Petr Grossmann

Charles University in Prague, Praha, Praha, Czech Republic

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Publications (42)87.62 Total impact


  • No preview · Article · Jan 2016 · Applied immunohistochemistry & molecular morphology: AIMM / official publication of the Society for Applied Immunohistochemistry
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    ABSTRACT: Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome secondary to germline fumarate hydratase (FH) mutation presents with cutaneous and uterine leiomyomas, and a distinctive aggressive renal carcinoma. Identification of HLRCC patients presenting first with uterine leiomyomas may allow early intervention for renal carcinoma. We reviewed the morphology and immunohistochemical (IHC) findings in patients with uterine leiomyomas and confirmed or presumed HLRCC. IHC was also performed on a tissue microarray of unselected uterine leiomyomas and leiomyosarcomas. FH-deficient leiomyomas underwent Sanger and massively parallel sequencing on formalin-fixed paraffin-embedded tissue. All 5 patients with HLRCC had at least 1 FH-deficient leiomyoma: defined as completely negative FH staining with positive internal controls. One percent (12/1152) of unselected uterine leiomyomas but 0 of 88 leiomyosarcomas were FH deficient. FH-deficient leiomyoma patients were younger (42.7 vs. 48.8 y, P=0.024) and commonly demonstrated a distinctive hemangiopericytomatous vasculature. Other features reported to be associated with FH-deficient leiomyomas (hypercellularity, nuclear atypia, inclusion-like nucleoli, stromal edema) were inconstantly present. Somatic FH mutations were identified in 6 of 10 informative unselected FH-deficient leiomyomas. None of these mutations were found in the germline. We conclude that, while the great majority of patients with HLRCC will have FH-deficient leiomyomas, 1% of all uterine leiomyomas are FH deficient usually due to somatic inactivation. Although IHC screening for FH may have a role in confirming patients at high risk for hereditary disease before genetic testing, prospective identification of FH-deficient leiomyomas is of limited clinical benefit in screening unselected patients because of the relatively high incidence of somatic mutations.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0/.
    Full-text · Article · Nov 2015 · The American journal of surgical pathology
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    ABSTRACT: The characteristic morphologic spectrum of tubulocystic renal cell carcinoma (TC-RCC) may include areas resem- bling papillary RCC (PRCC). Our study includes 15 RCCs with tubulocystic pattern: 6 TC-RCCs, 1 RCC-high grade with tubulocystic architecture, 5 TC-RCCs with foci of PRCC, 2 with high-grade RCC (HGRCC) not otherwise specified, and 1 with a clear cell papillary RCC/renal angiomyoadenomatous tumor-like component. We analyzed aberrations of chromosomes 7, 17, and Y; mutations of VHL and FH genes; and loss of heterozygosity at chromosome 3p. Genetic analysis was performed separately in areas of classic TC-RCC and in those with other histologic patterns. The TC-RCC component demonstrated disomy of chromosome 7 in 9/15 cases, polysomy of chromosome 17 in 7/15 cases, and loss of Y in 1 case. In the PRCC component, 2/3 analyzable cases showed disomy of chromosome 7 and polysomy of chromosome 17 with normal Y. One case with focal HGRCC exhibited only disomy 7, whereas the case with clear cell papillary RCC/renal angiomyoadenomatous tumor-like pattern showed polysomies of 7 and 17, mutation of VHL, and loss of heterozygosity 3p. FH gene mutation was identified in a single case with an aggressive clinical course and predominant TC-RCC pattern. The following conclusions were drawn: (1) TC-RCC demonstrates variable status of chromosomes 7, 17, and Y even in cases with typical/uniform morphology. (2) The biological nature of PRCC/HGRCC-like areas within TC-RCC remains unclear. Our data suggest that heterogenous TC-RCCs may be associated with an adverse clinical outcome. (3) Hereditary leiomyomatosis-associated RCC can be morphologically indistinguishable from “high-grade” TC-RCC; therefore, in TC-RCC with high-grade features FH gene status should be tested.
