In this report, we present for the first time the coexistence of a conventional renal cell carcinoma (RCC) and an undefined Xp11 translocation renal neoplasm in distinct kidneys, which was difficult to definitively classify as either carcinoma or PEComa (perivascular epithelioid cell tumor). While one of the tumors showed the morphological and immunohistochemical features of clear RCC, the other had an unusual morphology with a prominent nested pattern. Microscopically this tumor showed nests of cells with clear and eosinophilic cytoplasm and nuclei with prominent nucleoli; some hyaline globules were evident. Immunohistochemical panel showed negativity for cytokeratin-pan, cytokeratin-7, PAX8, and CD10 but positive immunostaining for cathepsin K, racemase, Melan-A, and TFE3. A subsequent, metaphase, dual-color fluorescence in situ hybridization confirmed the Xp11 translocation. Attention should be paid to the routine immunohistochemical profile that, in case of negativity of specific RCC markers, may suggest an Xp11 translocation renal tumor. The addition of TFE3 can easily identify the specific subtype.

Translocation-type renal carcinoma has been recently discovered, and it is possible that this tumor may have been previously diagnosed as other types of renal tumor. We have subjected 41 renal tumors, including VHL gene mutation-negative clear cell renal cell carcinoma (RCC), papillary RCC, and chromophobe RCC, to immunohistochemistry of transcription factor E3 (TFE3) and TFEB. All tumors were histologically evaluated by additional immunohistochemical study. As a result, 5 tumors showed a positive reaction for TFE3 with a range from 1+ to 2+ in intensity. No tumors were positive for TFEB. In 5 tumors immunohistochemically positive for TFE3, chimeric transcripts including ASPL-TFE3, PRCC-TFE3, CLTCTFE3, PSF-TFE3, or Nono-TFE3 were not detected. The diagnosis of 6 tumors was changed by reevaluation through retrospective histological and immunohistochemical study. In 4 of 6 tumors, the diagnosis of clear cell RCC was changed to chromophobe RCC. In 1 tumor, oncocytoma was detectable, and RCC with rhabdoid features and sarcomatoid changes was detected in 1 tumor. Finally, the cutoff value of TFE3 immunohistochemistry should be more than 2+ with a wide range. The translocation-type renal carcinoma seems to be quite rare.

OBJECTIVE

To study the clinicopathologic features, immunophenotype and genetic changes of perivascular epithelioid cell neoplasms (PEComa).

METHODS

A total of 25 cases of PEComa located in various anatomic sites were selected for immunohistochemical staining (SP or EnVision method). TFE3 fluorescence in-situ hybridization was also performed to determine the TFE3 gene status.

RESULTS

The age of patient ranged from 21 to 61 years (mean = 43 years). The male-to-female ratio was 1: 1.3. Histologically, 22 cases represented conventional angiomyolipomas, composed of a mixture of adipose tissue, spindle element, epithelioid smooth muscle cells and abnormal thick-walled blood vessels in various proportions. Three cases involving lung, soft tissue and broad ligament had subtle but distinctive morphologic features. Nested or sheet-like architecture with epithelioid or spindle cells was observed. Immunohistochemical study showed that HMB 45, melan A, smooth muscle actin and cathepsin K were expressed in 80% (20/25), 88% (22/25), 88% (22/25) and 100% (25/25) of PEComa, respectively. Within positive cases, the average proportion of positive tumor cells was 36%, 41%, 35% and 90% respectively for HMB 45, melan A, smooth muscle actin and cathepsin K. TFE3 was negative in all of the 22 renal and hepatic PEComa studied, while it was positive in the 3 cases of extra-hepatorenal PEComa. None of the 25 cases exhibited evidence of TFE3 gene fusion or amplification.

CONCLUSIONS

Extra-hepatorenal PEComa have distinctive morphologic features and are associated with TFE3 overexpression. Cathepsin K immunostaining demonstrates high sensitivity and specificity in PEComa, better than other commonly employed immunomarkers. This marker is thus useful in diagnosis of PEComa and distinction with other neoplasms.

