Review of TFEB-amplified renal cell carcinoma with focus on clinical and pathobiological aspects.

The disease entity of TFEB-amplified renal cell carcinoma (RCC) has been recently established. In this article, we review such cases. Clinically, the age of patients ranged from 28 to 83 years with a mean age of 62.8 years. The size of the tumor ranged from 1.9 to 19.5 cm with a mean size of 8.7 cm. The tumor demonstrated a variety of architectural patterns such as solid, alveolar, papillary, pseudopapillary, nested or tubular. The International Society of Urological Pathology (ISUP) grade usually corresponds to grade 3 or 4. Cytomorphology shows eosinophilic, clear, amphophilic or even oncocytic cytoplasm. Necrosis can be frequently observed. Neoplastic cells with TFEB-amplified RCC show diffuse or patchy positivity for TFEB. Fluorescence in situ hybridization frequently show the amplification of more than 10 or 20 copies of the TFEB gene. Most TFEB-amplified RCCs behave in an aggressive fashion. Metastasis frequently occurs. In conclusion, this tumor seems to be characterized by occurrence in older patients, frequent necrosis, papillary/pseudopapillary growth pattern, high-grade nuclear grade, TFEB gene amplification, and aggressive clinical behavior. In order to clarify whether this tumor is a distinct entity from previously described renal tumors or not, a further examination in a large scale study will be required in the future.

Renal Cell Carcinoma With Leiomyomatous Stroma: A Group of Tumors With Indistinguishable Histopathologic Features, But 2 Distinct Genetic Profiles: Next-Generation Sequencing Analysis of 6 Cases Negative for Aberrations Related to the VHL gene.

We have studied a cohort of renal cell carcinomas (RCCs) with smooth-muscle stroma (N=6), which lacked any of following genetic aberrations: mutations in the VHL-gene-coding sequence, loss of heterozygosity of chromosome 3p, or hypermethylation of VHL. Using targeted next-generation sequencing, no intronic VHL mutations or mutations in selected genes involved in angiogenesis and genes frequently mutated in clear cell RCC were identified. Tumors were also tested for the presence of hotspot mutations in the TCEB1 gene with negative results in all cases. We conclude that there exists a group of RCCs with abundant leiomyomatous stroma, where the epithelial component is indistinguishable from conventional clear cell RCC and distinct from clear cell (tubulo-) papillary RCC and that these tumors lack aberrations related to the function of the VHL gene, mutations in genes involved in angiogenesis, and hotspot mutations in the TCEB1 gene.

Cystic and necrotic papillary renal cell carcinoma: prognosis, morphology, immunohistochemical, and molecular-genetic profile of 10 cases.

Conflicting data have been published on the prognostic significance of tumor necrosis in papillary renal cell carcinoma (PRCC). Although the presence of necrosis is generally considered an adverse prognostic feature in PRCC, we report a cohort of 10 morphologically distinct cystic and extensively necrotic PRCC with favorable biological behavior. Ten cases of type 1 PRCC with a uniform morphologic pattern were selected from the 19 500 renal tumors, of which 1311 were PRCCs in our registry. We focused on precise morphologic diagnosis supported by immunohistochemical and molecular-genetic analysis. Patients included 8 men and 2 women with an age range of 32-85 years (mean, 62.6 years). Tumor size ranged from 6 to 14 cm (mean, 9.4 cm). Follow-up data were available in 7 patients, ranging from 0.5 to 14 years (mean, 4 years). All tumors were spherical, cystic, and circumscribed by a thick fibrous capsule, filled with hemorrhagic/necrotic contents. Limited viable neoplastic tissue was present only as a thin rim in the inner surface of the cyst wall, consistent with type 1 PRCC. All cases were positive for AMACR, OSCAR, CAM 5.2, HIF-2, and vimentin. Chromosome 7 and 17 polysomy was found in 5 of 9 analyzable cases, 2 cases demonstrated chromosome 7 and 17 disomy, and 1 case showed only chromosome 17 polysomy. Loss of chromosome Y was found in 5 cases, including 1 case with disomic chromosomes 7 and 17. No VHL gene abnormalities were found. Papillary renal cell carcinoma type 1 can present as a large hemorrhagic/necrotic unicystic lesion with a thick fibroleiomyomatous capsule. Most cases showed a chromosomal numerical aberration pattern characteristic of PRCC. All tumors followed a nonaggressive clinical course. Large liquefactive necrosis should not necessarily be considered an adverse prognostic feature, particularly in a subset of type 1 PRCC with unilocular cysts filled with necrotic/hemorrhagic material.