    Full-text · Article · Oct 2015 · Applied immunohistochemistry & molecular morphology: AIMM / official publication of the Society for Applied Immunohistochemistry
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    ABSTRACT: We have studied the viability of targeted molecular screening for the identification of female patients with hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. Affected patients harbor a germ-line heterozygous mutation of the fumarate hydratase (FH) gene. Clinically, some patients present with aggressive renal cell carcinoma. Concerning women, in almost all cases, this is preceded by symptomatic uterine leiomyoma. We aimed to identify women operated on for symptomatic leiomyoma by the age of 30. Archived paraffin-embedded leiomyoma tissue was tested for the FH gene mutation in 14 cases. Two patients with multiple leiomyomas and with the confirmed germ-line mutations c.1433_1434dupAAA, p.(Lys477dup) and c.953A>T, p.(His318Leu) were identified and enrolled in a surveillance program. Statistically significant correlation between the presence of multiple uterine leiomyomas (more than seven in our experience) and the FH gene mutation was found. The immunohistochemical expression pattern, of simultaneous FH absence and S-(2-succino)cysteine (2SC) positivity, correlated with the results of the molecular genetic study in only one case. The histomorphologically simultaneous detection of enlarged nucleoli with a clear halo of leiomyocyte nuclei, their fibrillary cytoplasm, the presence of eosinophilic globules, and staghorn vessels proved to be only a partially sensitive indicator of HLRCC-associated leiomyoma and fully correlated with immunohistochemistry and molecular genetic study only in one case. Molecular genetic testing is presently the only reliable diagnostic tool able to identify HLRCC patients. The sensitivity and specificity of the presence of multiple leiomyomas in women with the FH gene mutation who are younger than 30 years old should be confirmed in larger scale studies. The applied targeted molecular screening protocol proved to be effective, resulting in identification of two positive patients out of fourteen tested individuals.
    No preview · Article · May 2015 · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin
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    ABSTRACT: Chromophobe renal cell carcinoma (CRCC) with neuroendocrine differentiation (CRCCND) has only recently been described. 18 cases of CRCC with morphologic features suggestive of neuroendocrine differentiation were selected from among 624 CRCC in our registry. The tissues were fixed in neutral formalin, embedded in paraffin, cut into 4 -5 μm thin sections and stained with Hematoxylin and Eosin (H&E). As CRCC with neuroendocrine features were suggested tumors with following morphology: 1, trabecular/palisading/ribbon-like, gyriform, insular, glandular and solid pattern. 2, uniform polygonal cells formed in small islets. 3, cribriform pattern in combination with palisading.
    Full-text · Article · May 2015 · Annals of Diagnostic Pathology
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    ABSTRACT: Papillary architecture and mostly clear cell cytology are features suggestive of translocation Xp11.2 renal cell carcinoma (TRCC) origin. Immunohistochemical (IHC) confirmation of TFE3 is unreliable. We analyzed 10 TRCC-like in detail. Ten cases of RCC with tubopapillary architecture composed of voluminous clear cells were retrieved out of 17,500 archived renal tumors. Tumors were examined using morphological and IHC methods. Status of chromosomes 7.17, and status of VHL, TFE3 genes (mutation, methylation, translocation), LOH3p were examined. Patients were 6 males and 4 females, age range 22-84 years. Tumor size ranged from 2.5 to 15 cm. Four of 10 tumors were positive for TFE3, 6/10 for cathepsin K and 5/10 for CANH 9. All 10 were positive for CD10 and vimentin. Three of 10 showed polysomy of chromosomes 7,17 and LOH3p or VHL gene mutation. One of 10 showed polysomy of chromosomes 7,17 and no VHL mutation / hypermethylation / LOH3p. All 10 were negative for TFE3 gene translocation. The group of 10 TRCC-like was heterogenous. Three TFE3 positive cases were negative for TFE3 translocation by FISH, IHC profile was variable and VHL gene was non-mutated. Another 3 cases showed overlapping morphological, IHC and genetic features between papillary (PRCC) and clear cell RCC (CRCC). Two cases were compatible with diagnosis of CRCC, two with PRCC.