Objective: To investigate the morphological features and immunophenotypes of eosinophilic renal tumors in order to provide references for the differential diagnosis of this tumor. Methods: A cohort of 75 cases of eosinophilic renal tumors were collected. The morphological features of the tumors were observed under microscope, and the immunophenotypes of the tumors were detected using tissue microarray and immunoshistochemistry. Results: There were some overlaps between the different types of eosinophilic renal tumors in morphology, but each had its distinct characteristics. Immunohistochemically, renal oncocytoma (RO) and eosinophilic chromophobe renal cell carcinoma (ChRCC) shared some common immumophenotypes, except for the expression of CK7, with the expression rates of 2/19 in RO and 17/20 in eosinophilic ChRCC, respectively. Eosinophilic clear cell renal cell carcinoma mainly showed positive immunostaining for Vimentin and CAⅨ, whereas negative for CK7 and CD117 in most cases (10/15). AMACR was diffusely expressed in the majority of eosinophilic papillary renal cell carcinoma (PRCC, 10/13). Furthermore, vimentin, CK7 and CD10 were positively expressed in eosinophilic PRCC with the expression rates of 8/13, 9/13 and 6/13, respectively; while CAⅨ, CD117 and TFE3 were all negatively expressed in eosinophilic PRCC.Epithelioid angiomyolipoma generally showed positive expression of vimentin, SMA and HMB45, but negative expression of CAⅨ and CK7. Vimentin, CD10, AMACR and TFE3 were strongly expressed in XP11.2 translocation renal cell carcinoma; on the contrary, CK7, CD117 and HMB45 were not expressed in the majority of the tumor. Conclusion: With full understanding of the morphology of different types of eosinophilic renal tumors, the immunostaining of vimentin, CAⅨ, CK7, CD10, AMACR, CD117, TFE3 and HMB45 could play a crucial role in the differential diagnosis of these tumors.

Epithelioid hemangioendothelioma (EHE) is a rare malignant angiocentric vascular neoplasm. Around 90% of classic EHE has a t(1;3)(p36;q25) that results in a WWTR1-CAMTA1 fusion gene, a histologically distinctive subset of EHE has been recently shown to have a t(10;14)(p13;q42)that results in a different fusion gene, YAP1-TFE3. Twenty-one cases of TFE3 Rearranged Epithelioid Hemangioendothelioma have been reported in the literature, and only two cases occurred in bone. In the report, we report additional two cases occurred in the femur and skull and review the related literature.

Hemangioblastomas (HBs) histologically overlap with TFE3 rearrangement-associated tumors, which present as alveolar architecture and clear or eosinophilic granular cytoplasm. However, whether TFE3 is expressed in HBs remains unexplored. Herein, we analyzed the clinicopathologic features of 42 HBs emphasizing studies of TFE3 expression. Of 42 cases, 38 were sporadic and 4 were regarded as a part of von Hippel-Lindau (VHL) syndrome according to clinical presentation. Nineteen patients were male and 23 were female. Patient age ranged from 17 to 70 years (median 43). Tumor size ranged from 0.4 to 4.8 cm (mean 2.2 cm). Follow-up ranged from 1 to 60 months and 6 patients developed recurrence. Immunohistochemistry staining showed that 36 (86%) of 42 HBs expressed TFE3 in nuclei of tumor cells, of which 21 were evaluated as high TFE3 expression levels. Increased TFE3 expression was significantly associated with older ages (P=0.018) and larger tumor size (P=0.001). Seventeen HBs with high TFE3 expression were negative for rearrangement and amplification of TFE3 by FISH analysis, 3 of which including 2 sporadic and 1 VHL-related HBs demonstrated trisomies or tetrasomies of X-chromosome in 7%~18% of tumor cells. All 3 cases occurred in female, presented with a larger tumor size and displayed a similar morphologic appearance with high cellularity and hyperchromatic nuclei. Our study first reports TFE3 expression and its clinicopathological relevance in HBs. We hypothesize that TFE3 might be involved in the pathogenesis of non-VHL-related HBs. Furthermore, HBs with strong TFE3 expression should be differentiated from brain-metastatic TFE3-rearranged tumors.

