes be absent or ruptured.13

Conservative treatment of lipomas involves complete surgical excision by excisional biopsy, especially in cases of infiltrative lipoma.14 Recurrence is rare when the lesion is completely excised.2,3,6,10

As evidenced by the case reported here, lipoma of the oral cavity can be treated successfully through conservative treatment.

REFERENCES

1. Weiss SW, Goldblum JR. Benign lipomatous tumours. In: Weiss SW, Goldblum JR, editors. Enzinger and Weiss’s soft tissue tumours. 4th ed. St. Louis: Mosby; 2001. p. 571-639.

2. Fregnani ER, Pires FR, Falzoni R, Lopes MA, Vargas PA. Lipomas of the oral cavity: clinical findings, histological

Figure 1 – Initial clinical appearance of the lesions, which were located in the lateral border of the tongue.

Figure 2 – Surgical excision of the lipomas.

23

Bilateral lingual lipoma: a case report Autopsy and Case Reports 2012; 2(2): 21-23

classification and proliferative activity of 46 cases. Int J Oral Maxillofac Surg. 2003;32(1):49-53. PMid:12653233. http://dx.doi.org/10.1054/ijom.2002.0317

3. Tommasi AF. Diagnóstico em patologia bucal. São Paulo: Artes Médicas; 1982. Português.

4. Gnepp DR. Diagnostic surgical pathology of the head and neck. Philadelphia: WB Saunders; 2001.

5. Ribeiro Neto N, Marques JAF, Santos MAM, Parra GR, Mota GCC, Barreto AP. Limpoma de Tamanho Incomum em Lábio Inferior. Rev Cir Traumatol Buco-Maxilo-Fac. 2010;10(4):9-12. Português.

6. Marzola C. Fundamentos de cirurgia buco-maxilo-facial. Bauru: Independente; 2005. Português.

7. Furlong MA, Fanburg-Smith JC, Childers EL. Lipoma of the oral and maxillofacial region: site and subclassification of 125 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2004;98(4):441-50. PMid:15472660. http://dx.doi.org/10.1016/j.tripleo.2004.02.071

8. Neville BW, Damm DD, Allen CM, Bouquot. Patologia oral & maxilofacial. 2a. ed. Rio de Janeiro: Guanabara Koogan; 2008. Português.

9. Assis GM, Silvam SRP, Moraes PH, Amaral JIQ, Germano AR. Lipoma facial removido por acesso intrabucal: caso clínico. Rev Bras Cir Traumatol Buco-Maxilo-Fac. 2010;10(2):89-93.

10. Prado R, Ribeiro DPB, Fontoura RA, Sampaio RKPL, Moreira LC. A case of sublingual lipoma. Rev Bras Odontol. 1998;55(4):226-8.

11. Hattori H. Atypical lipomatous tumor of the lip with pleomorphic lipoma-like myxoid area, clinically simulating mucocele. J Oral Pathol Med. 2002;31(9):561-4. PMid:12269996. http://dx.doi.org/10.1034/j.1600-0714.2002.00151.x

12. Zhong LP, Zhao SF, Chen GF, Ping FY. Ultrasonographic appearance of lipoma in the oral and maxillofacial region. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2004;98(6):738-40. PMid:15583549. http://dx.doi.org/10.1016/j.tripleo.2004.04.022

13. Epivatianos A, Markopoulos AK, Papanayotou P. Benign tumors of adipose tissue of the oral cavity: a clinicopathologic study of 13 cases. J Oral Maxillofac Surg. 2000;58(10):1113-7. PMid:11021705. http://dx.doi.org/10.1053/joms.2000.9568

14. Salvatore C, Antonio B, Del Vecchio W, Lanza A, Tartaro G, Giuseppe C. Giant infiltrating lipoma of the face: CT and MR imaging findings. AJNR Am J Neuroradiol. 2003;24(2):283-6. PMid:12591650.

Conflict of interest: None

Submitted on: 5th January 2012 Accept on: 16th January 2012

Correspondence: Divisão de Odontologia Av. Prof. Lineu Prestes, 2565 – Cidade Universitária - São Paulo/SP – Brazil CEP: 05508-900 – Phone: +55 (11) 3091-9290 E-mail: jr.odonto@gmail.com

Article / Clinical Case ReportsArtigo / Relato de Caso Clínico

25

Copyright © 2012 Autopsy and Case Reports – This is an Open Access article distributed of terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any médium provided article is properly cited.

a Diagnostic Imaging Service - Hospital Universitário - Universidade de São Paulo, São Paulo/SP - Brazil. b Heart Institute - Hospital das Clínicas - Faculdade de Medicina - Universidade de São Paulo, São Paulo/SP - Brazil. c Department of Radiology - Faculdade de Medicina - Universidade de São Paulo, São Paulo/SP - Brazil.

Autopsy and Case Reports 2012; 2(2): 25-29

25

Calcification of the ligamentum flavum in the thoracolumbar spine: an unusual cause of compressive myelopathy

João Augusto dos Santos Martinesa, Brenda Margatho Ramos Martinesa, José de Arimatéia Batista Araújo Filhob, Lorena Elaine Amorim Pintob, Cláudio Campi de Castroa,c

Martines JAS, Martines BMR, Araujo Filho JAB, Pinto LEA, Castro CC. Calcification of the ligamentum flavum in the thoracolumbar spine: an unusual cause of compressive myelopathy. Autopsy Case Rep [Internet]. 2012;2(2):25-29. http://dx.doi.org/10.4322/acr.2012.013

ABSTRACT

The focal calcification or ossification of the ligamentum flavum is a rare cause of thoracic myelopathy and most often occurs among individuals of Japanese descent. It is rare in other ethnic groups and in individuals below the age of 50. It is most often described at the lower thoracic level, being uncommon in the lumbar region and rare in the cervical region. Here, we present the case of a 44-year-old White female patient who sought medical attention with an eight-month history of paraesthesia of the lower limbs and progressive difficulty in walking. The clinical profile, together with computed tomography and nuclear magnetic resonance imaging of the spine, led to a diagnosis of compressive thoracic myelopathy due to ossification of the ligamentum flavum in the thoracic and lumbar spine. The patient underwent laminectomy and dissection of some of the affected ligamentum flavum, without any intraoperative complications. After three months of clinical follow-up, the patient had progressed favorably, having no sensory complaints and again becoming ambulatory.

Keywords: Ossification of the posterior longitudinal ligament; Spine; Ligamentum flavum; Spinal cord compression.

CASE REPORT

A previously healthy 44-year-old White female patient sought medical attention at our hospital. The patient presented with a 2-month history of ascending paresthesia of the left leg, with progressive worsening and right leg involvement, accompanied by reduced (right and left) leg muscle strength. She reported lower back discomfort and abdominal paresthesia. Clinical findings were normal. Neurological examination revealed paraparesis (grade 1/2 muscle power in the right

leg and grade 2/3 muscle power in the left), as well as pyramidal signs and brisk reflexes in the legs, together with a sensory level of T8 on both sides and pain on movement of the thoracic spine. A computed tomography (CT) scan of the thoracolumbar spine revealed the following (Figures 1–4): in the thoracic region—ligamentum flavum (LF) hypertrophy and calcification, which caused narrowing of the spinal canal and lateral recess, the narrowing being greatest at T6 and at T10–T11; and, in the lumbar

26

Autopsy and Case Reports 2012; 2(2): 25-29 Martines JAS, Martines BMR, Araujo Filho JAB, Pinto LEA, Castro CC.

Figure 1 - Axial soft tissue window and bone window computed tomography scans (A and B, respectively) of the thoracic spine showing hypertrophied and calcified ligamenta flava (arrows) causing spinal canal narrowing.

Figure 2 - Axial soft tissue window and bone window computed tomography scans (A and B, respectively) of the lumbar spine showing calcified ligamenta flava (arrows) causing no spinal canal narrowing.

region—LF hypertrophy and calcification at L1–L2, with a herniated disc at L4–L5 and diffuse marginal osteophytes.

Magnetic resonance imaging (MRI) showed hyperintense signals on T2-weighted images at T6–T7 and T10–T11; those vertebrae were slightly thinner, suggesting concomitant myelomalacia (Figure 5). Laboratory test results were normal, metabolic disorders being therefore ruled out.

The patient underwent laminectomy and dissection of some of the affected LF, without any intraoperative complications. After three months of clinical follow-up, the patient had progressed favorably, having no sensory complaints and again becoming ambulatory.

DISCUSSION

Although uncommon, ossification or calcification of the LF as a cause of thoracolumbar myelopathy has been extensively described in Eastern populations, particularly in individuals of Japanese descent.1–7 Despite the significant number of Japanese immigrants in Brazil, there is an obvious lack of studies on the topic in the country.

The LF are elastic connective tissue ligaments that lie on a crest bone located on the lower border of the vertebral lamina, extending to the upper border of the lamina of the underlying vertebral body and contributing to forming the posterior limit of the intervertebral foramen (Figure 6). The elasticity of the LF decreases with age; in elderly individuals,

27

Calcification of the ligamentum flavum in the thoracolumbar spine Autopsy and Case Reports 2012; 2(2): 25-29

sudden and forced extension movements can cause cervical cord compression.8

Histologically, there is a variety of pathological conditions affecting the LF, including hypertrophy, calcification, and ossification. In cases of hypertrophy, the normal fibrous structure of the LF is replaced by hypertrophic fibrous tissue containing numerous fibrocartilaginous cells with abundant matrix.9 Such calcification consists of

Figure 3 - Coronal reconstruction of soft tissue window and bone window computed tomography scans (A and B, respectively) of the thoracic spine showing hypertrophied and calcified ligamenta flava causing spinal canal narrowing, which is most evident at T6, T10, and T11.

