SWI/SNF-deficient undifferentiated/rhabdoid carcinoma of the gallbladder carrying a POLE mutation in a 30-year-old woman: a case report.

BACKGROUND: Undifferentiated carcinoma of the biliary tract are highly aggressive malignancies. In other organs, a subgroup of undifferentiated carcinoma related to SWI/SNF complex-deficiency have been described. CASE PRESENTATION: A 30-year-old woman presented with rising inflammatory markers (C-reactive protein (CRP)). Ultrasound examination revealed a large tumor of the liver. A computed tomography scan was performed and was primarily interpreted as a tumor-forming liver abscess, possibly caused by gallbladder perforation. Subsequent liver segment resection was performed. Microscopic examination showed an undifferentiated carcinoma with rhabdoid morphology and prominent inflammatory infiltrate in the gallbladder base. With SWI/SNF immunohistochemistry, intact expression of SMARCB1, SMARCA4, ARID1A, but loss of SMARCA2 and PBRM1 was detected. Next-generation-sequencing detected KRAS, PBRM1 and ARID1B mutations, a deleterious splice-site mutation in the POLE-gene and a mutation in the TP53-gene. CONCLUSIONS: We were able to demonstrate loss of SMARCA2 expression and mutations characteristic of an SWI/SNF-deficient carcinoma in a tumor derived from the gallbladder. This is the first reported case of an undifferentiated carcinoma with rhabdoid features in the gallbladder carrying a POLE mutation and SWI/SNF-deficiency of PBRM1 and SMARCA2.

Undifferentiated large cell/rhabdoid carcinoma presenting in the intestines of patients with concurrent or recent non-small cell lung cancer (NSCLC): clinicopathologic and molecular analysis of 14 cases indicates an unusual pattern of dedifferentiated metastases.

Undifferentiated carcinoma metastatic to the bowel is uncommon in surgical pathology practice and might be confused with primary gastrointestinal carcinoma, melanoma, lymphoma, and others. We present 14 cases of uni- (n = 9) or multifocal (n = 5) undifferentiated large cell/rhabdoid carcinoma presenting in the bowel of patients with concurrent (n = 9) or recent (diagnosed 1 to 25 months earlier; median, 4) non-small cell lung cancer (NSCLC). Patients were 6 females and 8 males, aged 52 to 85 years. Primary NSCLC was verified histologically in 10 cases and by imaging in 4. The undifferentiated histology was present in the lung biopsy in 4/10 patients (as sole pattern in 3 and combined with adenocarcinoma in 1) and was limited to the intestinal metastases in the remainder. PDL1 was strongly expressed in 7/9 cases (CPS: 41 to 100). Loss of at least one SWI/SNF subunit was detected in 7/13 cases (54%). SMARCA2 loss (n = 6) was most frequent and was combined with SMARCA4 loss in one case. PBRM1 loss was observed in one tumor. Successful molecular testing of 11 cases revealed BRAF mutations in 4 (3 were non-V600E variants), KRAS mutations in 3, and wildtype in 4. None had EGFR mutations. Analysis of 4 paired samples revealed concordant KRAS (2) and BRAF (1) mutations or wildtype (1). Our study indicates that undifferentiated carcinoma within the intestines of patients with concurrent/recent NSCLC represents dedifferentiated metastasis from the NSCLC. Recognition of this unusual presentation is cardinal to avoid misdiagnosis with inappropriate therapeutic and prognostic implications.

[SCCOHT/ovarian rhabdoid tumor: A case report]. / SCCOHT/tumeur rhabdoïde ovarienne : à propos d'un cas.

We report the case of a 22-year-old patient with acute abdominopelvic pain. The diagnosis of hypercalcemic small cell carcinoma (SCCOHT)/ovarian rhabdoid tumor has been made. Small cell carcinoma of hypercalcemic type is a rare and aggressive tumor that occurs in young women. The diagnosis of this tumor and the management must be rapid in view of its aggressiveness. Through this observation, we specify the epidemiological, diagnostic, molecular aspects and discussions about its name.

