Lymphomatoid granulomatosis: a practical review for pathologists dealing with this rare pulmonary lymphoproliferative process

Cited in Index Medicus/MEDLINE, BIOSIS Previews, SCOPUS

Journal of the Italian Society of Anatomic Pathology and Diagnostic Cytopathology,Italian Division of the International Academy of Pathology

Vol. 105 August 2013

ORIGINAL ARTICLES

111 Lymphomatoid granulomatosis: a practical review for pathologists dealing with this rare pulmonary lymphoproliferative process

E. Tagliavini, G. Rossi, R. Valli, M. Zanelli, A. Cadioli, M.C. Mengoli, A. Bisagni, A. Cavazza, G. Gardini

117 About the necessity of improving the current nodal classification of non-small cell lung carcinoma

M. Mlika, A. Ayadi-Kaddour, S. Boudaya, A. Marghli, T. Kilani, F. Mezni

122 Intraparenchymal leiomyoma of the breast: report of a case with emphasis on needle core biopsy-based diagnosis

G.M. Vecchio, A. Cavaliere, F. Cartaginese, A. Lucaccioni, T. Lombardi, R. Parenti, L. Salvatorelli, G. Magro

128 Primary mucinous carcinoma of the thyroid gland: case report with review of the literature

H. Mnif, A. Chakroun, S. Charfi, S. Ellouze, M. Ghorbel, T. Sallemi-Boudawara

CASE REPORTS

132 A solitary polypoid gastric metastasis 20 years after renal cell carcinoma: an event to be considered, and a brief review of the literature

M. Onorati, G. Petracco, P. Uboldi, D. G. Redaelli, S. Romagnoli, M. Albertoni, F. Di Nuovo

137 Coexistence of xanthogranulomatous cholecystitis and gallbladder adenocarcinoma: a fortuitous association?

F. Limaiem, B. Chelly, F. Hassan, I. Haddad, S. Ben Slama, A. Lahmar, S. Bouraoui, S. Mzabi-Regaya

140 Pinkus tumour: an unusual case S. Sehli Attafi, M. Jones, B. Fazaa, R. Zermani, S.R. Rommany

142 Mammary myofibroblastoma with leiomyomatous differentiation: case report and literature review

H. Mnif, S. Charfi, N. Abid, T. Sallemi-Boudawara

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Società Italiana di Anatomia Patologica e Citopatologia Diagnostica,Divisione Italiana della International Academy of Pathology

ISSN 0031-2983

Editor-in-ChiefMarco Chilosi, Verona

Associate EditorRoberto Fiocca, Genova

Managing EditorRoberto Bandelloni, Genova

Scientific BoardR. Alaggio, PadovaG. Angeli, VercelliM. Barbareschi, TrentoC.A. Beltrami, UdineG. Bevilacqua, PisaM. Bisceglia, S. Giovanni R.A. Bondi, BolognaF. Bonetti, VeronaC. Bordi, ParmaA.M. Buccoliero, FirenzeG.P. Bulfamante, MilanoG. Bussolati, TorinoA. Cavazza, Reggio EmiliaG. Cenacchi, BolognaP. Ceppa, GenovaC. Clemente, MilanoM. Colecchia, MilanoG. Collina, BolognaP. Cossu-Rocca, SassariP. Dalla Palma, TrentoG. De Rosa, NapoliA.P. Dei Tos, TrevisoL. Di Bonito, TriesteC. Doglioni, MilanoV. Eusebi, BolognaG. Faa, CagliariF. Facchetti, BresciaG. Fadda, RomaG. Fornaciari, PisaM.P. Foschini, BolognaF. Fraggetta, CataniaE. Fulcheri, GenovaP. Gallo, RomaF. Giangaspero, RomaW.F. Grigioni, Bologna

G. Inghirami, TorinoL. Leoncini, SienaM. Lestani, ArzignanoG. Magro, CataniaA. Maiorana, ModenaE. Maiorano, BariT. Mara� oti, LondraA. Marchetti, ChietiD. Massi, FirenzeM. Melato, TriesteF. Menestrina, VeronaG. Monga, NovaraR. Montironi, AnconaB. Murer, MestreV. Ninfo, PadovaM. Papotti, TorinoM. Paulli, PaviaG. Pelosi, MilanoG. Pettinato, NapoliS. Pileri, BolognaR. Pisa, RomaM.R. Raspollini, FirenzeL. Resta, BariG. Rindi, ParmaM. Risio, TorinoA. Rizzo, PalermoJ. Rosai, MilanoG. Rossi, ModenaL. Ruco, RomaM. Rugge, PadovaM. Santucci, FirenzeA. Scarpa, VeronaA. Sidoni, PerugiaG. Stanta, TriesteG. Tallini, BolognaG. Thiene, PadovaP. Tosi, SienaM. Truini, Genova V. Villanacci, BresciaG. Zamboni, VeronaG.F. Zannoni, Roma

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Governing Board SIAPEC-IAP President: C. Clemente, Milano

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Past President: G.L. Taddei, Firenze

Members:A. Bondi, BolognaP. Dalla Palma, TrentoA. Fassina, PadovaR. Fiocca, GenovaD. Ientile, PalermoL. Resta, BariL. Ruco, RomaM. Santucci, FirenzeG. Zamboni, Verona

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CopyrightSocietà Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology

PublisherPacini Editore S.p.A.Via Gherardesca, 156121 Pisa, ItalyTel. +39 050 313011Fax +39 050 [email protected]

Cited in Index Medicus/MEDLINE, BIOSIS Previews, SCOPUS

Journal of the Italian Society of Anatomic Pathology and Diagnostic Cytopathology,Italian Division of the International Academy of Pathology

Vol. 105 August 2013

Società Italiana di Anatomia Patologica e Citopatologia Diagnostica,Divisione Italiana della International Academy of Pathology

CONTENTS

Original articles

Lymphomatoid granulomatosis: a practical review for pathologists deal-ing with this rare pulmonary lymphoproliferative processE. Tagliavini, G. Rossi, R. Valli, M. Zanelli, A. Cadioli, M.C. Mengoli, A. Bisa-gni, A. Cavazza, G. GardiniLymphomatoid granulomatosis (LYG) is a rare B-cell lymphoproliferative disor-der predominantly involving the lungs, but poorly-recognized among clinicians and pathologists. It is an Epstein-Barr virus (EBV)-driven disease mimicking several other diseases on clinical and radiological grounds, generally showing multiple, bilateral nodular, ill-defined infiltrates of the lungs tending to coales-cence and/or cavitation. LYG often affects middle-aged males with an underly-ing immunodeficiency and commonly involves skin and central nervous system during disease progression. Diagnosis requires a generous biopsy and careful his-tologic examination with immunohistochemical staining and molecular demon-stration of EBV genome in large atypical B-cells. LYG is graded as I to III based on the number of large EBV-positive B-cells; grades II/III are now considered as a peculiar variant of T-cell rich diffuse large B-cell lymphoma. In this brief review, clinical, radiologic and pathologic features of LYG will be analyzed with focus on differential diagnosis, the most appropriate treatment and prognosis.

About the necessity of improving the current nodal classification of non-small cell lung carcinomaM. Mlika, A. Ayadi-Kaddour, S. Boudaya, A. Marghli, T. Kilani, F. Mezni Background. The current classification of lymph node status in non-small cell lung carcinoma has not been revised since 1997. This fact has prompted many authors to point out the limits of this classification.Methods. We tried to explore the prognostic relevance of the current TNM classification in comparison with the nodal classification based on the ratio of metastatic lymph nodes (LNR) and the nodal classification based on the number of metastatic LNs (nLN). Additionally, we tried to explore the recom-mended number of resected LNs. This was done through a retrospective study of 39 cases. We compared the survival curves of patients using the current, RLN and nLN classifications. In the nLN classification, we grouped patients into three categories: nN0 (no metastatic LNs), nN1 (1 to 2 metastatic LNs) and nN2 (> 2 metastatic LN). In the LNR classification, we grouped patients into three categories: rNO (0%), rN1 (≤ 12) and rN2 (> 12). Concerning the total number of the resected LNs, patients were categorized into two groups accord-ing to the number of LNs: < 10 versus ≥ 10 and < 15 versus ≥ 15.Results. Our results showed that the LNR classification highlighted a differ-ence in prognosis between the rN1 and rN2 groups. Moreover, survival of patients seemed to be better when the number of the resected LNs was higher.Conclusion. The ratio of metastatic LNs seems to be an important prognostic factor, but further studies are necessary to standardize this classification.

Intraparenchymal leiomyoma of the breast: report of a case with emphasis on needle core biopsy-based diagnosisG.M. Vecchio, A. Cavaliere, F. Cartaginese, A. Lucaccioni, T. Lombardi, R. Parenti, L. Salvatorelli, G. Magro Objective. We report the clinicopathologic features of a rare case of leio-myoma of the breast parenchyma in a 36-year-old female, diagnosed preop-eratively at core biopsy. A complete review of the literature on the topic is provided and differential diagnostic problems are discussed. Methods. Standard histological examination and immunohistochemical analy-ses using a large panel of antibodies were performed in both the core biopsy and surgical specimen.Results. Ultrasonography revealed a well-circumscribed tumour mass with-out calcifications. Histological examination of the core biopsy showed pro-liferation of bland-looking eosinophilic spindle cells arranged in a fascicular growth pattern. Mitoses, pleomorphism and necrosis were absent. Immuno-histochemistry, revealing diffuse staining for a-smooth muscle actin, desmin and h-caldesmon, confirmed the leiomiomatous nature of neoplastic cells. Histological and immunohistochemical analyses of the surgical specimen confirmed the definitive diagnosis of leiomyoma.Conclusions. The present case emphasizes that diagnosis of leiomyoma of the breast parenchyma can be confidentially rendered on needle core biopsy. We believe that correct diagnosis is primarily dependent on the awareness that this tumour can arise in this unusual site on rare occasions.

Primary mucinous carcinoma of the thyroid gland: case report with review of the literatureH. Mnif, A. Chakroun, S. Charfi, S. Ellouze, M. Ghorbel, T. Sallemi-BoudawaraPrimary mucinous thyroid carcinoma (PMTC) are extremely rare lesions that are histologically indistinguishable from mucinous carcinoma of other sites. We describe the clinicopathological, histological and immunohistochemical features of this rare tumour with a review of the literature. We describe a case of thyroid tumour, in 56-year-old Tunisian man, composed of small nests and sheets of malignant epithelial cells associated with extensive extracellular

mucin that entrapped the follicular parenchyma of thyroid. Thyroglobulin and thyroid-specific-transcription factor 1 (TTF1) were focally positive. Follow-up did not reveal another neoplasm at other sites. Based on these fea-tures, we classified this tumour as PMTC. Mucinous carcinoma of the thyroid gland can be a cause of pitfall in differential diagnosis. For correct diagnosis, complete clinical history, restricted histological criteria and immunohisto-chemical panel are necessary.

Case reports

A solitary polypoid gastric metastasis 20 years after renal cell carcinoma: an event to be considered, and a brief review of the literatureM. Onorati, G. Petracco, P. Uboldi, D.G. Redaelli, S. Romagnoli, M. Albertoni, F. Di Nuovo Background. The incidence of gastric metastasis is 2.6%. Although all primary neoplasms can metastasize to the stomach, most originate from melanoma or breast and lung cancer. Their most common endoscopic appearance is a “vol-cano-like” polypoid mass covered by normal mucosa that may show a central ulceration. Renal cell carcinoma (RCC), clear cell type, is known to spread hematogenously, and isolated metastasis to the stomach is a rare event. Case presentation. In this report, we describe a gastric recurrence of RCC, clear-cell type, in a 80-year-old patient who underwent nephrectomy 20 years ago. We also performed a brief review of the literature to update the number of cases described to date.Conclusion. Metastatic involvement of the stomach should be suspected in any patient with a previous history of RCC, clear cell type, presenting with gastro-intestinal symptoms, even if many years after nephrectomy. The peculiarity of our case is due to the very late presentation of the gastric metastasis. In reality, only two cases of very late gastric metastases from RCC, clear cell type, have been described in the literature.

Coexistence of xanthogranulomatous cholecystitis and gallbladder adeno-carcinoma: a fortuitous association?F. Limaiem, B. Chelly, F.Hassan, I. Haddad, S. Ben Slama, A. Lahmar, S. Bouraoui, S. Mzabi-Regaya Xanthogranulomatous cholecystitis is a relatively uncommon variant of chronic cholecystitis, characterized by marked thickening of the gallblad-der wall and dense local adhesions. Not only does xanthogranulomatous cholecystitis mimic malignancy, it can also be infrequently associated with gallbladder carcinoma in 0.2% to 35.4% of cases. Herein, the authors report a new case of xanthogranulomatous cholecystitis concomitant with gallblad-der adenocarcinoma in a 65-year-old female patient. Because of its overlap-ping clinical, radiological and macroscopic findings with gallbladder cancer, definitive diagnosis of xanthogranulomatous cholecystitis relies on extensive sampling and thorough microscopic examination of the surgical specimen to exclude the possibility of coexisting tumour. It is still a matter of debate whether xanthogranulomatous cholecystitis is truly a precursor of gallblad-der carcinoma or if it is just an incidental finding. This aspect needs to be explored in the future with further studies.

Pinkus tumour: an unusual caseS. Sehli Attafi, M. Jones, B. Fazaa, R. Zermani, S.R. RommanyFibroepithelioma of Pinkus is a rare cutaneous tumour. Its classification is controversial and is considered as a variant of either basal cell carcinoma or trichoblastoma 1. Its presentation as a multiple tumour is rare. We are report-ing such a case occurring in a 55-year-old man presenting with multiple seb-orrheic keratosis-like lesions corresponding histologically to Pinkus tumours. The clinical diagnosis of Pinkus tumour represents a challenge. Histological examination is extremely useful in aiding in the diagnosis of difficult cases.

Mammary myofibroblastoma with leiomyomatous differentiation: case report and literature reviewH. Mnif, S. Charfi, N. Abid, T. Sallemi-BoudawaraIntroduction. Myofibroblastoma of the breast (MFB) is an unusual benign tumour that belongs to the family of benign spindle cell tumours of the mam-mary stroma. The detection of smooth muscle cells in MFB is explained by its histogenesis from CD34+ fibroblasts of mammary stroma capable of multidi-rectional mesenchymal differentiation, including smooth muscle.Aims. The purpose of this case is to highlight characteristics of this rare neoplasm. Immunohistochemical features, in MFB with predominant leiomyomatous differ-entiation, are provided to offer a practical approach to a correct diagnosis.Case report. We report a right MFB in a 60-year-old male. The tumour was unusual due to its morphological features, with predominant leiomyomatous differentiation. Immunohistochemical findings, based on the negativity of h-caldesmon, helped in reaching a diagnosis.Conclusion. The detection of leiomyomatous rather than myofibrolastic fea-tures in MFB may reflect only the predominant cell types of examined area, and this is not necessarily representative of the remaining tumour which may have a different basic cellular composition. Immunohistochemical expression of h-caldesmon is a reliable marker in distinguishing smooth muscle versus myofibrolastic cellular differentiation in spindle cells lesions of the breast.

pathologica 2013;105:111-116

Introduction

Lymphomatoid granulomatosis (LYG) is a misnomer coined by Liebow in 1972 1 actually designating a rare Epstein-Barr virus (EBV)-driven lymphoproliferative disorder with different aggressiveness, ranging from low-grade to high-grade angiocentric and angiodestruc-tive lymphoma 2-8. The lungs are the most commonly involved organ, but the skin and nervous system are also frequently affected 7 8. The disease mainly affects middle-aged patients with a male prevalence; clinical outcome is generally poor and an effective therapy is lacking 7-14. Imaging work-up generally reveals multiple, bilateral nodules tending to central cavitation 15-21. At histology, LYG appears as a polymorphic lymphopro-liferative, angiogentric and necrotic process with a pre-dominant T-cell rich infiltrate obscuring large lympho-matous B-cells 1-8 22 23. Diagnosis is almost impossible on cytology and rarely feasible on small biopsies, most

often requiring a generous amount of pathologic tissue as a surgical specimen 22 23. Demonstration of EBV RNA genome is a crucial point for correct diagnosis, and LYG is graded from I to III based on the rate of EBV-positive large B-cells 3-8 22 23. From a practical standpoint, LYG is suggested to represent an EBV-driven T-cell rich diffuse large B-cell lymphoma 22 23.In this brief report, the main clinico-radiologic and pathologic findings of LYG are reviewed in order to highlight the most helpful diagnostic features for routine practice when dealing with this controversial and diffi-cult entity.

Clinical Findings

LYG has a predilection for men in a 2:1 ratio and may affect both children and elderly, with the highest preva-lence in the forth and fifth decades of life 2 3 7 8 10-14. The

Originale article

Lymphomatoid granulomatosis: a practical review for pathologists dealing

with this rare pulmonary lymphoproliferative processE. TAGLIAVINI1, G. ROSSI1, R. VALLI1, M. ZANELLI1, A. CADIOLI2, M.C. MENGOLI1, A. BISAGNI1, A. CAVAZZA1,

G. GARDINI1

1 Unità Operativa di Anatomia Patologica, Azienda Ospedaliera Arcispedale Santa Maria Nuova/Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Reggio Emilia, Italy; 2 Struttura Complessa di Anatomia Patologica, Azienda Ospedaliera-Universitaria

Policlinico di Modena, Modena, Italy

Key words

Lung • Lymphoma • EBV • Immunohistochemistry • Immunodeficiency

Summary

CorrespondenceGiulio Rossi, Unità Operativa di Anatomia Patologica, Azienda Ospedaliera Arcispedale Santa Maria Nuova/IRCCS, viale Risorgimento 80, 42123 Reggio Emilia, Italy - Tel. +39 0522 295656 - Fax +39 0522 296945 - E-mail: [email protected]

Lymphomatoid granulomatosis (LYG) is a rare B-cell lympho-proliferative disorder predominantly involving the lungs, but poorly-recognized among clinicians and pathologists. It is an Epstein-Barr virus (EBV)-driven disease mimicking several other diseases on clinical and radiological grounds, generally showing multiple, bilateral nodular, ill-defined infiltrates of the lungs tend-ing to coalescence and/or cavitation. LYG often affects middle-aged males with an underlying immunodeficiency and commonly involves skin and central nervous system during disease progres-

sion. Diagnosis requires a generous biopsy and careful histologic examination with immunohistochemical staining and molecular demonstration of EBV genome in large atypical B-cells. LYG is graded as I to III based on the number of large EBV-positive B-cells; grades II/III are now considered as a peculiar variant of T-cell rich diffuse large B-cell lymphoma. In this brief review, clinical, radiologic and pathologic features of LYG will be ana-lyzed with focus on differential diagnosis, the most appropriate treatment and prognosis.