Figure 4 - Sagittal reconstruction of soft tissue window and bone window computed tomography scans (A and B, respectively) of the thoracic spine showing hypertrophied and calcified ligamenta flava causing spinal canal narrowing, which is most evident at T6, T10, and T11.

thickening of the deep layers of the LF, whereas the corresponding ossification affects only the most superficial layers.10

Ossification or calcification of the LF is an idiopathic endochondral calcification that affects approximately 20% of individuals who are of Eastern origin and who are older than 60 years of age,11 being rare in those who are not of Eastern origin and in those who are younger than 50 years

28

Autopsy and Case Reports 2012; 2(2): 25-29 Martines JAS, Martines BMR, Araujo Filho JAB, Pinto LEA, Castro CC.

of age, as was the case here. In fact, the etiology of this calcification/ossification remains unclear. Although the role of initial trauma has yet to be demonstrated, it is known that such trauma can worsen the neurological symptoms.12 Ossification or calcification of the LF is most common at the lower thoracic level, being uncommon in the lumbar region (as was the case here) and rare in the cervical region.11 The region most often affected in women is

the cervical region, whereas it is the thoracic and lumbar regions in men.11

The typical clinical presentation is chronic myelopathy with cervicothoracic cord compression, which can be accompanied by radiculopathy and sphincter dysfunction. Ossification or calcification of the LF can be associated with Paget’s disease, rickets, chondrocalcinosis, ankylosing spondylitis, hypoparathyroidism, skeletal hyperostosis, obesity, diabetes, hyperinsulinemia, and disorders of calcium metabolism.11 None of the abovementioned conditions were confirmed in the case reported here.

Although X-ray and myelography findings can suggest the diagnosis, the two methods generally have limited value. A CT scan can reveal a calcified/ossified extradural mass located under the vertebral lamina and protruding into the intervertebral foramen, with a loss of extradural fat.11 In determining the degree of spinal cord compression and the characteristics of ossification, MRI is extremely useful, the LF appearing hypointense on T1- and T2-weighted images. The typical indentation is best seen on T2-weighted images.11 The use of CT and MRI in combination provides information that is more accurate and useful for treatment planning than does the use of either alone.4,9

The treatment of ossification or calcification of the LF generally consists of posterior surgical decompression by laminectomy or laminoplasty with joint preservation, which increases the stability of the spinal column.11 The prognosis is variable but typically favorable. However, the course of the disease is sometimes severe because of the size and extent of the stenosis. Nevertheless, a physical therapy rehabilitation program should be started gradually, as early as in the immediate postoperative period.11

In conclusion, albeit rare (except in individuals of Japanese descent), ossification or calcification of the LF can lead to spinal cord compression due to spinal canal stenosis. The diagnosis is preferably made by MRI and CT in combination. The prognosis is variable, sometimes being poor because of the size and extent of stenosis. A better understanding of the disease could increase the number of cases diagnosed in patients who are not of Japanese descent.

Figure 5 - Magnetic resonance imaging of the thoracic spine: T2-weighted sequence showing hyperintense areas in the spinal cord at T6–T7 and T10–T11, suggesting compressive myelopathy.

Figure 6 - Topographic anatomy of the ligamentum flavum.Source: Netter, FH. Atlas de anatomia humana. 2a ed. Porto Alegre: Artmed; 2000.

29

Calcification of the ligamentum flavum in the thoracolumbar spine Autopsy and Case Reports 2012; 2(2): 25-29

radiologic and histologic evaluations. AJNR. 1983;4:629-32. PMid:6410817.

7. Yamashita Y, Takahashi M, Matsuno Y, et al. Spinal cord compression due to ossification of ligaments: MR imaging. Radiology. 1990;175:843-8. PMid:2111569.

8. Johnson RM, Murphy MJ, Sothwick WO. Surgical approaches to the spine. In: Rothman RH, Simeone FA, editors. The Spine. 3rd ed. Philadelphia: WB Saunders; 1992. p. 1623-8.

9. Okada K, Oka S, Tohge K, Ono K, Tunenobu K, Hosoya T. Thoracic myelopathy caused by ossification of the ligamentum flavum. Spine. 1991;16:280-7. PMid:1902988. http://dx.doi.org/10.1097/00007632-199103000-00005

10. Akino M, Abe H, Iwasaki Y, et al. A case of cervical myelopathy due to calcified mass in the cervical yellow ligament. Neurol Surg (Tokyo). 1983;11:173-8.

11. Gondim, J, Ramos Junior, F. Compressão medular torácica em dois níveis por calcificação de ligamento amarelo: relato de caso. Arq neuropsiquiatr. 1998; 56:312-6.

12. Vitale C. Ossification du ligament vertebrál commun postérieur de la region cervicale. In: De Sèze S, Ryckewaert A, Kahn MF, Guérin CL. L’actualité rhumatologique. Paris: Expansion Scientifique Française; 1985. p. 144-8.

REFERENCES

1. Kubota M, Baba I, Sumita T. Myelopathy due to ossification of the ligamentum flavum of the cervical spine: a report of two cases. Spine. 1981;6:553-9. PMid:6801782. http://dx.doi.org/10.1097/00007632-198111000-00005

2. Takayama S, Kuribayashi K, Miyamoto Y, Nakasu Y, Handa J. Ossification and calcification of the cervical ligamentum flavum. No To Shinkei. 1993;9:859-63.

3. Yoshida H, Murao S, Nakajima T, Tsutsumi T. Paraplegia caused by ossification of the ligamentum flavum. Nippon Rinsho. 1976;10:3085-90 .

4. Hanakita J, Suwa H, Ohta F, Nishi S, Sakaida H, Iihara K. Neuroradiological examination of thoracic radiculo-myelopathy due to ossification of ligamentum flavum. Neuroradiology. 1990;32:38-42. PMid:2110325. http://dx.doi.org/10.1007/BF00593939

5. Hukuda S, Mochizuki T, Ogata M, Schichikawa K. The pattern of spinal and extraspinal hyperostosis in patients with ossification of the posterior longitudinal ligament and the ligamentum flavum causing myelopathy. Skeletal Radiol. 1983;10:79-85. PMid:6612370. http://dx.doi.org/10.1007/BF00360789

6. Myakasa K, Kaneda K, Sato S, et al. Myelopathy due to ossification or calcification of the ligamentum flavum:

Conflict of interest: None

Submitted on: 100h February 2012Accept on: 26th February 2012

Correspondence: Instituto do Coração - Incor HCFMUSP Av. Dr. Enéas Carvalho de Aguiar, 44 - São Paulo/SP - Brazil 05403-900 - Phone: 55 (11) 2661.5000 E-mail: ariaraujocg@hotmail.com

Article / Clinical Case Reports Artigo / Relato de Caso Clínico

31

Copyright © 2012 Autopsy and Case Reports – This is an Open Access article distributed of terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any médium provided article is properly cited.

a Anatomic Pathology Service - Hospital Universitário - Universidade de São Paulo, São Paulo/SP - Brazil. b Department of Internal Medicine - Hospital Universitário - Universidade de São Paulo, São Paulo/SP - Brazil. c Instituto do Câncer do Estado de São Paulo, São Paulo/SP - Brazil. d Department of Surgery - Hospital Universitário - Universidade de São Paulo, São Paulo/SP - Brazil. e Department of Pathology - Faculdade de Medicina - Universidade de São Paulo, São Paulo/SP - Brazil.

Autopsy and Case Reports 2012; 2(2): 31-36

31

Enteropathy-associated T-cell lymphoma (type II): a Brazilian case report

Aloísio Felipe-Silvaa, Fernando Peixoto Ferraz de Camposb, Raphael Salles Scortegagna de Medeirosc, Rodrigo Montenegro Lourençãod,

Maria Claudia Nogueira Zerbinia,e

Felipe-Silva A, Campos FPF, Medeiros RSS, Lourenção RM, Zerbini MCN. Enteropathy-associated T-cell lymphoma (type II): a Brazilian case report. Autopsy Case Rep [Internet]. 2012;2(2):31-36. http://dx.doi.org/10.4322/acr.2012.014

ABSTRACT

Enteropathy-associated T-cell Lymphoma (EATL) is a rare form of aggressive T-cell lymphoma. It is more prevalent in men over 60 years and the prognosis is very poor. EATL is classified into two groups based on morphology, immunohistochemistry, and genetic profile. EATL type I is highly associated with celiac disease and is more common in Western countries. EATL type II predominates over type I in Asia, where celiac disease is uncommon. We report a case of a 78-year-old previously healthy white male who presented with a 2-month history of diarrhea, weight loss and edema. The abdomen was distended and painful, and a tumor mass was palpable in the hypogastrium. Laboratory tests showed hypoalbuminemia. Serological tests for HIV, viral hepatitis and HTLV-1 were negative. The chest radiography showed pneumoperitoneum, and an exploratory laparotomy revealed perforation of the small bowel. An advanced stage (Ann Arbor IV B/Lugano IIE2B) EATL type II was diagnosed. Four cycles of chemotherapy were interspersed with several complications (anthracycline-induced cardiotoxicity, chemotherapy-induced neutropenic fever and severe sepsis). Performance status progressively worsened and he died 6 months after the diagnosis. This is an illustrative report of a rare and aggressive primary intestinal lymphoma. To the best of our knowledge, this is the first report of EATL type II in Brazil.

Keywords: Enteropathy-Associated T-Cell Lymphoma; Celiac Disease; Lymphoma, Non-Hodgkin; Intestinal Perforation; Lymphoma, T-Cell.