PGR Gene Fusions Identify a Molecular Subset of Uterine Epithelioid Leiomyosarcoma With Rhabdoid Features.

Genetic aberrations among uterine epithelioid leiomyosarcomas are unknown. Following identification of an index case with NR4A3-PGR fusion demonstrating monomorphic morphologic features, we interrogated additional uterine tumors demonstrating similar histology and sought to describe the morphologic and immunohistochemical characteristics of PGR-rearranged sarcomas. Targeted next-generation RNA sequencing was performed on RNA extracted from formalin-fixed paraffin-embedded tissue of the index case. Fluorescence in situ hybridization using custom probes flanking PGR and NR4A3 genes was applied to 17 epithelioid leiomyosarcomas, 6 endometrial stromal tumors, and 3 perivascular epithelioid cell tumors. NR4A3-PGR fusion (n=4) and PGR rearrangement (n=2) were detected in 6 (35%) epithelioid leiomyosarcomas. Median patient age was 45 years, and all presented with FIGO stage I or II tumors, 2 being alive with disease at 75 and 180 months. All tumors were centered in the cervical stroma or myometrium and consisted of cells with abundant eosinophilic cytoplasm (epithelioid), including many displaying dense intracytoplasmic inclusions (rhabdoid). Myxoid matrix and hydropic change imparted a microcystic growth pattern in 4 tumors. Five also showed a minor spindle cell component which was low-grade in 3, consisting of bland spindle cells with low mitotic activity. High-grade spindle cell morphology was seen in 2 tumors, exhibiting a storiform pattern of atypical spindle cells associated with brisk mitotic activity. Desmin, estrogen receptor, and progesterone receptor were positive in all 6 tumors, while CD10 and HMB45 were negative. PGR rearrangements define a genetic subset of epithelioid leiomyosarcomas with often biphasic morphology consisting of epithelioid and rhabdoid as well as spindle cell components.

Neuroendocrine tumor of the pancreas with rhabdoid feature.

Imaging of a 53-year-old Japanese man revealed two tumors in the liver and a tumor in the head of the pancreas with a swelling lymph node. A needle biopsy for the liver tumors was performed, revealing a neuroendocrine tumor. Enucleation, lymphadenectomy, and partial hepatectomy were performed. The microscopic examination identified many tumor cells with intracytoplasmic inclusions arranged in a nested, cord, or tubular fashion. The intracytoplasmic inclusions displayed densely eosinophilic globules and displaced the nuclei toward the periphery, which constitutes "rhabdoid" features. The tumor cells were positive for synaptophysin and weakly positive for NCAM, but negative for chromogranin A. Epithelial markers (AE1/AE3 and CAM5.2) accentuated intracytoplasmic globules. Pancreatic neuroendocrine tumors with rhabdoid features are very rare. Generally, rhabdoid features are aggressive and dedifferentiated characteristics of various types of tumor. Pancreatic neuroendocrine tumors containing rhabdoid cells tend to display extrapancreatic spread at the time of presentation, although some of these tumors with rhabdoid features are not always associated with aggressive behavior.

SMARCA4 (BRG1) loss of expression is a useful marker for the diagnosis of ovarian small cell carcinoma of the hypercalcemic type (ovarian rhabdoid tumor): a comprehensive analysis of 116 rare gynecologic tumors, 9 soft tissue tumors, and 9 melanomas.