DisclosuresThe author(s) have no conflicts of interest or funding to disclose.

E. tagliaViNi Et al.112

disease more commonly occurs in patients with im-munodeficiency or predisposing conditions, such as Wiskott-Aldrich syndrome, human immunodeficiency virus infection (HIV), allogenic organ transplantation, common variable immunodeficiency, X-linked hypo- or agammaglobulinaemia, rheumatoid arthritis, previous history of solid or haematologic neoplasms and chronic treatment with methotrexate (Table I) 2 3 7-14 22-27. The mean time from onset of symptoms to diagnosis is about 8 months 2 3 7-14.It is a common view that LYG may derive from a deficit of CD8 T lymphocytes that cannot control EBV-specific immunity 3 7 8 10-14 22 23. LYG may be localized to the lungs or rather presents as a systemic disease involving skin (50%), central nervous system (25%) and less common-ly the kidneys 3 7-14. Of note, lymph nodes, bone marrow and spleen are rarely involved. 3,7-14 Cough, chest pain and dyspnoea are the main pulmonary symptoms, while haemoptysis usually indicates cavitation of the paren-chymal nodules 3 7-14 16 28-30. However, patients with LYG often suffer from systemic symptoms including fever, asthenia, night sweats and weight loss 11-16 28-30.Cutaneous involvement often occurs in the arms and legs with a very heterogeneous manifestation, ranging from an erythematous maculopapular eruption to subcu-taneous nodules with non-confluent rash 11-16 28-30. Neu-rologic presentation may present as an isolated periph-eral or cranial neuropathy, as a central mass lesion or with seizures 11-16 28-30.Predictors of poor prognosis are central nervous system involvement, high grade, young age at diagnosis (< 25 years), leukocytosis and hepatomegaly 11-16 28-30.

Radiological Features

The most common radiographic feature is multiple lung nodules, occurring in approximately 80% of cases, pre-

dominantly involving the lung bases 15-21. Lesions can progress rapidly, coalesce and commonly cavitate, mimicking Wegener’s granulomatosis or metastases (Fig. 1) 15-21 26. Dee et al. 18 described two distinct radio-graphic manifestations of LYG. In their series of five patients, diffuse reticulonodular opacities correlated mi-croscopically with angiocentric granulomatous infiltra-tion without pulmonary infarction, whereas larger mass-like opacities corresponded to biopsy-proven pulmonary infarcts 18. There is a wide range in the number (5-60) and diameter of the nodules (up to 6.5 cm), but they gen-erally measure about 1 cm and tend to be located along

Table I. conditions associated with lymphomatoid granulomatosis.

hematological disordersleukemia (acute lymphoblastic; chronic lymphocytic)hodgkin lymphomaNon-hodgkin lymphomaMyelofibrosis

Wiskott-aldrich syndromecommon variable immunodeficiencyacquired immune deficiency syndromeSolid tumorsRenal transplantationautologous stem-cell transplantationRheumatoid arthritisSarcoidosisBiliary cirrhosischronic hepatitisRetroperitoneal fibrosispsoriasisDermatitis herpetiformis

Table II. Main pathologic conditions mimicking lYg in the lungs.

infectionsFungalMycobacterialNocardiaactinomycesparagonomiasis

autoimmune diseasesWegener’s granulomatosischurg-Strauss syndromeMicroscopic polyangiitisRheumatoid arthritisigg4 syndrome

Neoplasmsprimary lung carcinomasMetastatic tumorslymphoproliferative disease (i.e., leukaemia)Sarcoidosisamyloidosislipcoppneumoconioses

lYg: lymphomatoid granulomatosis; lip: lymphocytic interstitial pneumonia; cop: cryptogenic organizing pneumonia.

Fig. 1. thorax ct scan of lYg showing bilateral, ill-defined nodular opacities along the bronchovascular bundles.

113pulMoNaRY lYMphoMatoiD gRaNuloMatoSiS

the bronchovascular bundles and interlobular septa 15-21. Less common radiological appearances include coarse linear opacities along the bronchovascular bundles and thin-walled cysts 15 18. Nodules can disappear or migrate spontaneously, and may display central ground-glass opacity surrounded by denser consolidation at least 2 mm thick-the so-called “reversed halo sign” 20. How-ever, this is a non-specific sign, most commonly seen in organizing pneumonia. Differential diagnosis at imag-ing may be very challenging and includes several other, more common diseases, including metastases, lympho-cytic interstitial pneumonia (LIP), sarcoidosis, Wegen-er’s granulomatosis and cryptogenic organizing pneu-monia (Table II) 15-21. In contrast with other lymphomas involving the thoracic region, mediastinal lymphade-nopathy is very uncommon in LYG 15-21.

Immunomorphologic & Molecular Features

Histology is characterized by poorly-defined pulmonary nodules (Fig. 2A) along the bronchovascular bundles and interstitial inflammatory infiltrates consisting of lym-phocytes, plasma cells, histiocytes and intermediate-to-large centroblast-like lymphoid cells (Fig. 2B-C) 1-8 22 23. Vascular and bronchiolar involvement by lymphoid in-filtrates is frequently noted. In fact, venous and arteri-ous vessels tend to be infiltrated by a mixture of small sized and large atypical lymphocytes justifying the pe-culiar angiocentric involvement (Fig. 2D) 1-8,22,23. At the periphery of lymphoid proliferation, lung parenchyma commonly shows an acute lung injury with fibrin and hyaline membranes 14,27. At immunohistochemistry, there is a background of small T-lymphocytes (CD3+) predominantly with helper phenotype (CD4+) (Fig. 3A) and CD68+ histiocytes intermingled in a population of large B-cells (CD20+, PAX5+, CD79a+) (Fig. 3B-C) with a high proliferative index by Ki67/MIB-1 3-8 22 23.

In-situ hybridization for EBV-encoded RNA (EBER) re-veals a consistent number of EBV-positive large B-cells (Fig. 3D), while molecular analyses generally demon-strate B-cell clonality by immunoglobulin heavy chain gene rearrangement 3-8 10-13 16 22 23.Despite the misnomer, no granulomas or multinucleated giant cells are generally observed in LYG. According to the WHO classification criteria based on the number of EBV-positive large atypical B-cells, three grades are recognized in LYG. Grade I is very rare and shows a polymorphous infiltrate with minimal angiocentric le-sions and fewer than 5 EBV-positive large B-cells per high-power-field (hpf) 3 8 22 23. Grade II has 5-20 EBV-positive atypical B-cells per hpf, while grade III LYG contains aggregates of EBV positive large B-cells (> 20/hpf), prominent angiocentric lesions and necrosis 3 8 22 23.

Prognosis & Therapy

The current view is that LYG is a form of EBV-induced B-cell lymphoma, and so far about 600 cases of LYG have been described in the literature. Despite this, no standard therapy has been established, and treatment is controversial and problematic, basically depending on the disease grade 7 9 10-13 30-37. Several regimens have been considered in the past, from observation to cyclophos-phamide plus prednisone or combination chemotherapy with different agents with variable success 10.However, the outcome is poor and most patients with LYG succumb to the disease after a short period of time. In addition, patients often respond initially, but relapse is very common and the immunosuppressive effects of therapy may actually worsen the condition. During ther-apy, close follow-up for possible superimposed infec-tions is required.Since this is an EBV-driven process, grade I LYG is of-ten treated with interferon alpha (starting dose of 7.5 x

Fig. 2. low magnification of a surgical lung specimen of lYg showing several “blue” nodules (A) that at higher magnification consisted of polymorphous mononuclear infiltrates (B, C) with vessel infiltration (D).

Fig. 3. lYg displays, at immunohistochemistry, a background of cD4+ t-cells (A) with cD20+ (B) and paX-5+ (C) large atypical, cen-troblast-like B-cells with nuclear positivity for EBV-RNa (D, EBER probe, in-situ hybridization).

E. TAGLIAVINI ET AL.114

106 U administered subcutaneously 3 times per week, then dose-escalation to best response or complete re-mission and therapy continued at that dose for a year or longer) 7 10-13. In contrast, grades II and III should be considered high-grade lymphomas, requiring more ag-gressive treatment including cyclophosphamide, doxo-rubicin, vincristine and prednisone (CHOP) combined with the anti-CD20 monoclonal antibody rituximab (R-CHOP). Etoposide, prednisone, vincristine, cyclophos-phamide doxorubicin and rituximab (DAEPOCH-R) are also considered an effective treatment strategy in grade III LYG 7 10-13 30-37.Of note, patients with grade I LYG can relapse with grade II or grade III disease, but this is sampling-depen-dant due to the presence of discordant disease at differ-ent sites. Re-biopsy should then be highly recommended in patients who are progressing on therapy in order to switch treatment strategies. At a median follow-up time of 5 years, the progression-free survival (PFS) of pa-tients with grade I LYG was 56% with a median time to remission of 9 months 7 10-13. Almost all deaths are re-corded in the first 36 months after diagnosis. For grades II-III disease at diagnosis treated with immunochemo-therapy, PFS was 40 % with a median follow-up of 28 months 7 10-13.

Conclusion

LYG is an angiocentric large B-cell lymphoprolifera-tive disorder due to a defective immune response to EBV and characterized by a mixed polymorphic mon-onuclear infiltrate with small and large lymphocytes, plasma cells and histiocytes arranged in ill-defined nodules with transmural angiocentric infiltration lead-ing to an angiodestructive process 7 10-13 22 23. The dis-ease generally occurs in middle-aged patients (mean, 40-50 years; range, 2-85 years) with systemic symp-toms (fever, malaise, arthralgia, weight loss) mimick-ing infections (especially tuberculosis and acute histo-plasmosis), vasculitides (Wegener’s granulomatosis) or malignancies 7 10-13 16 22 23. Given the rarity of LYG and the non-specific symptoms, correct diagnosis is frequently delayed, requiring a mean time of 8 months from disease onset 14 30. When LYG is restricted to the lungs, fever is the main and often unique symptom, followed by general malaise, weight loss, arthralgia, but clinical manifestations are mainly organ-related (skin, central nervous system, kidney) 7 10-13. Lungs are almost always involved by LYG, but respiratory symp-toms may be absent in 20% of cases, while imaging studies invariably show parenchymal nodules, opaci-ties or poorly-defined masses with a peculiar tropism for bronchoalveolar bundles and interlobular septa without mediastinal lymphadenopathy 15-21. Otherwise, LYG may appear as pulmonary cystic disease, pleu-ral-based mass or prominent interstitial process 15 18. Patients with LYG should be investigated for altera-tions of cytotoxic T-cell function, since a significant

association between LYG and immunodeficiencies has been well-demonstrated (i.e. AIDS, Wiskott-Aldrich, post-transplantation, collagen-vascular diseases treated with methotrexate, sarcoidosis, haematologic and solid malignancies, chronic liver and cutaneous diseases, medications) 3 7 8 10-13 24 25 27. Interestingly, recent obser-vations by Yamashita et al. 38 have suggested that some cases of EBV-negative grade 1 LYG are indistinguish-able from pulmonary IgG4-related sclerosing disease,

an autoimmune disorder affecting several organs and characterized by elevated serum IgG4 titre, increased IgG4-positive plasma cells in tissues with vascular in-volvement and dramatic clinical response to steroids.Diagnosis of LYG requires accurate histopathologic examination on generous biopsies. Bronchoalveolar lavage cytology does not permit a confident diagnosis, basically evidencing a non-specific mixed inflammatory infiltrate. Transbronchial or transthoracic CT-guided bi-opsies may be diagnostic when sampling a large amount of pathologic tissue and in the hands of expert patholo-gists. In addition, in the majority of cases reported to date in the literature, diagnosis is performed on surgical specimens and the tissue sampled should be analysed in its entirely, since correct diagnosis mainly depends on careful examination of various areas of the pathologic process coupled to adequate immunohistochemical stains and molecular analysis 22 23. In other words, LYG may actually show grade I and grade III disease in dif-ferent pathologic areas of the same case. Based on the number of EBV-positive large B-cell counted per high-power-field, LYG is subdivided into three grades 7 8. According to recent observations by Katzenstein et al. 22 and Colby 23, grade I LYG is a formidable challenge to diagnose and probably represent a early or poorly sam-pled lymphoma. Grades II/III LYG likely raise the sus-picion of a malignant lymphoproliferative disease even in the hands of general pathologist. Sharing these com-plicated cases with more expert colleagues and perform-ing EBER-EBV analysis on multiple sections or blocks is very helpful in discriminating LYG from other mim-icking processes. Differential diagnosis at histology includes other lym-phoproliferative (primary or secondary) and inflamma-tory diseases 22 23. Knowledge of a previous diagnosis of lymphoma (Hodgkin or large B-cell lymphomas) is mandatory before performing a diagnosis of LYG. Since post-transplant lymphoproliferative disorder and iatro-genic immunodeficiency-associated lymphoprolifera-tive disorder are quite similar to LYG, such a diagnosis should be posed with caution in patients receiving organ transplant or those heavily treated with methotrexate or other immunosuppressive agents 7 22.There may be substantial overlap between some indolent EBV-positive angiocentric lymphoproliferative processes (e.g. HIV infection, iatrogenic lymphoproliferative dis-eases, secondary drug toxicity) and LYG. In these dif-ficult cases, pathologic criteria may be fragile and need prominent integration with clinical and imaging data.The main differential diagnosis is with Wegener’s gran-

115Pulmonary lymPhomatoid granulomatosis

ulomatosis (WG). However, WG shows a true granu-lomatous inflammation with scattered multinucleated giant cells, dirty “blue” necrosis and/or granulocytic mi-croabscesses. Neutrophils, plasma cells and eosinophils represent the major cellular components in a necrotic background 1 2 22 23. Vascular infiltration of WG takes the form of a inflammatory necrotizing vasculitis with a mixture of granulocytes and mononuclear cells with or without giant cells leading to at least segmental vessel wall necrosis 1 2 22 23. Special stains for mycobacteria and fungi should be performed in all cases before consider-ing a diagnosis of LYG. Spontaneous remission or waxing-and-waning course has been reported in grade I LYG, while grades II and III are basically a unique variant of “T-cell-rich diffuse large B-cell lymphoma”, with a mortality ranging from 50-90% and an overall median survival of 14 months 3 7 8 10-13 22 23. No standard therapies are available at present for patients with LYG. Monotherapy using steroids, rituximab or in-terferon-alpha has been adopted mainly in grade I LYG 10. Combined chemotherapy with CHOP ± rituximab in pa-tients with grade II-III LYG seems to represent the best therapeutic option available 3 10-14 29 30 32 34.

Practical Remarks

• LYG is an EBV-driven lymphoproliferative disease, ranging from grade I to grades II and III; these latter are considered as a form of diffuse large B-cell lym-phoma (T-cell rich diffuse large B-cell lymphoma). LYG primarily occurs in the lungs, less frequently involving skin and central nervous system.

• Mean age at diagnosis is 48 years with a male preva-

lence. Cough, dyspnoea, fever and malaise are the main symptoms.

• CT key features: bilateral, round, poorly defined nodules ranging from 0.5 to 8 cm in diameter with basal predominance and peribronchovascular distri-bution. The nodules may coalesce and cavitate, and even show a “reversed halo sign’’, while “migrato-ry’’ nodules due to ‘‘waxing and waning’’ may also be present.

• Diagnosis always relies on histology and cannot be made on cytology. Morphologic examination requires the presence of a polymorphic, angio-centric lymphoid proliferation including a back-ground of T-cells, plasma cells and histiocytes intermingled by varying numbers of large B-cells. Necrosis may be focal to extensive, and the sur-rounding parenchyma frequently shows acute lung injury. Demonstration of EBV genome in large B-cells is mandatory and determines the grade of disease. Grade II and III contain clusters of EBV-positive large B-cells. Of note, grade I is very rare and requires careful clinico-pathologic correla-tions, since it may represent an unsampled/poorly sampled grade II or III LYG rather than an EBV-positive inflammatory process secondary to drug toxicity (e.g. methotrexate).

• Prognosis in grade II and III is dismal, with a median survival ranging from 14 months to 4 years from di-agnosis. Mortality rates range from 53-64%.

• Therapy depends on the grade of disease. Grade I is usually treated with immunomodulators, namely interferon alpha, while grades II and III require im-munochemotherapy combining chemotherapeutic agents with rituximab.

References

1 Liebow AR, Carrington CR, Friedman PJ. Lymphomatoid granu-lomatosis. Hum Pathol 1972;3:457-558.

2 Katzenstein AL, Carrington CB, Liebow AA. Lymphomatoid granulomatosis: a clinicopathologic study of 152 cases. Cancer 1979;43:360-73.

3 Jaffe ES, Harris NL, Stein H, et al., eds. Pathology and genetics of tumours of the haematopoietic and lymphoid tissues. WHO Clas-sification of Tumours. Lyon: IARC Press 2001.

4 Katzenstein AL, Peiper SC. Detection of Epstein-Barr virus ge-nomes in lymphomatoid granulomatosis: analysis of 29 cases by the polymerase chain reaction technique. Mod Pathol 1990;3:435-41.

5 Guinee D Jr, Jaffe E, Kingma D, et al. Pulmonary lymphomatoid granulomatosis: evidence for a proliferation of Epstein-Barr virus infected B-lymphocytes with a prominent T-cell component and vasculitis. Am J Surg Pathol 1994;18:753-64.

6 Myers JL, Kurtin PJ, Katzenstein AL, et al. Lymphomatoid granulomatosis: evidence of immunophenotypic diversity and relationship to Epstein-Barr virus infection. Am J Surg Pathol 1995;19:1300-12.

7 Jaffe ES, Wilson WH. Lymphomatoid granulomatosis: patho-genesis, pathology and clinical implications. Cancer Surv 1997;30:233-48.

8 Travis WD, Brambilla E, Muller-Hermelink HK, eds. Tumours of

the lung, pleura, thymus and heart. Pathology and Genetics. WHO Classification of Tumours. Lyon: IARC Press 2004.

9 Fauci AS, Haynes BF, Costa J, et al. Lymphomatoid granulomato-sis: prospective clinical and therapeutic experience over 10 years. N Engl J Med 1982;306:68-74.

10 Dunleavy K, Roschewski M, Wilson WH. Lymphomatoid granu-lomatosis and other Epstein-Barr virus associated lymphoprolif-erative processes. Curr Hematol Malig Rep 2012;7:208-15.

11 Calfee CS, Shah SJ, Wolters PJ, et al. Anchors away. N Engl J Med 2007;356:504-9.

12 Hochberg EP, Gilman MD, Hasserjian RP. Case records of the Massachusetts General Hospital. Case 17-2006: a 34-yer-old man with cavitary lung lesions. N Engl J Med 2006;354:2485-93.

