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immunoprofile’ as benign giant cell tumours is a simplistic and inappropriate approach. Nevertheless, a diagnosis of giant cell tumour was adequately justified in our case, supported by accumulative clinicopathological and follow-up data. The tumour was mucosal based with no infiltrative growth, and despite extensive sampling and microscopic examination of the entire tumour, and comprehensive immunohistochemical studies on multiple blocks, no evidence of epithelial differentiation was affirmed. There was no radiological or clinical evidence of locoregional or metastatic disease at the time of diagnosis. Finally, on 20month follow-up to date, the patient is clinically well with no recurrence or metastasis. Spindle cell tumours rich in osteoclast-like giant cells with low malignant potential are not limited to the gallbladder or biliary tree. The prototypical example is giant cell tumour of the bone and soft tissue, which is an indolent, locally recurrent neoplastic lesion with extremely low risk of metastasis.5 While giant cell tumours in the bone are generally considered neoplastic based on discovered genetic abnormalities and chromosomal aberrations,9 it has been argued that these lesions may represent an exuberant fibrohistiocytic reaction to persistent or recurrent haemorrhage in the bone owing to weak stromal support.10 This hypothetical reaction is mediated by plasma proteins and chemokines which result in activation and proliferation of stromal cells together with recruitment and conformation of monocytic cells into osteoclastic giant cells. Further gene expression modifications and enhanced telomerase activity in susceptible patients results in excessive neoplastic proliferation of mononuclear and multinucleated osteoclast-like giant cells. Synonymously in the ovary and peritoneum, rare occurrences of mucinous cystic tumours with spindle cell sarcoma-like mural nodules containing osteoclast-like giant cells have been reported. Although a subset of these nodules are actually confirmed to be sarcomas or anaplastic carcinomas on morphological, immunohistochemical and gene expression studies, benign spindle cell nodules of genuine reactive nature and indolent clinical behaviour have been reported.11,12 Exuberant proliferation of mesenchymal cells underlying the mucinous epithelium as a reactive response to haemorrhage or extruded mucin in the cyst wall, or alternatively a reaction to tumour related chemokines, have been suggested as the theoretical pathogenesis of these nodules.11 In contrast, the nodules of true sarcomatous or carcinomatous differentiation appear to be a clonal de-differentiation from the pre-existing mucinous tumour.13 In summary, we have described a rare case of giant cell tumour of the gallbladder, which appears to be a clinicopathologically distinct entity, analogous to the low-grade giant cell rich tumours of the other organs, in particular giant cell tumour of the bone. The exact pathogenesis and biological behaviour of this tumour is not clear due to its rarity. However analogous to giant cell rich lesions in the other organs, it may represent a local exuberant reactive response to persistent or recurrent local damage and haemorrhage in genetically predisposed individuals. Importantly, this tumour should be distinguished from undifferentiated carcinoma with osteoclast-like giant cells, which pursues a more aggressive clinical course. We believe this current case adds to the four previously reported cases of this unique entity. Conflicts of interest and sources of funding: The authors state that there are no conflicts of interest to disclose.

Nima Mesbah Ardakani1 Dennis Lum2 Lydia Ng1,2 Marian Priyanthi Kumarasinghe1,3 1

PathWest Laboratory Medicine, QEII Medical Centre, Perth, Western Diagnostic Pathology, Perth, and 3School of Pathology and Laboratory Medicine, University of Western Australia, Perth, WA, Australia