CASE REPORT

A 78-year-old previously healthy white male patient sought medical care with a 2-month history of diarrhea accompanied by 20 kg of weight loss. He denied fever or night sweats. One month

prior the hospital admission a slight lower-limb edema started, which progressively worsened reaching the thighs. An erythematic eruption also appeared on the anterior surface of both legs. On

32

Autopsy and Case Reports 2012; 2(2): 31-36 Felipe-Silva A, Campos FPF, Medeiros RSS, Lourenção RM, Zerbini MCN.

5.5 cm ulcerated, infiltrated, whitish and soft tumor (Figure 1). Tumor perforation was detected in one segment as well as suppurative serositis. Whitish and soft enlarged lymph nodes (up to 3.0 cm) adhered to the segment. Surrounding mucosa and bowel wall were somewhat thickened and rubbery.

On microscopic examination, tumor masses invaded through the wall of the intestine (Figure 2A) and were composed by cells with medium-sized round or irregular, darkly staining nuclei with a rim of pale or eosinophilic cytoplasm (Figure 2B). Frequent mitotic figures and some enlarged nucleoli were seen. Intestinal crypts and surface epithelium were diffusely infiltrated by malignant cells. Villous atrophy and crypt hyperplasia were also present (Figure 2C and 2D). Two adjacent lymph nodes were invaded by tumor cells. No other foci of infiltration were detected.

On immunohistochemistry analysis, neoplastic cells were CD3+, CD8+ and CD56+, which was consistent with a natural killer like (NK-like) T cell or even NK phenotype (Figure 3A and C). Immunostaining for CD20, CD30, ALK, CD4 and CD5 were all negative. Proliferation index by Ki67 was 60-70%. Pancytokeratin immunostaining with AE1+AE3 highlighted villous atrophy and intraepithelial infiltration by both individual and clusters of tumor cells (Figure 3D). These findings were consistent with enteropathy-associated T-cell lymphoma type II (EATL type II).

the day of hospital admission he referred an intense and diffuse abdominal pain radiating to the back.

The physical examination revealed an ill-looking, pale, and dehydrated patient. The pulse rate was 120 beats per minute and blood pressure was 90/50 mmHg. The lower limbs were edematous, with bullous lesions over an erythematous skin (consistent with erysipela) on the anterior surface of both legs. The heart and lungs examination was unremarkable. The abdomen was distended, painful, and a tumor mass was palpable in the hypogastrium. Bowel sounds were absent and the rebound tenderness (Bloomberg sign) was positive.

Laboratory tests are shown in Table 1. Serological tests for HIV, hepatitis (B and C) and HTLV-1 were negative.

The chest radiography showed the image of pneumoperitoneum. The patient underwent an exploratory laparotomy, which revealed a large amount of enteric fluid in the abdominal cavity and perforation of the small intestine at 15 cm and 220 cm from the Treitz angle. The two perforated segments were resected. The post-operative follow up was marked by generalized edema and hypoalbuminemia.

Gross examination of enterectomy specimens revealed two segments of jejunum (42 cm length each). Each segment presented a

Table 1 – Laboratory work up

Exam Result RV Exam Result RV

Hemoglobin 13.2 12.3-15.3 g/dL Creatinine 1.4 0.4-1.3 mg/dL

Hematocrit 40 36.0-45.0% Urea 57 10-50 mg/dL

Leukocytes 9.1 4.4-11.3×10³/mm³ Ionized Ca+ 1.07 1.15-1.35 Mmol/L

Promyelocytes 1 0 Sodium 138 136-146 mEq/L

Myelocytes 3 0 Potassium 5.3 3.5-5.0 mEq/L

Metamyelocytes 5 0 AST 20 10-31 IU/L

Bands 25 1-5% ALT 21 9-36 IU/L

Segmented 50 46-75% Alkaline phosphatase 83 10-100 IU/L

Eosinophils 0 1-4% γGT 46 2-30 IU/L

Basophils 0 0-2.5% Total bilirubin 0.7 0.3-1.2 mg/dL

Lymphocytes 15 18-40% Total protein 3.7 6.0-8.0 g/dL

Monocytes 1 2-9% Albumin 1.0 3.0-5.0 g/dL

Platelets 509×10³ 150-400×10³/ mm³ LDH 168 120-246 IU/L

ALT = alanine aminotransferase, AST = aspartate aminotransferase, γGT = gamma-glutamyl transferase, LDH = serum lactate dehydrogenase, RV = reference value.

33

Enteropathy-associated T-cell lymphoma (type II): a Brazilian case report Autopsy and Case Reports 2012; 2(2): 31-36

Post-operative abdominal computed tomography (CT) revealed the presence of confluent lymph nodes, near the superior mesenteric vascular bundle, measuring up to 2.5 cm with homogeneous enhancement by the contrast medium. Neck and chest CT did not detect lymphadenopathy.

The patient developed nosocomial pneumonia, which delayed the start of the specific treatment. After clinical improvement he was referred to an oncology center. Bone marrow biopsy revealed no lymphoma infiltration. Disease was staged Ann Arbor IV B/Lugano IIE2B. Treatment started with CHOP chemotherapy and was changed to COP scheme after 2 cycles. The patient developed anthracycline-induced cardiotoxicity, chemotherapy-induced neutropenic fever and severe sepsis. Performance status progressively worsened and he died 6 months after the diagnosis. Postmortem examination was not requested.

DISCUSSION

The gastrointestinal tract is the most common location of extranodal lymphomas. The stomach is the most frequent site of involvement (mainly due to Helicobacter pylori associated mucosal associated lymphoid tissue - MALT – lymphoma), followed by the small intestine.1,2 Primary large bowel and rectum lymphomas are much less common.3

Most gastrointestinal primary lymphomas are of B phenotype (MALT lymphoma, large B cell lymphoma, mantle cell lymphoma, follicular

lymphoma, Burkitt lymphoma and immunoproliferative small intestinal disease- IPSID).4

Primary gastrointestinal tract T-cell lymphomas are mostly associated with malabsorption, as a complication of celiac sprue. These cases have been designated as ‘‘enteropathy-associated T-cell lymphoma’’ (EATL) and they are characterized by prominent intraepithelial lymphomatous spread and villous atrophy of uninvolved mucosa. T cells show varying degrees of transformation, frequently with an inflammatory background.5,6,7

EATL is considered a rare form of aggressive T-cell lymphoma accounting for less than 1% of non-Hodgkin lymphomas. The estimated annual incidence rate is 0.5-1 per million people in Western countries. It is more prevalent in men over 60 years.8,9 The outcome is very poor with an overall survival rate of 15-20% in 2-year.10

Based on morphology, immunohistochemistry and genetic profile EATL can be divided into two groups. EATL type I is a large-size cell lymphoma which is highly associated with celiac disease and mostly, presents with malabsorption, weight loss and celiac disease-related symptoms. Geographic distribution follows that of celiac disease, with a high prevalence in Northern Europe. Most patients show adult onset celiac disease, sometimes with an initial period of refractory disease and ulcerative jejunitis. Tumor cells are typically CD3+, CD5–, CD7+, CD8+/–, CD4–, CD30+ and contain cytotoxic granule associated proteins by immunohistochemistry.7,11

EATL type II comprises about 10-20% of EATL and is composed of monomorphic, small to medium-sized cells. Obstruction or perforation of the small bowel is common. EATL type II is not associated with celiac disease and may occur sporadically. The immunophenotype is somewhat different from EATL type I (CD3+, CD4–, CD8+, CD56+).5,12,13 Prognosis of EATL type II seems to be even worse, with median overall survival of 7 months and progression-free-survival of 1 month.14

Other T-cell lymphomas may also develop in the intestine and sometimes simulate the histologic pattern of EATL.15 T-cell lymphomas can involve any part of the gastrointestinal tract, especially in patients in the Far East, where most cases are peripheral T-cell lymphomas, not otherwise specified (NOS),

Figure 1 – View of a section through small bowel EATL type II.

34

Autopsy and Case Reports 2012; 2(2): 31-36 Felipe-Silva A, Campos FPF, Medeiros RSS, Lourenção RM, Zerbini MCN.

known as Mediterranean lymphoma or α heavy chain disease, it mainly occurs in the Middle East and arises in association with a morphologically benign-appearing infiltrate, often characterized by a dense, plasma cell proliferation in the intestinal mucosa.24

This patient did not have a history of celiac disease. Actually, this was a quite recent onset with a clinical history of 2 months, which is consistent with EATL type II. Despite that, the patient presented with severe diarrhea and malabsorption, hypoalbuminemia and peripheral edema. In a recent large multicenter analysis of 38 patients with EATL type II, diarrhea and hypoalbuminemia were present in 21% and 90% of the cases, respectively.14

In summary, this is an illustrative report of a rare and aggressive primary intestinal lymphoma. To the best of our knowledge, this is the first report of EATL type II in Brazil.

NK/T-cell lymphomas of nasal type, and cases linked with the HTLV-1 virus.16-21

NK-cell enteropathy has recently been described as an entity that mimics EATL, especially the type II. In the case series reported by Mansoor et al., 8 patients presented with vague gastrointestinal symptoms and a mucosal infiltrate of atypical cells with an NK-cell phenotype. No patient developed progressive disease or died of lymphoma. In contrast with EATL type II, NK-cell enteropathy cells are CD8- and do not show marked epitheliotropism. Furthermore, clonal T-cell gene rearrangement is absent in NK-cell enteropathy.22

Differential diagnosis could also include IPSID, which is an uncommon type of gastrointestinal B cell lymphoma that tends to manifest as malabsorption, presents in the duodenum or proximal jejunum, and exhibits villous atrophy as well as plasma cell infiltration of the adjacent intestine.23 Formerly

Figure 2 – Photomicrography – small bowel surgical pathology specimen. A - (H&E, 12.5x) Tumor cells invade through the entire bowel wall. Serosal exudate secondary to perforation can be seen at the bottom; B - (H&E, 400x) Lymphoma cells with medium-sized round or irregular, darkly staining nuclei with a rim of pale or eosinophilic cytoplasm; C - (H&E, 100x) Villous atrophy and crypt hyperplasia; D - (H&E, 400x) Marked intraepithelial infiltration by lymphoma cells.