    No preview · Article · Oct 2014 · Pathology
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    ABSTRACT: Unlabelled: Renal cell carcinoma (RCC) with leiomyomatous stroma (RCCLS) is a recently recognized entity with indolent biological behavior. The diagnostic implication of absence/presence of VHL gene mutation, VHL hypermethylation, or/and loss of heterozygosity of chromosome 3p (LOH 3p) is widely discussed. Criteria for establishing a diagnosis of RCCLS are still lacking. Fifteen RCCLSs were retrieved from our registry. The cases were studied with consideration to the morphology, immunohistochemistry, and molecular genetics. All cases were composed of low-grade epithelial cells with clear cytoplasm arranged in nests intermingled with abundant leiomyomatous stroma. Age range of the patients was 33 to 78 years. The tumor size ranged from 1.5 to 11 cm. Six of the patients were males, and 9, females. Of the 15 tumors sent for molecular genetic testing, only 12 cases were analyzable. All cases were analyzable immunohistochemically. Of 12 of these cases, 5 showed complete absence of VHL gene mutation, VHL hypermethylation, and LOH 3p. Of these 5 cases, 3 were positive for cytokeratin 7 (CK 7). All of the 5 cases were positive for carbonic anhydrase 9, vimentin, and CD10. The remaining 7 of 12 genetically analyzable cases were found to have had VHL hypermethylation, LOH 3p, VHL gene mutation, or a combination of the former 2 characteristics. These 7 cases were positive for vimentin. Variable reactivity was found for CK 7, carbonic anhydrase 9, α-methylacyl-CoA racemase, and CD10. In 1 of these 7 cases, gains on chromosomes 7 and 17 as well as hypermethylation of VHL gene were found. This case was considered as clear cell RCC with aberrant status of chromosomes 7 and 17. Conclusions: (1) Leiomyomatous stroma is not specific for the so called RCCLS. It can be seen also in otherwise typical clear cell RCCs. (2) There are no characteristic morphological/immunohistochemical features unique for "RCCLS." (3) Our results indicate that only tumors with the absence of the VHL gene mutation, hypermethylation, and LOH 3p can be diagnosed as RCCLS. (4) Relation of RCCs with a prominent smooth muscle stroma to the renal angiomyoadenomatous tumor/clear cell papillary (tubopapillary) RCC is not clearly evident from our study and has to be further analyzed on larger cohort of the patients.
    No preview · Article · Aug 2014 · Annals of Diagnostic Pathology
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    ABSTRACT: Mammary analogue secretory carcinoma of salivary gland origin (MASC) is a recently described tumor resembling secretory carcinoma of the breast characterized by strong S-100 protein, mammaglobin, and vimentin immunoexpression and which harbors a t(12;15) (p13;q25) translocation resulting in ETV6-NTRK3 fusion product. Histologically, conventional MASC displays bland histomorphology and a lobulated growth pattern and is often composed of microcystic, tubular, and solid structures with abundant eosinophilic homogenous or bubbly secretions. Colloid-like secretory material stains positively for periodic acid-Schiff with and without diastase as well as for Alcian Blue. We present for the first time, 3 patients with MASC of the parotid gland in which high-grade (HG) transformation developed in each case characterized by an accelerated clinical course and poor outcome. The HG component revealed strong membrane staining for EGFR and β-catenin, cytoplasmic/nuclear staining for S-100 protein, and nuclear staining for cyclin-D1, whereas HER-2/neu was absent. Analysis for the presence of the ETV6-NTRK3 fusion transcript revealed positivity in both HG and low-grade component of MASC in 2 of the 3 studied cases. The tumor in case 2 was negative in both its elements for the t(12;15) translocation, but ETV6 gene rearrangement was detected in both components in all 3 cases. Analysis of TP53 and CTNNB1 gene mutations in the HG component of MASCs as well as detection of copy number aberration of EGFR and CCND1 gene did not harbor any abnormalities. All 3 patients with HG-transformed MASC died of disseminated disease within 2 to 6 years after diagnosis. Recognizing HG-transformed MASC and testing for ETV6 rearrangement may be of potential value in patient treatment, because the presence of the ETV6-NTRK3 translocation may represent a therapeutic target in MASC.