2

Contact Dr Nima Mesbah Ardakani. E-mail: [email protected] 1. Albores-Saavedra J, Klo¨ppel G, Adsay NV, et al. Tumours of the gallbladder and extrahepatic bile duct. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, editors. WHO Classification of Tumours of Digestive System. 4th ed. Geneva: World Health Organization, 2010. 2. Manouras A, Genetzakis M, Lagoudianakis EE, et al. Undifferentiated giant cell type carcinoma of the gallbladder with sarcomatoid dedifferentiation: a case report and review of the literature. J Med Case Rep 2009; 3: 1–5. 3. Misra S, Chaturvedi A, Misra NC, Sharma ID. Carcinoma of the gallbladder. Lancet Oncol 2003; 4: 167–76. 4. Albores-Saavedra J, Grider DJ, Wu J, Henson DE, Goodman ZD. Giant cell tumor of the extrahepatic biliary tree: a clinicopathologic study of 4 cases and comparison with anaplastic spindle and giant cell carcinoma with osteoclast-like giant cells. Am J Surg Pathol 2006; 30: 495–500. 5. Balke M, Schremper L, Gebert C, et al. Giant cell tumor of bone: treatment and outcome of 214 cases. J Cancer Res Clin Oncol 2008; 134: 969–78. 6. Gjerdrum LM, Lauridsen MC, Sørensen FB. Breast carcinoma with osteoclast-like giant cells: morphological and ultrastructural studies of a case with review of the literature. Breast 2001; 10: 231–6. 7. Dworak O, Wittekind C, Koerfgen H, Gall F. Osteoclastic giant cell tumor of the pancreas: An immunohistological study and review of the literature. Pathol Res Pract 1993; 189: 228–31. 8. Dhall D, Klimstra DS. The cellular composition of osteoclastlike giant cellcontaining tumors of the pancreatobiliary tree. Am J Surg Pathol 2008; 32: 335–7. 9. Morgan T, Atkins GJ, Trivett MK, et al. Molecular profiling of giant cell tumor of bone and the osteoclastic localization of ligand for receptor activator of nuclear factor kB. Am J Pathol 2005; 167: 117–28. 10. Anwar Ul Haque AM. Giant cell tumor of bone: a neoplasm or a reactive condition? Int J Clin Exp Pathol 2008; 1: 489. 11. Demirel D, Gun I, Kucukodaci Z, Balta AZ, Ramzy I. Primary retroperitoneal mucinous cystadenoma with a sarcoma-like mural nodule: an immunohistochemical study with histogenetic considerations and literature review. Int J Gynecol Pathol 2013; 32: 15–25. 12. Russell P, Wills E, Schweitzer P, Bannatyne P. Mucinous ovarian tumors with giant cell mural nodules. A report of two cases. Diagn Gynecol Obstet 1980; 3: 233–49. 13. Desouki MM, Khabele D, Crispens MA, Fadare O. Ovarian mucinous tumor with malignant mural nodules: dedifferentiation or collision? Int J Gynecol Pathol 2015; 34: 19–24.

DOI: 10.1097/PAT.0000000000000341

B3 thymoma arising within thymolipoma Sir, Thymolipoma is a rare tumour of the mediastinum with about 200 cases described in the literature. The hallmark characteristic is the presence of thymic tissue scattered through the lipomatous component. Since this biphasic tumour encompasses epithelial tissue, a neoplastic transformation of the epithelial component is theoretically possible, but only five such cases have been reported. We present a unique case of B3 thymoma arising within a thymolipoma. A 59-year-old woman was addressed to our institution for a huge mediastinal tumour (Fig. 1). She had a previous medical

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CORRESPONDENCE

A

B

C

D

E

F

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Fig. 1 (A) CT scan, axial plane; huge lipomatous tumour with a stellar area (arrow). (B) Gross examination showing a lipomatous tumour with the stellar area (arrow). (C) Haematoxylin eosin saffron (HES); area of typical thymolipoma with normal thymic tissue intermixed with adipocytes. (D) HES; B3 thymoma with lobulated architecture. (E) HES; B3 thymoma with atypical epithelial cells with numerous mitoses (arrow). (F) Immunohistochemistry; anti-TdT antibody staining immature T lymphocytes within the thymoma.

history of shortness of breath, labelled and treated as asthma for several years. As the patient arrived from an underdeveloped country, no further examination had been performed. This tumour was discovered on a chest radiograph because her dyspnoea had worsened. The patient did not suffer from mysthenia gravis. On computed tomography (CT) imaging, a tumour with fat tissue density compressing the right lung was discovered. A stellar zone and macro-calcifications were seen (Fig. 1). Pulmonary function test showed a restrictive pattern. A surgical biopsy was performed and microscopic examination revealed a lipomatous tumour without any other component. Because of the size and the deep localisation of the tumour, MDM2 FISH which showed no amplification was performed in order to rule out an atypical lipoma. Complete surgical excision was then possible and was achieved. Pathological examination showed a 2.8 kg, 39  22  11 cm lipomatous tumour with multiple macrocalcifications and a stellar focus of 3  1.2 cm (Fig. 1). Microscopic examination showed a biphasic tumour with well-differentiated lipomatous areas intermixed with epithelial foci containing Hassal corpuscles (Fig. 1). This aspect was typical of a thymolipoma. Under the microscope, the stellar lesion was made of a central fibrotic zone surrounded by nests