13 Dolgonos L, Janssen WJ. A 75-year-old woman with dyspnea and a sore throat. Chest 2008;133:1014-20.

14 Rossi G, Marchioni A, Guicciardi N, et al. A rare cause of fever and PET-positive nodules in the lungs. Clin Respir J 2009;3:118-20.

15 Bartosik W, Raza A, Kalimuthu S, et al. Pulmonary lymphomatoid granulomatosis mimicking lung cancer. Interactive CardioVascu-lar and Thoracic Surgery 2012;14:662-4

16 Lee JS, Tuder R, Lynch DA. Lymphomatoid granulomatosis: ra-diologic features and pathologic correlations. Am J Roentgenol 2000;175:1335-9.


17 Pisani RJ, DeRemee RA. Clinical implications of the histopath-ologic diagnosis of pulmonary lymphomatoid granulomatosis. Mayo Clin Proc 1990;65:151-63.

18 Hicken P, Dobie JC, Frew E. The radiology of lymphomatoid gran-ulomatosis in the lung. Clin Radiol 1979;30:661-4.

19 Dee PM, Arora NS, Innes DJ Jr. The pulmonary manifestations of lymphomatoid granulomatosis. Radiology 1982;143:613-8.

20 Sheehy N, Bird B, O’Briain DS, et al. Synchronous regression and progression of pulmonary nodules on chest CT in untreated lym-phomatoid granulomatosis. Clin Radiol 2004;59:451-4.

21 Benamore RE, Weisbrod GL, Hwang DM, et al. Reversed halo sign in lymphomatoid granulomatosis. Br J Radiol 2007;80:e162-6.

22 Hare SS, Souza CA, Bain G, et al. The radiological spectrum of pulmonary lymphoproliferative Disease. The British Journal of Radiology 2012;85:848-64.

23 Katzenstein AL, Doxtader E, Narendra S. Lymphomatoid granu-lomatosis. Insights gained over 4 decades. Am J Surg Pathol 2010;34:e35-e48.

24 Colby TV. Current histological diagnosis of lymphomatoid granu-lomatosis. Mod Pathol 2012;25, S39-S42.

25 Sebire NJ, Haselden S, Malone M, et al. Isolated EBV lymphopro-liferative disease in a child with Wiskott-Aldrich syndrome mani-festing as cutaneous lymphoid granulomatosis and responsive to anti-CD20 immunotherapy. J Clin Pathol 2003;56:555-7.

26 Haque AK, Myers JL, Hudnall SD, et al. Pulmonary lymphomatoid granulomatosis in acquired immunodeficiency syndrome: lesions with Epstein-Barr virus infection. Mod Pathol 1998;11:347-56.

27 McCloskey M, Catherwood M, McManus D, et al. A case of lym-phomatoid granulomatosis masquerading as a lung abscess. Tho-rax 2004;59:818-9.

28 Kameda H, Okuyama A, Tamaru J, et al. Lymphomatoid granulo-matosis and diffuse alveolar damage associated with methotrex-ate therapy in a patient with rheumatoid arthritis. Clin Rheumatol 2007;26:1585-9.

29 Jaffre S, Jardin F, Dominique S, et al. Fatal haemoptysis in a case of lymphomatoid granulomatosis treated with rituximab. Eur Respir J 2006;27:644-6.

30 Erickson BW, Cripe L, Rieger K, et al. A Woman with Facial Pap-ules and Pulmonary Nodules. Respiration 2007;74:471-4.

31 Vahid B, Salerno DA, Marik PE. Lymphomatoid granuloma-tosis: a rare cause of multiple pulmonary nodules. Respir Care 2008;53:1227-29.

32 Johnston A, Coyle L, Nevell D. Prolonged remission of refractory lymphomatoid granulomatosis after autologous hemopoietic stem cell transplantation with posttransplantation maintenance inter-feron. Leuk Lymphoma 2006;47:323-8.

33 Jung KH, Sung HJ, Lee JH, et al. A case of pulmonary lymphoma-toid granulomatosis successfully treated by combination chemo-therapy with rituximab. Chemotherapy 2009;55:386-90.

34 Wilson WH, Kingma DW, Raffeld M, et al. Association of lym-phomatoid granulomatosis with Epstein-Barr viral infection of B lymphocytes and response to interferon-alpha 2b. Blood 1996;87:4531-7.

35 Drasga RE, Williams SD, Wills ER, et al. Lymphomatoid granu-lomatosis: successful treatment with CHOP combination chemo-therapy. Am J Clin Oncol 1984;7:75-80.

36 Raez LE, Temple JD, Saldana M. Successful treatment of lympho-matoid granulomatosis using cyclosporin-A after failure of inten-sive chemotherapy. Am J Hematol 1996;53:192-5.

37 Zaidi A, Kampalath B, Peltier WL, et al. Successful treatment of systemic and central nervous system lymphomatoid granulomato-sis with rituximab. Leuk Lymphoma 2004;45:777-80.

38 Yamashita K, Haga H, Kobashi Y, et al. Lung involvement in IgG4-related lymphoplasmacytic vasculitis and interstitial fi-brosis. Report of 3 cases and review of the literature. Am J Surg Pathol 2008;32:1620-6.

39 Kobayashi S, Kikuchi Y, Sato K, et al. Reversible iatrogenic, MTX-associated EBV-driven lymphoproliferation with histopathological features of a lymphomatoid granulomatosis in a patient with rheu-matoid arthritis. Ann Hematol DOI 10.1007/s00277-013-1741-1.

pathologica 2013;105:117-121

Introduction

The TNM staging system for lung cancer, especially for non-small cell lung carcinoma, has not been re-vised since the first edition of the tumor, node and metastasis classification published in 1997 1. Initial-ly, this edition remained unaltered in the sixth edi-tion published in 2002, and a revised classification was published in 2009 2-3. The new recommendations concerned tumour and metastasis classification. Con-sidering node classification, tumours remained sub-divided according to the metastatic lymph node sta-tions, but many concerns have been pointed out by several authors. In fact, the N1 and N2 patient groups seem to be heterogeneous with regards to progno-sis. Moreover, patients with multiple-station metas-tases have been reported to have a poorer prognosis compared with those with single-station metastases in both N1 and N2 patients 4-6. In addition, patients

with skip metastases have been reported to belong to a more favourable prognostic subgroup 7. Many authors seem to be disappointed when classifying patients with only hilar lymph node metastasis. In order to an-swer to some of these questions and in accordance with the TNM staging of major malignancies such as colorectal carcinoma, gastric carcinoma and breast carcinoma, some authors have attempted to highlight the prognostic relevance of including the number of metastatic lymph nodes (LNs) 8. The ratio of metastat-ic to examined LNs (LNR) has been suggested to be a more favourable prognostic indicator than the number of metastatic LNs in some malignancies 9-11. In this study, we explored the prognostic relevance of the current TNM classification in comparison with the nodal classification based on the LNR and the nodal classification based on the number of metastatic LNs (nLN). Moreover, we tried to explore the best prog-nostic cut-off number of resected lymph nodes.

Original article

About the necessity of improving the current nodal classification of non-small cell lung carcinoma

M. MLIKA*1, A. AYADI-KADDOUR*1, S. BOUDAYA2, A. MARGHLI2, T. KILANI2, F. MEZNI*1

* Search Unit: 02/SU/08-08; 1 Department of Pathology, 2 Department of Thoracic & Cardiovascular Surgery, Abderrahman Mami Hospital, Ariana, Tunisia

Key words

TNM classification • Ratio of metastatic lymph nodes • Non-small cell lung carcinoma

Summary

CorrespondenceMona Mlika, Department of Pathology, Abderrahman Mami Hospital, Ariana 2037, Tunisia - Tel. +21698538862 - Fax +21671710780 - E-mail: [email protected]

Background. The current classification of lymph node status in non-small cell lung carcinoma has not been revised since 1997. This fact has prompted many authors to point out the limits of this classification.Methods. We tried to explore the prognostic relevance of the current TNM classification in comparison with the nodal classi-fication based on the ratio of metastatic lymph nodes (LNR) and the nodal classification based on the number of metastatic LNs (nLN). Additionally, we tried to explore the recommended num-ber of resected LNs. This was done through a retrospective study of 39 cases. We compared the survival curves of patients using the current, RLN and nLN classifications. In the nLN classifica-tion, we grouped patients into three categories: nN0 (no meta-

static LNs), nN1 (1 to 2 metastatic LNs) and nN2 (> 2 metastatic LN). In the LNR classification, we grouped patients into three categories: rNO (0%), rN1 (≤ 12) and rN2 (> 12). Concerning the total number of the resected LNs, patients were categorized into two groups according to the number of LNs: < 10 versus ≥ 10 and < 15 versus ≥ 15.Results. Our results showed that the LNR classification high-lighted a difference in prognosis between the rN1 and rN2 groups. Moreover, survival of patients seemed to be better when the num-ber of the resected LNs was higher.Conclusion. The ratio of metastatic LNs seems to be an important prognostic factor, but further studies are necessary to standardize this classification.


Patients and methods

PatientsBetween January and December 2008, 53 patients with non-small cell lung carcinoma underwent surgical resec-tion at our hospital. We excluded patients with small cell carcinoma, stage IIIb disease and stage IV disease. Fur-thermore, we excluded patients with induction treatment or with less than six LNs removed because examination of six or more LNs stations is recommended according to the 7th edition of the TNM classification. Finally, 39 patients met these criteria; patient characteristics are shown in Table I. The Abderrahman Mami Hospital re-view board approved this retrospective study and waived the requirement of patient consent.All patients underwent physical examination, chest X-ray, bronchoscopic examination and CT-scan of the chest as well as the upper part of the abdomen and mag-netic resonance imaging of the brain. A LN > 1 cm in its short axis shown in CT was considered as metastatic.

LN dissectionMediastinal LN metastasis was not considered as a contraindication for surgery unless the swollen LNs ap-peared unresectable. Systemic nodal dissection involves the complete resec-tion of ipsilateral mediastino-hilar LNs. Hilar, inter-lobar and lobar LNs were resected with affected lung lobes in the hilar LN dissection and remote mediastinal LN station such as subcarinal LNs in the upper lobe

tumour, were not resected in selective mediastinal dis-section.

Microscopic examinationThe LNs stations varying from 1 to 10 were individually removed by surgeons and were either examined extem-poraneously or fixed immediately in formalin and cut at their equator, stained with haematoxylin and eosin and examined by light microscopy. Interlobar LNs were resected in combination with the lung, and these nodes were classified into each nodal station. The pathological stage was classified according to the 7th edition of the TNM classification. Hilar lymph node metastasis was classified as N2 stage.

Statistical analysisThe cut-off numbers for each category in the two new nodal classifications (nNC and LNR NC) were defined so that the numbers corresponded with paired catego-ries within the current NC. This was done to compare the prognosis of each category in the two new nodal classifications. In the number NC, we classified pa-tients into three categories: nN0 when there was no metastatic lymph node, nN1 when 1 to 2 lymph nodes were metastatic and nN2 when more than 2 lymph nodes were metastatic. The LNR was calculated by dividing the number of metastatic lymph nodes by the total number of the resected LNs multiplied by100. In the LNR NC, we classified patients into three cat-egories: rNO when the ratio reached O, rN1 when the ratio was less or equal to 12 and rN2 with the ratio was superior to 12.Concerning the total number of the resected lymph nodes, patients were categorized into two groups accord-ing to the number of RLNs: < 10 versus ≥ 10 and < 15 versus ≥ 15. The survival period was calculated from the date of surgery to the time of death or the endpoint. Survival curves were calculated using the Kaplan-Meier method and differences in survival were determined by the log-rank test. The comparison of survival was per-formed using a nonparametric test (Mann-Whitney test). All tests were two sided and p values of less than 0.05 were considered statistically significant. All tests were performed using the Statistical Package for the Social Sciences (SPSS) ver.13 (SPSS Inc, IL, USA).

Results

The most employed surgical procedure was lobectomy with systemic nodal dissection. As shown in Table 1, the number of patients in each category and subcategory were quite similar thus allowing their comparison.

Survival and current LN classificationAccording to the current LN classification, patients were categorized into 3 groups according to the station of the involved LNs. The N0 group contained 26 patients with

Table I. patient characteristics.

Variable Category n (%)

ageMean 62.9Range 44-81

SexMen 36 (32)Women 3 (7.6)

histopathology

adenocarcinoma 16 (41.02)Squamous cell carcinoma

18 (46.15)

other 5 (12.82)

pathological stagei 20 (51.28)ii 11 (28.2)iii 8 (20.5)

tumour locationRight side 22 (56.41)left side 17 (43.59)

Surgical procedurelobectomy 25 (64.10)Bilobectomy 1 (2.56)pneumonectomy 13 (33.33)

current NcN0 26 (66.66)N1 4 (10.26)N2 9 (23.07)

Number metastatic lNsnNo (0) 26 (66.6)nNi (1-2) 6 (15.38)nNii (> 2) 7 (17.94)

Ratio of metastatic lNsrN0 (0) 26 (66.6)rN1 (1-16%) 5 (12.82)rN2 (> 16%) 8 (20.51)

119NEcESSitY oF iMpRoViNg thE cuRRENt NoDal claSSiFicatioN oF luNg caNcER

a mean survival of 9.8 months. The N1 group contained 4 patients with a mean survival of 9.25 months. The N2 group contained 9 patients with a mean survival of 6.0 months. The largest difference was found between the N0 and N2 groups (p = 0.163). Survival curves are shown in Figure 1.

Survival and classification according to the number of involved LNsAccording to this classification, patients were catego-rized into 3 groups according to the number of the meta-static LNs: nNO, nN1 and nN2. The nN0 group contained 26 patients with a mean survival of 15.94 months. The nN1 group contained 6 patients with a mean survival of 7.33 months. The nN2 group contained 7 patients with a mean survival of 6.71 months. The largest difference was found between the N0 and N1 groups (p = 0.482). These survival curves are shown in Figure 2.

Survival and classification according to the ratio of involved LNsAccording to this classification, patients were catego-rized into 3 groups according to the ratio: rN0, rN1, rN2. The rN0 group contained 26 patients with a mean survival of 15.71 months. The rN1 group contained 5 patients with a mean survival of 14.13 months. The rN2 group contained 8 months with a mean survival of 7.72 months. The largest difference was found between the rN1 and rN2 groups (p = 0.212). Survival curves are shown in Figure 3.

Survival and number of resected LNsWe investigated the prognostic impact of the number of resected LNs. Patients were categorized into 2 represen-tative groups according to the total number of resected LNs: < 10 versus ≥ 10 and < 15 versus ≥ 15 (Fig. 4). The largest difference was found in the total number of

Fig. 1. Survival curves according to the current lymph node clas-sification.

Fig. 2. Survival curves according to the number of metastatic lymph nodes.

Fig. 3. Survival curves according to the ratio of metastatic lymph nodes.

Fig. 4. Survival curves according to the number of resected lymph nodes at the time of complete resection.

M. MLIKA et AL.120

resected LNs categorized between < 10 and ≥ 10 with p value of 0.204, but we also noticed that in both groups survival was better when the number of the resected LNs was higher.

Comment

Since 1946, the classification of lung cancer has been modified and the recent recommendations concerned only the Tumour and Metastasis classification 3. In fact, the T1 and T2 stages were subclassified according to tumour size. T2 tumours measuring more than 7 cm were reclassified as T3 tumours. T4 tumours with ad-ditional nodules in the same lobe were reclassified as T3 tumours. M1 tumours with additional nodules in ip-silateral lobes were reclassified as T4. T4 tumours with malignant pleural effusion were reclassified as M1a. Finally, M1 tumours were subclassified into M1a and M1b. The N classification was not modified, and clas-sification of LNs metastasis was maintained based on the LN station as shown in Table II. This was based on the idea that LN metastases occur in LNs neighbour-ing the primary tumour, and then spread to more distant nodes. However, recent studies on skip metastasis and sentinel lymph nodes have assessed that patients with skip metastasis, defined as mediastinal LNs without N1 metastasis, show a better prognosis than patients with non-skip N2 disease 7 12-14. From these results, many au-thors have investigated the impact of the number of re-sected LN, the ratio of the metastatic LN or the number of resected LNs (RLN) 15 16. Two studies have reported the usefulness of determining the number of metastatic LNs. Fukui et al. classified nodal categories according to the number of metastatic LNs as 1-3, 4-6 and > 6, and Lee et al. classified them as 1-4, 4-14 and > 14 17 18. Both studies demonstrated that the number of metastatic LNs was a stronger prognostic indicator than current NC based on the location. In addition, Saji and colleagues showed that 4 involved LNs seemed to be a benchmark for NSCLC prognosis 19.

On the other hand, Matsuguma and colleagues pro-posed new nodal classifications for non-small cell lung cancer based on the number and ratio of metastatic LNs. They concluded that the LNR followed by the number of metastatic LNs may be more effective prog-nostic indicators than the current nodal classification 20. In our study, we observed a more important difference between the subgroups rN1 and rN2 in the LNR classi-fication. Despite the lack of a significant statistical dif-ference between the 2 groups, the survival curves show a tendency towards better prognosis in rN1 group. This classification seems to be more accurate to differentiate the prognosis of these 2 sub-groups. As the number of LNs resected can influence the accuracy of nodal stag-ing, even in current NC, examination of a minimum number of LNs seems to be necessary 21 22. Saji and coworkers retrospectively investigated the prognostic impact of the number of resected LNs and involved LNs in a series of 928 patients with non-small cell lung cancer. They examined many LNs cut-offs and con-cluded that complete resection including 10 or more LNs influenced survival with favourable prognosis in large number resected LNs 19. This fact was also shown in our study. We studied only 2 groups with a cut-off of 10 and 15 resected LN. We excluded all patients with less than 6 LNs because this cut-off was recommend-ed in the latest TNM classification. Although the fact that our results are not statistically significant because the p value was greater than 0.05, the survival curves showed a trend to better survival in the group with 10 or more resected LNs. These results are not in complete agreement. In fact, the results of the American College of Surgeons Oncology Group showed poorer outcome in patients with a high number of resected LN 23. This is possibly due to the predominance of N1 and N2 stag-es, which are more likely to be LN-positive at the time of surgery. In fact, in our study, N0 stage was predomi-nant and accounted for 66.6% of the cases. One limitation of our study was the lack of a statistically significant difference either because of the low number of patients included or to the unfairness of the cut-off values used. We believe that in order to determine the most effective cut-off, data accumulated from multiple institutions from several countries should be analyzed. Moreover, a consensus should be achieved concerning the removal of all, some or none of the mediastinal LNs at the time of surgical resection. In fact, practices vary worldwide. In some groups, LN sampling is standard, whereas systematic LN dissection is standard in others. The different practices, especially in case of fragmenta-tion of LNs, may influence the ratio of metastatic LNs and its real prognostic value.