Mixed Epithelial and Stromal Tumor of the Kidney: Mutation Analysis of the DICER 1 Gene in 29 Cases.

Cystic nephroma (CN) and mixed epithelial stromal tumor (MEST) of the kidney have been considered as synonymous terms describing a single nosologic entity in adult patients. Cystic nephroma in pediatric patients (PCN) is, apparently, a completely different nosologic entity. Although the presence of DICER 1 mutations is well established in PCN, nothing is currently known about the DICER 1 gene status in adult MEST/CN. About 33 cases of MEST/CN were selected from the Plzen Tumor Registry; 4 cases were later excluded from the study due to low DNA quality. About 28 of the studied tumors displayed a benign morphology, whereas 1 was diagnosed as a malignant MEST/CN with sarcomatoid differentiation of the stromal component. All 29 samples analyzed using polymerase chain reaction and direct sequencing, including the case with the malignant morphology, were negative for mutation in DICER 1 hot-spot codons 1705, 1709, 1809, 1810, 1813, and 1814. Our results show that MEST/CN has no relation to PCN on a molecular genetic level. On the basis of our findings and the established morphologic differences between PCN and MEST/CN, we conclude that the term CN should be used for pediatric cases only and should be avoided in adult cases of MEST.

Mixed epithelial and stromal tumor of the middle ear: The first case report.

We report a tumor arising in the middle ear of a 65-year-old female patient that was composed of an ovarian-type stroma (OS) and an epithelial component. The tumor consisted of irregular, polypoid masses containing multiple variably sized cystic spaces, which were invariably surrounded by the OS. The cystic spaces were lined by flat, cuboidal, or columnar epithelial cells, in most parts showing mucinous differentiation. The epithelial lining of the cysts strongly expressed cytokeratins AE1-3, CK7, CK8, CK18, CK19, EMA, and S100 protein. The stroma expressed CD34 and smooth muscle actin. No cytological atypia or mitoses were present, and the proliferative activity was less than 1% in both components. The clonality analysis proved the clonal nature of the neoplasm. We believe that this tumor is a new member in the family of neoplasms containing the OS, and therefore we propose the term mixed epithelial and stromal tumor of the middle ear.

Morphological, immunohistochemical, and chromosomal analysis of multicystic chromophobe renal cell carcinoma, an architecturally unusual challenging variant.

Chromophobe renal cell carcinoma (ChRCC) is typically composed of large leaf-like cells and smaller eosinophilic cells arranged in a solid-alveolar pattern. Eosinophilic, adenomatoid/pigmented, or neuroendocrine variants have also been described. We collected 10 cases of ChRCC with a distinct multicystic pattern out of 733 ChRCCs from our registry, and subsequently analyzed these by morphology, immunohistochemistry, and array comparative genomic hybridization. Of the 10 patients, 6 were males with an age range of 50-89 years (mean 68, median 69). Tumor size ranged between 1.2 and 20 cm (mean 5.32, median 3). Clinical follow-up was available for seven patients, ranging 1-19 years (mean 7.2, median 2.5). No aggressive behavior was documented. We observed two growth patterns, which were similar in all tumors: (1) variable-sized cysts, resembling multilocular cystic neoplasm of low malignant potential and (2) compressed cystic and tubular pattern with slit-like spaces. Raisinoid nuclei were consistently present while necrosis was absent in all cases. Half of the cases showed eosinophilic/oncocytic cytology, deposits of pigment (lipochrome) and microcalcifications. The other half was composed of pale or mixed cell populations. Immunostains for epithelial membrane antigen (EMA), CK7, OSCAR, CD117, parvalbumin, MIA, and Pax 8 were positive in all tumors while negative for vimentin, TFE3, CANH 9, HMB45, cathepsin K, and AMACR. Ki67 immunostain was positive in up to 1 % of neoplastic cells. Molecular genetic examination revealed multiple chromosomal losses in two fifths analyzable tumors, while three cases showed no chromosomal numerical aberrations. ChRCC are rarely arranged in a prominent multicystic pattern, which is probably an extreme form of the microcystic adenomatoid pigmented variant of ChRCC. The spectrum of tumors entering the differential diagnosis of ChRCC is quite different from that of conventional ChRCC. The immunophenotype of ChRCC is identical with that of conventional ChRCC. Chromosomal numerical aberration pattern was variable; no chromosomal numerical aberrations were found in three cases. All the cases in this series have shown an indolent and non-aggressive behavior.