    Full-text · Article · Oct 2013 · The American journal of surgical pathology
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    ABSTRACT: The recurrent translocations t(11;19) and t(11;15) resulting in CRTC1-MAML2 or CRTC3-MAML2 fusion oncogenes, respectively, are identified in a large proportion of mucoepidermoid carcinomas (MECs) of the salivary gland and have impact on prognosis. However, there are conflicting data on the specificity of this translocation, in particular, on its putative occurrence in Warthin tumor (WT) of the parotid gland as reported in few previous cases. It was speculated that extensive squamous metaplasia could explain the presence of t(11;19) translocation in a subset of WTs. We evaluated 76 salivary gland tumors, including 16 cases of metaplastic WT and 8 cases of pleomorphic adenoma (PA) with squamous and/or mucinous metaplasia, extensive enough morphologically to mimic MEC. Detection of CRTC1-MAML2 and CRTC3-MAML2 fusion transcripts and MAML2 gene break was performed using nested reverse transcription-polymerase chain reaction and fluorescence in situ hybridization (FISH), respectively. None of 16 analyzed metaplastic WTs showed positivity for fusion transcripts CRTC1-MAML2 or CRTC3-MAML2, and none showed rearrangement of the MAML2 gene by FISH. Similarly, we did not detect these transcripts or break of MAML2 gene in any case of PA with extensive squamous/mucinous metaplasia. For comparison, 40 cases of low-grade MEC were also evaluated. CRTC1-MAML2 and CRTC3-MAML2 fusion transcripts were detected in 17 and 5 cases, respectively. The FISH method using break-apart probe demonstrated the MAML2 gene rearrangement in 25 cases of low-grade MEC. In contrast to low-grade MEC, neither metaplastic WTs nor metaplastic PAs harbored translocations t(11;19) and anticipated t(11;15) resulting in CRTC1-MAML2 and CRTC3-MAML2 fusion transcripts, respectively, and/or MAML2 gene rearrangement.
    No preview · Article · Oct 2013 · The American journal of surgical pathology
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    ABSTRACT: Genetically, chromophobe renal cell carcinoma (ChRCC) is characterized by multiple chromosomal changes, especially losses. The most common losses include chromosomes 1, 2, 6, 10, 13, 17, and 21. The Fuhrman grading system lacks prognostic relevance for ChRCC, and recently, a new grading system for ChRCC was proposed by Paner. The objective of this study was to map the spectrum of chromosomal aberrations (extent and location) in a large cohort of ChRCCs and relate these findings to the Paner grading system (PGS). A large cohort of ChRCC was reviewed and graded according to the PGS. All the cases were reevaluated and separated into groups according to their PGS. The final study set was 37 patients. ChRCCs were divided into PG 1-3, sarcomatoid, and aggressive groups. "Aggressive ChRCCs" were designated cases with known metastatic activity, local recurrence, aggressive growth to the adjacent organs, or invasive growth into the renal sinus (with/without angioinvasion). Sarcomatoid tumors were divided into their epithelial and sarcomatoid component (further molecular genetic analyses were performed separately). Array comparative genome hybridization and/or fluorescence in situ hybridization analysis was applied to 42 samples from the 37 cases. Multiple losses, as well as gains, were detected in different chromosomes. Regardless of the PGS groups, the most frequently detected losses involved chromosomes 1 (27/37), 2 (26/37), 6 (23/37), 10 (26/37), 13 (19/37), and 17 (24/37). Loss of chromosome 21 was found in 12/37 cases. The most frequently detected gains were found on chromosomes 4 (22/37), 7 (24/37), 15 (20/37), 19 (22/37), and 20 (21/37). Cluster analysis showed that there is no relation between PGS and particular pattern of chromosomal changes (losses or gains) in ChRCCs. Conclusions are as follows: (1) ChRCCs showed a significantly broader spectrum of chromosomal aberrations than previously recognized. While previously published chromosomal losses were found in our cohort, gains of multiple chromosomes were also identified in a high percentage. The most frequently detected gains involved chromosomes 4, 7, 15, 19, and 20. (2) There is no relation between chromosomal numerical changes and Paner grading system.
