The University of Illinois Hospital & Health Sciences System Combined

Residency Program

Illinois Registry of Anatomic Pathology (IRAP)

Case Summaries

4/18/2016

Case #1: Papillary thyroid carcinoma with squamous de-differentiation (spindle cell squamous cell carcinoma variant of anaplastic thyroid carcinoma)

Presenter: Andres M. Acosta, MD Attendings: Michael R. Pins MD; Brian P. Adley, MD

Clinical History: The patient is a 63-year-old gentleman with a right lower lobe lung mass that showed significant growth between two follow up CT scans. His clinical history is significant for papillary thyroid carcinoma, conventional type, diagnosed 10 years ago. The patient showed locally advanced thyroid disease at initial presentation, with extrathyroidal extension, vascular invasion and metastases to cervical lymph nodes. The clinical course was characterized by multiple recurrences, including a supraclavicular lymph node metastasis and a brain metastasis at three and eight years of follow up, respectively. All these recurrences showed histopathologic features of papillary thyroid carcinoma, conventional type. The patient provided two biopsies of the lung lesion performed at an outside institution, one of them showing squamous cell carcinoma, and the other one showing papillary thyroid carcinoma. A lower lung lobectomy was performed, which showed a 5.2 cm solid mass with a tan cut surface.

Diagnosis: Papillary thyroid carcinoma with squamous dedifferentiation (spindle cell squamous cell carcinoma variant of anaplastic carcinoma)

Differential Diagnosis: Papillary thyroid carcinoma with squamous dedifferentiation Adenosquamous carcinoma of the lung Collision metastases Papillary thyroid carcinoma metastatic to squamous cell carcinoma of the lung

Key microscopic features: The lesion was composed of a central area showing sheets of spindle cells with focal squamous

differentiation, and a peripheral rim of papillary thyroid carcinoma.

Immunohistochemical: The papillary components stained positive for TTF-1 and thyroglobulin The spindle and squamous cell components stained positive for p40 and CK 5/6

Molecular Studies: BRAF V600E mutation was demonstrated in both of the microdissected tumor components

Take Home Points: Spindle cell squamous cell carcinoma is a highly aggressive form of anaplastic thyroid carcinoma It can present primarily in the thyroid or develop late in the course of the disease, usually after

multiple recurrences It is more often associated with the tall-cell variant of PTC When it is first diagnosed in an organ that can harbor a primary SCC, the possibility of a tumor to

tumor metastasis should be ruled out if papillary elements are present The presence of a BRAF V600E mutation in our case suggest that BRAF inhibitors could be

included as part of the treatment

References:1. Gopal PP, Montone KT, Baloch Z, Tuluc M, LiVolsi V. The variable presentations of anaplastic

spindle cell squamous carcinoma associated with tall cell variant of papillary thyroid carcinoma. Thyroid 2011;21:493-499.

2. Bronner MP, LiVolsi VA. Spindle cell squamous carcinoma of the thyroid: an unusual anaplastic tumor associated with tall cell papillary cancer Mod Pathol 1991;4:637-643.

3. Saunders CA, Nayar R. Anaplastic spindle-cell squamous carcinoma arising in association with tall-cell papillary cancer of the thyroid: A potential pitfall. Diagn Cytopathol 1999;21:413-418.

Case 2: Nodular FasciitisPresenter: Yanmin Zhang, MD, MS

Attending: Tibor Valyi-Nagy MD, PhD

Clinical History: A 41-year-old female with past medical history of Behcet syndrome, lymphocytic colitis, fibrocystic breast mass, hyperhidrosis, uterine fibroids, IgA deficiency, vasculitis, and uveitis presented to the clinic for a left jugular digastric region mass with left-sided neck pain. CT scan revealed a small area of hyperdensity within the left levator scapulae muscle. MRI further revealed a left jugulodigastric region mass, measuring 1.8 x 1.5 x 1.0 cm, as well as lymph node enlargement.