35

Enteropathy-associated T-cell lymphoma (type II): a Brazilian case report Autopsy and Case Reports 2012; 2(2): 31-36

editors. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon: International Agency of Research in Cancer; 2008. v. 2, p. 289-91.

6. Chott A, Dragosics B, Radaszkiewicz T. Peripheral T-cell lymphomas of the intestine. Am J Pathol. 1992;141(6):1361-71. PMid:1466400 PMCid:1886751.

7. Delabie J, Holte H, Vose JM, et al. Enteropathy-associated T-cell lymphoma: clinical and histological findings from the international peripheral T-cell lymphoma project. Blood. 2011;118(1):148-55. PMid:21566094. http://dx.doi.org/10.1182/blood-2011-02-335216

8. Di Sabatino A, Corazza GR. Coeliac disease. Lancet. 2009;373(9673):1480-93. http://dx.doi.org/10.1016/S0140-6736(09)60254-3

9. Verbeek WH, Van De Water JM, Al-Toma A, Oudejans JJ, Mulder CJ, Coupé VM. Incidence of enteropathy--associated T-cell lymphoma: a nation-wide study of a population-based registry in The Netherlands. Scand J Gastroenterol. 2008;43(11):1322-8. PMid:18618372. http://dx.doi.org/10.1080/00365520802240222

10. Al-Toma A, Verbeek WH, Hadithi M, Von Blomberg BM, Mulder CJ. Survival in refractory coeliac disease

REFERENCES

1. Groves FD, Linet MS, Travis LB, Devesa SS. Cancer surveillance series: non-Hodgkin’s lymphoma incidence by histologic subtype in the United States from 1978 through 1995. J Natl Cancer Inst. 2000;92(15):1240-51. http://dx.doi.org/10.1093/jnci/92.15.1240

2. Koch P, Del Valle F, Berdel WE, et al. Primary gastrointestinal non-Hodgkin’s lymphoma: I. Anatomic and histologic distribution, clinical features, and survival data of 371 patients registered in the German Multicenter Study GIT NHL 01/92. J Clin Oncol. 2001;19(18):3861-73. PMid:11559724.

3. Shepherd NA, Hall PA, Coates PJ, Levison DA. Primary malignant lymphoma of the colon and rectum. A histopathological and immunohistochemical analysis of 45 cases with clinicopathological correlations. Histopathology. 1988;12(3):235-52. PMid:3366441. http://dx.doi.org/10.1111/j.1365-2559.1988.tb01939.x

4. Isaacson PG. Gastrointestinal lymphoma. Hum Pathol. 1994;25(10):1020-9. http://dx.doi.org/10.1016/0046-8177(94)90060-4

5. Isaacson PG, Chott A, Ott G, Stein H. Enteropathy-associated T-cell lymphoma. In: Swerdlow SH, Campo E, Harris NL, et al.,

Figure 3 – Phootomicrography – Immunohistochemistry. A - (CD3, 12.5x) CD3+ T-cells invade through the entire bowel wall; B - (CD3, 200x) Striking intraepithelial infiltration by CD3+ lymphoma cells; C - (CD56, 200x) CD56+ cells featuring EATL type II; D - (AE1+AE3, 400x) Pan-cytokeratin stains intestinal epithelium, highlighting clusters of intraepithelial lymphoid cells.

36

Autopsy and Case Reports 2012; 2(2): 31-36 Felipe-Silva A, Campos FPF, Medeiros RSS, Lourenção RM, Zerbini MCN.

Hum Pathol. 2008;39(7):1018-25. PMid:18482744. http://dx.doi.org/10.1016/j.humpath.2007.11.003

18. Chuang SS, Chang ST, Chuang WY, et al. NK-cell lineage predicts poor survival in primary intestinal NK-cell and T-cell lymphomas. Am J Surg Pathol. 2009;33(8):1230-40. PM id :19561449 . h t t p : / / dx .do i . o rg /10 .1097 /PAS.0b013e3181a95c63

19. Ko YH, Karnan S, Kim KM, et al. Enteropathy-associated T-cell lymphoma-a clinicopathologic and array comparative genomic hybridization study. Hum Pathol. 2010;41(9):1231-7. PMid:20399483. http://dx.doi.org/10.1016/j.humpath.2009.11.020

20. Takeshita M, Nakamura S, Kikuma K, et al. Pathological and immunohistological findings and genetic aberrations of intestinal enteropathy-associated T cell lymphoma in Japan. Histopathology. 2011;58(3):395-407. PMid:21323966. http://dx.doi.org/10.1111/j.1365-2559.2011.03768.x

21. Sun J, Lu Z, Yang D, Chen J. Primary intestinal T-cell and NK-cell lymphomas: a clinicopathological and molecular study from China focused on type II enteropathy-associated T-cell lymphoma and primary intestinal NK-cell lymphoma. Mod Pathol. 2011;24(7):983-92. PMid:21423155. http://dx.doi.org/10.1038/modpathol.2011.45

22. Mansoor A, Pittaluga S, Beck PL, Wilson WH, Ferry JA, Jaffe ES. NK-cell enteropathy: a benign NK-cell lymphoproliferative disease mimicking intestinal lymphoma: clinicopathologic features and follow-up in a unique case series. Blood. 2011;117(5):1447-52. PMid:20966166 PMCid:3056587. http://dx.doi.org/10.1182/blood-2010-08-302737

23. Al-Saleem T, Al-Mondhiry H. Immunoproliferative small intestinal disease (IPSID): a model for mature B-cell neoplasms. Blood. 2005;105(6):2274-80. PMid:15542584. http://dx.doi.org/10.1182/blood-2004-07-2755

24. Burke JS. Lymphoproliferative disorders of the gastrointestinal tract: a review and pragmatic guide to diagnosis. Arch Pathol Lab Med. 2011;135(10):1283-97. http://dx.doi.org/10.5858/arpa.2011-0145-RA

and enteropathy-associated T-cel l lymphoma: retrospective evaluation of single-centre experience. Gut. 2007;56(10):1373-8. PMid:17470479 PMCid:2000250. http://dx.doi.org/10.1136/gut.2006.114512

11. Wright DH. Enteropathy associated T cell lymphoma. Cancer Surv. 1997;30:249-61. PMid:9547996.

12. Chott A, Haedicke W, Mosberger I, et al. Most CD56+ intestinal lymphomas are CD8+CD5-T-cell lymphomas of monomorphic small to medium size histology. Am J Pathol. 1998;153(5):1483-90. http://dx.doi.org/10.1016/S0002-9440(10)65736-7

13. Van De Water JM, Cillessen SA, Visser OJ, Verbeek WH, Meijer CJ, Mulder CJ. Enteropathy associated T-cell lymphoma and its precursor lesions. Best Pract Res Clin Gastroenterol. 2010;24(1):43-56. http://dx.doi.org/10.1016/j.bpg.2009.11.002

14. Tse E, Gill H, Loong F, et al. Type II enteropathy-associated T-cell lymphoma: A multicenter analysis from the Asia Lymphoma Study Group. Am J Hematol [Internet]. 2012 May 28; [Epub ahead of print; cited 2012 Jun 12]. Available from: http://onlinelibrary.wiley.com/doi/10.1002/ajh.23213/pdf doi: 10.1002/ajh.23213.

15. Domizio P, Owen RA, Shepherd NA, Talbot IC, Norton AJ. Primary lymphoma of the small intestine. A clinicopathological study of 119 cases. Am J Surg Pathol. 1993;17(5):429-42. PMid:8470758. http://dx.doi.org/10.1097/00000478-199305000-00001

16. Kohno S, Ohshima K, Yoneda S, Kodama T, Shirakusa T, Kikuchi M. Clinicopathological analysis of 143 primary malignant lymphomas in the small and large intestines based on the new WHO classification. Histopathology. 2003;43(2):135-43. PMid:12877728. http://dx.doi.org/10.1046/j.1365-2559.2003.01659.x

17. Tung CL, Hsieh PP, Chang JH, Chen RS, Chen YJ, Wang JS. Intestinal T-cell and natural killer-cell lymphomas in Taiwan with special emphasis on 2 distinct cellular types: natural killer-like cytotoxic T cell and true natural killer cell.

Conflict of interest: None

Submitted on: 7th June 2012 Accept on: 11th June 2012

Correspondence: Serviço de Anatomia Patológica Av. Prof. Lineu Prestes, 2565 – Cidade Universitária - São Paulo/SP – Brazil CEP: 05508-900 – Phone: +55 (11) 3091-9384 E-mail: aloisiosilva@hu.usp.br

Article / Clinical Case Reports Artigo / Relato de Caso Clínico

37

Copyright © 2012 Autopsy and Case Reports – This is an Open Access article distributed of terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any médium provided article is properly cited.

a Department of Dentistry - Hospital Universitário - Universidade de São Paulo, São Paulo/SP - Brazil. b Department of Surgery - Prosthesis and Maxillofacial Trauma - Faculdade de Odontologia - Universidade de São Paulo, São Paulo/SP - Brazil.