Ovarian small cell carcinoma of the hypercalcemic type (SCCOHT)/ovarian rhabdoid tumor is a rare and highly malignant tumor that typically occurs in young women. Up until now the diagnosis has been made on the basis of morphology without any specific immunohistochemical (IHC) markers. However, several authors have shown recently that SCCOHTs are characterized by inactivation of the SMARCA4 gene (encoding the BRG1 protein) resulting in a loss of BRG1 protein expression in IHC. We evaluated BRG1 and INI1 expression in 12 SCCOHTs and in a series of 122 tumors that could mimic SCCOHT morphologically: 9 juvenile granulosa cell tumors, 47 adult granulosa cell tumors, 33 high-grade ovarian serous carcinomas, 9 desmoplastic round cell tumors, 13 Ewing sarcomas (5 from the pelvis and 8 from soft tissues), 1 round cell sarcoma associated with CIC-DUX4 translocation from soft tissue (thigh), 1 case of high-grade endometrial stromal sarcoma of the ovary, and 9 melanomas. Forty-four adult granulosa cell tumors were interpretable by IHC. All 12 SCCOHTs were devoid of BRG1 expression and expressed INI1. All other interpretable 119 tumors showed BRG1 nuclear positivity, with variable staining proportions, ranging from 10% to 100% of positive cells (mean: 77%, median: 80%), variable intensities (weak: 5%, moderate: 37%, strong: 58%), and distributions: diffuse in 82 cases (70%) and heterogenous in 36 cases (30%). BRG1 positivity was heterogenous in desmoplastic round cell tumors and adult granulosa cell tumors. Overall, BRG1 is a useful diagnostic marker in SCCOHT, showing the absence of expression in SCCOHT. Nevertheless, the possible heterogeneity and the variable intensity of this staining warrant caution in the interpretation of BRG1 staining in biopsy specimens.

Primary atypical teratoid/rhabdoid tumor of the optic nerve: a rare entity in an exceptional location.

Atypical teratoid/rhabdoid tumors are rare and highly malignant central nervous system tumors. They have no specific radiological features and often present several histological components that make a problem in differential diagnosis with medulloblastoma and primitive neuroectodermal tumors. We present the case of a newborn girl complained of a gradual proptosis of the left eye secondary to an expansive lesional process of the optic nerve. The location at the optic nerve, reported only twice in the literature, and an exclusive rhabdoid appearance on biopsy added additional differential diagnosis problems. The proptosis worsened and the infant died few days after two cycles of chemotherapy. VIRTUAL SLIDES: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2037718783145212 .

Review of renal cell carcinoma with rhabdoid features with focus on clinical and pathobiological aspects.

Rhabdoid morphology in renal cell carcinoma (RCC) may, like sarcomatoid change, be perceived as a type of dedifferentiation, and is a poor prognostic factor. Histologically, rhabdoid neoplastic cells are round to polygonal cells with globular eosinophilic cytoplasmic inclusions and eccentric vesicular nuclei and enlarged nucleoli. All types of RCC, including clear cell, papillary, chromophobe, collecting duct carcinoma, renal medullary carcinoma, acquired cystic disease-associated RCC, ALK-positive renal cancer and unclassified RCC, may display a variably prominent rhabdoid phenotype. Immunohistochemically, the cytoplasm of rhabdoid cells shows positivity for vimentin and/or cytokeratin. Ultrastructurally, cytoplasmic whorls/aggregates of intermediate filaments correspond to light microscopically observed inclusions. Genetically, a previous report suggests that combined loss of BAP1 and PBRM1 may be associated with rhabdoid morphology. As with sarcomatoid change, pathologists should describe, estimate and state the proportion of tumor cells with a rhabdoid phenotype in the routine pathology report of RCC.

Primary atypical teratoid/rhabdoid tumor of central nervous system in children: a clinicopathological analysis and review of literature in China.

Atypical teratoid/rhabdoid tumor (AT/RT) is a very rare and highly malignant embryonal tumor in the central nervous system (CNS). Five patients (4 girls and 1 boy) with AT/RT were treated in our hospital. The clinical histories, symptoms, neuroimaging aspects, therapies, histological and immunohistochemical findings and follow-up information were reviewed. The patients ranged from 8 to 40 months with a mean age of 20.6 months. One tumor was located in the spinal cord, two in cerebellum and two in the pineal region. The imagings of the tumors resemble medulloblastomas. Pathological examinations showed that one patient had medulloblastoma differentiation, one had choroid plexus carcinoma differentiation, and one had mesenchymal components. Immunohistochemical staining showed that all of the tumors lost the nuclear expression of integrase interactor 1 (INI1), and were positive for Vimentin, S-100 protein and epithelial membrane antigen. One case with no recurrence after 24 months may have benefited from radical excision and postoperative radiotherapy. The other 4 patients died 8, 4, 1 and 1-month respectively after operation without radiotherapy. The diagnosis of AT/RT depends on full sampling, careful observation the morphological characteristics and INI1 examination, even when the tumor are presented in uncommon sites, such as the spinal cord and the pineal region.