Diagnosis: Nodular Fasciitis (intramuscular) with USP6 (17p13) rearrangement

Differential diagnosis:• Proliferative Fasciitis• Proliferative Myositis• Inflammatory Myofibroblastic Tumor• Fibromatosis• Low Grade Fibromyxoid Sarcoma• Nodular Fasciitis

Key Microscopic Features:• Plump spindle shaped cells lacking atypia and hyperchromasia • Focal moderate cellularity alternating with other fields that were more discohesive with a myxoid

appearing background• Surrounding skeletal muscle was focally involved.

Immunohistochemical stains: Positive : Vimentin, SMA, MSA Negative : Beta-catenin (nuclear), S100

Molecular cytogenetic studies: Positive for rearrangement of the USP6 (17p13) locus in 24% of the 350-interphase cells analyzed from a representative paraffin-embedded tissue section

Take Home Points:• Nodular fasciitis is a reactive soft tissue lesion composed of undulating bundles of loosely

arranged fibroblasts and myofibroblasts• It is commonly misdiagnosed as sarcoma due to the extremely rapid growth and high mitotic

activity • Recent research suggests that nodular fasciitis may be a model of “transient neoplasia” since most

cases have a balanced translocation t(17;22)(p13;q13) resulting in MYH9-USP6 gene fusion• This case suggests that molecular cytogenetic analysis plays an important role and is a helpful tool

in nodular fasciitis diagnosis

References:1. Konwaler BE, Keasbey L, Kaplan L. Subcutaneous pseudosarcomatous fibromatosis (fasciitis).

American journal of clinical pathology 1955;25(3):241.2. Erickson-Johnson MR, Chou MM, Evers BR, Roth CW, et al. Nodular fasciitis: a novel model of

transient neoplasia induced by MYH9-USP6 gene fusion. Laboratory investigation 2011;91(10):1427-33.

Case 3: Anaplastic Large Cell LymphomaPresenter: Asma Sharif, MD; Attending: Ronald Sirota, MD

Clinical History: Our patient is a previously healthy 15-year-old female. Over the past three months, she has been experiencing recurring lymphadenopathy, abdominal pain, back pain, emetic episodes, and subjective fevers. The pain has become refractory to over the counter ibuprofen, and the fever has responded to acetaminophen.

Diagnosis: Anaplastic large cell lymphoma, lymphohistiocytic pattern

Differential Diagnosis: Rosai-Dorfman Disease Metastatic Melanoma Metastatic Carcinoma

Key Microscopic Features: Mixture of larger and small cells Larger cells with abundant clear to eosinophilic cytoplasm Predominant population of background histiocytes

Immunohistochemical Stains:Negative: CD 2, CD 3, CD 5, CD 20, CD 21, CD 34, CD 56, CD 1a Positive: CD 68, S-100, CD 30, ALK-1

Discussion:Anaplastic large cell lymphoma, ALK-1 + can demonstrate a wide range of morphologic patterns. The lymphohistiocytic pattern demonstrates abundant histiocytes which may mask the distinctive hallmark cells. Histiocytes may also demonstrate erythrophagocytosis, a feature which may mimic Rosai-Dorfman Disease. The possibility of losing several T-cell antigens should also be noted in ALCL, ALK + which may lead to a “null cell phenotype.” Flow cytometry studies may not always provide a conclusive answer; however, a negative result via flow should not preclude a diagnosis of lymphoma if in fact other findings are suggestive of a lymphoproliferative process.

References:1. Delsol G, Falini B, Muller-Hermelink H, Campo E, et al. Anaplastic large cell lymphoma (ALCL),

ALK-positive. In: Swerdlow S, Campo E, Harris N, Jaffee E, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th edition. Lyon: IARN; 2008.

2. Benharroch D, Meguerian-Bedoyan Z,Lamant L, Amin C, Brugieres L, Terrier-Lacombe MJ, Haralambieva E, Pulford K, Pileri, S, Morris SW, Mason Y, Delsol G (1998).ALK-positive lymphoma: a single disease with abroad spectrum of morphology. Blood 91:2076-2084.