Autopsy and Case Reports 2012; 2(2): 37-41

37

Intra-oral surgical access for the treatment of bilateral submandibular sialolithiasis: case report

Ricardo Martinsa, Carlos Augusto Ferreira Alvesa, Edson Martins de Oliveira Juniora, Fernando Melhem Eliasa,b, Antônio Carlos de Camposa,b

Martins R, Alves CAF, Oliveira Junior EM, Elias FM, Campos AC. Intra-oral surgical access for the treatment of bilateral submandibular sialolithiasis: case report. Autopsy Case Rep [Internet]. 2012;2(2):37-41. http://dx.doi.org/10.4322/acr.2012.015

ABSTRACT

Sialolithiasis is a disease that affects the salivary glands. It is characterized by the presence of calcified structures within the duct system or within the glandular parenchyma. Those calculi, or sialoliths, can obstruct normal salivary flow, potentially leading to infectious sialadenitis, with pain, local swelling, and purulent discharge. Treatment typically consists of the surgical removal of the calculus, often in conjunction with sialoadenectomy. The authors report an atypical case of bilateral submandibular gland sialolithiasis treated conservatively, using intra-oral access to remove the calculi.

Keywords: Salivary gland calculi; Submandibular gland; Surgical procedures, Operative.

INTRODUCTION

Salivary duct calculi, also known as sialoliths, constitute the leading cause of salivary gland obstruction. Sialoliths can occur in the glandular parenchyma or in the salivary duct system, obstructing the flow of saliva and causing episodes of local pain and edema, especially during meals. Sialoliths can be single or multiple, can be unilateral or bilateral, and can vary in shape and size. They affect approximately 1.2% of the population, and the most commonly affected site is the submandibular gland (involved in approximately 83% of cases), followed by the parotid gland (in 10% of cases), and the sublingual gland (in 3% of cases).1

Although some etiological aspects remain unknown, anatomical and biochemical components are certainly involved,2 leading to calcium salt deposition around accumulations of organic debris

in the lumen of the duct or glandular parenchyma. This organic debris consists of condensed mucus, bacteria, desquamated epithelial cells, or foreign bodies.3,4

The salivary flow obstruction caused by sialoliths can lead to salivary gland infection, which is known as sialolithiasis. As previously mentioned, sialolithiasis is most commonly seen in the submandibular glands, which is due to the anatomical features of these glands—including the fact that the trajectory of the duct is long and tortuous, running counter to the force of gravity—and to the fact that the secretion produced by the glands is predominantly mucous.5

Although the diagnosis of sialolithiasis is primarily based on clinical findings, diagnostic

38

Autopsy and Case Reports 2012; 2(2): 37-41 Martins R, Alves CAF, Oliveira Junior EM, Elias FM, Campos AC.

near the orifice (in the hila) of both submandibular salivary glands (Figures 2A and 2B).

After a clinical diagnosis of bilateral submandibular sialolithiasis had been established, the proposed treatment was intra-oral removal of the sialoliths, with the primary objective of maintaining submandibular gland function. In case of intra-oral removal failure, right sialoadenectomy (removal of the entire submandibular gland) has to be performed, the left gland being maintained and a further procedure being employed in order to remove the sialolith on that side.

With the patient under general anesthesia and after careful palpation to determine the exact location of the calculi, incisions were made in the floor of the mouth, immediately above the calculi, followed by blunt dilatation, clamping, and removal of both calculi. As shown in Figures 3A and C, the incisions were closed with a single layer of absorbable polyglycolic acid sutures (Vicryl 3.0; Ethicon, Inc., Somerville, NJ, USA).

On postoperative day 1, no motor or sensory impairment was observed by us or reported by the patient, who was therefore discharged on antibiotics. At this writing, 6 months after the surgical procedure, the patient was under outpatient follow-up, with no pain or clinical signs of submandibular gland obstruction or infection. In addition, submandibular gland function and salivary function were preserved (Figure 4).

DISCUSSION

Sialolithiasis is the most common disease of the major salivary glands and is the leading cause of major salivary gland dysfunction.8 The main

imaging methods include panoramic radiographs, occlusal radiographs, sialography, ultrasound, and computed tomography (CT).6 Conventional treatment depends on the location of the sialolith and can be intra- or extra-oral. Small sialoliths located near the orifice of the submandibular duct can be removed by manipulation or by submandibular duct catheterization and dilatation. Sialoliths located up to the anterior half of the duct are generally treated by conservative surgery, preferably via an intra-oral approach.7 In cases of large sialoliths, particularly those in the glandular parenchyma, the calculus and the gland should be removed, which is generally done via an extra-oral approach.

CASE REPORT

A 34-year-old male patient with a good overall health status (American Society of Anesthesiologists physical status 1, i.e., normal healthy) reported an 18-month history of swelling and pain (particularly during meals) in the floor of his mouth. He also reported mild dry mouth and spontaneous pus discharge under the tongue. Clinical examination revealed bilateral swelling in the submandibular region, together with submandibular lymphadenopathy, purulent discharge in the sublingual caruncle (upon milking of the right submandibular gland), and slightly reduced salivary flow. Palpation of the floor of the mouth revealed two sialoliths, one on each side, with no local swelling (Figures 1A and 1B). After the initial evaluation, we requested a CT scan of the submandibular region and started the patient on a 15-day course of antibiotic therapy with oral clindamycin.

The CT scan showed an image that was consistent with two sialoliths of approximately 10 mm in diameter each. The sialoliths were lodged

Figure 1 – A - Initial clinical appearance; B - Purulent discharge in the right sublingual caruncle upon milking of the submandibular gland (arrow).

39

Intra-oral surgical access for the treatment of bilateral submandibular sialolithiasis... Autopsy and Case Reports 2012; 2(2): 37-41

is a commonly affected site. However, bilateral involvement is considered rare.3,5,9 According to Shafer et al.10 and Nahiele et al.,6 sialolithiasis primarily affects males, as in the present case.

Various theories have been put forward in an attempt to explain the etiopathogenesis of sialolithiasis. According to Epker,11 the disease results from calcium salt deposition around a nidus of organic material, consisting of altered salivary mucin, bacteria, and desquamated epithelial cells. The formation of salivary duct calculi occurs in two phases. In the first phase, the core layer is formed by calcium salt precipitation. In the second, there is deposition of organic and inorganic material. Subsequently, mineralization occurs as a result of calcium accumulation and changes in salivary pH.

feature of sialolithiasis is the formation of calcified structures (i.e., sialoliths) in the duct system or glandular parenchyma.3

Sialoliths, also known as salivary stones, can affect individuals of all ages. However, they are more common in youths and middle-aged adults. Sialoliths are rarely seen in children. Sialoliths can affect the submandibular gland (in 80-90% of cases), the parotid gland (in 5-20% of cases), and the sublingual gland (in 1-2% of cases). They rarely affect the minor salivary glands.9 It is estimated that sialolithiasis affects 12 of every 1,000 adults.

In the present case, the sialoliths were lodged in both submandibular glands, specifically in the glandular hilum, which, according to the literature,

Figure 3 – A and B - Intra-oral removal of the sialoliths; C - the removed sialoliths (one from each side).

Figure 2 – A - Computed tomography scan showing the presence of bilateral submandibular calculi (arrows), each approximately 10 mm in diameter; B - Three-dimensional reconstruction showing the submandibular calculi.

40

Autopsy and Case Reports 2012; 2(2): 37-41 Martins R, Alves CAF, Oliveira Junior EM, Elias FM, Campos AC.

opening of the duct. Other forms of treatment include the use of diet rich in acidic foods or other foods that stimulate saliva production and can therefore expel the calculi from the ducts.14

Park et al.15 recommend that submandibular calculi be removed intra-orally in order to preserve the gland, especially if the sialolith is palpable distal to the gland. Surgical excision of the affected gland might be required in cases in which the sialoliths are extremely close to the glandular parenchyma, as well as in those in which there are recurrent episodes of salivary gland infection.14 According to Torroni et al.,16 surgical excision of the submandibular gland is a relatively simple procedure that poses little risk to adjacent structures and is of little esthetic consequence. However, we believe that the procedure poses a risk of injury to the marginal mandibular branch of the facial nerve, which can in turn cause motor impairment of the lower lip. Therefore, surgical excision of the affected gland should not be the treatment of first choice.

In the case reported here, both calculi were palpable in the floor of the mouth, what facilitated the surgical access, despite the fact that the sialoliths were located in the glandular hila. Therefore, we chose the intra-oral approach, contrary to the recommendations of Bsou & Flint,1 Quellete & Stack,17 and Gabrielli et al.14 Despite the narrow surgical field, the intra-oral approach reduced the possibility of injury to adjacent structures.

CONCLUSION

In the case reported here, an intra-oral approach via the floor of the mouth proved effective for the removal of two sialoliths located in the initial portion of the submandibular duct (one on each side). Therefore, the intra-oral approach is warranted, particularly in cases in which the sialoliths are palpable. The esthetic results of the intra-oral approach are better than those of the extra-oral approach, the former accompanied by low morbidity.

REFERENCES

1. Bsoul AS, Flint DJ. Clinical images in oral medicine and maxillofacial radiology: sialolithiasis. Quintessence Int. 2003;34(4):316-7. PMid:12731621.

The diagnosis of sialolithiasis is based primarily on clinical history and clinical presentation. The vast majority of patients present with pain and swelling in the submandibular gland region, which are due to salivary duct obstruction by the sialolith. Extra-oral palpation of the submandibular region reveals a hard swelling, which can be accompanied by inflammatory lymphadenopathy. The milking of the submandibular gland can result in purulent discharge from the ostium of the gland, as well as in reduced salivary flow.

The differential diagnosis should include obstructive sialadenitis (without sialolithiasis), mumps, and salivary gland tumors.12 Approximately 80% of all sialoliths are radiopaque and can be seen in most radiographic examinations. Panoramic and occlusal radiographs provide good visualization of sialoliths in the submandibular gland.13 In the case reported here, because of the presence of bilateral submandibular swelling and because palpation of the floor of the mouth revealed two hard structures (one on each side), CT was requested in order to rule out other diseases. In our experience, CT should be used as the primary imaging test for the differential diagnosis of diseases of the salivary glands, especially because it can show the precise location of sialoliths.