    No preview · Article · Aug 2013 · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin
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    ABSTRACT: In this article the basic methods of reading nucleotide sequences in DNA molecules are summarized. Sanger sequencing is described most thoroughly as it is the most frequent routine method currently being utilized. The article describes in detail the principle of sequence determination through the production of fragments with a known end base using chain termination synthesis of DNA and ways of separation and detection of the fragments. Some alternative methods of sequencing are mentioned in short. Basic approaches of analyzing sequence data are explained as well as different outcomes, obstacles and challenges. Key words: sequencing - Sanger - synthesis - ddNTP - fluorescence - capillary electrophoresis - mutation - electropherogram.
    No preview · Article · Jul 2013 · Ceskoslovenska patologie
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    ABSTRACT: : The authors present 2 cases of a subcutaneous biphasic synovial sarcoma with marked apocrine differentiation that potentially may be confused with cutaneous epithelial neoplasms, including malignant apocrine mixed tumor or metaplastic carcinoma with an apocrine glandular component. Microscopically, both neoplasms had a biphasic architecture with the epithelial and spindle cell components. The epithelial component was prominent and consisted of simple glands with round lumina and complex glandular structures with intraluminal bridges forming cribriform areas. The glands were lined by cuboidal to columnar cells with eosinophilic or clear cytoplasm manifesting apical apocrine-like and intraluminal eosinophilic secretions. The spindle cell component was less prominent and was composed of relatively uniform or slightly atypical spindle sells surrounding and merging focally with the glandular structures. Immunohistochemically, the tumor cells in both components were positive for vimentin, AE1/AE3, CK7, and epithelial membrane antigen. Desmin, smooth muscle actin, muscle-specific actin, CD34, and S-100 protein were all negative. SYT-SSX1 gene fusion using fluorescence in situ hybridization and RT-PCR methods was detected in both cases.
    No preview · Article · Apr 2013 · The American Journal of dermatopathology
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    Semir Vranic · Ondrej Hes · Petr Grossmann · Zoran Gatalica
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    ABSTRACT: Cellular hypoxia is a hallmark of cancer. Hypoxia-inducible factor-1α (HIF-1α) and von Hippel-Lindau protein (pVHL) are the key mediators of cellular response to hypoxia. Little is known about their role in germ cell tumors of the testis. We therefore examined their status in a cohort of germ cell tumors of the testis. Thirty-six primary germ cell tumors of the testis (11 seminomas, 24 mixed germ cell tumors, and 1 case of pure intratubular germ cell neoplasia) were included in the study. HIF-1α and pVHL expression were studied using immunohistochemical (IHC) methods in the tumor and adjacent benign tissue. Selected cases with a low pVHL expression were further tested for genetic alterations using polymerase chain reaction. HIF-1α protein expression was not detectable in adjacent atrophic seminiferous tubules. In contrast, HIF-1α was expressed in one third of the malignancies, but in a low percentage of cells (mean, 3%; range, 0% to 20%). No difference in HIF-1α expression was observed between seminomas and nonseminomas (P=0.71). pVHL was expressed in atrophic tubular epithelium and in the Leydig cells, whereas a substantial loss of pVHL expression was observed in germ cell tumors regardless of the histologic type (mean, 45.6%; range, 0% to 100%). No genetic alterations of the VHL gene were observed in the cases with low pVHL expression. No significant correlation between HIF-1α and pVHL expression was observed (P=0.16). Germ cell tumors of the testis, regardless of the histologic type, are characterized by consistently low HIF-1α protein overexpression and a partial loss of pVHL without underlying VHL gene alterations. Further studies are necessary to clarify the functional importance of such alterations in testicular germ cell tumors.