3. Rosai J. Rosai and Ackerman’s Surgical Pathology. 10th ed. New York: Elsevier; 2011.

Case 4: Acquired Cystic Disease Associated Renal Cell CarcinomaPresenter: Snehal Sonawane, MBBS

Attending: John Groth, MD

Clinical History: A 59-year-old male presented for a cadaveric renal transplant, due to end-stage-renal disease on dialysis, thought to be secondary to autosomal dominant (adult) polycystic kidney disease, associated with possible liver and pancreatic cysts. He has a past medical history significant for chronic Hepatitis B and D infection, congestive heart failure and hypertension. We received the bilateral kidneys (Right: 22.3 x 9.8 x 9.3 cm and Left: 17.1 x 9.9 x 9.4 cm), both of which were diffusely replaced with variably sized cysts ranging in size from 0.4 cm up to 4.5 cm, some of which were hemorrhagic. A representative section from a hemorrhagic area from the right kidney is submitted for your review. An additional image, image 1, is submitted for your review on a separate sheet of paper, which contains the gross photographs and representative images from the remaining cysts and background kidney. A review of the patients chart identified no family history of autosomal dominant polycystic kidney disease and that the cysts began to form in atrophic kidneys after the onset of starting dialysis for end stage renal disease secondary to hypertension.

Diagnosis: Acquired cystic disease associated renal cell carcinoma

Differential Diagnosis: Autosomal dominant (Adult) polycystic kidney disease (ADPKD) Acquired Cystic disease of Kidney (ACDK) Acquired Cystic disease of Kidney associated renal cell carcinoma (ACC-RCC)

Key Microscopic Features: Tumor:

o Acinar, tubular, multicystic, papillary and solid pattern in various combinationso Presence of inter or intracytoplasmic lumina imparting sieve like appearanceo Large tumor cells with eosinophilic cytoplasm and prominent nucleoli admixed with some

clear cellso Calcium oxalate crystals in stroma and lumina

Background kidney:o Cysts:

Cysts predomiantly lined by a flattend epithelium Occasional atypical “Eosinophilic” cysts Occasional atypical “papillary” cysts Occasional atypical “clear cell” cysts

o Noncystic kidney: Globally sclerosed glomeruli Interstitial fibrosis Thyrodization of tubules Hypertensive related arteriosclerosis

Immunohistochemical stains: • Positive: AE1/AE3, CD10, AMACR• Negative : CK7

Take Home Points: • Acquired Cystic Kidney Disease (ACKD) can morphologically mimic autosomal dominant polycystic

kidney disease• Acquired cystic disease associated RCC is uniquely associated with ACKD recognized as a distinct

clinical entity in WHO-2016• Pancreatic cysts and possibly liver cysts can be seen in patients on hemodialysis

References:

1. Srigley J, Delahunt B, Eble J, Egevad L, Epstein J, Grignon D et al. The International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia. The American Journal of Surgical Pathology 2013;37(10):1469-1489.

2. Neureiter D, Frank H, Kunzendorf U, Waldherr R, Amann K. Dialysis‐associated acquired cystic kidney disease imitating autosomal dominant polycystic kidney disease in a patient receiving long‐term peritoneal dialysis. Nephrol. Dial. Transplant 2002;17(3):500-503.

3. Goyal R, Lin X, Yang X. Characterization of Renal Epithelial Neoplasms Arising in Non- Functioning Kidneys – A Study of 259 Cases. Mod Pathol 2015:226A.

4. Tickoo SK, dePeralta-Venturina MN, Harik LR, Worcester HD, Salama ME, Young AN, Moch H, Amin MB. Spectrum of epithelial neoplasms in end-stage renal disease: an experience from 66 tumor-bearing kidneys with emphasis on histologic patterns distinct from those in sporadic adult renal neoplasia., Am J Surg Pathol 2006;30(2):141-53.

5. Rioux-Leclercq NC, Epstein JI. Renal Cell Carcinoma With Intratumoral Calcium Oxalate Crystal Deposition in Patients With Acquired Cystic Disease of the Kidney. Arch Pathol Lab Med 2003;127:e89–e92.