In cases of sialolithiasis, the severity of the symptoms varies with the size and location of the calculus, as well as with the extent of the obstruction. Intraparenchymal sialoliths tend to cause symptoms that are less severe. However, if the duct is occluded, the probability of salivary gland infection is far higher.1

Small sialoliths can sometimes be treated conservatively with massage towards the glandular drainage, in order to direct the calculus to the

Figure 4 – Photograph taken at postoperative month 6, showing the absence of infection and the presence of salivary secretion.

41

Intra-oral surgical access for the treatment of bilateral submandibular sialolithiasis... Autopsy and Case Reports 2012; 2(2): 37-41

11. Epker BN. Obstructive and inflammatory diseases of the major salivary glands. Oral Surg. 1972;33(1):2-27. http://dx.doi.org/10.1016/0030-4220(72)90203-4

12. Uluc ME, Vidinli BD, Erdogan N, Gelal F. Giant cystic dilatation that includes multiple sialolithiasis of submandibular gland. Otolaryngol Head Neck Surg. 2006;134(3):533-4. PMid :16500461. ht tp : / /dx .do i .o rg /10 .1016/ j .otohns.2005.03.073

13. Kawata LT, Baldan RCF, Moraes NP, Biazolla ER. Sialolitíase em ducto de glândula submandibular: relato de dois casos clínicos. Rev Odontol Araçatuba. 2006;27(1):14-8.

14. Gabrielli M, Paleari A, Conte Neto N, Silva L, Dantas J. Tratamento de sialolitíase em glândulas submandibulares: relato de dois casos. Robrac: Rev Odontol Bras Central. 2008;17(44):110-16.

15. Park JS, Sohn JH, Kim JK. Factors influencing intraoral removal of submandibular calculi. Otolaryngol Head Neck Surg. 2006;135(5):704-9. PMid:17071298. http://dx.doi.org/10.1016/j.otohns.2006.07.013

16. Torroni AA, Muztazza MC, Bartoli DD, Iannetti GG. Transcervical submandibular sialiadenectomia. J Craniofac Surg. 2007;18(3):613-21. PMid:17538327. http://dx.doi.org/10.1097/01.scs.0000249352.43849.04

17. Quellete AL, Slack CL. Shrapnel-induced sialolith - a rare etiology for saladenitis: case report. J Oral Maxillofac Surg. 2003;61(5):636-7. PMid:12730847. http://dx.doi.org/10.1053/joms.2003.50123

2. Yu CQ, Yang C, Zheng LY, Wu DM, Zhang J, Yun B. Selective management of obstructive submandibular sialadenitis. Br J Oral Maxillofac Surg. 2008;46(1):46-9. PMid:17703856. http://dx.doi.org/10.1016/j.bjoms.2007.06.008

3. Neville BW, Damm D, Allen CM, Bouquot JE. Patologia oral e maxilofacial. 2. ed. Rio de Janeiro: Guanabara Koogan; 2008.

4. Lee LT, Wong YK. Pathogenesis and diverse histologic findings of sialolithiasis in minor salivary glands. J Oral Maxillofac Surg. 2010;68(2):465-70. PMid:20116725. http://dx.doi.org/10.1016/j.joms.2009.03.041

5. Ellis III E, Hupp JR, Tucker MR. Cirurgia oral e maxilofacial contemporânea. 5. ed. Rio de Janeiro: Elsevier; 2009.

6. Nahlieli O, Neder A, Baruchin AM. Salivary gland endoscopy: A new technique for diagnosis and treatment of sialolithiasis. J Oral Maxillofac Surg. 1994;52(12):1240-2. http://dx.doi.org/10.1016/0278-2391(94)90043-4

7. Oliveira CMB, Mizuno EHF, Favaro JC, Mizuno LT. Cálculo salivar “gigante” (25mm x 15mm): relato de caso. Rev Ciênc Odontol. 2003;6(11):7-11.

8. Williams MF. Sialolithiasis. Otolaryngol Clin North Am. 1999;32(5):819-34. http://dx.doi.org/10.1016/S0030-6665(05)70175-4

9. Siddiqui SJ. Sialolithiasis: an unusually large submandibular salivary stone. Br Dent J. 2002;193(2):89-91. PMid:12199129. http://dx.doi.org/10.1038/sj.bdj.4801491

10. Shafer WG, Maynard KH, Barnet ML, Tomich CE. Tratado de patologia bucal. 4. ed. Rio de Janeiro: Guanabara Koogan; 1987. 837 p.

Conflict of interest: None

Submitted on: 2nd January 2012 Accept on: 26th January 2012

Correspondence: Divisão de Odontologia Av. Prof. Lineu Prestes, 2565 – Cidade Universitária - São Paulo/SP – Brazil CEP: 05508-000 – Phone: +55 (11) 3091-9290 E-mail: ricardomartins.cirurgiabmf@gmail.com

Article / Clinical Case Reports Artigo / Relato de Caso Clínico

43

Copyright © 2012 Autopsy and Case Reports – This is an Open Access article distributed of terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any médium provided article is properly cited.

a Heart Institute - Hospital das Clínicas - Faculdade de Medicina - Universidade de São Paulo, São Paulo/SP - Brazil. b Diagnostic Imaging Service - Hospital Universitário - Universidade de São Paulo, São Paulo/SP - Brazil. c Department of Clinical Surgery - Faculdade de Medicina - Universidade de São Paulo, São Paulo/SP - Brazil. d Department of Radiology - Faculdade de Medicina - Universidade de São Paulo, São Paulo/SP - Brazil.

Autopsy and Case Reports 2012; 2(2): 43-47

43

Segmental omental infarction: an unusual cause of acute abdomen

José de Arimatéia Batista Araújo Filhoa, João Augusto dos Santos Martinesb, Brenda Margatho Ramos Martinesb, Rodrigo Montenegro Lourençãoc,

Lorena Elaine Amorim Pintoa, Cláudio Campi de Castrob,d

Araújo Filho JAB, Martines JAS, Martines BMR, Lourenção RM, Pinto LEA, Castro CC. Segmental omental infarction: an unusual cause of acute abdomen. Autopsy Case Rep [Internet]. 2012;2(2):43-47. http://dx.doi.org/10.4322/acr.2012.016

ABSTRACT

Omental infarction is a rare cause of acute abdominal pain, and the cause of omental infarction itself remains unknown. The diagnosis of omental infarction is occasionally made intra-operatively, because it is poorly known and presents no specific clinical features. Therefore omental infarction should always be considered in the differential diagnosis of abdominal inflammatory processes, mainly those affecting the right lower quadrant. The increasing use of computed tomography in cases of acute abdomen has facilitated the diagnosis of omental infarction in the pre-operative period. Here, we present the case of a 36-year-old, overweight female patient with clinical symptoms of acute abdomen. Computed tomography of the abdomen revealed indications of omental infarction. The patient was treated conservatively with analgesics and a nonsteroidal anti-inflammatory. The clinical evolution was favorable.

Keywords: Abdomen, Acute; Infarction; Omentum; Tomography; X-Ray computed.

CASE REPORT

A 36-year-old female patient presented to the emergency room with a 5-day history of severe abdominal pain and constipation. She reported nausea, vomiting, and fever on the first day of the symptoms. Her medical history included diabetes mellitus, for which she was taking oral hypoglycemic agents and insulin. Physical examination revealed good overall health. The patient was afebrile and hydrated, with a ruddy complexion. She had a blood pressure of 220/120 mmHg, a pulse rate of 110 bpm, and a body mass index of 27 kg/m2. Abdominal examination showed diffuse tenderness and signs of peritoneal irritation with positive rebound (Bloomberg sign). Bowel sounds were normal.

Laboratory test results were normal except for mild leukocytosis (12,000 cells/mm3) with no shift to the left. Amylase and urinalysis were normal, and urine culture was negative for bacterial growth. Given the clinical suspicion of acute inflammatory abdomen, the patient underwent computed tomography (CT) of the abdomen with oral contrast. The CT scan showed a circumscribed heterogeneous mass permeated with streaks of low attenuation (fat), accompanied by increased density of the adjacent fat tissue, confined to the right lower quadrant. The lesion measured 7.4 × 3.0 cm on its longest axis and was located between the abdominal wall and the small bowel, not involving the wall of the colon. A

44

Autopsy and Case Reports 2012; 2(2): 43-47 Araújo Filho JAB, Martines JAS, Martines BMR, Lourenção RM, Pinto LEA, Castro CC.

thin layer of free fluid was detected in the abdominal cavity; the appendix and other abdominal organs were normal in appearance (Figures 1 and 2). All of these findings are suggestive of segmental infarction of the omentum. Therefore, a conservative therapeutic regimen was addopted, consisting of analgesics, a nonsteroidal anti-inflammatory, and clinical follow up.

The patient experienced recurrence of the pain and returned to the emergency room some days later. A new CT scan showed no significant changes, and the conservative treatment was maintained. Further follow-up evaluations were unremarkable.

DISCUSSION

Acute abdomen refers to a variety of disorders that are characterized by sudden abdominal pain of variable intensity. There is a broad spectrum of diagnostic possibilities, ranging from benign to life-threatening conditions. The

duration of symptoms can be from hours to days but never exceeds seven days. Acute abdomen typically requires medical intervention, surgical or otherwise.1 According to the nature of the dominant process; acute conditions of the abdomen are produced by inflammatory, obstructive, or vascular mechanisms.2

In the topography of the right lower quadrant, the differential diagnosis of acute abdomen encompasses a variety of inflammatory diseases, including appendicitis, diverticulitis, cholecystitis, acute terminal ileitis, appendagitis, mesenteric panniculitis, omental infarction,3 and adnexal disease. Given the non-specificity and overlap of clinical findings in these conditions, imaging methods are of great importance in the diagnostic work-up. Mindelzun et al.4 reported that approximately two thirds of all patients with acute abdominal pain have an abnormality identifiable by imaging studies. The positive results obtained with multidetector CT (MDCT) in the diagnosis of acute abdomen justify its widespread use and the fact that, despite its high cost and intrinsic morbidity, MDCT is typically chosen over other methods, such

Figure 1 - Axial computed tomography of the abdomen with oral contrast media, showing a heterogeneous mass permeated by streaks of low attenuation in the right lower quadrant (white arrows), between the abdominal wall and the small bowel, to the wall of the colon. Note the preserved caliber of the appendix.