Selected Case From the Arkadi M. Rywlin International Pathology Slide Seminar: Benign Warthin Tumor of the Thyroid.

We report on an exceedingly rare lesion of the thyroid probably of a branchial cleft origin, which was not published in the world literature before. A 58-year-old woman underwent a total thyroidectomy for bilateral goiter. Grossly, there was one yellowish nodule sized 15 mm in the largest dimension found in the right lobe. Microscopically, the thyroid parenchyma showed signs of Hashimoto thyroiditis. The nodule in the right lobe was composed of a part of solid cell nests appearance, another part resembling a branchial cleft cyst, and a part resembling Warthin tumor. This lesion may belong to the histogenetically similar group of entities in the head and neck region which are derived from branchial cleft derivatives and which, under the inflammatory influence, have the ability to a cystic dilatation and proliferation of the epithelial component. The epithelium can afterwards become papillary and may undergo oncocytic transformation, thus gaining features that impart the resemblance of a Warthin tumor. Club members generally agreed with a submitted diagnosis of benign Warthin tumor of the thyroid.

Littoral cell angioma of the spleen: a study of 25 cases with confirmation of frequent association with visceral malignancies.

AIMS: Littoral cell angioma (LCA) is a rare primary splenic tumour that is frequently associated with internal malignancies. Immunohistochemistry can demonstrate a distinct hybrid endothelial-histiocytic phenotype of littoral cells, and is a helpful adjunct for making the correct diagnosis. The aims of this study were to present a series of 25 LCAs, with an emphasis on the frequent association of the neoplasm with visceral malignancies, and to provide a detailed immunohistochemical analysis by employing new markers. METHODS AND RESULTS: All 25 cases with available tissue blocks were immunohistochemically stained for endothelial and histiocytic markers. Clinical and follow-up data were retrieved from the respective institutions. The tumours were obtained from 16 males and nine females, whose age ranged from 32 to 86 years (mean 56.2 years). Clinical information was available for 24 of 25 patients, and follow-up for 11 of 25 patients (range 2-19 years; mean 11.6 years). Immunohistochemically, all cases were positive for LYVE-1, factor VIII, FLI-1, vascular endothelial growth factor receptor (VEGFR)-2, VEGFR-3, claudin-5, ERG, LMO2, CD31, CD163, lysozyme, and CD4, but negative for D2-40, CD8, and factor XIIIa. Fifteen of 25 cases were associated with various malignancies, including epithelial, mesenchymal and haematological tumours. CONCLUSIONS: The cohort of 25 patients is the largest series of LCAs published to date. By using antibodies against recently introduced endothelial markers, we have expanded the immunoprofile of LCA. We have further highlighted the clinical significance of LCA, as more than half of the patients in this study also harboured a coexisting visceral malignancy. Therefore, we conclude that the finding of splenic LCA mandates a thorough clinical evaluation for a concomitant malignancy.

Histiocytosis With Raisinoid Nuclei: A Unifying Concept for Lesions Reported Under Different Names as Nodular Mesothelial/Histiocytic Hyperplasia, Mesothelial/Monocytic Incidental Cardiac Excrescences, Intralymphatic Histiocytosis, and Others: A Report of 50 Cases.

We report 50 cases of peculiar histiocytic proliferations occurring in diverse body sites that currently bear various names, including nodular mesothelial/histiocytic hyperplasia, nodular histiocytic aggregates, mesothelial/monocytic incidental cardiac excrescences, reactive eosinophilic pleuritis, histioeosinophilic granuloma of the thymus, and intralymphatic histiocytosis. They can sometimes cause considerable differential diagnostic difficulties by resembling a metastatic carcinoma or Langerhans cell histiocytosis. Several previous publications have established a link between some of these conditions, suggesting that these are merely variations within a histopathologic spectrum, affecting different organs and bearing different names based on a particular location. However, no publication has ever comprehensively addressed all of these lesions together in one study in an attempt to explain and discuss their striking analogy. Having studied a large series of cases we provide evidence that all these lesions share the same morphologic, immunohistochemical, and pathogenetic properties, thus they all represent the same pathologic process and should be referred to as such. Taking into account their typical nuclear features we propose a collective term "histiocytosis with raisinoid nuclei" for this spectrum of conditions.