No small surprise - small cell carcinoma of the ovary, hypercalcaemic type, is a malignant rhabdoid tumour.

Whole-exome sequencing (WES) is revolutionizing medical diagnostics and taxonomy. In less than 5 years since its first use, WES has revealed unexpected molecular drivers of numerous cancers. Here, we describe our use of WES to uncover the true nature of an enigmatic pathological entity, small-cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), which has resisted definitive characterisation since it was first described in 1979. We conducted WES using three families with SCCOHT and identified deleterious mutations in the chromatin-remodelling gene SMARCA4 (encoding BRG1) in all cases. Follow-up of these findings, using both Sanger sequencing and WES of formalin-fixed paraffin-embedded tumours, showed that virtually all SCCOHTs we studied lacked functional SMARCA4/BRG1. Notably, this gene, and the related SMARCB1 gene, is mutated in most, if not all, atypical teratoid/rhabdoid tumours and malignant rhabdoid tumours. Other groups have similar findings. We review the relationship between these three neoplasms, discuss how they were distinguished from morphologically similar neoplasms, consider their similarities and show how WES has revealed that SCCOHTs are in fact rhabdoid tumours. We propose that SCCOHT be renamed 'malignant rhabdoid tumour of the ovary' (MRTO) to reflect these observations.

SMARCB1 (INI1)-negative rhabdoid carcinomas of the gastrointestinal tract: clinicopathologic and molecular study of a highly aggressive variant with literature review.

Gastrointestinal (GI) neoplasms with rhabdoid features have been reported since 1989 under diverse names (giant cell carcinoma, pleomorphic carcinoma, malignant rhabdoid tumor, adenocarcinoma with rhabdoid features/phenotype, anaplastic carcinoma, etc.), but their clinicopathologic spectrum, SMARCB1 (INI1) status and relationship to common GI carcinomas have not been clarified yet. We describe 2 carcinomas from the stomach and the cecum with exclusive rhabdoid morphology. The patients died of disease at 6 and 10 months, respectively. The tumors coexpressed vimentin, pancytokeratin, and EMA. Both showed complete loss of nuclear SMARCB1/INI1. Molecular analysis (KRAS, EGFR, BRAF, PIK3CA, and microsatellite studies) revealed a CpG-island methylator phenotype in the cecal tumor (CIMP(+)/MLH1(-)/BRAF(V600E)/MSI-H), confirming epithelial origin. The gastric tumor showed poorly differentiated adenocarcinoma in regional nodes, again confirming epithelial derivation. Other genes tested were wild type in both cases. Review of reported cases (total: 39) revealed a glandular component in 33%. Affected sites are: stomach (13), colon (11), small bowel (10), and distal esophagus (5). Of the 34 patients with follow-up ≥12 months, 29 (85%) died within 1 year (mean: 4 mo). Molecular tests were performed in 8/39 cases. A CIMP(+)/BRAF(V600E)/MLH1(-) phenotype was found in 3/4 right colon tumors. Loss of nuclear SMARCB1 protein was noted in 3/6 cases tested. This study highlights the heterogeneity of rhabdoid GI neoplasms and supports their epithelial derivation. Rhabdoid phenotype likely represents a common pathway of dedifferentiation with frequent loss of SMARCB1 and highly aggressive course. The CIMP phenotype represents a novel subset of rhabdoid GI carcinomas. This rare variant should be distinguished from proximal-type epithelioid sarcoma and other SMARCB1-deficient mimics.

Atypical teratoid rhabdoid tumor in childhood, 15 cases of a single institute experience.