Conclusion

Lymph node metastasis has been reported to represent an important prognostic factor in NSCLC. According to the current TNM classification, many aspects concern-

Table II. Nodal stations.

Station Denomination1 highest mediastinal2 upper paratracheal3 a, p prevascular, retrotracheal4 lower paratracheal5 Subaortic6 para-aortic7 Subcarinal8 para-oesophageal9 pulmonary ligament10 hilar11 interlobar12 lobar13 Segmental15 Subsegmental

121Necessity of improviNg the curreNt Nodal classificatioN of luNg caNcer

ing the cut-off value of the number of metastatic LNs, the number of resected LNs, the ratio of metastatic LNs, the real prognostic impact of hilar lymph node metasta-sis and the prognostic importance of single station ver-sus multi-station metastases remain unclear. Additional studies may be necessary in order to improve the abil-

ity to indicate the prognostic group of patients. In this regard, the ratio of metastatic LNs seem to be an im-portant prognostic factor, but further studies including large-scale cohort studies with prospective validation analyses and multi-institutional analyses will be neces-sary in order to standardize this classification.

References

1 Sobin LH, Wittekind C, eds, International Union Against Cancer (UICC). TNM classification of Malignant Tumors. 5th ed. New York: Wiley-Liss 1997; pp. 93-7.

2 Sobin LH, Wittekind C, eds, International Union Against Cancer (UICC). TNM classification of Malignant Tumors. 6th ed. New York: Wiley-Liss 1997; pp. 99-103.

3 Sobin LH, Gospodarowicz MK, Wittekind C. TNM Classification of Malignant Tumours, 7th ed. New York: Wiley-Liss 2009.

4 Fujimoto T, Cassivi SD, Yang P, et al. Completely resected N1 non-small cell lung cancer: factors affecting recurrence and long-term survival. J Thorac Cardiovasc Surg 2006;132:499-506.

5 Ichinose Y, Kato H, Koike T, et al. Completely resected stage IIIA non-small cell lung cancer: the significance of primary tumor lo-cation and N2 station. J Thorac Cardiovasc Surg 2001;122:803-8.

6 Andre F, Grunenwald D, Pignon JP, et al. Survival of patients with resected N2 non-small-cell lung cancer: evidence for a subclas-sification and implications. J Clin Oncol 2000;18:2981-9.

7 Riquet M, Assouad J, Bagan P, et al. Skip mediastinal lymph node metastasis and lung cancer: a particular N2 subgroup with a bet-ter prognosis. Ann Thorac Surg 2005;79:225-33.

8 Greene FL, Page DL, Fleming ID, et al. AJCC Cancer Staging Manual. 6th ed., New York: Springer 2002.

9 Peschaud F, Benoist S, Julie C, et al. The ratio of metastatic to examined lymph nodes is a powerful independent prognostic factor in rectal cancer. Ann Surg 2008;248:1067-73.

10 Marchet A, Mocellin S, Ambrosi A, et al. The ratio between metastatic and examined lymph nodes (N ratio) is an independent prognostic factor in gastric cancer regardless of the type of lymph-adenectomy: results from an Italian multicentric study in 1853 pa-tients. Ann Surg 2007;245:543-52.

11 Jonnalagadda S, Arcinega J, Smith C, et al. Validation of the lymph node ratio as a prognostic factor in patients with N1 nonsmall cell lung cancer. Cancer 2011;117:4724-31.

12 Prenzel KL, Monig SP, Sinning JM, et al. Role of skip metastasis to mediastinal lymph nodes in non-small cell lung cancer. J Surg Oncol 2003;82:256-60.

13 Nomori H, Horio H, Naruke T, et al. Use of technetium-99m tin colloid for sentinel lymph node identification in non-small cell lung cancer. J Thorac Cardiovasc Surg 2002;124:486-92.

14 Liptay MJ, Grondin SC, Fry WA, et al. Intraoperative sentinel lymph node mapping in non-small-cell lung cancer improves de-tection of micrometastases. J Clin Oncol 2002;20:1984-8.

15 Bria E, Milella M, Sperduti I, et al. A novel clinical prognostic score incorporating the number of resected lymph-nodes to predict recurrence and survival in non-small-cell lung cancer. Lung Can-cer 2009;66:365-71.

16 Jonnalagadda S, Smith C, Mhango G, et al. The Number of Lymph Node Metastases as a Prognostic Factor in Patients With N1 Non-small Cell Lung Cancer. Chest 2001;140:433-440.

17 Fukui T, Mori S, Yokoi K, et al. Significance of the number of pos-itive lymph nodes in resected non-small cell lung cancer. J Thorac Oncol 2006;1:120-5.

18 Lee JG, Lee CY, Park IK, et al. Number of metastatic lymph nodes in resected non-small cell lung cancer predicts patient survival. Ann Thorac Surg 2008;85:211-5.

19 Saji H, Tsuboi M, Yoshida K, et al. Prognostic Impact of Num-ber of Resected and Involved Lymph Nodes at Complete Resec-tion on Survival in Non-small Cell Lung Cancer. J Thorac Oncol 2011;6:1865-71.

20 Matsugumaa H, Okib I, Nakaharaa R, et al. Proposal of new nodal classifications for non-small-cell lung cancer based on the num-ber and ratio of metastatic lymph nodes. Eur J Cardio-Thorac 2012;4:19-24.

21 Ludwig MS, Goodman M, Miller DL, et al. Postoperative survival and the number of lymph nodes sampled during resection of node-negative non-small cell lung cancer. Chest 2005;128:1545-50.

22 Gajra A, Newman N, Gamble GP, et al. Effect of number of lymph nodes sampled on outcome in patients with stage I non-small-cell lung cancer. J Clin Oncol 2003;21:1029-34.

23 Darling GE, Allen MS, Decker PA, et al. Number of lymph nodes harvested from a mediastinal lymphadenectomy: results of the randomized, prospective American College of Surgeons Oncology Group Z0030 trial. Chest 2011;139:1124-9.

pathologica 2013;105:122-127

Introduction

Leiomyomas are benign smooth muscle tumours that can potentially occur anywhere, including the breast. Most cases of breast leiomyomas usually arise in the skin or periareolar region 1, while they are only rarely detected in breast parenchyma. A Pub-Medline-based search reveals only 26 reported cases of leiomyomas of the breast parenchyma 2-26. However, we would like to underline that even the most recent review on the topic 26 fails to include the largest series of leiomyomas of breast parenchyma, reported by Jones et al. in 1994 27. In that paper, the authors described the clinicopathologic fea-tures of 11 cases of leiomyomas that occurred within the breast 27. Thus, to the best of our knowledge, 37 cases of leiomyomas of the breast parenchyma have been re-

ported in the English literature to date, with only one case diagnosed preoperatively by needle core biopsy 23. We herein report the clinicopathologic features of a case of leiomyoma of the breast parenchyma, emphasizing needle core biopsy-based diagnosis. Differential diagno-sis with spindle cell tumour and tumour-like lesions of the breast is provided. Correct preoperative diagnosis of leiomyoma is crucial for conservative surgical treatment.

Clinical history

A 36-year-old woman presented with a palpable, pain-less, mobile nodule in her right breast. Ultrasonography revealed a hypoechoic, 2 cm nodular mass with well circumscribed margins and without microcalcifications,

Originale article

Intraparenchymal leiomyoma of the breast: report of a case with emphasis on needle core

biopsy-based diagnosisG.M. VECCHIO1, A. CAVALIERE2, F. CARTAGINESE3, A. LUCACCIONI3, T. LOMBARDI4, R. PARENTI5, L.

SALVATORELLI1, G. MAGRO1

1 Dipartimento G.F. Ingrassia, Anatomia Patologica, Università di Catania, AOU Policlinico-Vittorio Emanuele, Catania; 2 Istituto di Anatomia Patologica, Azienda Ospedaliera di Perugia, Perugia; 3 Anatomia Patologica, Ospedale Città di Castello,

Città di Castello; 4 U.O. di Senologia, Ospedale Città di Castello, Città di Castello; 5 Dipartimento Scienze Biomediche, Sezione di Fisiologia, Università di Catania, Catania

Key words

Breast • Leiomyoma • Differential diagnosis • Spindle cell tumors • Immunohistochemistry

Summary

CorrespondenceGaetano Magro, Department G.F. Ingrassia, Azienda Ospedaliero-Universitaria “Policlinico-Vittorio Emanuele”, Section of Anatomic Pathology, via S. Sofia 87, 95123 Catania, Italy - Tel. +39 095 3782024 - Fax +39 095 3782023 - E-mail: [email protected]

Objective. We report the clinicopathologic features of a rare case of leiomyoma of the breast parenchyma in a 36-year-old female, diagnosed preoperatively at core biopsy. A complete review of the literature on the topic is provided and differential diagnostic problems are discussed. Methods. Standard histological examination and immunohis-tochemical analyses using a large panel of antibodies were per-formed in both the core biopsy and surgical specimen.Results. Ultrasonography revealed a well-circumscribed tumour mass without calcifications. Histological examination of the core biopsy showed proliferation of bland-looking eosinophilic

spindle cells arranged in a fascicular growth pattern. Mitoses, pleomorphism and necrosis were absent. Immunohistochemistry, revealing diffuse staining for a-smooth muscle actin, desmin and h-caldesmon, confirmed the leiomiomatous nature of neoplastic cells. Histological and immunohistochemical analyses of the sur-gical specimen confirmed the definitive diagnosis of leiomyoma.Conclusions. The present case emphasizes that diagnosis of leio-myoma of the breast parenchyma can be confidentially rendered on needle core biopsy. We believe that correct diagnosis is pri-marily dependent on the awareness that this tumour can arise in this unusual site on rare occasions.

123Necessity of improviNg the curreNt Nodal classificatioN of luNg caNcer

and fibroadenoma was suspected (Fig. 1). There were no skin or nipple abnormalities and no axillary lymphade-nopathy was noted. Fine needle core biopsy (FNCB) was performed and a diagnosis of “smooth muscle tumour, likely benign (leiomyoma)” was proposed with the rec-ommendation of evaluating the entire tumour mass after surgical excision. A lumpectomy was performed.

Materials and methods

The surgical specimen was fixed in 10% buffered forma-lin, routinely processed and embedded in paraffin. 4 mm-thick sections were stained with haematoxylin and eosin. Additional sections were cut for immunohistochemical procedures. Immunohistochemical studies were per-formed with the labelled streptavidin–biotin peroxidase detection system using the Ventana automated immu-nostainer (VentanaMedicalSystems, Tucson, AZ, USA). The antibodies tested were: vimentin (dilution 1:100), α-smooth muscle actin (dilution 1:200), desmin (dilu-tion 1:100), h-caldesmon (dilution 1:100), myogenin (dilution 1:100), S-100 protein (dilution 1:500), CD68 (dilution 1:200), CD99 (dilution 1:100), CD34 (dilution 1:50), CD117 (dilution 1:400), pancytokeratins (dilu-tion 1:50), EMA (dilution 1:100), p63 (dilution 1:200), and HMB45 (dilution 1:300; all from DakoCytomation, Glostrup, Denmark). Negative controls for staining were slides stained with omission of the primary antibody.

Pathologic findings

The core biopsy specimen showed interlacing bundles of bland-looking deeply eosinophilic spindle-shaped cells, closely reminiscent of leiomyoma (Fig. 2). Mitoses, ne-crosis and nuclear pleomorphism were absent. Immuno-histochemical analyses revealed a diffuse staining for vimentin, desmin, a-smooth muscle actin and h-calde-smon. No immunoreactivity was obtained with any of

the other markers tested, including cytokeratins (AE1/AE3), EMA, CD34, S-100 protein, HMB-45, myogenin, CD99, CD68, p63, CD117. Based on morphological and immunohistochemical features, a diagnosis of “smooth muscle tumour, likely benign (leiomyoma) of the breast” was proposed.The surgically-excised tumour mass presented as an un-encapsulated, well circumscribed, 2 cm nodule, firm in consistency and whitish in colour. Histological exami-nation revealed an unencapsulated, well-circumscribed

Fig. 1. ultrasonography. a well circumscribed nodular mass, with-out microcalcifications, is evident.

Fig. 2. core Biopsy. a proliferation of eosinophilic spindle-shaped cells, arranged in a fascicular pattern, is seen.

Fig. 3. Surgical specimen. tumour showing pushing borders with compressed mammary glandular structures at the periphery.

g.M. VEcchio Et al.124

tumour with the features of a classic leiomyoma, as typically seen in the uterus (Fig. 3). The tumour was composed of interlacing fascicles of spindle-shaped cells with abundant, deeply eosinophilic cytoplasm and elongated nuclei with blunt ends (Fig. 4). Nuclear chro-matin was delicate and evenly distributed, and nucleoli were not prominent. Mitoses, nuclear pleomorphism and necrosis were absent. Residual mammary lobules were present at the periphery of the lesion (Fig. 3). Immuno-histochemical analyses, revealing a diffuse staining for vimentin, desmin, a-smooth muscle actin (Fig. 5) and h-caldesmon, confirmed the leiomyomatous nature of neoplastic cells. Notably, diffuse (> 90%) nuclear stain-ing was obtained with ER/PR. No immunostaining was observed with CD34, bcl-2, CD99, HMB-45, S-100 pro-tein, p63, CD68, CD99, CD117, myogenin, cytokera-tins or EMA. Morphological and immunohistochemical features were consistent with the definitive diagnosis of “intraparenchymal leiomyoma of the breast”.

Discussion

Although leiomyomas of the breast arising in the muscle-rich subareolar region are relatively common tumours, leiomyomas of the breast parenchyma are extremely rare. Since the first description in 1913, only additional 37 cases have been reported to date 2-27. Interestingly, these tumours have been documented exclusively in

women with ages ranging from 30 to 60 years (mean age of 47.6 years), usually involving the outer quadrant of the right breast 26. Their size varied from 5 mm to 13.8 cm, and most patients presented a history of painless tu-mour mass with a duration ranging from 1 month to 26 years 2-27. Some cases may present with discomfort, pain, tenderness or may be incidentally detected by screen-ing mammography. On mammography, they appear as dense homogeneous masses with well defined margins without calcifications, architectural distortion, skin or nipple retraction 10 11 16 17 19 20. On ultrasonographic exam-ination, leiomyomas present as solid, hypoechoic, ho-mogeneous, circumscribed nodules 16 21. Based on these observations, it is noteworthy that radiological features of leiomyoma of the breast are non-specific, and similar to those described in other breast lesions such as fibro-adenoma, myofibroblastoma, muscular hamartoma and breast myxoma 28-32. Although the histological diagnosis of leiomyoma is usually straightforward due to its typical cytological and architectural features, it may be challenging when this tumour occurs in unusual sites, including breast pa-renchyma. Additional diagnostic difficulties may arise when, evaluating needle core biopsies, the pathologist is faced with an intraparenchymal spindle cell prolif-eration. In this regard, leiomyoma can potentially pose differential diagnostic problems with a wide variety of benign and malignant spindle cell lesions. Among be-nign lesions, especially nodular fasciitis, inflammatory

Fig. 4. high magnification. tumour showing the typical features of leiomyoma, as seen in the uterus: deeply eosinophilic spindle cells arranged in intersecting fascicles.

Fig. 5. immunohistochemistry. tumour cells diffusely stain with a-smooth muscle actin.

125Intraparenchymal leIomyoma of the breast

pseudotumour, myofibroblastoma and peripheral nerve sheath tumours (schwannoma, neurofibroma) enter dif-ferential diagnosis with leiomyoma. Nodular fasciitis is a fibroblastic/myofibroblastic pseudosarcomatous le-sion of unknown aetiology, which only rarely occurs in the breast parenchyma. Nodular fasciitis usually occurs as a solitary and rapidly growing (1-2 weeks) nodular mass that is successfully treated with local excision alone, with local recurrence extremely rare (1-2%) after complete excision. This lesion showed, at least focally, infiltrative margins, and was composed of pale to eosin-ophilic spindle-shaped cells with bland nuclei, arranged in short, irregular bundles and fascicles. The stroma is generally fibromyxoid and contains thin-walled vessels, extravasated blood red cells and lymphocytes 33 34. As nodular fasciitis typically shows immunoreactivity for α-smooth muscle actin and focally for desmin in some cases, h-caldesmon is a useful marker in distinguishing smooth muscle from myofibroblastic proliferations 35. Inflammatory pseudotumour is a fibro-inflammatory lesion that can be rarely encountered in breast paren-chyma 36. This reactive lesion is composed of spindle-shaped cells arranged in a fascicular, and less frequently, stroriform growth pattern, and embedded in a variable fibromyxoid stroma. Typically, the spindle-shaped cells are admixed with inflammatory cells, especially plasma cells, lymphocytes, and eosinophils 36. The myofibro-blastic nature of the spindle-shaped cells is confirmed by immunostaining with a-smooth muscle actin, along with the lack of desmin and h-caldesmon expression. Al-though mammary myofibroblastoma may show a wide variety of morphological features, the classic type myo-fibroblastoma is a benign spindle cell tumour composed of cells closely packed in short, haphazardly intersect-ing fascicles or clusters of cohesive cells, interrupted by thick, eosinophilic keloid-like collagen fibres 30-32 37. Notably, cells show a variable degree of fibroblastic and myofibroblastic differentiation at the morphological, immunohistochemical and ultrastructural level 30-32 37. Like leiomyoma, myofibroblastoma usually shows a fascicular growth pattern and a diffuse expression of desmin, a-smooth muscle actin and oestrogen/proges-terone receptors 38. Accordingly, there is the possibility of potential confusion between these two tumours, es-pecially when evaluating needle core biopsy. However, unlike leiomyoma, myofibroblastoma exhibits cells with less abundant and eosinophilic cytoplasm, and is also of-ten variably positive for CD34, Bcl-2 protein, CD99 and CD10. H-caldesmon is usually absent or only focally ex-pressed in myofibroblastoma 35. Benign peripheral nerve sheath tumours rarely arise in the breast parenchyma. Schwannoma and neurofibroma, especially the cellular variant, are easily distinguished by leiomyoma for their diffuse expression of S-100 protein 27.Although a wide variety of malignant spindle cell lesions should be potentially included in differential diagnosis, in principle however, only desmoid-type fibromatosis, leiomyosarcoma, malignant myoepithelioma, fibroma-tosis/nodular fasciitis-like low-grade sarcomatoid/meta-