6. Bakira AA, Hasnaina M, Youngb S, Duneaa G. Dialysis-Associated Renal Cystic Disease Resembling Autosomal Dominant Polycystic Kidney Disease: A Report of Two Cases; Am J Nephrol 1999;19:519–522.

7. Ishikawa T, Takeda K, Itoh M, Imaizumi T, et al. Prevalence of Pancreatic Cystic Lesions Including Intraductal Papillary Mucinous Neoplasms in Patients With End-Stage Renal Disease on Hemodialysis. Pancreas 2009;38:175-179.

8. Bonsib SM. The Classification of Renal Cystic Disease of the Kidney and other Congenital Malformations of the Urinary Tract. Arch Pathol Lab Med 2010;134:554–568.

9. Torres VE, Harris PC. Autosomal dominant polycystic kidney disease: the last 3 years. Kidney Int 2009; 76:149–68.

10. Bear JC, McManamon P, Morgan J, Payne RH, Lewis H, Gault MH, et al. Age at clinical onset and at ultrasonographic detection of adult polycystic kidney disease: data for genetic counselling. Am J Med Genet 1984; 18:45–53.

11. Pei Y, Obaji J, Dupuis A et al. Unified criteria for ultrasonographic diagnosis of ADPKD. J Am Soc Nephrol 2009; 20: 205–212.

12. Bernstein J, Evan AP, Gardner KD. Epithelial Hyperplasia in Human Polycystic Kidney Diseases Its Role in Pathogenesis and Risk of Neoplasia. AJP 1987;129(1):92-101.

13. Matoso A, Chen YB, Rao V, Wang L, et al. Atypical Renal Cysts A Morphologic, Immunohistochemical, and Molecular Study. Am J Surg Pathol 2015:1-10.

14. Walters W, Braasch WF. Surgical aspects of polycystic kidney. Surg Obstet Gynecol 1934:647–650.

15. Keith DS, Torres VE, King BF, Zincki H, et al. Renal Cell Carcinoma in Autosomal Dominant Polycystic Kidney Disease. J Am Soc Neprol 1994;4:1661-1669.

16. Bonsib SM. Renal Cystic Disease and Renal Neoplasms: A Mini-Review. Clin J Am Soc Nephrol;2009;4:1998–2007.

17. Dunhill MS, Millard PR, Oliver D. Acquired cystic disease of the kidneys: a hazard of long-term intermittent maintenance haemodialysis. J Clin Path 1977;30:868-877.

18. Chandhoke PS, Torrence RJ, Clayman RV, Rothstein M. Acquired cystic dis- ease of the kidneys: a management dilemma. J Urol. 1992;147:969–974.

19. Dry SM, Renshaw AA. Extensive calcium oxalate crystal deposition in pap- illary renal cell carcinoma. Arch Pathol Lab Med. 1998;122:260–261.

20. Sule N, Yakupoglu U, Shen SS, Krishnan B, et al. Calcium Oxalate Deposition in Renal Cell Carcinoma Associated With Acquired Cystic Kidney Disease A Comprehensive Study. Am J Surg Pathol 2005;29:443–451.

21. Mills S, Greenson J, Hornick J, Longacre T, Reuter V. Sternberg's diagnostic surgical pathology. 6th edn. China: Wolters Luwer Health, 2015.

22. Rosai J. Rosai and Ackerman’s Surgical Pathology. 10th edn. China: Elsevier, 2011.

Case 5: Distinctive Ovarian Tumor with Sexual Precocity in Peutz-Jeghers Syndrome (Sex Cord Stromal Tumor, unclassified)

Presenter: Kristina Wakeman, MD Attendings: Steven Garzon, MD and John Groth, MD

Clinical History: A 17-year-old female with a past medical history significant for removal of an adnexal tumor at age 4 presented with abdominal pain and menometrorrhagia.  Family history is significant for Peutz-Jeghers syndrome on her paternal side.  Pelvic MRI demonstrated a midline, heterogeneous solid and multicystic mass with thickened internal septations.  A 12 x 12 x 7 cm solid cystic mass was subsequently removed.  A representative slide is submitted for you review. 