OBJECTIVE: Atypical teratoid rhabdoid tumor is a rare neoplasm with a distinct cytogenetic profile that predominates in infancy. Many cases show predominance of small cells with scanty rhabdoid cells, making recognition of this tumor difficult. We aim at describing our experience with atypical teratoid rhabdoid tumor cases diagnosed over a 6-year period. MATERIAL AND METHOD: Clinicopathologic features and immunohistochemical staining of atypical teratoid rhabdoid tumor cases diagnosed between 2006 and 2011 are presented. RESULTS: Fifteen cases were identified including 9 males with a median age of 26 months. The most common presenting symptom was recurrent vomiting with a mean duration of 6 weeks. Nine cases (60%) were infratentorial and cerebrospinal fluid was positive in 2 cases (13.3%) at time of diagnosis. The median overall survival of the group was 9.5 months. All cases except one showed admixture of rhabdoid and/or small round blue cells in variable proportions. Only 5 out of fourteen referred cases (35.7%) were correctly diagnosed. Three cases showed unusual growth patterns. In 2 cases, nodular medulloblastoma-like growth pattern predominated, with loss of INI-1/BAF47 staining both within the nodules and the inter-nodular areas. The third case contained scattered individual and small groups of large cells with abundant acidophilic cytoplasm and eccentric nuclei, reminiscent of rhabdomyoblasts that were positive for GFAP and desmin, and retained nuclear staining for INI-1/BAF47, consistent with reactive gemistocytes. CONCLUSION: Pathologists should be aware of the various, and unusual histopathologic patterns of atypical teratoid rhabdoid tumor. INI-1/ BAF47 immunostain should be performed on all central nervous system embryonal tumors, especially in infants and young children.

Cutaneous location of atypical teratoid/rhabdoid tumour.

Atypical teratoid/rhabdoid tumour is a rare and highly malignant tumour of the posterior fossae nervous system that occurs in children especially in the first few years of life. Cutaneous location is not previously reported. A newborn boy was referred for both aqueductal stenosis detected antenatally and skin tags mimicking hamartoma. The cerebral tumour increased in size during a few months leading to both skin and cerebral biopsies. Integrase Interactor-1 (INI-1) immunostaining and tumoural and leukocytes INI-1 gene sequencing confirmed the atypical teratoid/rhabdoid tumour nature of the cerebral tumour. INI-1 immunostaining in skin biopsy confirmed the dermal location of rhabdoid tumour. Thus, unusual cutaneous lesions may be part of atypical teratoid/rhabdoid tumour. The loss of Integrase INI-1 on immunohistochemical staining is characteristic.

Epidermal growth factor receptor abnormalities in atypical teratoid/rhabdoid tumors and an unusual case with gene amplification.

Atypical teratoid/rhabdoid tumor (AT/RT) is a rhabdoid tumor of the central nervous system comprising a mixture of small round cells and mesenchymal and/or epithelial elements, showing mutation of the SMARCB1 gene or SMARCA4 gene. The epidermal growth factor receptor (EGFR) is one of the tyrosine kinase receptors whose overexpressed protein plays important roles in the malignant characteristics of various tumors. We analyzed 8 Japanese cases of AT/RT for EGFR protein overexpression and egfr gene amplification using immunohistochemistry and fluorescence in situ hybridization. The patients included 7 boys and 1 girl (age range 13 days to 2 years), and the tumors were localized in the frontal lobe (1 case), lateral ventricle (1 case), third ventricle (1 case), fourth ventricle (3 cases), and cerebellum (2 cases). We found that all (100%) of them partially expressed a high level of EGFR protein, and that one case showed amplification of egfr, the amplified area being localized and limited to a specific area within the tumor. We speculate that AT/RT is a tumor with heterogeneous egfr amplification, and that the frequency of amplification may depend on loss of function of the specific chromatin-remodeling member.

[Atypical teratoid rhabdoid tumor: case report]. / Atipik teratoid rabdoid tümör: olgu sunumu.