plastic carcinoma and fibrosarcoma/malignant fibrous histiocytoma must be distinguished from leiomyoma. Desmoid-type fibromatosis of the breast parenchyma is a relatively rare tumour that can occur sporadically or in the context of genetic syndromes 40-42. Unlike leiomyoma, fibromatosis of the breast shows infiltrating borders with entrapment of fat and glandular mammary tissue 40-42. It is composed of long, sweeping fascicles composed of bland-looking spindle-shaped cells with slightly to mod-erate eosinophilic cytoplasm, embedded in a variable, often prominent, fibrous stroma. Fibromatosis, which is usually immunoreactive for b-catenin and a-smooth muscle actin, does not express desmin (occasionally on-ly focal staining), h-caldesmon and CD34. Leiomyosar-coma is the most important malignant tumour that needs to be distinguished from an intraparenchymal leiomyo-ma. This distinction is crucial for appropriate treatment and prognostic information (recurrence rates, potential distant metastases, worse prognosis) 27 43-45. At ultra-sound examination, leiomyosarcoma frequently appears similar to leiomyoma, exhibiting well-circumscribed margins. However, leiomyosarcoma differs from leio-myoma in that the former has infiltrating margins at microscopic examination and diffuse cytological atypia with high mitotic activity 27. Necrosis and/or atypical mitoses may be seen. Immunohistochemical analyses are not helpful as both tumors express the same myo-genic markers, even if leiomyosarcoma has the tendency to lack h-caldesmon and desmin in the more poorly dif-ferentiated tumors. Although differential diagnosis be-tween leiomyoma versus leiomyosarcoma is relatively easy in the surgical specimen, we admit that it may be challenging at needle core biopsy and, thus, histological evaluation of the surgically excised tumour is manda-tory. Malignant myoepithelioma is a tumour composed predominantly/exclusively of spindle cells, arranged in haphazardly interlacing bundles, sometimes with a fo-cal storiform pattern. This tumour usually displays cy-tological atypia and a low to high mitotic activity. Im-munocytochemistry, demonstrating the myoepithelial nature of cells (variable co-expression of cytokeratins, vimentin, a-smooth muscle actin, S-100 protein, CD10, p63) is an important ancillary diagnostic tool 46. Fibro-matosis/nodular fasciitis-like low-grade sarcomatoid/metaplastic carcinoma is predominantly/exclusively composed of spindle cells with a minority of neoplastic cells exhibiting a more ovoid/epithelioid morphology, which tend to aggregate in small nests or, more rarely, in pseudo-glandular structures 47. This variant of meta-plastic carcinoma can be easily excluded with the use of immunohistochemistry for low molecular weight kera-tins which identify epithelial neoplastic cells with both spindle to ovoid/epithelioid morphology 47. The possi-bility that a significant number of neoplastic cells are also stained with a-smooth muscle actin is not rare 47. Lastly, fibrosarcoma/malignant fibrous histiocytoma of breast parenchyma is a category that covers a continu-ous morphological spectrum of low to high grade lesions sharing features of classic type fibrosarcoma and malig-

G.m. vecchio et al.126

nant fibrous histiocytoma 48. Unlike our case, fibrosar-coma/malignant fibrous histiocytoma is a tumour exhib-iting infiltrative margins and a prominent herringbone and/or storiform growth pattern. Immunohistochemistry reveals diffuse staining for vimentin, while a-smooth muscle actin and CD34 may only be focally detected.The present case emphasizes that diagnosis of leio-myoma of the breast parenchyma can be confidentially rendered on core needle biopsy. We believe that correct diagnosis is primarily dependent on the awareness that this tumour can arise in this unusual site, albeit rarely. When dealing with a breast tumour that exhibits bland-looking spindle-shaped cells with deeply eosinophilic cytoplasm, arranged in fascicles, without mitoses and nuclear pleomorphism, pathologists should keep in mind the possibility of leiomyoma, including appropri-ate myogenic markers in the list of the immunohisto-chemical panel. Immunohistochemical analysis, reveal-ing a diffuse expression of desmin, a-smooth muscle actin and h-caldesmon, is extremely helpful to confirm diagnosis of leiomyoma at core biopsy, ruling out other

References

1 Kaufman HL, Hirsch EF. Leiomyoma of the breast. J Surg Oncol 1996;62:62-4.

2 Strong LW. Leiomyoma of the breast. Am J Obstet 1913;68:53-5.3 Schauder H. Uber leiomyome der brustdruse. Dtsch Z Chir

1927;205:58-68.4 Melnick PJ. Fibromyoma of the breast. Arch Pathol 1932;14:794-98.5 Lebowich RJ, Lenz G. Primary fibromyoma of the breast. Am J

Cancer 1940;38:73-5.6 Stein RJ. Fibroleiomyoma of the breast. Arch Pathol 1942;33:72-4.7 Craig JM. Leiomyoma of the female breast. Arch Pathol

1947;44:314-17.8 Libcke JH. Leiomyoma of the breast. J Pathol 1969;98:89-90.9 Haagensen CD. Nonepithelial neoplasms of the breast. In: Haa-

gensen CD, ed. Diseases of the breast. 2nd ed. Philadelphia: WB Saunders Co 1971, pp. 297-9.

10 Diaz-Arias AA, Hurt MA, Loy TS, et al. Leiomyoma of the breast. Hum Pathol. 1989;20:396–99.

11 Lauwers G, De Roux S, Terzakis J. Leiomyoma of the breast. Arch Anat Cytol Pathol 1990;38:108-10.

12 Manna P, Giuseppetti GM, Latini L, et al. A case of leiomyoma of the breast. Radiol Med 1993;86:155-8.

13 Roncaroli F, Rossi R, Severi B, et al. Epithelioid leiomyoma of the breast with granular cell change: a case report. Hum Pathol 1993;24:1260-3.

14 Tamir G, Yampolsky I, Sandbank J. Parenchymal leiomyoma of the breast. Report of a case and clinicopathological review. Eur J Surg Oncol 1995;21:88-9.

15 Nazario AC, Tanaka CI, de Lima GR, et al. Leiomyoma of the breast. A case report. Sao Paulo Med J 1995;113:992-4.

16 Weldon C, Jones B, Daroca P, et al. Breast leiomyoma. J La State Med Soc 1998;150:367-70.

17 Son EJ, Oh KK, Kim EK, et al. Leiomyoma of the breast in a 50-year-old woman receiving tamoxifen. Am J Roentgenol 1998;171:1684-6.

18 Sidoni A, Luthy L, Bellezza G, et al. Leiomyoma of the breast: case report and review of the literature. Breast 1999;8:289-90.

19 Kotsuma Y, Wakasa K, Yayoi E, et al. A case of leiomyoma of the breast. Breast Cancer 2001;8:166-9.

20 Pourbagher A, Pourbagher MA, Bal N, et al. Leiomyoma of the breast parenchyma. Am J Roentgenol 2005;185:1595-7.

21 Heyer H, Ohlinger R, Schimming A, et al. Parenchymal leiomyo-ma of the breast – clinical, sonographic, mammographic and his-tological features. Ultraschall Med 2006;27:55-8.

22 Abd El, All HS. Breast spindle cell tumours: about eight cases. Diagn Pathol 2006;1:1-13.

23 Ende L, Mercado C, Axelrod D, et al. Intraparenchymal leiomy-oma of the breast: a case report and review of the literature. Ann Clin Lab Sci 2007;37:268-73.

24 Mandal S, Dhingra K, Khurana N. Parenchymal leiomyoma of breast, mimicking cystosarcoma phylloides. ANZ J Surg 2008;78:108-9.

25 Koirala K, Shrestha ML, Chalise PR, et al. Leiomyoma of breast: a report of rare case. NMCJ 2008;10:207-8.

26 Minami S, Matsuo S, Azuma T, et al. Parenchymal leiomyoma of the breast: a case report with special reference to magnetic reso-nance imaging findings and an update review of literature. Breast Cancer 2011;18:231-6.

27 Jones MW, Norris HJ Wargotz ES. Smooth muscle and nerve sheath tumors of the breast. A clinico-pathologic study of 45 cases. Int J Surg Pathol 1994;2:85-92.

28 Magro G, Bisceglia M. Muscular hamartoma of the breast. Case re-port and review of the literature. Pathol Res Pract 1998;194:349-55.

29 Magro G, Cavanaugh B, Palazzo J. Clinico-pathological features of breast myxoma: report of a case with histogenetic consider-ations. Virchows Arch 2010;456:581-6.

30 Magro G, Bisceglia M, Michal M, et al. Spindle cell lipoma-like tumor, solitary fibrous tumor and myofibroblastoma of the breast: a clinicopathological analysis of 13 cases in favor of a unifying histologic concept. Virchows Arch 2002;440:249-60.

31 Magro G, Michal M, Bisceglia M. Benign spindle cell tumors of the mammary stroma: diagnostic criteria, classification, and his-togenesis. Pathol Res Pract 2001;197:453-66.

32 Magro G. Mammary myofibroblastoma. A tumor with a wide mor-phologic spectrum. Arch Pathol Lab Med 2008;132:1813-20.

benign and/or malignant tumours. However, due to the morphological and immunohistochemical overlap be-tween leiomyoma and leiomyosarcoma, we recommend a diagnosis of “smooth muscle tumour, likely leiomyo-ma” at core biopsy, suggesting that a final diagnosis can be rendered on the surgically excised nodule. Various theories have been proposed about the origin of leiomyoma of breast parenchyma. Kaufman and Hirsch 1 suggested that this tumour arises from the smooth-muscle cells that surround capillaries in the subcutaneous tissues of the breast. Diaz-Arias et al. 10 proposed five sources: i) teratoid origin with extreme overgrowth of the myomatous elements; ii) embryo-logically displaced smooth muscle from the nipple; iii) angiomatous smooth muscle; iv) a multipotent mesen-chymal cell; v) myoepithelial cells. Although the fre-quent occurrence of leiomyoma near the nipple may be related to the abundance of smooth-muscle cells around the nipple and areola, the histogenesis of le-sions occurring within the breast parenchyma still re-mains controversial.


33 Iwatani T, Kawabata H, Miura D, et al. Nodular fasciitis of the breast. Breast Cancer 2012;19:180-2.

34 Hayashi H, Nishikawa M, Watanabe R, et al. Nodular fasciitis of the breast. Breast Cancer 2007;14:337-9.

35 Magro G, Gurrera A, Bisceglia M. H-caldesmon expression in myofibroblastoma of the breast: evidence supporting the distinc-tion from leiomyoma. Histopathology 2003;42:233-8.

36 Vecchio GM, Amico P, Grasso G, et al. Post-traumatic inflamma-tory pseudotumor of the breast with atypical morphological fea-tures: A potential diagnostic pitfall. Report of a case and a critical review of the literature. Pathol Res Pract 2011;207:322-6.

37 Magro G, Michal M, Vasquez E, et al. Lipomatous myofibroblas-toma: a potential diagnostic pitfall in the spectrum of the spindle cell lesions of the breast. Virchows Arch 2000;437:540-4.

38 Magro G, Bisceglia M, Michal M. Expression of steroid hormone receptors, their regulated proteins, and bcl-2 protein in myofibro-blastoma of the breast. Histopathology 2000;36:515-21.

39 Magro G, Caltabiano R, Di Cataldo A, et al. CD10 is expressed by mammary myofibroblastoma and spindle cell lipoma of soft tis-sue: an additional evidence of their histogenetic linking. Virchows Arch 2007;450:727-8.

40 Devouassoux-Shisheboran M, Schammel MD, Man YG, et al. Fibromatosis of the breast: age-correlated morphofunctional fea-tures of 33 cases. Arch Pathol Lab Med 2000;124:276-80.

41 Magro G, Gurrera A, Scavo N, et al. Fibromatosis of the breast: a clinical, radiological and pathological study of 6 cases. Patho-logica 2002;94:238-46.

42 Magro G, Mesiti M. Breast and pectoralis musculo-aponeurotic fibromatosis: two independent lesions occurring in the same pa-tient. A case report. Pathol Res Pract 1998;194:867-71.

43 Rane SU, Batra C, Saikia UN. Primary leiomyosarcoma of breast in an adolescent girl: a case report and review of the literature. Case Report Pathol 2012;2012:491984.

44 Sandhya B, Babu V, Parthasarathy G, Kate V, Ananthakrishnan N, Krishnan R. Primary leiomyosarcoma of the breast: A case report and review of literature. Indian J Surg.2010;72:286-8.

45 Stafyla VK, Gauvin JM, Farley DR. A 53-year-old woman with a leiomyosarcoma of the breast. Curr Surg 2004:61:572-5.

46 Tavassoli FA, Soares J. Myoepithelial lesions in the breast. In: WHO. Classification Tumour Pathology & Genetics Tumours of the Breast and female Genital Organs. Lyon 2003, pp. 86-8.

47 Sneige N, Yaziji H, Mandavilli SR, et al. Low-grade (fibromato-sis-like) spindle cell carcinoma of the breast. Am J Surg Pathol 2001;25:1009-16.

48 Jones MW, Norris HJ, Wargotz ES, et al. Fibrosarcoma-malignant fibrous histiocytoma of the breast. A clinicopathological study of 32 cases. Am J Surg Pathol 1992;16:667-74.

pathologica 2013;105:128-131

Introduction

Mucinous carcinoma occasionally arises in various or-gans of the human body, but rarely occurs in the thyroid gland, with only six cases reported in literature. Accord-ingly, its clinicopathological and histopathological fea-tures have not been extensively documented 7.We present a case of primary mucinous thyroid carci-noma (PMTC). We describe the clinicopathological, histological and immunohistochemical features of this rare tumour with a review of the literature.

Case presentation

A 56-year-old Tunisian man presented with rapidly en-larging mass in his neck 2 months before admission. He complained of recent dysphagia. On physical ex-amination, there was a palpable and painless nodule in the right lobe of the thyroid and a second nodule in the left lobe. There were palpable bilateral subclavian lymph nodes. There were no other abnormal physical findings. The patient was euthyroid. There was no his-tory of neck irradiation or familial thyroid disease. Re-

sults of thyroid function tests, routine blood counts and biochemical tests were within normal limits. Ultraso-nography and CT identified hypodense nodules involv-ing both lobes of the thyroid associated with bilateral lymph nodes in the neck and at the mediastinum. There were no lung lesions. The patient underwent a total thy-roidectomy with resection of local lymph nodes with no postoperative complications. Macroscopically, the tumours located in the right and left lateral lobe of the gland thyroid measured, respectively, 3 x 3 x 2 cm and 4 x 3 x 2 cm. The tumours were well circumscribed, appearing as a soft and yellowish grey solid mass on cut sections and adherent to surrounding structures. A focal gelatinous appearance and areas of necrosis and haemorrhage were present. No calcifications were iden-tified. Frozen-section diagnosis suggested poorly dif-ferentiated thyroid carcinoma. The mediastinal lymph nodes were not resectable. We decided to not perform neck dissection to avoid excessive surgical morbidity. In final histological examination, both tumours showed a similar appearance with an infiltrative growth pattern entrapped residual atrophic thyroid follicules. Tumours consisted of extracellular mucin around strands, small solid nests (Fig. 1a) and trabeculae of epithelial malig-

Original article

Primary mucinous carcinoma of the thyroid gland: case report with review of the literature

H. MNIF1, A. CHAKROUN2, S. CHARFI1, S. ELLOUZE1, M. GHORBEL2, T. SALLEMI-BOUDAWARA1

1 Department of pathology, Habib Bourguiba Hospital, Sfax-Tunisia; 2 Department of ORL Surgery, Habib Bourguiba Hospital, Sfax-Tunisia

Key words

Mucinous carcinoma • Thyroid gland • Differential diagnosis • Immunohistochemistry

Summary

CorrespondenceHéla Mnif, Department of pathology, Habib Bourguiba Hospital, 3029 Sfax, Tunisia - Tel. 00216 74 240 341 - Fax +216 74 243 427 - E-mail: [email protected]

Primary mucinous thyroid carcinoma (PMTC) are extremely rare lesions that are histologically indistinguishable from muci-nous carcinoma of other sites. We describe the clinicopatho-logical, histological and immunohistochemical features of this rare tumour with a review of the literature. We describe a case of thyroid tumour, in 56-year-old Tunisian man, composed of small nests and sheets of malignant epithelial cells associated with extensive extracellular mucin that entrapped the follicular

parenchyma of thyroid. Thyroglobulin and thyroid-specific-transcription factor 1 (TTF1) were focally positive. Follow-up did not reveal another neoplasm at other sites. Based on these features, we classified this tumour as PMTC. Mucinous carci-noma of the thyroid gland can be a cause of pitfall in differen-tial diagnosis. For correct diagnosis, complete clinical history, restricted histological criteria and immunohistochemical panel are necessary.


nant cells, similar to that of mucinous carcinoma of the gastrointestinal tract. Glandular-like structures were scanty. The mucus positively stained for mucicarmine, Alcian blue (Fig. 1b) and PAS before and after diastase treatment. The cells were of polygonal to round shape with large nuclei and prominent nucleoli, but no cyto-plasmic inclusions or nuclear grooves. Mitotic figures were present. The mucus pool merged progressively with solid areas of poorly differentiated carcinoma and glandular differentiation. There were no areas of typical thyroid carcinoma. Common vascular invasions were found (Fig. 1c). The tumours grew in an aggres-sive manner and invaded the fibrous capsule, neigh-bouring cervical structures and skeletal muscle of the neck (Fig. 1d). Immunohistochemical study showed immunoreactivity to epithelial markers (CK MNF 116, CK7). Thyroglobulin (Fig. 2a) and thyroid-specific-transcription factor 1 (TTF1) (Fig. 2b) were focally positive in both tumors. CK 20, carcinoembryonic antigen (CEA) (Fig. 2c) and calcitonin (Fig. 2d) were negative. Follow-up did not reveal another neoplasm at other sites. From these features, a diagnosis of PMTC was made. One month later the patient died of disease. Autopsy was not allowed.