Diagnosis: Distinctive Ovarian Tumor with Sexual Precocity in Peutz-Jeghers Syndrome best classified as Sex Cord Stromal Tumor, unclassified

Differential Diagnosis: • Sex-cord Stromal Tumor with Annular Tubules• Sertoli-Leydig Cell Tumor• Sertoli Cell Tumor• Juvenile Granulosa Cell Tumor• Sex cord-stromal tumor, unclassified

Key Microscopic Features:• Heterogeneous tumor with:

• Focal areas resembling “Sex-cord Stromal Tumor with Annular Tubules” • Diffuse areas with prominent nucleoli, amphophilic cytoplasm and some nuclei with nuclear

grooves admixed with tubular areas with abundant cytoplasm and rare possible leydig cells• Retiform areas• Abundant microcysts with dense eosinophilic secretions

Immunohistochemical and special stains: Positive : Inhibin, calretinin, CD99, WT1 Negative : EMA

Take Home Points: A diagnosis of Peutz-Jeghers Syndrome rests on a combination of:

o The identification of the prototypical polypso Mucocunteous pigmentationo Family history

Ovarian tumors can be helpful, but are not diagnostic of Peutz-Jeghers Syndromeo Most common SCTATo Second most common Sertoli cell tumorso Third possible is “Distinctive” in association with precocious puberty”

Best classified as Sex cord-stromal tumor, unclassified

References:1. Young RH, Dickersin GH, Scully RE. A distinctive ovarian sex-cord-stromal tumor causing sexual

precocity in the Peutz-Jeghers syndrome. Am J Surg Pathol 1983;7:233-243. 2. Young RH, Welch WR, Dickersin R, Scully RE. Ovarian Sex Cord Tumor with Annular Tubules.

Review of 74 Cases Including 27 with Peutz-Jeghers Syndrome and With Adenoma Malignum of the Cervix. Cancer 1982;50:1384-1402.

3. Jeghers H, McKusick VA, Katz KH. Generalized Intestinal Polyposis and Melanin Spots of the Oral Mucosa, Lips and Digitis A Syndrome of Diagnostic Significance. NEJM 1949;241(26):1031-1036.

4. Scully RE. Sex Cord Tumor with Annular Tubules a Distinctive Ovarian Tumor of the Peutz-Jeghers Syndrome. Cancer 1970;25(5):1107-1121.

5. Young RH. Sex cord-stromal tumors of the ovaryand testis: their similarities and differences with consideration of selected problems. Modern Pathology 2005;18:S81–S98.

6. Crum CP, Nucci MR, Lee KR. Diagnostic Gynecologic and Obstetric Pathology. 2nd edn. Philadelphia: Elsevier Saunders, 2011.

7. Connor J. Aesculapian Society of London. Lancet. 1895;2:1169.8. Hutchinson, J., Pigmentation of lips and mouth. Arch Surg (London), 1896.9. Peutz J. Over een zeer merkwaardige, gecombineerde familiaire polyposis van de slijmvliezen van den

tractus intestinalis met die van de neuskeelholte en gepaard met eigenaardige pigmentaties van huid-en slijmvliezen. hrederl. tijdschr. gefieesk. 1921; 10: 134- 146.

10. Bosman FT, Carneiro F, Hruban RH, Theise ND. WHO Classification of Tumours of the Digestive System. 4th edn. Lyon: International Agency for Research on Cancer, 2010: 168-170.

11. Volikos E, Robinson J, Aittomaki K, Mecklin JP, et al. LKB1 exonic and whole gene deletions are a common cause of Peutz-Jeghers syndrome. J Med Genet 2006;43(5):e18.

12. Burdick D, Prior JT, Scanlon GT. Peutz-Jeghers Syndrome: A Clinical-Pathological Study of a Large Family with a 10-year Follow-up. Cancer 1962;16(7):854-867.