Keywords: Hemangioblastoma; TFE3; clinicopatholgical features; immunohistochemistry staining.

OBJECTIVE

To study the clinicopathologic features, immunophenotype, differential diagnosis and prognosis of renal cell carcinoma (RCC) associated with t(6;11)(p21.2;q13)/MALAT1-TFEB gene fusion.

METHODS

A total of 9 cases of such rare tumor were selected for clinicopathologic, immunohistochemical and molecular analysis, with review of literature.

RESULTS

The age of the patients ranged from 21 to 42 years (mean=31.3 years). The patients included four men and five women. Histologically, 4 of the 9 cases studied showed classic morphologic features of TFEB RCC, with hyaline material, pigments and psammoma bodies frequently identified. The remaining 5 cases demonstrated uncommon morphology, mimicking perivascular epithelioid cell neoplasm, clear cell RCC, chromophobe RCC or papillary RCC. Immunohistochemical study showed that TFEB and vimentin were positive in all cases. Most of the tumors studied also expressed Ksp-cadherin, E-cadherin, CD117, HMB45, Melan A and Cathepsin K. CKpan showed immunostaining in only 1 case. The staining for TFE3, CD10 and CK7 were all negative. TFEB gene rearrangement was detected in all the 9 cases studied using fluorescence in-situ hybridization. MALAT1-TFEB fusion gene was identified in 2 cases by polymerase chain reaction and direct sequencing. TFEB RCC seemed to be an indolent tumor. During a mean follow-up of 31 months, none developed tumor recurrence, progression, or metastasis.

CONCLUSIONS

TFEB fusion-associated RCC is a rare neoplasm, tends to occur in young age group and carries an indolent behavior. Diagnosis relies on clinicopathologic findings and immunohistochemical analysis. TFEB break-apart FISH assay is a reliable tool in confirming the diagnosis.

Ossifying fibromyxoid tumor (OFMT) is an uncommon mesenchymal neoplasm of uncertain differentiation and intermediate malignant potential. Recurrent PHF1 gene rearrangements are detected in up to 80% of OFMTs. We describe the clinicopathologic features of five OFMTs harboring a novel PHF1-TFE3 fusion. In two cases, RNA sequencing identified a fusion transcript composed of PHF1 exon 11 fused to TFE3 exon 3, whereas in a third case PHF1 exon 12 was fused to TFE3 exon 7. A FISH break-apart assay revealed rearrangements in both PHF1 and TFE3 genes in all cases. The cohort included three males and two females with a median age of 64 years. One OFMT originated in the scapula, while four occurred in the deep soft tissues. Two OFMTs had typical features, whereas three were classified as malignant. Despite uniform cytologic features and fibromyxoid stroma compatible with an OFMT diagnosis, none showed a peripheral shell of lamellar bone. S100 expression was focally present in only one case, while desmin was positive in three cases. All tumors showed strong nuclear immunopositivity for TFE3. All three malignant OFMTs developed metastases, either regionally or to the lung. One patient died of disease 1 year after diagnosis, while the remaining two are alive with disease. In summary, we report novel recurrent PHF1-TFE3 fusions in a subset of OFMTs with aggressive clinical behavior. The PHF1-TFE3 fusions resulted in consistent protein TFE3 overexpression which can be used as a reliable screening tool, adding OFMT as another tumor driven by TFE3 oncogenic activation pathway.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) has been incorporated into the recent international histological classification of renal tumors. However, to date, there are limited studies describing the clinicopathological features of fumarate hydratase (FH)-deficient RCC, including the hereditary (HLRCC) and sporadic forms. Herein, we present a clinicopathological study of seven cases with FH-deficient RCC. The age of patients ranged from 26 to 70 years with mean and median age of 51.7 and 57 years, respectively. The follow-up data of all patients were available. One patient was alive without the disease and five patients were alive with active disease. One patient died of the disease. Family history of RCC, or skin or uterine smooth muscle tumor within second degree of kinship was present in four of seven patients. Metastasis was observed in all tumors. Metastatic sites included bone, lungs, liver, peritoneum, ovaries, tonsils, or lymph nodes. Grossly, the cut surface of the tumor usually showed light brown, brown, or whitish color. Microscopically, the cytoplasm of the tumor cells was predominantly eosinophilic and all tumors displayed various architectural patterns such as papillary, tubular, solid, or microcystic patterns. Furthermore, two tumors demonstrated a tubulocystic pattern. Sarcomatoid change and rhabdoid features were seen in five tumors and two tumors, respectively. Large cytomegaloviral (CMV) inclusion-like eosinophilic nucleoli surrounded by a clear halo were identified in all tumors. All tumors showed negative immunohistochemical reaction for FH protein. False positive results of TFE3 protein were observed in three tumors. Furthermore, a germline mutation of FH gene was identified in one patient with family history of the disease. In conclusion, FH-deficient RCC includes hereditary and sporadic forms. Grossly, this tumor is solitary and occurs unilaterally. Histologically, the tumor is characterized by various patterns such as papillary, tubular, solid, tubulocystic, or microcystic, has eosinophilic cytoplasm and CMV-like high-grade nuclei. FH-deficient RCCs frequently metastasize to other anatomic sites. TFE immunoreactivity may occur in some FH-deficient RCCs, and immunohistochemistry can accurately diagnose these tumors and mutational analysis of FH gene.