Discussion

Mucinous carcinoma occasionally arises in various organs of the human body including the gastrointesti-nal tract and breast 7. Diaz-Perez et al. 6 first described PMTC in 1976, although it is extremely rare in this gland, and only 6 cases having been reported in litera-ture 3 7. Thus, virtually nothing is known about its epide-miology, and its clinicopathological and histopathologi-cal features have not been extensively documented 4 7. The reported cases of PMTC are summarized in Table I. These tumours presented as a rapid or slow growing, occasionally painful “cold” thyroid nodules with or without palpable regional lymph nodes 2 3 6 8 9. Tumours were well-or poorly-circumscribed grey-brown gelati-nous nodules ranging up to several cm in diameter. In the World Health Organization classification system 4, PMTC is characterized by clusters of neoplastic cells surrounded by extensive extracellular mucin deposition. Tumours usually show focal thyroglobulin, TTF1, low molecular weight cytokeratins and MUC2 immunoreac-tivity, and are negative for calcitonin 4. Differential diag-nosis would fall between PMTC and others histological types of thyroid carcinoma showing mucin production

Fig. 1. (a) a large pool of extra-cellular mucin (haematoxylin-eosin,20x). (b) Mucinous material was positive for alcian blue stain (alcian blue, 20x). (c) Vascular invasion (haematoxylin-eosin, 40x). (d) invasive growth of tumour that invaded skeletal muscle (haematoxylin-eosin, 20x).

h. MNiF Et al.130

(follicular neoplasm, papillary carcinoma, anaplastic and medullary carcinoma) 1 4 5 10. In these cases, the tu-mour is characterized by a pool of mucin that is often extracellular and admixed with areas of typical thyroid carcinoma 3 4. In our case, the tumour did not have typi-cal features of follicular neoplasms such as a fibrous

capsule or a distinctive follicular architecture. We failed to demonstrate the nuclear features of papillary thyroid carcinoma such as ground-glass appearance, grooving, or pseudoinclusion. Mucin-producing medullary car-cinoma was excluded based on immunohistochemical findings: positivity for thyroglobulin and negative for

Fig. 2. (a) positive immunostaining for thyroglobulin (immunoperoxidase, 20x). (b) Focal immunopositivity with ttF1 (immunoperoxidase, 20x). (c) Neoplastic cells were negative for calcitonin (immunoperoxidase, 40x). (d) Neoplastic cells were negative for cEa (immunoperoxi-dase, 40x).

Table I. Reported cases of pMtc.

Age Sex Tumour size (cm) Treatment Metastases Follow-upDiaz-perez et al. (1976) 6 44 M 5 x 4 x 3 partial thyroidectomy - 8 yearsSobrinho-Simões et al. (1985) 8 40 M 2.8 x 2.5 x 1.5 left lobectomy - 15 monthsSobrinho-Simões et al. (1986) 9 56 M 8 x 6 x 2 total thyroidectomy

chemotherapy Radiotherapy

N+lung +

2 years

cruz Mc et al. (1991) 2 32 F 6 x 2.5 x 1.5 total thyroidectomychemotherapy Radiotherapy

N+lung +Skin +

8 months

Kondo t et al. (2005) 7 82 F 3 x 2 x 2 total thyroidectomy Radioisotope therapy

N+Skin +

4 years

D’antonio a et al. (2007) 3 62 F - totalthyroidectomy

N+ 6 months

present case 56 M 4 x 3 x 2 (left)3 x 3 x 2 (right)

total thyroidectomy N+ 1 month

M: male; F: female ; N+: lymph node metastases.

131Primary mucinous carcinoma of the thyroid gland

CEA and calcitonin. We ruled out mucoepidermoid car-cinoma as the tumour lacked a squamoid component and mucous cells. Furthermore, a metastasis from a muci-nous adenocarcinoma arising in other sites should be considered in differential diagnosis. A key feature that can help in this differential diagnosis is the absence of solid or glandular areas that progressively merged with areas of mucinous stroma and a pool of extracellular mucin. If a PMTC is suspected, immunohistochemical study is necessary to provide a final diagnosis (Tab. II). Based on the limited follow-up information available, PMTC is a highly aggressive malignant neoplasm typi-fied by rapidly progressive local disease, lymph node and distant metastases. Of the 6 previously reported pa-tients in the literature, 4 had lymph node metastases and 3 had distant metastases to the lung and/or skin. Survival periods ranged from 8 months to 4 years 4. The prognos-

tic outcome of our present case is similar to that of each of the previously reported cases. Our patient had meta-static tumours in the lymph nodes and died of disease one month after his primary operation.Histogenesis of PMTC is still controversial. The ultimo-branchial body, solid cell nest and intrathyroidal minor salivary gland are suggested to be the origins of muci-nous carcinoma 3 4. Despite a lack of follicular structure and colloid substance, focal expression of thyroglobulin and TTF1 in this tumour suggests the possibility of a poorly differentiated carcinoma derived from thyroid follicular cells 3.In conclusion, mucinous carcinoma is a rare and unusual tumour of the thyroid gland that can be a cause of pitfall in differential diagnosis. For diagnosis of PMTC, his-tological criteria, an immunohistochemical panel and complete clinical history are necessary 3 7.

References

1 Cretney A, Mow C. Mucinous variant of follicular carcinoma of the thyroid gland. Pathology 2006;38:184-6.

2 CruzMC, Marques LP, Sambade C, et al. Primary mucinous carci-noma of the thyroid. Surg Pathol 1991;4:266-73.

3 D’Antonio A, Addesso M, De Dominicis G, et al. Mucinous car-cinoma of thyroid gland. Report of a primary and a metastatic mucinous tumour from ovarian adenocarcinoma with immuno-histochemical study and review of literature. Virchows Arch 2007;451:847-51.

4 DeLellis RA, Lloyd RV, Heitz PU, et al., eds. World Health Or-ganisation classification of tumours, tumours of endocrine organs. Lyon (France): IARC press 2004.

5 Deligdisch L, Subhani Z, Gordon RE. Primary mucinous carci-noma of the thyroid gland: report of a case and ultrastructural study. Cancer 1980;45:2564-7.

6 Diaz-Perez R, Quiroz H, Nishiyama RH. Primary mucinous ad-enocarcinoma of thyroid gland. Cancer 1976;38:1323-5.

7 Kondo T, Kato K, Nakazawa T, et al. Mucinous carcinoma (poorly differentiated carcinoma with extensive extracellular mucin de-position) of the thyroid: a case report with immunohistochemical studies. Hum Pathol 2005;36:698-701

8 Sobrinho-Simões MA, Nesland JM, Johannessen JV. A mu-cin-producing tumor in the thyroid gland. Ultrastruct Pathol 1985;9:277-81.

9 Sobrinho-Simões M, Stenwig AE, Nesland JM, et al. A mucinous carcinoma of the thyroid. Pathol Res Pract 1986;181:464-71.

10 Uccella S, La Rosa S, Finzi G, et al. Mixed mucus-secreting and oncocytic carcinoma of the thyroid: pathologic, histochemical, immunohistochemical, and ultrastructural study of a case. Arch Pathol Lab Med 2000;124:1547-52.

Table II. criteria for differential diagnosis in primary and secondary mucinous thyroid carcinoma.

Clinical history Histology Immunohistochemistry

Primary MTC local recurrences Mucus pool with transition to solid and glandular areas

thyroglobulin +and/orttF1+

Secondary MTC tumour in other sites, lymph nodes and visceral metastases

large mucus pool with small clusters of epithelial cells

thyroglobulin -ttF1-

Other type Not relevant Mucus pool and typical thyroid carcinoma

thyroglobulin +ttF1+

pathologica 2013;105:132-136

Introduction

The age-adjusted incidence of renal cell carcinoma (RCC), clear cell type, has been increasing at an annual rate of around 3%. A quarter of patient present with advanced disease, including locally-invasive or metastatic cancer. RCC spreads hematogenously and has a strong potential for metastasis. Metastatic disease to the lung (in up to 60% of patients with metastases) and bone (in up to 40% of patients with metastases) represent the two most com-mon sites of advanced disease. However, unusual sites of metastasis are characteristic of RCC, clear cell type, and virtually any organ site can be involved, including the thyroid, pancreas, skeletal muscle and skin or under-lying soft tissue. Among metastatic sites, the stomach is quite rare, and such metastases are usually reported only in post-mortem series 1-4. Here, we present and discuss a case with a gastric recurrence of RCC, clear cell type, in a patient who had undergone nephrectomy 20 years before.

Case report

An 82-year-old man was admitted to the hospital of Gar-bagnate Milanese with a persistent rectal bleeding. On admission severe anaemia was present. He had a history of weight loss, epigastric pain and weakness. On physi-cal examination neither rebound tenderness nor a palpable mass was observed. Laboratory tests revealed only a low haemoglobin value of 7 g/dl (reference range: 10-14 g/dl). Urine analysis did not reveal the presence of red blood cells. Because of the symptoms and signs, the patient un-derwent colonoscopy and gastroscopy. Colonoscopy was negative while gastroscopy revealed a 30 mm, irregu-lar, polypoid bleeding lesion with superficial erosions in the upper part of the fundus near the lesser curvature (Fig. 1a). The lesion was removed by snare polipectomy, since the endoscopist did not suspect its histological na-ture, and to prevent post-polipectomy bleeding. The exci-sion biopsy was fixed in formalin, paraffin-embedded and stained with haematoxilin and eosin. Microscopically, the

case repOrt

A solitary polypoid gastric metastasis 20 years after renal cell carcinoma: an event to be considered,

and a brief review of the literatureM. ONORATI1, G. PETRACCO1, P. UBOLDI1, D.G. REDAELLI2, S. ROMAGNOLI3, M. ALBERTONI1, F. DI NUOVO1

1 Pathology Unit, 2 Gastroenterology Unit, Garbagnate Milanese, AO “G. Salvini” Garbagnate Milanese, Italy; 3 Department of Health Sciences, AO “S. Paolo”, University of Milan, Medical School, Italy

Key words

Polypoid gastric metastasis • Renal cell carcinoma • Snare polipectomy

Summary

CorrespondenceMonica Onorati, Pathology Unit, Garbagnate Milanese, A.O. “G. Salvini”, viale Carlo Forlanini 121, 20024 Garbagnate Milanese, Italy - Tel. +39 02 994302631-2 - E-mail: [email protected]

Background. The incidence of gastric metastasis is 2.6%. Although all primary neoplasms can metastasize to the stomach, most originate from melanoma or breast and lung cancer. Their most common endoscopic appearance is a “volcano-like” poly-poid mass covered by normal mucosa that may show a central ulceration. Renal cell carcinoma, clear cell type, is known to spread hematogenously, and isolated metastasis to the stomach is a rare event. Case presentation. In this report, we describe a gastric recurrence of RCC, clear-cell type, in a 80-year-old patient who had undergone

nephrectomy 20 years before. We also performed a brief review of the literature to update the number of cases described to date.Conclusion. Metastatic involvement of the stomach should be suspected in any patient with a previous history of renal cell carcinoma, clear cell type, presenting with gastrointestinal symptoms, even if many years after nephrectomy. The pecu-liarity of our case is due to the very late presentation of the gastric metastasis. Only two cases of very late gastric metas-tases from RCC, clear cell type, have been described in the literature, todate.

133Primary mucinous carcinoma of the thyroid gland

polypoid lesion, covered by gastric mucosae, revealed nests of neoplastic cells with a solid pattern of growth (Fig. 1b). The neoplastic population was represented by cells with abundant clear cytoplasm and the nuclei were round, hyperchromatic with prominent nucleoli (Fig. 1c). Firstly, in the absence of clinical information, cytokera-tin-7, cytokeratin-20, CDX2 and TTF-1 immunostaining were performed to exclude/confirm a gastric origin, and were all negative. Subsequently, clinicians informed us that the patient had a past medical history of left nephrec-tomy for a RCC, clear cell type, in 1992. A second set of antibodies was tested [CD10, CAM 5.2, epithelial mem-brane antigen (EMA), vimentin] on the basis of updated clinical information. The neoplastic cells strongly stained with CD10 (Fig. 1d), CAM 5.2, EMA and vimentin. On the basis of the clinical and immunohistochemical data, the diagnosis was consistent with gastric metastasis from clear cell type RCC. Endoscopic margins were free of dis-ease. Computed tomagraphy scan whole body showed no evidence of other metastatic sites.

Conclusions

RCC, clear cell type, accounts for 3% of all adult ma-lignancies, and is more than twice as common in males than females with the majority of cases occurring in the sixth decade of life 1 2. Although the localizing findings of haematuria, pain and a flank mass are the classic triad of presenting symptoms, many patients with renal cell carcinoma lack any of these and have systemic symp-toms such as fever, malaise or anaemia. Metastases at the time of diagnosis occur in 25-33% of patients since this neoplasm frequently presents as a metastasis of unknown origin, sometimes in unusual sites 3. The extent of spread of RCC, clear cell type, is notoriously unpredictable with well-documented cases of spontaneous regression of me-tastases, prolonged course and recurrence 10 years or more after nephrectomy in more than 10% of surviving patients. Gastric metastases from RCC, clear cell type, follow-ing radical excision of the primary tumour is extremely rare 4. They may be single or multiple, grossly polypoid or plaque-like, appearing as a submucosal lesion, gradu-

Fig. 1. Endoscopic image and morphology of the polypoid lesion. the endoscopic image shows a polypoid lesion with superficial erosions in the upper part of the gastric fundus (a). Microscopically, the polypoid lesion, covered by gastric mucosae, shows nests of neoplastic cells with a solid pattern of growth (b), abundant clear cytoplasm and round, hyperchromatic nuclei with prominent nucleoli (c). the neoplastic cells strongly stain with cD10 (d). [B: haematoxylin-eosin (h&E); original magnification (o.M.): 10X; c: h&E; o.M.: 40X; D: cD10 stain, o.M.: 40X].

d

b

c

a

M. oNoRati Et al.134

ally ulcerating the mucosa. Immunohistochemical evalua-tion is mandatory due to the clear appearance of neoplastic cells in the context of gastric mucosa. The most common presenting symptom is abdominal pain, although nausea, vomiting and gastrointestinal bleeding can also be present. Gastrointestinal bleeding is mainly related to acid erosion of the metastatic lesion. Diagnosis is confirmed by upper gastrointestinal endoscopy and histological examination of the lesion 2. Despite the strong potential for hematog-enous metastases of RCC, clear cell type, and due to its rarity, stomach metastases are often not suspected as a cause of gastrointestinal bleeding. This case highlights the importance of clinical information to better treat patients with metastases. Investigation for such metastatic tumours should be performed routinely in the follow-up of patients who have been treated for RCC, clear cell type. To date about 53 cases of gastric metastases from RCC 1-3 5-35, in-cluding the present one, have been reported (obtained by

systemic review of publications, including patients with metastasis identified on autopsy). Eslick et al. 33 reported that in their series females are younger than males, and overall patient age is younger than that previously re-ported in other case series (66 vs. 73 years). Moreover, they argue that on average there is a long interval between nephrectomy and presentation of gastric metastases. They confirmed, as Greendyke et al. 36 stated, that in 25% of new patients with renal cell carcinoma there is radiologic evi-dence of metastases at presentation. Surgical excision of gastric metastasis is mandatory as these lesions can bleed again after endoscopic coagulation treatment. An isolated metastasis should be treated as a new tumour. This often results in a significantly increased survival with a good quality of life 2. The peculiarity of our case is due to the very late presentation of the gastric metastasis. Actually, only two cases of very late gastric metastases from RCC, clear cell type, have been described in the literature. The

Table I. clinicopathological data of cases with gastric metastasis of Rcc, clear cell type, reported in the literature.

References Age/Gender

Symptoms/Signs

Histological type

Period (years)

Surgery Outcome

Willis et al (1967)5 ? ? Rcc ? ? autopsy study

Sullivan et al (1980)6 69/M Melena, anaemia Rcc 7 antrectomy unknown

cosme et al (1984)7 84/F Melena Rcc 24 ? ?

Bisesti et al (1984)8 64/M chest pain Rcc 14 Subtotal gastrectomy

?

Maeda et al (1984)9 65/M melena Rcc 9 partial gastrectomy

Died 33 days after operation

Nakamura et al (1984)10 65/M ? Rcc 9 ? ?

Maeda et al (1989)9 70/F Melena Rcc 1 ? ?

ibanez et al (1989)11 60/F Melena Rcc 2 Resection Died 7 weeks after discharge

Dorous et al (1992)12 66/M anaemia Rcc 12 None alive with disease at 11 months

ibanez et al (1992)11 67/M Melena Rcc 0,1 None ?

Maeda et al (1992)9 61/F haematemesis Rcc Simulta-neously

Died 3 months after operation

otowa et al (1992)13 61/F ? Rcc 0 ? 3 months survival

Mayeur et al (1993)14 ?/ ? ? ? ? ? ?

herrera et al (1993)15 63/M Melena Rcc 0,1 None Died after 4 weeks

Boruchowicz et al (1995)16 48/M Dysphagia Rcc 1,3 None Died at 4 weeks

Blake et al (1995)17 63/M haematemesis Rcc 6 None alive at 5 months

Maeda et al (1996)9 ?/ ? ? ? ? ? ?

odori et al (1998)18 55/M None Rcc 4 total gastrectomy alive at 17 months

Marquez et al (2000)19 64/F Melena ? 14 Subtotal gastrectomy

No recurrence at 6 months

Maeda et al (2000)9 47/M Epigastric pain Rcc 6 Endoscopic excision

?

picchio et al (2000)20 64/F Melena, anaemia Rcc 14 Subtotal gastrectomy

No tumour recurrence at 6 months

135A solitAry polypoid gAstric metAstAsis 20 yeArs After renAl cell cArcinomA

Mascarenhas et al (2001)21 66/M Melena Rcc 4 partial gastrectomy

alive after 3 years

Maeda et al (2002)9 40/M hearthburn Rcc 4 Endoscopic excision

lived for 9 months after operation

Suarez et al (2003)3 61/F Melena, epigastric pain

Rcc 4 None alive at 6 months

Maeda et al (2003)9 77/M anaemia Rcc 9 gastrectomy ?

Maeda et al (2003)9 64/M anaemia Rcc 13 gastrectomy ?

Maeda et al (2003)9 69/M heartburn Rcc 8 Endoscopic excision

?

Kok Wee et al (2004)22 60/M abdominal fullness, melena

Rcc 20 None unknown

Kobayashi et al (2004)23 78/M anaemia Rcc 4 Resection Died at 5 months

Maeda et al (2004)9 53/M asymptomatic Rcc 1.8 pyloric excision ?

Maeda et al (2004)9 70/M Dizziness Rcc 8 partial gastrectomy

?

lamb et al (2005)24 69/F upper gi hemorrage

Rcc 3 Embolization Died at 23 months

Maeda et al (2005)9 74/M asymptomatic Rcc 9 ? ?