    Full-text · Article · Mar 2013 · Applied Immunohistochemistry
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    ABSTRACT: We present a cohort of 8 renal carcinomas that displayed a variable (5%-95% extent) light microscopic appearance of renal angiomyoadenomatous tumor/clear cell papillary renal cell carcinoma (RAT/CCPRCC) without fulfilling the criteria for these tumors. All but 1 case predominantly (75%-95% extent) showed histopathologic features of conventional clear cell renal cell carcinoma. In 5 of 7 cases with mostly conventional clear renal cell carcinoma (CRCC) morphology, a diagnosis of CRCC was supported by the molecular genetic findings (presence of von Hippel-Lindau tumor suppressor [VHL] mutation and/or VHL promoter methylation and/or loss of heterozygosity [LOH] for 3p). Of the other 2 cases with predominantly characteristic CRCC morphology, 1 tumor did not reveal any VHL mutation, VHL promoter methylation, or LOH for 3p, and both chromosomes 7 and 17 were disomic, whereas the other tumor displayed polysomy for chromosomes 7 and 17 and no VHL mutation, VHL promoter methylation, or LOH for 3p. One tumor was composed primarily (95%) of distinctly RAT/CCPRCC-like morphology, and this tumor harbored a VHL mutation and displayed polysomy for chromosomes 7 and 17. Of the 5 cases with both histomorphologic features and molecular genetic findings of CRCC, we detected significant immunoreactivity for α-methylacyl-CoA racemase in 2 cases and strong diffuse immunopositivity for cytokeratin 7 in 3 cases. Despite the combination of positivity for α-methylacyl-CoA racemase and cytokeratin 7 in 2 cases, there was nothing to suggest of the possibility of a conventional papillary renal cell carcinoma with a predominance of clear cells.
    Full-text · Article · Feb 2013 · Human pathology
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    ABSTRACT: We report 3 cases of primary renal cell tumor simulating atrophic kidney with distinct gross, morphologic, immunohistochemical, and molecular genetic features. The tumors were retrieved out of more than 17 000 renal tumors from the Plzen Tumor Registry. Tissues for light microscopy had been fixed, embedded and stained with hematoxylin and eosin using routine procedures. The tumors were further analyzed using immunohistochemistry, arrayCGH, and HUMARA. Analyses of VHL gene and LOH3p were also performed. The patients were 2 females and 1 male, with age range 29–35 years (mean 31.3 years). Grossly, the neoplasms were encapsulated, round with largest diameter 3.5 cm (mean 3.2 cm). Follow up available for all patients ranged from 2 to 14 years (mean 8 years). No aggressive behavior was noted. Histologically, akin atrophic (postpyelonephritic) kidney parenchyma, the tumors were composed of follicles of varying sizes that were filled by eosinophilic secretion. Rare areas contained collapsed follicles. Each follicle was endowed with a small capillary. The stroma was loose, inconspicuous and focally fibrotic. Two types of calcifications were noted: typical psammoma bodies and amorphous dark blue stained calcified deposits. Immunohistochemically, tumors were strongly positive for cytokeratins (OSCAR), CD10 and vimentin, with weak immunopositivity for CAM5.2 and AE1-AE3. WT1 and cathepsin K were weakly to moderately focally to diffusely positive. Tumors were negative for CK 20, carbonic anhydrase IX, parvalbumin, HMB45, TTF1, TFE3, chromogranin A, thyroglobulin, PAX8, and ALK. Only 1 case was suitable for molecular genetic analyses. No mutations were found in the VHL gene; no methylation of VHL promoter was noted. No numerical aberrations were found by aCGH analysis. LOH for chromosome 3p was not detected. Analysis of clonality (HUMARA) revealed monoclonal nature of the tumor. We describe unknown tumor of the kidney which: 1) resembles renal atrophic kidney or nodular goiter of thyroidal gland; 2) contains a leiomyomatous capsule and two types of calcifications; 3) lacks mitoses, atypias, necroses, hemorrhages; nearly lack Ki-67 positivity; 4) so far showed benign biological behavior.