Keywords: Fumarate hydratase; Pathology; Renal cell carcinoma.

Objective: To study the clinicopathological features, immunohistochemical phenotype, molecular changes, differential diagnosis and prognosis of eosinophilic solid and cystic renal cell carcinoma (ESC RCC). Methods: A total of 15 cases were selected from 2005 to 2019 at Nanjing Jinling Hospital,Nanjing University School of Medicine for clinicopathological and immunohistochemical analysis, 10 of which were subject to cancer-associated mutation analysis using targeted next-generation sequencing (NGS) panel. A literature review was also performed. Results: The patients' ages ranged from 15 to 68 years (mean, 33 years). The male-to-female ratio was 1.1∶1.0. During a mean follow-up of 22 months, none of the patients developed tumor recurrence, progression or metastasis. Histologically, the tumors typically demonstrated solid and cystic architectures and the neoplastic cells contained voluminous eosinophilic cytoplasm with prominent granular cytoplasmic stippling. Immunohistochemically, tumor cells in all cases were immunoreactive for CK20. Signal pathway related protein mTOR and S6 were positive in 14/15 and 6/15 cases, respectively. Cathepsin K, Melan A and HMB45 were at least focally positive in 12/15, 6/15 and 2/15 cases, respectively. CK7 and CD10 showed focal immunostain positivity in some cases, while TFE3, TFEB, CA9 and CD117 were negative in all cases. NGS demonstrated TSC1/TSC2 mutations in all tested cases (10/10). Conclusions: ESC RCC is a rare tumor that tends to occur in young patients with an indolent behavior. Diagnosis can be established by its distinct clinical and histopathologic findings, immunohistochemical phenotype and molecular genetics. The tumor may be considered as a new subtype of RCC.

Epithelioid hemangioendothelioma is a rare vascular tumor of borderline malignancy characterized by recurrent WWTR1-CAMTA1 gene fusions in approximately 90 % of cases. In addition, a recurrent YAP1-TFE3 gene fusion has been identified in WWTR1-CAMTA1 negative epithelioid hemangioendotheliomas. This subset has been reported as having a distinct morphology with more obvious vasoformation, voluminous eosinophilic cytoplasm, and TFE3 positivity on immunohistochemistry. We report a case of a YAP1-TFE3 translocated epithelioid hemangioendothelioma arising in a groin lymph node in a 29-year-old male. Plump spindle cell morphology and absence of vasoformation made correct diagnosis particularly difficult. Immunohistochemistry showed nuclear positivity for both ERG and TFE3, fluorescence in situ hybridization showed break apart for TFE3 and RT-PCR identified a YAP1 exon1 to TFE3 exon 6 transcript, a previously unreported fusion variant. Awareness of this solid morphology and variant fusion will aid in identification of future cases of this rare vascular tumor.