"Mucin"-secreting papillary renal cell carcinoma: clinicopathological, immunohistochemical, and molecular genetic analysis of seven cases.

Mucin and mucin-like material are features of mucinous tubular and spindle renal cell carcinoma (MTS RCC) but are rarely seen in papillary renal cell carcinoma (PRCC). We reviewed 1311 PRCC and identified 7 tumors containing extracellular and/or intracellular mucinous/mucin-like material (labeled as PRCCM). We analyzed these using morphological, histochemical, immunohistochemical, and molecular genetic methods (arrayCGH, FISH). Clinical data were available for six of the seven patients (five males and one female, age range 61-78 years). Follow-up was available for four patients (2-4 years); one patient died of widespread metastases. Tumor size ranged from 3 to 5 cm (mean 3.8). Of all cases, histological architecture showed a predominantly papillary pattern. Mucin or mucin-like was extracellular in one, intracellular in three, and both intra/extracellular in three cases. All tumors were positive for AMACR, vimentin, and OSCAR, while CK7 was positive in four. Mucicarmine stain was positive in all cases, PAS in six and Alcian blue in three cases. Five tumors were positive for MUC 1, but none were positive for MUC 2, MUC 4, or MUC 6. In only four cases, genetic analysis could be performed. Gain of chromosomes 7 and 17 was found in two cases; gain of 17 only was found in one case. Loss of heterozygosity of 3p was found in one case together with polysomy of chromosomes 7 and 17. No abnormalities of VHL, fumarate dehydrogenase, and TFE3 genes were detected. We conclude that PRCCM is a rare but challenging subtype of RCC that deserves to be further studied. In all the tumors, the mucin-like material was found in those stained with mucicarmin, but other conventional and immunohistochemical stains did not reveal consistent features of a single mucin. The molecular-genetic profile of these tumors was most consistent with that of typical papillary RCC, although one case had mixed genetic features of papillary and clear RCC. PRCCM has metastatic potential, as evidenced by one case with widespread metastases. It remains to be determined whether PRCCM represents a unique tumor subtype, deserving to be distinguished from other subtypes of PRCC.

Biphasic Squamoid Alveolar Renal Cell Carcinoma: A Distinctive Subtype of Papillary Renal Cell Carcinoma?

Biphasic squamoid alveolar renal cell carcinoma (BSARCC) has been recently described as a distinct neoplasm. Twenty-one cases from 12 institutions were analyzed using routine histology, immunohistochemistry, array comparative genomic hybridization (aCGH) and fluorescence in situ hybridization. Tumors were removed from 11 male and 10 female patients, whose age ranged from 53 to 79 years. The size of tumors ranged from 1.5 to 16 cm. Follow-up information was available for 14 patients (range, 1 to 96 mo), and metastatic spread was found in 5 cases. All tumors comprised 2 cell populations arranged in organoid structures: small, low-grade neoplastic cells with scant cytoplasm usually lining the inside of alveolar structures, and larger squamoid cells with more prominent cytoplasm and larger vesicular nuclei arranged in compact nests. In 9/21 tumors there was a visible transition from such solid and alveolar areas into papillary components. Areas composed of large squamoid cells comprised 10% to 80% of total tumor volume. Emperipolesis was present in all (21/21) tumors. Immunohistochemically, all cases were positive for cytokeratin 7, EMA, vimentin, and cyclin D1. aCGH (confirmed by fluorescence in situ hybridization) in 5 analyzable cases revealed multiple numerical chromosomal changes including gains of chromosomes 7 and 17 in all cases. These changes were further disclosed in 6 additional cases, which were unsuitable for aCGH. We conclude that tumors show a morphologic spectrum ranging from RCC with papillary architecture and large squamoid cells to fully developed BSARCC. Emperipolesis in squamoid cells was a constant finding. All BSARCCs expressed CK7, EMA, vimentin, and cyclin D1. Antibody to cyclin D1 showed a unique and previously not recognized pattern of immunohistochemical staining. Multiple chromosomal aberrations were identified in all analyzable cases including gains of chromosomes 7 and 17, indicating that they are akin to papillary RCC. Some BSARCCs were clinically aggressive, but their prognosis could not be predicted from currently available data. Present microscopic, immunohistochemical, and molecular genetic data strongly support the view that BSARCC is a distinctive and peculiar morphologic variant of papillary RCC.