    No preview · Article · Jan 2013 · Annals of diagnostic pathology
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    ABSTRACT: Brooke-Spiegler syndrome (BSS) is a rare, inherited, autosomal dominant disorder characterized by development of multiple adnexal cutaneous neoplasms including spiradenoma, cylindroma, spiradenocylindroma, and trichoepithelioma. The syndrome of multiple familial trichoepitheliomas (MFT) is considered a phenotypic variant of BSS in which patients present with trichoepitheliomas only. We studied germline and somatic mutations of the CYLD gene by direct sequencing in patients with BSS (n = 49) and MFT (n = 18) using peripheral blood and 90 samples of frozen or formalin-fixed paraffin-embedded tumor tissue selected from 379 available histology specimens. Germline CYLD mutations were found in 51 patients (76%) from 36 families (75%). Germline CYLD mutations were found in 43 of the 49 patients with BSS (88%) but in only 8 of 18 MFT cohort (44%). Twenty-one frameshift, 15 nonsense, 3 missense, and 4 splice site mutations were found in patients with BSS, whereas 1 frameshift, 5 nonsense, and 2 splice site mutations were identified in the MFT cohort. Five novel mutations were identified including 4 frameshift mutations (c.1027dupA/p.T343NfsX7, c.2155dupA/p.M719NfsX5, c.2288_2289delTT/p.F763X, and c.2641delG/p.D881TfsX32) and 1 nonsense mutation (c.2713C>T/p. Q905X). Of the 76 tumors from 32 patients with a germline CYLD mutation, 12 were spiradenomas, 15 spiradenocylindromas, 26 cylindromas, 15 trichoepitheliomas, and 7 were other tumor types. Somatic mutations were detected in 67 specimens of these 76 tumors (88%). Of the 67 somatic mutations, 21 (31%) represented a sequence alteration and 46 (69%) showed loss of heterozygosity. In the remaining 9 cases (12%), the somatic changes remained unknown. A germline CYLD mutation was not detected in 14 tumor samples from 8 patients. In these 14 tumors, somatic mutations were identified in 6 samples (43%), all consisting of sequence alterations (1 sample showed 2 different sequence alterations). In the remaining 8 samples (53%), neither germline nor somatic mutations were found in the lesional tissue. Our study increases the catalog of known CYLD mutations in patients with BSS/MFT to 86 and documents the variability of somatic mutations that may occur in them. We confirm the absence of firm genotype-phenotype correlations and the existence of a subset of patients with BSS/MFT who lack a demonstrable germline CYLD mutation. Further studies are needed to explain the reasons for this phenomenon.