13. Young RH, Welch WR, Dickersin R, Scully RE. Ovarian Sex Cord Tumor with Annular Tubules. Review of 74 Cases Including 27 with Peutz-Jeghers Syndrome and With Adenoma Malignum of the Cervix. Cancer 1982;50:1384-1402.

14. Lele SM, Sawh RN, Zaharopoulos P, Adesokan A, et al. Malignant Ovarian Sex Cord Tumor with Annular Tubules in a Patient with Peutz-Jeghers Syndrome: A Case Report. Mod Pathol 2000;13(4):466-470.

15. Oliva E, Alvarez T, Young RH. Sertoli Cell Tumors of the Ovary A Clinicopathologic and Immunohistochemical Study of 54 Cases. Am J Surg Pathol 2005;29:143-156.

Case 6: BK virus associated micropapillary urothelial carcinomaPresenter: Rizwan Rasheed, MD; Attending: John Groth, MD

Clinical History:A 65-year-old African American male presented with partial small bowel obstruction. He has a past history of a cadaveric pancreas and renal transplant and BK virus nephropathy. Computed tomography scan of the abdomen and pelvis revealed a distal ureter stenosis recalcitrant to stenting and a 6.2 x 5.4 cm dense mass along the anterior margin of the urinary bladder abutting the nephrostomy tube. An exploratory laparotomy was performed and he was found to have multiple intra-abdominal nodules studding the peritoneum and omentum.

Diagnosis: BK virus associated micropapillary urothelial carcinoma

Differential Diagnosis for site of origin: Micropapillary carcinoma

o Breasto Salivary glando Pancreaticobiliaryo Lungo Colono Thyroido Kidneyo Prostateo Urothelium from bladder/ureter

Mesothelioma Serous carcinoma of peritoneum/peritesticular

Key Microscopic Features: Multiple groups of cells without true fibrovascular cores, clustered in lacunar spaces The cells are oriented with an ‘inverse polarization’ The cells form ‘epithelial ring forms’ The cells display intracytoplasmic vacuolization

Immunohistochemical stains: Positive: CK7; p53; CK20 (focal), p63+, SV40, p16, CD10, CK19Negative: PSA, PSAP, GCDFP-15, AMACR, Vimentin, WT1, Calretinin

Molecular Studies:BK virus quantification by real time PCR in tumor: 939 copies/ng DNASTR Analysis: Recipient OriginNext Generation sequencing illumina kit: •p.R176_V181del, located in the c-terminal α-helical domain, a novel mutation

Take Home Points: In case of micropapillary carcinomas, it is important to consider several possible primaries. Many of the differential diagnoses presented can have strikingly similar histologic features. With the aid of a good clinical history and ancillary testing, one can narrow the differential down to the correct diagnosis.

Micropapillary urothelial carcinoma is a rare but aggressive variant of urothelial carcinoma This rare carcinoma may be associated with the BK virus in immunocompromised/transplant patients

so perform the SV-40, p53, and p16 immunostains In such cases, a possible future cure could be to treat the virus

References:

1. Alexiev B, Randhawa P, Vazquez Martul E, Zeng G, Luo C, Ramos E et al. BK virus–associated urinary bladder carcinoma in transplant recipients: report of 2 cases, review of the literature, and proposed pathogenetic model. Human Pathology. 2013;44(5):908-917.

2. Dalianis T, Hirsch H. Human polyomaviruses in disease and cancer. Virology. 2013;437(2):63-72. 3. Bialasiewicz S, Cho Y, Rockett R, Preston J, Wood S, Fleming S et al. Association of

micropapillary urothelial carcinoma of the bladder and BK viruria in kidney transplant recipients. Transplant Infectious Disease. 2013;15(3):283-289.

4. Dalianis T, Hirsch H. Human polyomaviruses in disease and cancer. Virology. 2013;437(2):63-72. 5. Amin M, Smith S, Reuter V, Epstein J, Grignon D, Hansel D et al. Update for the practicing

pathologist: The International Consultation On Urologic Disease-European association of urology consultation on bladder cancer. Mod Pathol. 2014;28(5):612-630.

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