OBJECTIVE

To compare the differences of CT characteristics between renal cell carcinomas (RCCs) associated with Xp11.2 translocation/TFE3 gene fusions (Xp11.2 RCCs) and papillary cell renal cell carcinomas (PRCCs).

METHODS

CT images and clinical records of 64 patients (25 Xp11.2 RCCs, 15 type 1 and 24 type 2 PRCCs) were analyzed and compared retrospectively.

RESULTS

Xp11.2 RCC more frequently affected young (30.7 ± 8.7 years) women (16/25, 64%) with gross hematuria (12/25, 48%), while PRCC more frequently involved middle-aged (54.8 ± 11.1 years) men (28/39, 71.8%) asymptomatically. Xp11.2 RCC tended to be heterogeneous density with some showing circular calcification. Lesion sizes of Xp11.2 RCC (5.4 ± 2.2 cm) and type 2 PRCC (5.7 ± 2.5 cm) were significantly larger than that of type 1 PRCC (3.8 ± 1.8 cm). Xp11.2 RCC contained more cystic components (22/25, 88%) than type 1 PRCC (all solid) and type 2 PRCC (9/24, 36.0%). Type 1 PRCC (13/15, 86.7%) and Xp11.2 RCC (21/25, 84.0%) showed more clear boundary than type 2 PRCC (12/24, 50.0%).

CONCLUSIONS

CT features including diameter, boundary, attenuation, nature, and circular calcification of the tumor, combined with demographic information and symptoms, may be useful to differentiate Xp11.2 RCC from different subtypes of PRCC.

Renal cell carcinoma (RCC) is the most common renal tumour. RCC with Xp11.2 translocation/TFE3 (transcription factor E3) gene fusions (Xp11.2 RCC) is positive for immunostain labelling by TFE3 antibody. This tumour is rarely described in adults. This study aims to evaluate the frequency of RCC with Xp11.2 in a subset of Saudi adult patients with RCC. 112 RCCs diagnosed in 1995-2016 were retrieved from the Department of Pathology at King Abdulaziz University and King and Faisal Specialist Hospital and Research Centre, Saudi Arabia. Tissue microarrays were constructed and TFE3 immunostaining was performed. TFE3 immunostaining was considered positive when diffuse strong nuclear immunostaining was detected. TFE3 immunostaining-positive tumours were confirmed by fluorescence in situ hybridisation. 4.5% of RCCs were shown to be Xp11.2 RCC by TFE3 immunostaining. TFE3-positive tumours have a papillary configuration, nested pattern, or both. Positive tumours show male predominance, more occurrences in middle age, high grade, and large-sized tumours with necrosis. Two tumours were FISH-positive. Xp11.2 RCC is rare in Saudi adult patients. Xp11.2 RCCs tend to be large sized and higher grade. TFE3 immunostaining should be considered in RCC that are histologically suggestive to confirm the diagnosis of Xp11.2.

Objective: To analyze MRI findings of renal cell carcinoma associated with Xp11.2 translocation-TFE gene fusion(Xp11.2 RCC). Methods: MR imaging features of eleven patients with pathologically-proved Xp11.2 RCC were retrospectively analyzed from December 2008 to December 2015. The following MRI features of the lesions were analyzed in the study: location, maximal diameter, signal intensity, hemorrhage, necrosis, cystic change, enhancement features and metastasis. The data was analyzed by using t test. Results: Four men and seven women (mean age, 35.2 years; age range, 15-49 years) were included. Tumors occurred in the right kidney in 5 cases and the left kidney in 6 cases. On T1WI tumors showed heterogeneously hypo-intensity and iso-intensity, hyper-intensity in 10 cases, 1 cases, respectively. On T2WI tumors showed heterogeneously slight hypo-intensity, heterogeneously slight hyper-intensity and hyper-intensity in 6 cases, 4 cases, 1 case, respectively. On DWI tumors showed hyper-intensity and heterogeneously slight hype-intensity in 2 cases, 9 cases, respectively. ADC value of the tumors were statistically significant lower than that of renal cortex(×10-3mm2/s)(1.35±0.20 vs 2.09±0.11, P<0.05). Imaging findings were suggestive of hemorrhage(n=4) or necrosis (n=1) or cystic change (n=6) or lipid(n=1) in the tumors. On dynamic contrast-enhanced imaging, tumors showed lower signal intensity change (96%±93%, 110%±86% and 103%±46%, respectively) than did renal cortex (285%±109%, 254%±97% and 225%±90%, respectively) (P<0.05). Tumor capsule showed in 7 cases. Enlarged lymph node was found in renal hilum in one case. Conclusion: MRI findings may show characteristic features of Xp11.2 RCC combined with patients' age and assist in preoperative correct diagnosis.