Atypical teratoid rhabdoid tumor is a rare highly malignant embryonal tumor of the central nervous system that is often seen in early childhood. It is very important to distinguish it from other brain tumors because it has a very poor prognosis and there are differences in its treatment. A case of atypical teratoid rhabdoid tumor in a six-week-old male baby is presented. The tumor was located at posterior fossa. Histopathologically, the tumor has rhabdoid tumor cells and mesenchymal components beside the undifferentiated small cells. While EMA, vimentin, synaptophysin and smooth muscle actin have been stained with immunohistochemical staining, desmin, chromogranin, CD 99 and CD 56 have not been stained. The patient died four months after surgery despite the chemotherapy given. In conclusion, morphological characteristics can vary to a large extent that it is difficult to recognize atypical teratoid rhabdoid tumor. Immunohistochemical panel and molecular genetic study will help to establish the correct diagnosis.

Right-sided rhabdoid colorectal tumors might be related to the serrated pathway.

BACKGROUND: Rhabdoid colorectal tumor (RCT) is a rare, highly aggressive neoplasm recurrent in elderly patients, commonly at the caecum. The molecular mechanisms underlying RCT pathogenesis remain poorly elucidated. The differential diagnosis is with the malignant rhabdoid tumors of infancy characterized by genetic inactivation of SMARCB1 (INI1) or deletions of chromosome 22q12 locus. MATERIALS AND METHODS: To shed light on RCT pathogenesis, we investigated genetic and epigenetic alterations in two cases of pure and composite RCT and compared them with the profiles of matched adenomas and normal mucosa. Immunohistochemical analysis, FISH, methylation specific PCR and DNA sequencing analysis were performed on paraffin-embedded tissues. RESULTS: Loss of epithelial markers, (CK20, CDX2 and E-cadherin) and intense vimentin expression was observed in RCTs but neither in the normal mucosa or adenomas. INI1 expression was detected in normal mucosa, adenomas and retained in pure RCT, while it was undetected in composite RCT. Rearrangement of the 22q12 locus was found only in pure RCT. The APC/ß-catenin pathway was not altered, while MLH1 immunostaining was negative in RCTs and positive in adenomas and normal mucosa. These expression profiles were associated with V600E BRAF mutation, a progressive accumulation of promoter methylation at specific CIMP loci and additional genes from the normal mucosa to tubular adenoma and RCT. CONCLUSIONS: Right-sided RCT could be characterized by epigenetic events and molecular features likely similar to those occurring in the serrated pathway and associated with epithelial-mesenchymal transition. These extremely rare tumors may benefit from the use of new biological molecules specific for colorectal carcinoma. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1641385210804556.

Conventional chondrosarcoma in a survivor of rhabdoid tumor: enlarging the spectrum of tumors associated with SMARCB1 germline mutations.

SMARCB1 germline mutations mainly predispose to rhabdoid tumors. However, less aggressive tumors with a later onset have also been reported in a context of SMARCB1 constitutional mutation-that is, schwannomatosis and meningiomatosis. No other tumor type has formally been observed in such a context thus far. We report on a patient treated for a thoracic malignant rhabdoid tumor at 8 years of age who subsequently developed a mandibular conventional chondrosarcoma at 13 years of age. Both tumors showed a loss of BAF47 expression. The malignant rhabdoid tumor exhibited a large 22q11.2 deletion and an intragenic deletion of SMARCB1 (exons 1 to 3), thus leading to a biallelic inactivation. A 2.8 Mbp deletion encompassing SMARCB1 was found in the germline. This context was a strong incentive to investigate SMARCB1 alterations in the second tumor. As expected, the chondrosarcoma showed the large 22q11.2 deletion but also an additional c.243C>G(p.Tyr18X) premature stop codon in the remaining allele. This report relates for the first time a pediatric conventional chondrosarcoma to the wide family of SMARCB1-deficient tumors. Moreover, we report here the first case of conventional chondrosarcoma arising in a context of constitutional SMARCB1 deletion and, thus, enlarge the spectrum of this tumor predisposition syndrome.