Molecular Genetic Alterations in Renal Cell Carcinomas With Tubulocystic Pattern: Tubulocystic Renal Cell Carcinoma, Tubulocystic Renal Cell Carcinoma With Heterogenous Component and Familial Leiomyomatosis-associated Renal Cell Carcinoma. Clinicopathologic and Molecular Genetic Analysis of 15 Cases.

The characteristic morphologic spectrum of tubulocystic renal cell carcinoma (TC-RCC) may include areas resembling 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.

Cystic Renal Oncocytoma and Tubulocystic Renal Cell Carcinoma: Morphologic and Immunohistochemical Comparative Study.

Renal oncocytoma (RO) may present with a tubulocystic growth in 3% to 7% of cases, and in such cases its morphology may significantly overlap with tubulocystic renal cell carcinoma (TCRCC). We compared the morphologic and immunohistochemical characteristics of these tumors, aiming to clarify the differential diagnostic criteria, which facilitate the discrimination of RO from TCRCC. Twenty-four cystic ROs and 15 TCRCCs were selected and analyzed for: architectural growth patterns, stromal features, cytomorphology, ISUP nucleolar grade, necrosis, and mitotic activity. Immunohistochemical panel included various cytokeratins (AE1-AE3, OSCAR, CAM5.2, CK7), vimentin, CD10, CD117, AMACR, CA-IX, antimitochondrial antigen (MIA), EMA, and Ki-67. The presence of at least focal solid growth and islands of tumor cells interspersed with loose stroma, lower ISUP nucleolar grade, absence of necrosis, and absence of mitotic figures were strongly suggestive of a cystic RO. In contrast, the absence of solid and island growth patterns and presence of more compact, fibrous stroma, accompanied by higher ISUP nucleolar grade, focal necrosis, and mitotic figures were all associated with TCRCC. TCRCC marked more frequently for vimentin, CD10, AMACR, and CK7 and had a higher proliferative index by Ki-67 (>15%). CD117 was negative in 14/15 cases. One case was weakly CD117 reactive with cytoplasmic positivity. All cystic RO cases were strongly positive for CD117. The remaining markers (AE1-AE3, CAM5.2, OSCAR, CA-IX, MIA, EMA) were of limited utility. Presence of tumor cell islands and solid growth areas and the type of stroma may be major morphologic criteria in differentiating cystic RO from TCRCC. In difficult cases, or when a limited tissue precludes full morphologic assessment, immunohistochemical pattern of vimentin, CD10, CD117, AMACR, CK7, and Ki-67 could help in establishing the correct diagnosis.

Chromophobe renal cell carcinoma with neuroendocrine and neuroendocrine-like features. Morphologic, immunohistochemical, ultrastructural, and array comparative genomic hybridization analysis of 18 cases and review of the literature.