45

Segmental omental infarction: an unusual cause of acute abdomen Autopsy and Case Reports 2012; 2(2): 43-47

as plain radiographs and ultrasonography, for use in cases of acute abdomen.5 More recently, the use of CT without contrast has been proposed as an alternative to plain abdominal radiography for initial evaluation of patients with suspected acute abdomen. The availability CT has been increasing, as has its sensitivity and specificity.6

Considering the inflammatory processes of the abdominal right lower quadrant, acute appendicitis is considered the first hypothesis. Otherwise, clinical practice shows that, when the surgery is undertaken without a diagnostic imagining study, a diagnosis other than the one previously considered can be discovered. Omental infarction, with or without torsion, is one such incidental diagnosis. Omental infarction is a rare abdominal emergency that affects middle-aged patients, predominantly males (male/female ratio, 3:2),7 usually without an identifiable cause (idiopathic or primary infarction). The incidence of omental torsion is 0.0016%, compared with 0.37% for appendicitis, or less than 4 cases per 1,000 cases of appendicitis.8 Omental infarction can occur with or without torsion. Eitel et al. first described the former in 1899,9 who reported a case in which the omentum twisted along its long axis, cutting off its blood supply. However, Bush et al.10 had described infarction of the omentum without torsion in 1898, reporting a case of hemorrhage into the greater omentum. Anatomical malformations, such as a bifid

or accessory omentum, cause spontaneous torsion, sudden movements, violent exercise, and hyper peristalsis having been implicated as precipitating factors. Obesity and the presence of a redundant or overly mobile omentum are also considered predisposing factors. In the study conducted by Van Breda Vriesman et al.11 in 1999, nearly 70% of the patients with omental infarction were obese. Secondary torsions more often occur because of previous surgery, tumors, adhesions, and incarcerated hernias, with the dependent omentum becoming fixed in the contorted position and unable to untwist.7,8 Omental infarction without torsion occurs in the setting of systemic diseases such as vasculitis, as well as in hypercoagulable states and pancreatitis. Idiopathic segmental infarction can also occur. The distinction between omental torsion and omental infarction without torsion is thought to be only of academic importance.8 The literature also states that ischemic processes involve mainly the right side of the omentum, probably due to its greater size, weight, and mobility.7

Reports dating from before the advent of modern imaging modalities show the frequency of non-operative and pre-operative diagnosis of omental infarction to have been 0.6-4.8%.11,12 Even without intravenous contrast media, a CT scan usually furnishes the diagnosis. Findings include dense planes with the formation of a fat mass, consisting of fat necrosis, hemorrhage, and inflammatory infiltrate. The presence of linear streaking accompanied by a fat mass suggests that the omental vessels have twisted upon themselves, confirming the diagnosis of omental infarction. These findings have also been described as a whirl pattern of fat and vessels, plus caking and stranding of omental fat.11,13 In cases of secondary torsion, the CT scan can reveal concomitant or triggering processes.14

Among the treatment modalities for omental infarction, the conservative, or expected, management with analgesics, nonsteroidal anti-inflammatory drugs, and (occasionally) antibiotics seems to be the most attractive. However, complications of such conservative management include abscess and adhesions. More importantly, a missed diagnosis of acute appendicitis could have disastrous consequences. Van Breda Vriesman et al.11 reported a series of 40 cases of intra-abdominal fat infarction treated clinically without complications. In contrast, Nubi et al.15 reported a series of 10 children diagnosed with omental infarction. Although all

Figure 2 - MDCT of the abdomen, sagittal reformatted image showing displacement of the small bowel by the mass.

46

Autopsy and Case Reports 2012; 2(2): 43-47 Araújo Filho JAB, Martines JAS, Martines BMR, Lourenção RM, Pinto LEA, Castro CC.

of the children were initially treated clinically, 6 subsequently required surgical intervention. In cases of persistence of the clinical manifestations, omentectomy is indicated. Omentectomy promotes immediate symptom improvement and appears to decrease the rate of complications such as abscess, intestinal obstruction, and adherences. There have been numerous reports showing that early surgical intervention, especially a laparoscopic procedure, is an appropriate treatment for omental infarction.16-18 Therefore, it is difficult to determine which is the best therapeutic option in cases of omental infarction. However, there is a trend toward greater use of conservative management as the first-line treatment.

Given the current technological advances in radiology, especially in CT, the importance of imaging for the diagnosis of acute abdomen is undisputable. Because of the lack of specificity of clinical and laboratory data in cases of omental infarction, CT allows the timely and accurate diagnosis, as well as making surgical procedures unnecessary. Therefore, some authors now recommend the introduction of MDCT in the initial workup of acute abdomen. However, questions concerning professional training, availability, and operating costs of the method persist.

REFERENCES

1. Meneghelli UG. Elementos para o diagnóstico do abdômen agudo. Medicina (Ribeirão Preto). 2003;36(1):283-93. Portuguese.

2. Lopes AC, Reibscheid S, Szejnfeld J. Abdome agudo: clínica e imagem. São Paulo: Atheneu; 2004. Portuguese.

3. Houben CH, Powis M, Wright VM. Segmental infarction of the omentum: a difficult diagnosis. Eur J Pediatr Surg. 2003;13(1):57-9. PMid:12664418. http://dx.doi.org/10.1055/s-2003-38289

4. Mindelzun RE, Jeffrey RB. Unenhanced helical CT for evaluating acute abdominal pain: a little more cost, a lot more information. Radiology. 1997;205(1):43. PMid:9314959.

5. Freire Filho EO, Jesus PEM, D’Ippolito G, Szejnfeld J. Tomografia computadorizada sem contraste intravenoso no abdome agudo: quando e por que usar. Radiol Bras. 2006;39(1):51-62. Portuguese. http://dx.doi.org/10.1590/S0100-39842006000100011

6. Jeffrey RB. Imaging the acute abdome: the impact of computed tomography and sonography. In: Gore MR, Levine MS, editors. Textbook of gastrointestinal radiology. 2nd ed. Philadelphia: WB Saunders; 2000. p. 2186-95.

7. Viana PCC, Pinho MC, Ormond Filho A, Chate RC, Menezes MR. Qual o seu diagnóstico? Radiol Bras. 2004;37(3):v-vi. Portuguese.

8. Itenberg E, Mariadason J, Khersonsky J, Wallack M. Modern management of omental torsion and omental infarction: a surgeon’s perspective. J Surg Educ. 2010;67(1):44-7. PMid:20421090. http://dx.doi.org/10.1016/j.jsurg.2010.01.003

9. Eitel GG. Rare omental torsion. New York Med Rec.1899;55:715-6.

10. Bush P. A case of haemorrhage into the greater omentum. Lancet. 1896;1:286. http://dx.doi.org/10.1016/S0140-6736(01)91996-8

11. Van Breda Vriesman AC, Lohle PN, Coerkamp EG, Puylaert JB. Infarction of omentum and epiploic appendage: diagnosis, epidemiology and natural history. Eur Radiol. 1999;9(9):1886-92. PMid:10602970. http://dx.doi.org/10.1007/s003300050942

12. Varjavandi V, Lessin M, Kooros K, Fusunian R, McCauley R, Gilchrist B. Omental infarction: risk factors in children. J Pediatr Surg. 2003;38(2):233-5. PMid:12596111. http://dx.doi.org/10.1053/jpsu.2003.50051

13. Pilleul F, Bonifacio A, Atri M. CT appearance of primary omental torsion: description of a new finding. J Radiol [Internet]. 2003 [cited 2012 May 7]. Available from: http://www.jradiology.com/arts/57.pdf

14. Schwartzman GJ, Jacobs JE, Birnbaum BA. Omental infarction as a delayed complication of abdominal surgery. Clin Imaging. 2001;25(5):341-3. http://dx.doi.org/10.1016/S0899-7071(01)00314-X

15. Nubi A, McBride W, Stringel G. Primary omental infarct; conservative versus operative management in the era of ultrasound, computerized tomography and laparoscopy. J Pediatr Surg. 2009;44(4):953-6. PMid:19433177. http://dx.doi.org/10.1016/j.jpedsurg.2009.01.032

16. Sánchez J, Rosado R, Ramírez D, Medina P, Mezquita S, Gallardo A. Torsion of the greater omentum: treatment by laparoscopy. Surg Laparosc Endosc Percutan Tech. 2002;12(6):443-5. http://dx.doi.org/10.1097/00129689-200212000-00012

17. Costi R, Cecchini S, Randone B, Violi V, Roncoroni L, Sarli L. Laparoscopic diagnosis and treatment of primary torsion of the greater omentum. Surg Laparosc Endosc Percutan Tech. 2008;18(1):102-5. http://dx.doi.org/10.1097/SLE.0b013e3181576902

18. Ha JP, Tang CN, Siu WT, Tsui KK, Li MK. Laparoscopic management of acute torsion of the omentum in adults. JSLS. 2006;10(5):351-4. PMid:17212894 PMCid:3015694.