The World Health Organization 2016 edition assigned anaplastic lymphoma kinase (ALK) rearrangement-associated renal cell carcinoma (ALK-RCC) as an emerging renal tumor entity. Identifying ALK-RCC is important because ALK inhibitors have been shown to be effective in treatment. Here, we report the case of a 14-year-old young man with ALK-RCC. Computed tomography revealed a well-demarcated 5.3-cm enhancing mass at the upper pole of the left kidney. There was no further history or symptoms of the sickle-cell trait. The patient underwent left radical nephrectomy. Pathologically, the mass was diagnosed as an unclassified RCC. Targeted next-generation sequencing identified a TPM3-ALK fusion gene. The present report and literature review demonstrate that TPM3-ALK RCC may be associated with distinct clinicopathological features. Microscopically, the tumors showed diffuse growth and tubulocystic changes with inflammatory cell infiltration. Tumor cells were dis-cohesive and epithelioid with abundant eosinophilic cytoplasm and cytoplasmic vacuoles. If morphological features and TFE3 expression are present in adolescent and young patients, molecular tests for ALK translocation should be performed. This awareness is critically important, because ALK rearrangement confers sensitivity to ALK inhibitors.

BACKGROUND

Genetic alterations in renal cell carcinoma (RCC) involve tumor suppressor genes such as Von Hippel-Lindau (VHL); proto-oncogenes such as MET and transcription factors such as TFE3 oncoprotein.

OBJECTIVE

To examine the clinicopathologic features and the expression of some oncogenic molecules in various RCCs in patients from Upper Egypt.

METHODS

The authors examined the expression pattern of pVHL; MET; and TFE3 proteins in 59 RCC using immunoperoxidase staining methods. The study group consisted of clear cell RCCs (CRCC); papillary RCCs type 1 (PRCC1); papillary RCCs type 2 (PRCC2); Xp11-2 translocation RCCs (XP11.2RCC); chromophobe RCCs (ChRCC); and sarcomatoid RCCs (SRCC).

RESULTS

Variations were found in the expression of these molecules in the different types of RCCs. The mean age of RCCs among Egyptians was 52.70 ± 1.73 years; with male sex predominance. Mass lesion; pain; and hematuria were the main presenting features. Metastatic disease was more frequent with CRCC variant. pVHL expression was strong in PCRCC2; Xp11.2RCC; and ChRCC; moderate in CRCC; and weak in both PRCC1 and sarcomatoid RCC. MET protein expression was moderate in Xp11.2RCC; PRCC1; PRCC2; and sarcomatoid RCC. TFE3 protein expression was strong in Xp11.2RCC and PRCC2 variants. The expression was moderate in PRCC1; CRCC; ChRCC; and sarcomatoid RCC. Positive correlation was found in the expression of the different proteins (pVHL; MET; and TFE3) and some histological features (tumor grade; inflammation; necrosis and metastasis) and the presence of metastasis and some histological features (inflammation and/or necrosis).

CONCLUSIONS

This study provides the first indication about the clinicopathologic features of RCCs in Upper Egypt. The variable expression of these molecules in the different variants of RCC suggests that several oncogenic pathways are operational in their development.