Chromophobe renal cell carcinoma (CRCC) with neuroendocrine differentiation (CRCCND) has only recently been described. Eighteen cases of CRCC with morphologic features suggestive of neuroendocrine differentiation were selected from among 624 CRCCs in our registry. The tissues were fixed in neutral formalin, embedded in paraffin, cut into 4- to 5-µm-thick sections, and stained with hematoxylin and eosin. As CRCC with neuroendocrine features, tumors with following morphology were suggested: (1) trabecular/palisading/ribbon-like, gyriform, insular, glandular, and solid pattern; (2) uniform polygonal cells formed in small islets; and (3) cribriform pattern in combination with palisading. Selected cases were further analyzed using immunohistochemistry, electron microscopy, array comparative genomic hybridization, and fluorescence in situ hybridization. Cases were classified as CRCCND or CRCC with neuroendocrine-like features (CRCCND-L) based on the immunohistochemical expression of neuroendocrine markers: CRCCND, 4 cases, age range 49 to 79 years, size ranged from 2.2 to 22 cm, and CRCCND-L, 14 cases, age range 34 to 74 years, size range 3.8 to 16.5 cm. Follow-up information was available for 11 of 18 patients aged 0.5 to 12 years. Two of 4 CRCCNDs showed aggressive clinical course with metastatic spreading. Chromophobe renal cell carcinomas with neuroendocrine differentiation were focally positive for CD56 (4/4), synaptophysin (4/4), chromogranin A (1/4), and neuron-specific enolase (3/4). All 14 CRCCND-Ls were mostly negative or very weakly focally positive for some of the aforementioned markers. All 18 tumors were positive for cytokeratin 7 and CD117. Ultrastructural analysis showed poorly preserved neuroendocrine granules only in 2 of 4 analyzed CRCCNDs. Losses of chromosomes 1, 2, 6, and 10 were found in all analyzable CRCCNDs, whereas multiple losses (chromosomes 1, 2, 6, 10, 13, 17, and 21) and gains (chromosomes 4, 11, 12, 14, 15, 16, 19, and 20) were found in CRCCND-L.

Mucinous spindle and tubular renal cell carcinoma: analysis of chromosomal aberration pattern of low-grade, high-grade, and overlapping morphologic variant with papillary renal cell carcinoma.

The chromosomal numerical aberration pattern in mucinous tubular and spindle renal cell carcinoma (MTSRCC) is referred to as variable with frequent gains and losses. The objectives of this study are to map the spectrum of chromosomal aberrations (extent and location) in a large cohort of the cases and relate these findings to the morphologic variants of MTSRCC. Fifty-four MTSRCCs with uniform morphologic pattern were selected (of 133 MTSRCCs available in our registry) and divided into 3 groups: classic low-grade MTSRCC (Fuhrman nucleolar International Society of Urological Pathology grade 2), high-grade MTSRCC (grade 3), and overlapping MTSRCC with papillary renal cell carcinoma (RCC) morphology. Array comparative genomic hybridization analysis was applied to 16 cases in which DNA was well preserved. Four analyzable classic low-grade MTSRCCs showed multiple losses affecting chromosomes 1, 4, 8, 9, 14, 15, and 22. No chromosomal gains were found. Four analyzable cases of MTSRCC showing overlapping morphology with PRCC displayed a more variable pattern including normal chromosomal status; losses of chromosomes 1, 6, 8, 9, 14, 15, and 22; and gains of 3, 7, 16, and 17. The group of 4 high-grade MTSRCCs exhibited a more uniform chromosomal aberration pattern with losses of chromosomes 1, 4, 6, 8, 9, 13, 14, 15, and 22 and without any gains detected. (1) MTSRCC, both low-grade and high-grade, shows chromosomal losses (including 1, 4, 6, 8, 9, 13, 14, 15, and 22) in all analyzable cases; this seems to be the most frequent chromosomal numerical aberration in this type of RCC. (2) Cases with overlapping morphologic features (MTSRCC and PRCC) showed a more variable pattern with multiple losses and gains, including gains of chromosomes 7 and 17 (2 cases). This result is in line with previously published morphologic and immunohistochemical studies that describe the broad morphologic spectrum of MTSRCC, with changes resembling papillary RCC. (3) The diagnosis of MTSRCC in tumors with overlapping morphology (MTSRCC and PRCC) showing gains of both chromosomes 7 and 17 remains questionable. Based on our findings, we recommend that such tumors should not be classified as MTSRCC but rather as PRCC.

Molecular-genetic analysis is essential for accurate classification of renal carcinoma resembling Xp11.2 translocation carcinoma.