and lobules of epithelial atypical cells intermixed with small lymphocytes (Fig. 1). Numerous mitoses were noticed (Fig. 1). The epithelial cells were labelled by AE1/AE3, p63 (clone 4A4, 1/200; CliniSciences, France) and p40 (rp163, 1/75; CliniSciences) antibodies. Most intra-tumoural lymphocytes were stained by CD3 (clone F7,2,38, 1/100; Dako, Denmark), CD5 (clone 4c7, 1/100; Novocastra, UK), CD1a (clone O10, 1/200; Beckman Coulter, USA) and TdT (polyclonal, 1/20; Dako). Few CD20 (clone L26, 1/200; Dako) positive lymphocytes were present within the tumour. No staining of tumour cells was seen with TTF1 (8G7G3/1, 1/50; Dako), oestrogen receptor (SP1, 1/25; CliniSciences), Chromogranin A (DAKA3, 1/1500; Dako), Synaptophysin (SY38, 1/50; Dako), CD56 (4c7, 1/100; Novocastra), CD5 and CD117 (c-kit, 1/800; Dako). Surgical margins were tumour free and located 3 cm from the tumour. No tumour pleural implant was seen. Mutational screening was performed for EGFR (exons 18, 19, 20 and 21), KRAS (exon 2, 3 and 4), BRAF V600, HER2 (exon 20), PIK3CA and NRAS (exons 2, 3 and 4). This was negative, as was ALK (D5F3; Ventana, USA) immunohistochemistry. The final diagnosis was a B3 thymoma arising within a thymolipoma. Follow-up was decided on a multidisciplinary

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Pathology (2015), 47(7), December

No recurrence at 2 years

Not specified No recurrence at 2 years

60 mm/15 mm 390 mm/30 mm M, 68 F, 59

Typical thymic carcinoid B3 thymoma

Surgical resection and follow-up Surgical resection; complementary treatment not specified Surgical resection and follow-up Surgical resection and follow-up F, 36 F, 23

343 mm/not specified (50% of the whole mediastinal lesion) 320 mm/200 mm 200 mm/70 mm M, 49

B2 thymoma and thymic carcinoma B1 thymoma

Discharged at 1 week

Surgical resection and follow-up

Thymoma predominantly mixed under the Lattes-Bernatz classification and cortical under the Mu¨ller-Hermelink classification B1, B2 and B3 thymoma 100 mm/25 mm F, 67

Surgical resection and follow-up

Treatment Epithelial tumour type

case discussion without complementary treatment. The patient was free of disease 6 months after surgical resection. A literature search was performed through PubMed search engine with the following key words ‘thymolipoma [All Fields]’. Our review of the literature found five cases of epithelial tumours arising in thymolipoma (Table 1). Thymolipoma is a rare mediastinal tumour with about 200 cases described in the literature. It seems to occur more frequently in young adults.1 It is often an incidental finding, during imaging. Some cases present with a compression syndrome or with myasthenia gravis or immune phenomenon.2 This diagnosis should be evocated on the presence of a huge mediastinal mass with adipose tissue density on CT scan.2 The diagnosis relies on pathological examination and, as in our case, is difficult or impossible to make on biopsies if the epithelial component has not been sampled. In the reported cases, the presence of an epithelial tumour within thymolipoma was obvious on gross examination, but only represented a small part of the whole tumour.3–5 Careful gross examination and tumour sampling are therefore mandatory. Microscopic examination determines the tumour type, which is important since signs of aggressiveness should encourage physicians to more closely follow up these patients. The treatment of thymolipoma relies on complete, often curative excision.6 This tumour usually does not recur.6 Treatment of an epithelial tumour within a thymolipoma is not standardised, and because of its rarity, treatment of a thymoma is discussed upon the findings for each patient. However, in reported cases shown in Table 1, complete resection seemed to be curative.3–5,7,8 The histogenesis of thymolipoma remains discussed between a true tumour lesion and a congenital malformation.1 The genesis of thymoma within thymolipoma remains unknown and the molecular drivers of primary thymoma are poorly understood.9 Because rare cases of primary thymoma show isolated targetable mutations, we wondered if we could find a targetable mutation in our case, but the molecular screening was negative.10 Our case shows the importance of careful sampling and gross examination. The diagnosis could be suspected on CT scan by the presence of a stellar or heterogeneous part within a huge lipomatous tumour. Conflicts of interest and sources of funding: The authors state that there are no conflicts of interest to disclose. Violaine Yvorel1 Fabien Forest1 Eric Parietti2 Georgia Karpathiou1 Marie-Laure Stachowicz1 Arnaud Patoir2 Olivier Tiffet2 Michel Pe´oc’h1

Steger et al.5 Yvorel et al. (current case)

Haddad et al.8 Kaplan et al.4

Guimaraes et al.7

1

Argani et al.3

Thymolipoma size/Epithelial tumour size (greatest axis) Gender, age

Patients’ characteristics in reported cases of epithelial neoplasms within thymolipoma Table 1

No recurrence; alive at 10 years then lost to follow-up

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Follow-up

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Service D’anatomie et Cytologie Pathologiques, and 2Service de Chirurgie Thoracique, CHU de Saint E´tienne - Hoˆpital Nord, Saint E´tienne, France Contact Dr Fabien Forest. E-mail: [email protected] 1. Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG, editors. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. Lyon: International Agency for Research on Cancer, 2015.