Maeda et al (2005)9 68/M Melena Rcc 15 Endoscopic excision

lived for 5 months after operation

portanova et al (2006)25 67/F upper gi bleeding Rcc 5 gastrectomy unknown

Riviello et al (2006)2 68/M Melena Rcc 11 total gastrectomy Died after 2 years

Saidi et al (2007)26 ?/ ? Severe anaemia, melena

Rcc 10 Wedge resection of the stomach

Disease free at 18 months

pezzoli et al (2007)27 78/M anaemia Rcc 5 ? Died at 6 months

pollheimer et al 2008)1 69/M Epigastric pain, nausea

Rcc 4.2 None Died at 6 months

pollheimer et al 2008)1 77/M asymptomatic Rcc 6.3 None Died at 4 months

pollheimer et al 2008)1 65/F upper gi haemorrage,

melena, anaemia

Rcc 13,1 ablative endoscopic

Died at 3 months

pollheimer et al 2008)1 69/M anemia, epigastric pain

Rcc 9,3 ablative endoscopic

alive with diseases at 2 years

Ko et al (2008)28 71/M abdominal body pain

? 0 None alive with disease

Maeda et al (2009)9 49/M Dyspnoea Rcc 2 partial gastrectomy

Died 5 months after operation

Kibria et al (2009)29 53/M Melena Rcc 0 None Died at 2 months

Maeda et al (2009)9 74/M Melena Rcc 5 ? Died 1 month after operation

Yamamoto et al (2009)30 74/M Melena ? 5 Wedge resection Died 4 weeks after wedge resection

garcia-campelo et al (2010)31 75/M abdominal pain Rcc 3 None No recurrence 6 months after

treatmentSugasawa et al (2010)32 69/M Melena Rcc 19 Wedge resection No recurrence at 12

monthsEslich et al (2011)33 65/M Rectal bleeding,

diarrhoeaRcc 9 None alive 7 years after

diagnosiscruz et al (2011)34 56/F upper

gastrointestinal bleeding

Rcc 10 Subtotal gastrectomy

No recurrence after surgery

Mi-Young Kim et al (2012)35 79/M abdominal body pain

Rcc 0 Endoscopical submucosal dissection

No tumour recurrence at 6 months

current (2012) 82/M Rectal bleeding Rcc 20 Endoscopic excision

alive 3 months after diagnosis

Rcc: Renal cell carcinoma clear type; gi: gastrointestinal; M: Male; F: Female; ?: Data not found.

M. ONORATI eT Al.136

characteristics of the reported cases, including our, are summarized in Table I. Moreover, our case demonstrates the importance of dialogue between clinicians and pathol-ogists to obtain a rapid and accurate diagnosis of lesions which are histopathologically unlikely to be primary in origin, despite a usual presentation (a gastric fundic pol-yp). Although the nature of polypoid mass was unknown, the choice of the endoscopic polipectomy seemed to be

the best because it helped us to obtain a correct histologi-cal and immunohistochemical diagnosis. Correct diagno-sis was useful to avoid total gastrectomy (surgical stress) in an older patient, thus preventing worsening of patient’s quality of life. Moreover, our case underlies the impor-tance, in patients with a past history of RCC, clear cell type, of accurate follow-up of the gastrointestinal tract, even many years after nephrectomy for RCC.

References

1 Pollheimer MJ, Hintrleitner TA, Pollheimer VS, et al. Renal cell carcinoma metastatic to the stomach: single-center experience and literature review. BJU Int 2008;102:315-9.

2 Riviello C, Tanin I, Cipriani G, et al. Unusual gastric and pancre-atic metastatic renal cell carcinoma presentation 10 years after surgery and immunotherapy: a case report and a review of litera-ture. Worl J Gastroenterol 2006;12:5234-6.

3 Suarez FC, Carballido RJ, Gonzalez LY, et al. Metastasis gastric de un adenocarcinoma renal. Hipotesis patogenica y revision de la literature. Actas Urol Esp 2004;28:472-6.

4 Motzer RJ, Rini BI, Bukowski RM, et al. Sunitinib in patients with metastatic renal carcinoma. JAMA 2006;295:2516-24.

5 Willis RA. The spread of the tumor in the body. London Butter-worth 1967;216-220.

6 Sullivan WG, Cabot EB, Donohue Re. Metastatic renal cell carci-noma to stomach. Urology 1980;15:375-8.

7 Cosme A, Orive V, Alzate LF, et al. Metastasis gastric de un hip-ernefroma. Gastroenterol Hepatol 1984;7:400-1.

8 Bisesti V, Parrella E, Cataldi C, et al. Ser di un raro caso di metastasi gastrica di adenocarcinoma renale. Osp Ital Pediatr 1984;19:609-20.

9 Maeda T, Kozakai N, Nishiyama T, et al. Gastric metastasis from renal carcinoma 20 months after radical nephectomy; a case re-port. Hinyokika Kiyo-Acta Urologica Japonica 2009;55:137-40.

10 Nakamura R, Shimada A, Nakamura K. One case of intussuscep-tion due to intestinal metastasis of renal cell carcinoma. Jnp J Clin Surg 1984;43:1637-40.

11 Ibanez Olcoz J, Jimenez Lopez CE, Oteo Revuelta JA, et al. Gastric metastasis of renal adenocarcinoma. Presentation of case and re-view of the literature. Rev Esp Enferm Apar Dig 1989;76:259-61.

12 Dorous E, Isaac S, Dubreuil C, et al. Late gastric metastasis of cancer of the kidney. Presse Méd 1992;21:996.

13 Otawa T, Muto I. A case of synchronous gastric metastasis from renal cell carcinoma with the chief complain hematemesis. Jpn J Surg 1992;53:1219-22.

14 Mayeur D, David B, Boidart F, et al. Gastric metastasis of the kid-ney. Gastroentérol Clin Biol 1993;17:309-10.

15 Herrera Puerto J, Caballero Gomez M, Marquez Galan JL, et al. Meta-static hypernephroma of the stomach. Arch Esp Urol 1993;46:729-31.

16 Burochowicz A, Desreumaux P, Maunoury V, et al. Dysphagia revealing esophageal and gastric metastases of renal carcinoma. Am J Gastroenterol 1995;90:2263-4.

17 Blake MA, Owens A, O’Donoghue DP, et al. Emboltherapy for massive upper gastrointestinal haemorrhage secondary to metastat-ic renal cell carcinoma: report of three cases. Gut 1995;37:835-7.

18 Odori T, Tsuboi Y, Katoh K, et al. A solitary hematogenous metas-tasis to the gastric wall from renal cell carcinoma four years after radical nephrectomy. J Clin Gastroenterol 1998;26:153-4.

19 Marquez JL, Herrera JM, Herrera J, et al. Gastric metastasis of renal cell adenocarcinoma. Rev Esp Enferm Dig 1992;81:129-30.

20 Picchio M, Paioletti A, Santini E, et al. Gastric metastasis from re-nal cell carcinoma fourteen years after radical nephrectomy. Acta Chir Belg 2000;100:228-30.

21 Mascarenhas B, Konetty B, Rubin JT. Recurrent metastatic re-nal carcinoma presenting as a bleeding gastric ulcer after a complete response to high-dose interleukin-2 treatment. Urolgy 2001;57:168x-168xiii.

22 Kok Wee L, Shyu RY, SHeu LF, et al. Metastatic renal cell can-cer. Gastrointest Endoscop 2004;60:265.

23 Kobayashi O, Murakami H, Yoshida T, et al. Clinical diagnosis of metastatic gastric tumors: clinicopathologic findings and prognosis of nine patients in a single cancer center. World J Surg 2004;28:548-51.

24 Lamb GW, Moss J, Edwards R, et al. Octreotide as an adjunct to embolisation in the management of recurrent bleeding upper gastrointestinal metastases from primary renal cancer. Int Urol Nephrol 2005;37:691-3.

25 Portanova M, Yabar A, Lombardi E, et al. Concomitant gastric and pancreatic metastases from renal cell carcinoma: case study. Rev Gastroenterol Perù 2006;26:84-8.

26 Saidi RF, Remine SG. Isolated gastric metastasis from renal cell carcinoma 10 years after radical nephrectomy. J Gastroenterol Hepatol 2007;22:143-4.

27 Pezzoli A, Matarese V, Boccia S, et al. Gastrointestinal bleeding from gastric metastasis of renal cell carcinoma, treated by endo-scopic polypectomy. Endoscopy 2007;39:E52.

28 Ko Wo, Yang US, Kim NS, et al. A case of gastric metastasis of a renal cell carcinoma. Korean J Gastrointestinal Endoscop 2008;36:288-91.

29 Kibria R, Sharma K, Syed AA, et al. Upper gastrointestinal bleed-ing revealing the stomach metastases of renal cell carcinoma. J Gastrointest Canc 2009;40:51-4.

30 Yamamoto D, Hamad Y, Okazaki S, et al. Metastatic gastric tumor from renal cell carcinoma. Gastric Cancer 2009;12:170-3.

31 Garcia-Campelo R, Quindos M, Vazquez DD, et al. Renal cell carcinoma: complete pathological response in a patient with gastric metastasis of renal cell carcinoma. Anti-Cancer Drugs 2010;21(Suppl 1):S13-S15.

32 Sugasawa H, Ichikura T, Ono S, et al. Isolated gastric metastasis from renal cell carcinoma 19 years after radical nephrectomy. Int J Clin Oncol 2010;15:196-200.

33 Eslick G, Kalantar JS. Gastric metastasis in renal cell carci-noma: a case report and systematic review. J Gastrointest Canc 2011;42:296-301.

34 Cruz A, Ramírez LM, Sánchez E, et al. Gastric metastasis from renal cancer six years after nephrectomy. Rev Esp Enferm Dig 2011;103:660-1.

35 Kim MY, Jung HY, Choi KD, et al. Solitary synchronous meta-static gastric cancer arising from t1b renal cell carcinoma: a case report and systematic review. Gut and Liver 2012;6:388-94.

36 Greendyke WH, Rensick DL, Schellhammer PF. Clear cell carci-noma of the kidney simulating an intramural gastric tumor. Clin Radiol 1971;22:222-4.

pathologica 2013;105:137-139

Introduction

Xanthogranulomatous cholecystitis (XGC) is an unusual focal or diffuse destructive inflammatory process of the gallbladder, representing between 0.7 and 13.2% of all gallbladder diseases 1. The malignant potential of XGC is controversial and the relationship between XGC and gall-bladder carcinoma (GBC) is unclear. The coexistence of XGC and GBC is very infrequent and has been reported in 0.2% to 35.4% of cases 2-4. In this paper, the authors de-scribe the clinicopathological features of XGC and adeno-carcinoma arising in the same gallbladder, a circumstance only briefly alluded to in the existing literature.

Clinical history

A 65-year-old female patient with a medical history of hypertension and diabetes was admitted for repeated at-tacks of right hypochondriac pain and vomiting of 12 days duration. Upon admission, the patient’s tempera-ture was 38ºC. On physical examination, palpation of the abdomen revealed tenderness in the right upper quadrant and a palpable mass in gallbladder region. In addition, Murphy’s sign was positive. Laboratory findings were within normal range. Abdominal ultrasonographic ex-

amination showed multiple gallstones with evidence of gallbladder wall thickening and hydrops. CT scan of the abdomen demonstrated multiple thickenings of the gall-bladder wall with intramural hypoattenuated nodules. At the neck of the gallbladder, a focal irregular thickening of the wall was also noted. The gallbladder was excised by laparoscopic cholecystectomy. Macroscopically, the gallbladder specimen measured 11 x 5 cm. The cut sec-tion of the gallbladder showed gallstones with a mark-edly thickened wall and a 2.3 cm protruding lesion in the infundibulum of the gallbladder (Fig. 1a-b). Histological examination of the gallbladder revealed focal ulceration of the mucosa with severe chronic inflammation of the lamina propria and submucosa, associated with mild fibrosis and muscular hypertrophy. Numerous foamy macrophages and scattered multinucleated giant cells were also present, along with occasional cholesterol clefts (Fig. 2a-b). The protruding lesion in the gallblad-der infundibulum corresponded to a well differentiated adenocarcinoma that extended to the perimuscular con-nective tissue on the background of a moderate desmo-plastic reaction (Fig. 3a). The tubular glands were lined by cuboidal to tall columnar mild atypical cells resem-bling biliary epithelium (Fig. 3b). Postoperative course was unremarkable. A present, the patient is still being followed.

case repOrt

Coexistence of xanthogranulomatous cholecystitis and gallbladder adenocarcinoma: a fortuitous association?

F. LIMAIEM, B. CHELLY, F. HASSAN, I. HADDAD, S. BEN SLAMA, A. LAHMAR, S. BOURAOUI, S. MZABI-REGAYAUniversité de Tunis El Manar, Faculté de Médecine de Tunis, Department of Pathology, Mongi Slim Hospital, La Marsa, Tunisia

Key words

Gallbladder • Carcinoma • Xanthogranulomatous cholecystitis • Surgery

Summary

CorrespondenceFaten Limaiem, Department of Pathology, Mongi Slim Hospital-La Marsa, Tunisia - Tel. +216 96 55 20 57 - E-mail: [email protected]

Xanthogranulomatous cholecystitis is a relatively uncommon variant of chronic cholecystitis, characterized by marked thicken-ing of the gallbladder wall and dense local adhesions. Not only does xanthogranulomatous cholecystitis mimic malignancy, it can also be infrequently associated with gallbladder carcinoma in 0.2% to 35.4% of cases. Herein, the authors report a new case of xanthogranulomatous cholecystitis concomitant with gallbladder adenocarcinoma in a 65-year-old female patient. Because of its

overlapping clinical, radiological and macroscopic findings with gallbladder cancer, definitive diagnosis of xanthogranulomatous cholecystitis relies on extensive sampling and thorough micro-scopic examination of the surgical specimen to exclude the pos-sibility of coexisting tumour. It is still a matter of debate whether xanthogranulomatous cholecystitis is truly a precursor of gall-bladder carcinoma or if it is just an incidental finding. This aspect needs to be explored in the future with further studies.

M. ONORATI eT Al.138

Discussion

Xanthogranulomatous cholecystitis is a relatively uncom-mon form of chronic cholecystitis characterized by a focal or diffuse destructive inflammatory process, with varying proportions of fibrous tissue, acute and chronic inflamma-tory cells and accumulation of lipid-laden macrophages in areas of inflammation. It often mimics a gallbladder carcinoma, leading to a diagnostic dilemma. Pre- and intra-operatively, it is difficult to diagnose this entity and the final diagnosis is usually based on histological exami-nation of the resected specimen. The malignant potential of XGC is controversial and highly disputed 1 5. Several inflammatory conditions have neoplastic potential on long-term follow-up. For example, ulcerative colitis has shown evidence of such neoplastic potential; foci of dys-plasia and malignancy arising in this background are well documented. Such evidence is not available for XGC. A recent study supports the inflammatory nature of XGC, but does not show any evidence of a premalignant condi-tion 5. The association of XGC and GBC remains a matter of discussion. According to some authors, it may simply be that XGC and adenocarcinoma are both complications of cholelithiasis and cholecystitis of a particular duration or degree, or that tissue disruption by a carcinoma facili-tates the entry of bile in the stroma 6.

As in the present case, obstruction of the cystic duct by a neoplasm may also initiate the histiocytic inflamma-tory process of XGC. The association between XGC and gallbladder cancer has been shown in the literature in small case series and some single case reports. An Indian study reported that only 0.2% of patients with XGC have associated GBC 2. On the other hand, in an American study, among 40 cases of XGC, five (12.5%) also had GBC 7. In the United Kingdom, a study of 31 patients with XGC revealed carcinoma in three (9.7%) patients 4. In a Japanese study, 10% of XGC patients also had GBC. In a Mexican study, XGC was associated with carcinoma in five cases (3%) among a total of 182 cases of XGC 1. According to the authors of that study, the in-flammatory reaction followed by an associated immu-nologic cellular response may produce the appearance of cellular changes that degenerate into carcinoma 1. The possible association of XGC and GBC carries a

Fig. 1. (a) photograph of the resected gallbladder showing thick-ening of the gallbladder wall (black arrow) and a 2.3 cm lesion in the gallbladder infundibulum (white arrow). (b) Xanthogranulo-matous nodules appear as yellowish nodules in the thick wall of the gallbladder.

Fig. 2. (a) chronic inflammation of the gallbladder wall with a pre-dominance of foamy macrophages (haematoxylin & eosin, origi-nal magnification x 100). (b) Multinucleated giant cells admixed with foamy histiocytes and chronic inflammatory cells (haema-toxylin & eosin, original magnification x 400).

Fig. 3. (a) invasive adenocarcinoma of the gallbladder with variable-sized glandular structures invading the muscular layer (haematoxylin & eosin, original magnification x 200). (b) tubular glands lined by mild atypial cuboidal to tall columnar cells resem-bling biliary epithelium (haematoxylin & eosin, original magnifica-tion x 400).

139XaNthogRaNuloMatouS cholEcYStitiS aND gallBlaDDER aDENocaRciNoMa

References

1 Guzman-Valdivia G. Xanthogranulomatous Cholecystitis: 15 Years’ Experience. World J Surg 2004;28:254-7.

2 Dixit VK, Prakash A, Gupta A, et al. Xanthogranulomatous chole-cystitis. Dig Dis Sci 1998;43:940-2.

3 Lee HS, Joo KR, Kim DH, et al. A case of simultaneous xantho-granulomatous cholecystitis and carcinoma of the gallbladder. Korean J Intern Med 2003;18:53-6.

4 Houston JP, Collins MC, Cameron I, et al. Xanthogranulomatous cholecystitis. Br J Surg 1994;81:1030-2.

5 Ghosh M, Sakhuja P, Agarwal AK. Xanthogranulomatous chole-cystitis: a premalignant condition? Hepatobiliary Pancreat Dis Int 2011;10:179-84.

6 Benbow EW. Xanthogranulomatous cholecystitis associated with carcinoma of gallbladder. Postgrad Med J 1989;65:528-31.

7 Goodman ZD, Ishak KG. Xanthogranulomatous cholecystitis. Am J Surg Pathol 1981;5:653-9.

8 Krishnani N, Shukla S, Jain M, et al. Fine needle aspiration cytol-ogy in xanthogranulomatous cholecystitis, gallbladder adenocar-cinoma and coexistent lesions. Acta Cytol 2000;44:508-14.

potential risk of diagnostic confusion. In fact, patholo-gists might fail to notice the presence of GBC when it is associated with florid XGC. Furthermore, the exis-tence of florid XGC may lead to errors in determin-ing the exact stage of the malignant spread of GBC as macrophages can be confused with tumour cells 6. Fine needle aspiration cytology from the gallbladder mass lesions was used in differential diagnosis and found to have an important role in making a preoperative diag-nosis of XGC and malignancy 8. Because of its over-

lapping clinical, radiological and macroscopic findings with GBC, definitive diagnosis of XGC relies on ex-tensive sampling and thorough microscopic examina-tion of the surgical specimen to exclude the possibility of coexisting tumour. Although rare, it is important to be aware of the possible coexistence of XGC and GBC. At present, it is a matter of debate whether XGC are truly precursors of GBC or if they are merely an inci-dental finding. This aspect needs to be explored in the future with further studies.

pathologica 2013;105:140-141

Case report

A 55-year-old man presented to our clinic complaining of multiple small, blackish, nodular lesions clinically suggestive of multiple seborrheic keratosis. A biopsy of one of these lesions was taken.Histological examination showed an epithelial prolif-eration arising from the epidermis, composed of thin, branched and anastomosing trabeculae of basaloid cells. The stroma was fibrous (Figs. 1, 2). A diagnosis of fi-broepithelial tumour of Pinkus was made.