47

Segmental omental infarction: an unusual cause of acute abdomen Autopsy and Case Reports 2012; 2(2): 43-47

Conflict of interest: None

Submitted on: 16th March 2012 Accept on: 3rd May 2012

Correspondence: Serviço de Iconologia Av. Prof. Lineu Prestes, 2565 – Cidade Universitária - São Paulo/SP – Brazil CEP 05508-900 – Phone: +55 (11) 3091-9301. E-mail: ariaraujocg@hotmail.com

Article / Clinical Case ReportsArtigo / Relato de Caso Clínico

49

Copyright © 2012 Autopsy and Case Reports – This is an Open Access article distributed of terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any médium provided article is properly cited.

a Department of Surgery - Hospital Universitário - Universidade de São Paulo, São Paulo/SP - Brazil. b Anatomic Pathology Service - Hospital Universitário - Universidade de São Paulo, São Paulo/SP - Brazil.

Autopsy and Case Reports 2012; 2(2): 49-51

49

Subcutaneous bronchogenic cyst in a child: case report

Esperança Vidal Quipungoa, Giuliano Campolim Gagliottia, Aloísio Felipe-Silvab, Ricardo Frank Coelho da Rochaa

Gagliotti GC, Quipungo EV, Felipe-Silva A, Rocha RFC. Subcutaneous bronchogenic cyst in a child: case report. Autopsy Case Rep [Internet]. 2012;2(2):49-51. http://dx.doi.org/10.4322/acr.2012.017

ABSTRACT

Bronchogenic cysts are congenital anomalies originating from the primitive tracheobronchial tree in the fetal period. Although the middle mediastinum is the site most commonly affected (second only to the lungs), there have been reports of bronchogenic cysts at unusual sites, such as the retroperitoneum. We report the case of a 4-year-old boy with a cystic mass in the left scapular area since birth. The cyst grew progressively and was accompanied by recurrent episodes of local infection requiring drainage. It was then surgically removed. The histological findings were decisive for the diagnosis: a subcutaneous cyst lined by ciliated columnar epithelium and surrounded by a fibrous wall with smooth muscle tissue, cartilage, and bronchial glands. We also found chronic inflammatory infiltrate, which is consistent with previous episodes of infection. Bronchogenic cysts should be included in the differential diagnosis of cystic tumors of the chest wall and neck, particularly in children. Surgery is the treatment of choice because of the risk of infection, as in this case, and of malignant degeneration.

Keywords: Bronchogenic cyst; Skin; Scapula; Surgery.

INTRODUCTION

Bronchogenic cysts constitute a benign congenital anomaly that originates from the primitive tracheobronchial tree in the fetal period. The middle mediastinum is the site that is most commonly affected (second only to the lungs), bronchogenic cysts being rarely found at other sites.

We report the case of a 4-year-old boy with a subcutaneous tumor in the left scapular region since birth. The tumor grew progressively

and was accompanied by recurrent episodes of local infection requiring drainage, the boy having undergone surgical excision of the lesion. The histological findings were decisive for the diagnosis.

Bronchogenic cysts should be included in the differential diagnosis of congenital cysts and nodular lesions in the thoracic, dorsal, and cervical regions. Because of the risk of infection and malignancy, surgery is the treatment of choice.

50

Autopsy and Case Reports 2012; 2(2): 49-51 Quipungo EV, Gagliotti GC, Felipe-Silva A, Rocha RFC.

as cartilage and seromucous glands typical of the respiratory mucosa (Figure 1C). Moderate mixed inflammatory infiltrate was found in the subepithelial connective tissue, the epithelium being permeated by lymphocytes and neutrophils, which were consistent with previous episodes of infection/inflammation.

DISCUSSION

The first case of cutaneous bronchogenic cyst (CBC) was described by Seibold and Clagett in 1945.1 Since then, approximately 70 cases have been reported in the literature, most having been reported by dermatologists and pathologists.2 A rare entity, CBC is most common in children, the true incidence of CBC being unknown.2,3

Bronchogenic cysts originate from abnormal budding of the tracheal diverticulum of the foregut during the embryonic period.2 An anomaly that remains largely unknown, a bronchogenic cyst

CASE REPORT

We report the case of a 4-year-old boy with a subcutaneous lesion in the left scapular region since birth. The lesion grew progressively and indolently, being accompanied by three episodes of local infection requiring drainage, a large quantity of purulent secretion having been removed.

The lesion was excised en bloc—the skin ellipse being strongly adhered to the adjacent skin because of previous infectious processes—and sent for pathological examination. Macroscopic examination revealed a strip of skin measuring 4.5 × 3.0 cm, the epidermis being flattened. Dissection revealed a 3.0 cm cystic lesion with a brownish viscous liquid and shiny, irregular internal walls. Histology revealed that the lesion was located in the subcutaneous tissue and had fibrous tissue walls (Figure 1A). The lesion was found to be lined by pseudostratified ciliated columnar epithelium, typical of the bronchial mucosa, with lymphoid tissue arranged in follicles (Figure 1D). Other findings included smooth muscle tissue (Figure 1B), as well

Figure 1 – Photomicrography - A - (HE-25x) Cyst lesion with fibrous wall in the subcutaneous tissue (bottom); B - (HE-200x) Detail of bronchogenic cyst epithelium showing ciliated pseudostratified columnar epithelium (respiratory type) and smooth muscle; C - (HE-200x) Lymphoid tissue beneath the respiratory epithelium. Note mucous glands in the bottom left; D - (HE-400x) Mural cartilaginous tissue was detected at microscopic examination.

51

Subcutaneous bronchogenic cyst in a child: case report Autopsy and Case Reports 2012; 2(2): 49-51

melanoma or mucoepidermoid carcinoma.2,5,8 The differential diagnosis of bronchogenic cyst in the scapular region includes lymphangioma, epidermoid cysts, and other sebaceous cysts.5 Complete excision is curative.

REFERENCES

1. Adim SB, Baskan EB, Saricaoglu H, Elezoglu B. Cutaneous heterothopic bronchogenic tissue in the scapular area. Australas J Dermatol. 2010;51(1):42-4. PMid:20148842. http://dx.doi.org/10.1111/j.1440-0960.2009.00591.x

2. Ozel SK, Kazez A, Koseogullari AA, Akpolat N. Scapular bronchogenic cysts in children: case report and review of the literature. Pediatr Surg Int. 2005;21(10):843-5. PMid:16180006. http://dx.doi.org/10.1007/s00383-005-1531-5

3. Nakamura Y, Fujishima F, Ito S, et al. A case of cutaneous bronchogenic cyst in the scapular area. Pol J Pathol. 2011;62(2):120-1. PMid:21866472.

4. Zvulunov A, Amichai B, Grunwald MH, Avionach I, Halevy S. Cutaneous bronchogenic cyst: delineation of a poorly recognized lesion. Pediatr Dermatol. 1998;15(4):277-81. P M i d : 9 7 2 0 6 9 1 . h t t p : / / d x . d o i . o r g / 1 0 . 1 0 4 6 /j.1525-1470.1998.1998015277.x

5. Gaikwad P, Muthusami JC, Raj JP, Rajinikanth J, John GM. Subcutaneous bronchogenic cyst. Otolaringol Head Neck Surg. 2006;135(6):951-2. PMid:17141090. http://dx.doi.org/10.1016/j.otohns.2006.05.032

6. Miller 3rd OF, Tyler W. Cutaneous bronchogenic cyst with papilloma and sinus presentation. J Am Acad Dermatol. 1984;11(2 pt. II):367-71. http://dx.doi.org/10.1016/S0190-9622(84)70175-7

7. Magnussen JR, Thompson JN, Dickinson JT. Presternal bronchogenic cysts. Arch Otolaryngol. 1977;103(1):52-4. http://dx.doi.org/10.1001/archotol.1977.00780180090013

8. Tanita M, Kikuchi-Numagami K, Ogoshi K, et al. Malignant melanoma arising from cutaneous bronchogenic cyst of the scapular área. J Am Acad Dermatol. 2002;46(2 Suppl Case Reports):S19-21.

is diagnosed exclusively by histopathological examination, given that the clinical and radiological findings are nonspecific.4 Because bronchogenic cysts are typically located in the sternal and cervical regions, they are usually mistaken for branchial cleft cysts.

In 1948, Maier classified bronchogenic cysts into five groups by location: paratracheal cysts; carinal cysts; hilar cysts; paraesophageal cysts; and atypical cysts, which include diaphragmatic, abdominal, cutaneous, subcutaneous, and supraclavicular cysts.5 Two main theories have been postulated to explain the development of CBCs. According to the first theory, the bronchogenic cyst, arising from the developing tracheal bud, is left out of the thorax after sternal closure at gestational week 9 and migrates to the skin. According to the second theory, known as the “pinch-off” theory, the cyst simply pinches off from the developing tracheal bud during the closure of the mesenchymal plates, the cyst and the bud growing simultaneously.2,6

In most cases, there is no communication between the cyst and the thoracic cavity. Because CBCs are mostly solitary, the pinch-off theory seems to explain their occurrence in most cases.2

These lesions are four times as common in males as they are in females, and the site that is most commonly affected is the sternal notch, followed by the presternal area, the cervical area, and, more rarely, the scapular area.5 The pathological diagnosis is based on the finding of one or more tracheobronchial structures in the cyst wall.2 Hyaline cartilage, smooth muscle cells, elastic fibers, fibrous tissue, and seromucous glands are common findings.7

Surgical excision is the treatment of choice, which is due to the risk of infection (as was the case in our patient) and degeneration to malignant

Conflict of interest: None

Submitted on: 7th May 2012 Accept on: 24th May 2012

Correspondence: Divisão de Clínica Cirúrgica Av. Prof. Lineu Prestes, 2565 – Cidade Universitária - São Paulo/SP – Brazil CEP: 05508-000 – Phone: +55 (11) 3091-9291 E-mail: panchapretty84@yahoo.com.br