    No preview · Article · Dec 2012 · The American Journal of dermatopathology
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    ABSTRACT: We present a case of renal epithelioid angiomyolipoma (eAML)/perivascular epithelioid cell tumor (PEComa) with a TFE3 gene break visible by fluorescence in situ hybridization (FISH). Histologically, the tumor was composed of mainly epithelioid cells forming solid arrangements with small foci of spindle cells. In a small portion of the tumor, neoplastic cells displayed nuclear pleomorphism, such as polygonal and enlarged vesicular nuclei with prominent nucleoli. Marked vascularity was noticeable in the background, and perivascular hyaline sclerosis was also seen. Immunohistochemically, neoplastic cells were diffusely positive for α-smooth muscle actin and melanosome in the cytoplasm. Nuclei of many neoplastic cells were positive for TFE3. FISH analysis of the TFE3 gene break using the Poseidon TFE3 (Xp11) Break probe revealed positive results. Reverse transcriptase-polymerase chain reactions (RT-PCR) for ASPL/TFE3, PRCC/TFE3, CLTC/TFE3, PSF/TFE3, and NonO/TFE3 gene fusions all revealed negative results. This is the first reported case of renal eAML/PEComa with a TFE3 gene break, and it has unique histological findings as compared to previously reported TFE3 gene fusion-positive PEComas. Pathologists should recognize that PEComa with TFE3 gene fusion can arise even in the kidney.
    No preview · Article · Dec 2012 · Medical Molecular Morphology
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    ABSTRACT: Juxtaglomerular cell tumors (JGCTs) are rare tumors characterized by renin synthesis, hyperaldosteronism and hypertension. A curious immunohistochemical overlap between JGCT and gastrointestinal stromal tumor (GIST) including the expression of vimentin, CD34, CD117, α-smooth muscle actin was previously reported, prompting us to further investigate JGCT and its phenotypic and molecular genetic characteristics. Virtual karyotyping showed gain of chromosomes 3, 4, 10, 13, 17 and 18 in one JGCT, and fluorescence in situ hybridization (FISH) study confirmed this multiple gain pattern. Additionally, loss of chromosome 9 was observed in four of six cases analyzed with FISH. A whole genome expression analysis revealed 415 up-regulated (including renin, and CD117) and 325 down-regulated genes between the 2 cases. The study confirmed earlier reports on the gain of chromosomes 4 and 10, and provided further evidence of up-regulation of the genes located on these 2 chromosomes. For the first time our study indicated the importance of the loss of chromosome 9 and loss of expression of several tumor suppressor genes located on this chromosome as possible pathogenetic events important in development of JGCT.
    No preview · Article · Aug 2012 · Human pathology
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    ABSTRACT: Muir-Torre syndrome (MTS), a phenotypic variant of the more common hereditary nonpolyposis colorectal cancer syndrome, or Lynch syndrome, is an autosomal dominantly inherited condition that combines at least one cutaneous sebaceous neoplasm and at least one visceral malignancy. Most patients (~90%) with MTS carry mutations in the MSH2 gene; less than 10% of the cases are associated with a mutation MLH1 gene, and only 3 MTS patients with a pathogenic MSH6 mutation have been previously documented. We report a family affected with MTS in which 3 members (father and 2 sons) were found to harbor a missense mutation c.2633T>C (p.V878A) in exon 4 of the MSH6 gene.
    No preview · Article · Aug 2012 · The American Journal of dermatopathology
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    ABSTRACT: Two unusual Carney complex patients are described. In one of them, several cutaneous biopsies revealed myxoid lesions that were rather more close to authentic adnexal neoplasms with myxoid stroma than to a "myxoma with an epithelial component." These included lesions resembling trichofolliculoma, infundibular cyst, and trichodiscoma. Additionally, 1 soft tissue myxoma was unique in the sense that it greatly resembled a cardiac myxoma, begging the question whether this could represent an embolus from the patient's cardiac myxoma. Given the large size and complexity and heterogeneity of the cutaneous lesions, the authors suggest that these may represent authentic cutaneous neoplasms accompanied by myxoid stroma and not adnexal elements induced by the stroma. However, the latter mechanism is well recognized and demonstrated by our second patient in whom adnexal-type elements in the cutaneous lesion were clearly induced by the myxoid stroma but were unusually complex by manifesting panfollicular and also sebaceous differentiation.
    No preview · Article · May 2012 · The American Journal of dermatopathology