Comment

Fibroepithelioma of Pinkus (FEP) was first described by Herman Pinkus in 1953 2 as ‘premalignant fibroepithe-lial tumor of the skin’. Later, it has been considered to be an unusual subtype of basal cell carcinoma (BCC). Other authors have suggested that FEP is a variant of trichoblastoma 1.Like BCC, FEP is more frequent in lighter skin types and relatively rare in dark skin types; unlike it, there is no predilection for sun-exposed sites 3. Prior radiother-apy is a predisposing factor. FEP develops, typically, in persons aged between 40 and 60 years. A few pediatric cases have been reported 4. Clinically, FEP presents as a skin-colored, pink, red or brown nodule or plaque, with

occasional ulceration. They usually are located on the trunk or extremities. However, lesions occurring on the head, abdomen, anus, penis, scrotum and breasts have been reported 5. Multiple lesions are rare. In fact, only 10 cases of multiple FEP have been described 6-8; 9 of these were associated with BCC and previous radiotherapy, demonstrating the role of radiation damage in the onset of disease. Clinical features of FEP can mimic many le-sions such as seborrheic keratosis (as in our case), pe-dunculated fibroma, nevus sebaceus of Jadassohn, pap-illomatous melanocytic nevus, amelanotic melanoma and neurofibroma 5. Dermoscopy shows fine arborizing vessels that may be associated with dotted vessels and white streaks 9.Diagnosis relies on histological examination that shows that the tumour is superficial and well demarcated at its lower border. It consists of basaloid epithelial, long and thin strands, arising from the epidermis and anastomos-ing to create a fenestrating pattern. They surround a loose fibrovascular stroma 4. Nuclear pleomorphism may be present, and staining with Ki-67 shows an increased pro-liferative index 10. Merkel cells are quite prominent and their staining by androgen receptor and cytokeratin 20 may aid in diagnosis of FEP. Cyst formation and small follicle-like bulbs may be additional features. The main differential diagnoses of FEP are BCC, tricho-blastoma and trichoepithelioma. The histological ap-pearance of the tumour is often distinctive. FEP has a

case repOrt

Pinkus tumour: an unusual caseS. SEHLI ATTAFI1, M. JONES2, B. FAZAA2, R. ZERMANI1, S.R. ROMMANY1

1 Department of pathology, Charles Nicolle Hospital, Tunis, Tunisia; 2 Department of dermatology, Charles Nicolle Hospital, Tunis, Tunisia

Key words

Histology • Fibroepithelioma • Cutaneous

Summary

CorrespondenceS. Sehli Attafi, Charles Nicolle Hospital, 9 Avril 1938 Boulevard, Tunis, Tunisia - E-mail: [email protected]

Fibroepithelioma of Pinkus is a rare cutaneous tumour. Its clas-sification is controversial and is considered as a variant of either basal cell carcinoma or trichoblastoma 1. Its presentation as a mul-tiple tumour is rare. We are reporting such a case occurring in a 55-year-old man presenting with multiple seborrheic keratosis-

like lesions corresponding histologically to Pinkus tumours. The clinical diagnosis of Pinkus tumour represents a challenge. Histo-logical examination is extremely useful in aiding in the diagnosis of difficult cases.

141Pinkus tumour: an unusual case

strong histologic resemblance to reticulated seborrheic keratosis, but typical horn and pseudohorn pearls are ab-sent and hyperkeratosis is rare.FEP has an indolent behaviour with no metastatic po-

tential. Its treatment is typically surgical including com-plete excision, electrodessication followed by curettage and Moh’s micrographic surgery. Rarely, intralesional or topical chemotherapy may be useful 5.

References

1 Su WM, Fromer E, Fung AM. Fibroepithelioma of Pinkus. Derma-tology Online Journal 2006;12:2.

2 Pinkus H. Premalignant fibroepithelial tumors of skin. AMA Arch Derm Syphilol 1953;67:598-615.

3 Bowen AR, LeBoit PE. Fibroepithelioma of pinkus is a fenestrated trichoblastoma. Am J Dermatopathol 2005;27:149-54.

4 Pan Z, Huynh N, Sarma DP. Fibroepithelioma of pinkus in a 9-year-old boy: a case report. Cases J 2008;1:21.

5 Mehregan D, Elston DM, Heyl JM. Premalignant Fibroepithelial Tumor (Pinkus tumor). Clinical Presentation. Emedicine 2012. http://www. http://emedicine.medscape.com/article/1101357-treatment].

6 Rodriguez RA, Festa Neto C. Multiple fibroepithelial basal cell

carcinoma of Pinkus associated with seborrheic keratosis in a ne-void distribution. J Dermatol 2000;27:341-5.

7 Colomb D, Vittori F, Perraud R. Basal cell epithelioma and mul-tiple fibroepithelial Pinkus’ tumors in the lumbosacral region. Dis-cussion of the precipitating role of previous radiotherapy treat-ment. Apropos of 4 cases. Sem Hop 1975;51:2655-64.

8 Colomb D, Bréchard JL, Gho A, et al. On five new cases of asso-ciation of basal cell carcinoma and multiple Pinkus fibroepithelial tumors on the spine following radiation damage to the skin. Ann Dermatol Venereol 1979;106:875-82.

9 Zalaudek I, Leinweber B, Ferrara G, et al. Dermoscopy of fibroepi-thelioma of pinkus. J Am Acad Dermatol 2005;52:168-9.

10 Katona TM, Ravis SM, Perkins SM, et al. Expression of androgen receptor by fibroepithelioma of Pinkus: evidence supporting clas-sification as a basal cell carcinoma variant. Am J Dermatopathol 2007;29:7-12.

Fig. 1. Fibroepithelioma of pinkus: long, thin, and branching strands of basaloid cells, connected to the epidermis and anasto-mosing in fibrovascular stroma are apparent.

Fig. 2. Strands are formed by basaloid cells with nuclear periph-eral palisading and mitoses.

pathologica 2013;105:142-145

Introduction

Myofibroblastoma of the breast (MFB) is an unusual benign tumour that belongs to the family of benign spin-dle cell tumours of the mammary stroma. They derive from CD34+ fibroblasts of mammary stroma and may exhibit a wide spectrum of histological features. MFB with predominant leiomyomatous differentiation can be misinterpreted as a leiomyoma 1 2. We report a benign spindle stromal tumour of the breast in a 60-year-old man. Predominant leiomyomatous differentiation, focal typical morphological features and immunohistochemi-cal staining positive for h-caldesmon, helped in reaching a correct diagnosis.

Case report

A 60-year-old man was referred to our institution for a large lump in the right mammary region. He was oth-erwise healthy. There was no family history of breast

cancer. The lump, of 10 months duration, appeared ini-tially as a small and asymptomatic swelling, increased rapidly in size. Examination revealed a relatively firm mass in the upper inner quadrant of the right breast mea-suring 5 cm in maximum diameter. The lesion was well-defined and freely mobile with respect to the underlying muscular plane, but adherent to the overlying skin. The left breast was normal. There was no palpable axillary lymphadenopathy. Routine baseline investigations, in-cluding mammography and ultrasonography, showed a well-defined tumour measuring 5 cm x 4 cm. Ultraso-nography also displayed a mixed echogenic mass includ-ing adipose tissue. The tumour was completely excised with the overlaying skin. Gross examination revealed a 5 cm, spherical, soft nodular mass. The cut surface of the tumour varied in appearance, mostly brown with a firm white area and finely punctuated adipose tissue. Frozen-section diagnosis suggested a spindle cell lesion. The tumour was well-circumscribed and could be “shelled out” from the surrounding breast tissue (Fig. 1a). There was a free resection margin measuring 10 mm. In final

case repOrt

Mammary myofibroblastoma with leiomyomatous differentiation: case report and literature review

H. MNIF, S. CHARFI, N. ABID, T. SALLEMI-BOUDAWARADepartment of pathology, Habib Bourguiba Hospital, Sfax-Tunisia

Key words

Breast • Myofibroblastoma • Smooth muscle cells • H-caldesmon

Summary

CorrespondenceHéla Mnif, Department of pathology, Habib Bourguiba Hospital, Sfax-Tunisia 3029 - Tel. +216 74 240 341 - Fax +216 74 243 427 - E-mail : [email protected]

Introduction. Myofibroblastoma of the breast (MFB) is an unusual benign tumour that belongs to the family of benign spindle cell tumours of the mammary stroma. The detection of smooth muscle cells in MFB is explained by its histogenesis from CD34+ fibroblasts of mammary stroma capable of mul-tidirectional mesenchymal differentiation, including smooth muscle.Aims. The purpose of this case is to highlight characteristics of this rare neoplasm. Immunohistochemical features, in MFB with predominant leiomyomatous differentiation, are provided to offer a practical approach to a correct diagnosis.Case report. We report a right MFB in a 60-year-old male. The

tumour was unusual due to its morphological features, with pre-dominant leiomyomatous differentiation. Immunohistochemical findings, based on the negativity of h-caldesmon, helped in reach-ing a diagnosis.Conclusion. The detection of leiomyomatous rather than myo-fibrolastic features in MFB may reflect only the predominant cell types of examined area, and this is not necessarily repre-sentative of the remaining tumour which may have a different basic cellular composition. Immunohistochemical expression of h-caldesmon is a reliable marker in distinguishing smooth mus-cle versus myofibrolastic cellular differentiation in spindle cells lesions of the breast.


histological examination, the tumour was cellular and vaguely nodular with an abundant leiomyomatous ap-pearance (Fig. 1b). The muscular cells were arranged in ill-defined fascicles, haphazardly intermingled with bland-looking, slender, spindle-shaped cells, closely packed in short fascicles or clusters of cohesive cells, interrupted by thick, hyalinised collagen bundles. The latter cells have a varied appearance ranging from fibro-blastic-like cells with scanty cytoplasm and elongated nuclei to cells with myoid features consisting of abun-dant palely cytoplasm. The tumour cells were monomor-phic without atypia and mitotic activity (Fig. 1c). There were no areas of necrosis or hemorrhage. The lesion contained scattered islands of adipose tissue or separate adipocytes (Fig. 1d). In the tumour stroma, there were numerous mast cells without lymphoplasmacytic infil-trate. The tumour was well circumscribed and had no in-filtration to the adjacent breast tissue. The resection mar-gin was free of tumour. Immunohistochemistry revealed a strongly positive reaction of the leiomyomatous com-ponent for actin, desmin and h-caldesmon (Fig. 2a). The second component was positive for vimentin, desmin,

CD34 (Fig.2b) and CD10, while S100 protein (Fig. 2c), h-caldesmon (Fig. 2d), cytokeratins, EMA, CD117 and HMB-45 were negative. The present findings were con-sistent with a diagnosis of MFB with abundant mature leiomyomatous, heterologous component. The patient made an uneventful recovery and 18 months later re-mains well with no evidence of recurrence.

Discussion

MFB is an unusual benign tumour that belongs to the family of benign spindle cell tumours of the mammary stroma. The name MFB reflects its cellular composition, comprising neoplastic cells showing a variable fibromyo-fibroblastic differentiation at morphologic, immunohisto-chemical and ultrastructural levels 1-3. The first cases of a benign spindle cell stromal tumour of the breast were reported by Toker et al. in 1981 4. The term MFB of the breast was first coined by Wargotz et al. in 1987 5. This tumour is an extremely rare lesion with less than 70 cases reported in literature 1. Reported cases of MFB

Fig. 1. (a) MFB. low magnification showing a fascicular tumour with well defined borders (haematoxylin-eosin x 50). (b) MFB showing bland-looking, spindle-shaped cells with leiomyomatous differentiation (haematoxylin-eosin x 100). (c) the tumour cells are monomorphic without atypia and mitotic activity (haematoxylin-eosin x 200). (d) the spindle cell proliferation contains scattered islands of adipose tissue (haematoxylin-eosin x 100).

h. MNiF Et al.144

occur most often in older men aged 40-87 years. Several cases have also been documented in females, suggest-ing that it can occur in both sexes. It is likely that the increased incidence of MFB reported in women in the last 2 decades could be due to increased mammographic screening 1. There are no reported cases that indicate re-lation to gender, race, medical conditions, use of med-ication or other effects of growth factors 6. The usual clinical presentation is a unilateral painless lump, not ad-herent to overlying or underlying structures. Bilaterality and unilateral multicentricity are rare. Radiologically, they are homogenous, lobulated and well circumscribed lesions, typically lacking microcalcification. Ultrasono-graphic findings cannot often differentiate it from fibro-adenoma 7. Tumour size ranges from a few mm to 11 cm. By gross examination, MFB is generally a well-circumscribed, firm and rubbery, unencapsulated, round to oval mass. The cut surface usually reveals a solid lesion, with a smooth or lobulated external surface, pale white to grey-ish, with a variably whorling appearance. In some cases, the cut surface of the tumour may show focal to exten-sive mucoid- or lipomatous-appearing areas. Cystic de-

generation, necrosis and haemorrhage are not features of MFB 1. Histopathologically, the classic type MFB is an unen-capsulated tumour composed of uniform, bland looking spindle cells haphazardly arranged in short fascicles, separated by thick bands of hyalinized collagen bundles and devoid of mammary ducts and lobules. The spindle cells have abundant eosinophilic cytoplasm, round or oval nucleus with 1-2 small nucleoli. Mitotic activity is absent or rare when present (≤ 2/10 HPF). Prominent mast cells can be seen in tumour stroma, but lympho-plasmacytic infiltration is almost always absent 8. The morphologic spectrum of MFB has been expanded by the recognition of several morphologic variants, such as the cellular, infiltrative, epithelioid, deciduoid-like, lipomatous, collagenized/fibrous and myxoid vari-ants 1-8. Other unusual morphologic features have been described such as the presence of atypical cells, mul-tinucleated Floret-like cells, haemangiopericytoma-like pattern and heterologous components 8. These latter characteristics have been described as foci of heter-ologous mesenchymal components, apart from adi-pose tissue, such as mature leiomyomatous, osseous or

Fig. 2. (a) MFB. the leiomyomatous component is positive for h-caldesmon (h-caldesmon x 100). (b) MFB. the tumour cells are positive for cD34 (cD34 x 2oo). (c) MFB. No staining of pS100 in myofibroblastic cells (pS100 x 100). (d) MFB. No staining of h-caldesmon in myofibro-blastic cells with the exception of smooth muscle cells of blood vessels (h-caldesmon x 100).


References

1 Magro G. Mammary Myofibroblastoma. A Tumor with a Wide Morphologic Spectrum. Arch Pathol Lab Med 2008;132:1813-20.

2 Magro G, Bisceglia M, Michal M, et al. Spindle cell lipoma-like tumor, solitary fibrous tumor and myofibroblastoma of the breast: a clinicopathological analysis of 13 cases in favor of a unifying histologic concept. Virchows Arch 2002;440:249-60.

3 Magro G. Stromal tumors of the lower female genital tract: his-togenetic, morphological and immunohistochemical similarities with the “benign spindle cell tumors of the mammary stroma”. Pathol Res Pract 2007;203:827-9.

4 Toker C, Tang CK, Whitely JF, et al. Benign spindle cell breast tumor. Cancer 1981;48:1615-22.

5 Wargotz ES, Weiss SW, Norris HJ. Myofibroblastoma of the breast: sixteen cases of a distinctive benign mesenchymal tumor. Am J Surg Pathol 1987;11:493-502.

6 Melea M, Jensen W, Wronecki A, et al. Myofibroblastoma of the breast: Case report and literature review. Int J Surg Case Rep 2011;2:93-6.

7 Prasenjit D, Alok S, Raman A, et al. Myofibroblastoma of breast. Indian J Med Paediatr Oncol 2008;29:16-9.

8 Huang Y, Chen F. Review of Myofibroblastoma of Breast and Its Most Common Mimickers. North Am J Med Sci 2012;5:38-42.

9 Magro G, Gurrera A, Bisceglia M. H-caldesmon expression in myofibroblastoma of the breast: evidence supporting the distinc-tion from leiomyoma. Histopathology 2003,42:233-8.

10 Thomas TMM, Myint A, Mak CKL, et al. Mammary myobibro-blastoma with leiomyomatous differentiation. Am J Clin Pathol 1997;107:52-55.

cartilaginous tissues which can variably coexist in the same tumour 8. In some cases, as in our presentation, predominant smooth muscle differentiation can be seen. This possibility should be kept in mind for differential diagnosis with leiomyoma 9 10. There are at least two cases of MFB reported in the English literature with an important leiomyomatous component easily identifi-able by light microscopy 9. This occurrence is not sur-prising if we assume that this tumour arises from a com-mon precursor cell, namely the CD34+ fibroblast of the mammary stroma, which is capable of multidirectional mesenchymal differentiation including smooth muscle. Immunohistochemically, the neoplastic cells of classic MFB are typically positive for vimentin and CD34 with variable immunoreactivity to SMA, desmin, bcl-2 and CD99. Most MFB are positive for oestrogen, proges-terone and androgen receptors. However, cytokeratins, EMA, PS100, HMB-45 and CD117 are consistently negative 8. Actually, the availability of anti-h-caldemon antibody, which is regarded as a specific smooth muscle cell marker that is easily applied in paraffin-embedded tissues 9, allows resolution of problems due to the fact

that desmin and SMA are co-expressed by smooth mus-cle cells and variously by myofibroblasts. Margo G et al. 9 selected 12 cases of MFB which were evaluated immunocytochemically for expression of h-caldesmon. As expected, all MFB failed to express this protein. Conversely, focal staining, ranging from 2-10% of neo-plastic cells, as we identified in our case, was detected in 50% of the cases examined, supporting the separation of this tumour from leiomyoma.As was illustrated in this case, although an entity can be strongly suspected based upon frozen-section findings, it is not always possible to render a definitive diagnosis in all cases. Clinicians must be aware of the limitation of fro-zen-section sampling of spindle cell lesions of the breast, and pathologists must be cautious in their interpretation of them, particularly when there is a nuclear pleomorphism that can be observed focally in classic MFB. MFB is treated by local excision without recurrence and, as long as the resection margins are free, relapse is unlikely. Malignant transformation has not been re-ported 6. However, a minimum of 24 months follow-up is desirable.

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