Xp11.2-translocation renal carcinoma (TRCC) is suspected when a renal carcinoma occurs in young patients, patients with a prior history of exposure to chemotherapy and when the neoplasm has morphological features suggestive of that entity. We retrieved 20 renal tumours (from 17,500 archival cases) of which morphology arose suspicion for TRCC. In nine cases, TFE3 translocation was confirmed by fluorescence in situ hybridisation analysis. In 9 of the remaining 11 TRCC-like cases (7 male, 4 female, aged 22-84 years), material was available for further study. The morphological spectrum was diverse. Six tumours showed a mixture of cells with eosinophilic or clear cytoplasm in tubular, acinar and papillary architecture. One case was high grade with epithelioid, spindle cell and sarcomatoid areas. Another showed tubular, solid, and papillary areas and foci containing spindle cells reminiscent of mucinous tubular and spindle cell carcinoma. The third showed dyscohesive nests of large epithelioid and histiocytoid cells in a background of dense lymphoplasmacytic infiltrate. By immunohistochemistry, keratin AE1/AE3 was diffusely positive in three tumours, while CK7 strongly stained one tumour and another focally and weakly. CD10 and Pax8 were expressed by eight, AMACR and vimentin by seven, CA-IX by four and TFE3 and cathepsin K by two tumours. Of the two TFE3-positive tumours, one showed polysomy of chromosome 7 and the other of 17; they were VHL normal and diagnosed as unclassifiable RCC. Of the seven TFE3-negative tumours, three showed polysomy of 7/17 and VHL abnormality and were diagnosed as combined clear cell RCC/papillary RCC. One TFE3-negative tumour with normal 7/17 but LOH 3p (VHL abnormality) was diagnosed as clear cell RCC. One TFE3-negative tumour with polysomy 7/17 but normal VHL was diagnosed as papillary RCC, and two with normal chromosomes 7/17 and VHL gene were considered unclassifiable. As morphological features and IHC are heterogeneous, TRCC-like renal tumours can only be sub-classified accurately by multi-parameter molecular-genetic analysis.

Aggressive and nonaggressive translocation t(6;11) renal cell carcinoma: comparative study of 6 cases and review of the literature.

UNLABELLED: t(6;11) renal cell carcinoma (RCC) has been recognized as a rare and mostly nonaggressive tumor (NAT). The criteria for distinguishing aggressive tumors (AT) from NATs are not well established. A total of 6 cases were selected for the study. Five cases of t(6;11) RCCs behaved nonaggressively, and 1 was carcinoma with aggressive behavior. The tumors were analyzed morphologically using immunohistochemistry and by molecular-genetic methods. The specimen of aggressive t(6;11) RCC was from a 77-year-old woman who died of the disease 2.5 months after diagnosis. The specimens of nonaggressive t(6;11) RCCs were from 3 women and 2 men whose ages range between 15 and 54 years. Follow-up was available in all cases (2.5 months-8 years). The tumor size ranged from 3 to 14 cm in nonaggressive t(6;11) RCC. In the aggressive carcinoma, the tumor size was 12 cm. All tumors (6/6) were well circumscribed. Aggressive t(6;11) RCC was widely necrotic. Six (100%) of 6 all tumors displayed a solid/alveolar architecture with occasional tubules and pseudorosettes. Pseudopapillary formations lined by bizarre polymorphic cells were found focally in the aggressive t(6;11) RCC case. Mitoses, though rare, were found as well. All cases (AT and NAT) were positive for HMB-45, Melan-A, Cathepsin K, and cytokeratins. CD117 positivity was seen in 4 of 5 NATs, as well as in the primary and metastatic lesions of the AT. mTOR was positive in 2 of 5 NATs and vimentin in 4 of 5 NATs. Vimentin was negative in the primary lesion of the AT, as well as in the metastasis found in the adrenal gland. Translocation t(6;11)(Alpha-TFEB) or TFEB break was detected in 4 of 5 NATs and in the AT case. Aggressive tumor showed amplification of TFEB locus. Losses of part of chromosome 1 and chromosome 22 were found in 1 of 5 NATs and in the AT. CONCLUSIONS: (1) Aggressive t(6;11) RCCs generally occur in the older population in comparison with their indolent counterparts. (2) In regard to the histologic findings in ATs, 3 of 5 so far published cases were morphologically not typical for t(6;11) RCC. Of the 3 cases, 2 cases lacked a small cell component and 1 closely mimicked clear cell-type RCC. (3) Necroses were only present in aggressive t(6;11) RCC. (4) Amplification of TFEB locus was also found only in the aggressive t(6;11) RCC.

Renal cell carcinoma with leiomyomatous stroma--further immunohistochemical and molecular genetic characteristics of unusual entity.

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.