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CORRESPONDENCE

2. Rieker RJ, Schirmacher P, Schnabel PA, et al. Thymolipoma. A report of nine cases, with emphasis on its association with myasthenia gravis. Surg Today 2010; 40: 132–6. 3. Argani P, de Chiocca IC, Rosai J. Thymoma arising with a thymolipoma. Histopathology 1998; 32: 573–4. 4. Kaplan T, Han S, Han U, et al. Thymoma type B1 arising in a giant supradiaphragmatic thymolipoma. Asian Cardiovasc Thorac Ann 2014; 22: 1109–11. 5. Steger C, Steiner H-J, Moser K, et al. A typical thymic carcinoid tumour within a thymolipoma: report of a case and review of combined tumours of the thymus. BMJ Case Rep 2010; 2. 6. Damadoglu E, Salturk C, Takir HB, et al. Mediastinal thymolipoma: an analysis of 10 cases. Respirol 2007; 12: 924–7. 7. Guimara˜es MD, Benveniste MFK, Bitencourt AGV, et al. Thymoma originating in a giant thymolipoma: a rare intrathoracic lesion. Ann Thorac Surg 2013; 96: 1083–5. 8. Haddad H, Joudeh A, El-Taani H, et al. Thymoma and thymic carcinoma arising in a thymolipoma: report of a unique case. Int J Surg Pathol 2009; 17: 55–9. 9. Petrini I, Rajan A, Pham T, et al. Whole genome and transcriptome sequencing of a B3 thymoma. PLoS One 2013; 8: e60572. 10. Nakagiri T, Funaki S, Kadota Y, et al. Does gefitinib have effects on egfr mutation-positive thymoma? Case report of thymoma recurrence. Ann Thorac Cardiovasc Surg 2014; 20: 674–6.

DOI: 10.1097/PAT.0000000000000335

Nephrotic syndrome in a man with Carney–Stratakis syndrome Sir, We report a case of systemic amyloid A (AA) amyloidosis in a man with longstanding paraganglioma, metastatic to lung and bone. Six months after resection of a gastrointestinal stromal tumour (GIST), the patient presented with nephrotic syndrome and AA amyloid was diagnosed on kidney biopsy. Subsequently AA amyloid was also identified in blood vessels within the GIST and extensively throughout mucosal biopsies from the gastrointestinal tract. The GIST showed loss of succinate dehydrogenase (SDH) subunit B (SDHB) on immunohistochemistry. Patients with SDH-deficient GISTs may have germline mutations of SDH-subunits B, C or D, known as Carney–Stratakis syndrome when combined with paraganglioma. This is the first reported case of AA amyloidosis in a patient with Carney–Stratakis syndrome. AA amyloidosis is characterised by extracellular deposition of amyloid fibrils and mainly occurs in patients with chronic inflammatory diseases and some neoplasms.1 AA amyloidosis often leads to end-stage renal failure, particularly in patients with persistently high circulating levels of serum amyloid A. The mainstay of management is successful treatment of the underlying inflammatory process. This leads to stabilisation of or improvement in renal function, reduction in protein excretion, and possible resolution of amyloid deposits.1 A 59-year-old Caucasian man was referred to the kidney unit in March 2014 with proteinuria and hypoalbuminaemia on a background of non-specific symptoms of fatigue, anorexia and 6 kg loss of weight over several months. His past medical history included a paraganglioma of the carotid body (carotid body tumour), diagnosed in 1972, for which he had refused treatment. He had evidence of metastatic paraganglioma in lung, portocaval lymph nodes and lumbar vertebrae (biopsyproven in 2013). This biopsy was tested retrospectively with

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Congo red stain that was negative for amyloid. He underwent laparascopic resection of a 37 mm gastric GIST in January 2014. The GIST had a low mitotic rate and was c-kit positive on immunohistochemistry; excision margins were clear and no further treatment was indicated. It was noted that the blood vessels within the GIST showed extensive deposits of Congo red positive amyloid (Fig. 1A). On immunohistochemistry the amyloid deposits showed positive staining for amyloid A protein (Fig. 1B). Because of the clinical association of paraganglioma and GIST in patients with SDH deficiency (Carney– Stratakis syndrome), immunohistochemistry for SDHB was also performed on the GIST. There was absence of staining demonstrating SDHB deficiency in the GIST in this patient (Fig. 1C,D, positive control). On physical examination the patient appeared cachectic with a large right sided neck mass which was non-tender, nonerythematous and non-pulsatile. His blood pressure was 100/ 80. Investigations revealed normal kidney function with serum creatinine of 87 mmol/L (normal 64–104 mmol/L), normocytic anaemia, deranged liver function tests, with an elevated ALP of 439 U/L (normal 55–120 U/L) and GGT of 263 U/L (normal

B3 thymoma arising within thymolipoma.

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