Objective: To analyze the clinical characteristics, treatment methods and prognosis of renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusions (Xp11.2 tRCC). Methods: From January 2007 to February 2018, 48 patients were diagnosed with Xp11.2 tRCC at Nanjing Drum Tower Hospital. The epidemiological features, treatment methods and long-term follow-up results were retrospectively reviewed. Results: Of the 48 patients, 20 cases were female and 28 cases were male, aged from 2 to 72 years. Gross hematuria and flank pain were the most frequent symptoms, which occurred on 14 cases and 8 cases respectively. The mean tumor size of 48 cases was (5.3±2.5)cm. Among the 34 cases who were classified as stageⅠ/Ⅱ, 14 cases received laparoscopic nephron-sparing surgery(NSS)and 20 cases received radical nephrectomy(RN). The other 14 cases who were classified as stage Ⅲ/Ⅳ received RN but one case received target therapy. On univariate analysis, tumor diameter, adjuvant treatment, AJCC stage, lymph node metastasis and vein tumor thrombosis showed association with progression-free survival (PFS) and overall survival (OS) (P<0.05). Multivariate analysis indicated that AJCC stage (P=0.023, 95% CI: 0.048-0.081)and vein tumor thrombosis (P=0.046, 95% CI: 1.004-1.590)were independent prognostic factors of PFS. Conclusions: Xp11.2 tRCC mainly occurs in females. RN was the major method for Xp11.2 tRCC. However, NSS can also receive satisficed results for stage T1a case. High AJCC stage and the occurrence of vein tumor thrombosis indicated poor prognosis.

Renal cell carcinoma with leiomyomatous stroma (RCCLS) is an emerging entity frequently associated with tuberous sclerosis complex (TSC). We described herein a series of RCCLS in TSC patients at pathological and cytogenetic levels. Three male patients with TSC and RCCLS were identified between 2000 and 2019 at the University Hospital of Rennes. Histologically, the architecture was tubulo-papillary with thick bundles of smooth muscle cells. The tumor cells showed clear cytoplasm with eosinophilic globules. The immunohistochemical profile was identical with an intense positivity of CK7, CAIX, and CD10 and a heterogeneous positivity of CK20. SDHB was low but positive and TFE3 was not expressed. Comparative genomic hybridization (CGH) did not show any quantitative chromosome abnormality. No recurrence was observed with a median follow-up of 4 years. RCCLS in TSC patients has morphological, immunohistochemical, and cytogenetic distinct features that could constitute a distinct entity and a sentinel manifestation for the diagnosis of TSC.

Keywords: Leiomyomatous stroma; Renal cell carcinoma; TSC1; TSC2; Tuberous sclerosis complex.

Perivascular epithelioid cell tumor (PEComa) of the urinary bladder is a rare neoplasm showing distinct melanocytic and smooth muscle differentiation. We aimed to review the clinicopathologic features of bladder PEComa using all the available cases in the literature, along with 2 new cases from our database. The patients included 15 females and 15 males with a mean age of 39.2 ± 15.3 years. Painless hematuria was the most common clinical presentation. The tumors were usually well circumscribed with a mean tumor size of 4.4 ± 2.7 cm. Bladder PEComas demonstrated nests, trabeculae, or sheets of epithelioid cells with intermixed spindled cells and numerous thin-walled vessels. Immunohistochemical studies showed that the tumors were positive for HMB45 (27/27), cathepsin (4/4), SMA (20/22), and caldesmon (3/3) and were negative for pan cytokeratin (0/18) and EMA (0/4). Molecular studies revealed that PEComa was associated with the TFE3 (n = 3) and EWSR1 (n = 1) gene rearrangements. Treatment included partial cystectomy (n = 18), transurethral resection (n = 8), and radical cystectomy (n = 4). Twenty patients had no evidence of disease during a mean follow-up time of 19.4 ± 17.2 months. Two patients had recurrence, and 1 patient died of metastatic disease. In conclusion, bladder PEComas demonstrate distinct morphologic and immunohistochemical features. Although most tumors follow a benign course, a small subset may develop metastasis and cause death.

Emperipolesis has recently been described as a constant feature of "biphasic squamoid" papillary renal cell carcinoma (BPRCC). We also noticed this in some high-grade (HG) RCC, which promoted the present study to estimate the incidence of emperipolesis in RCCs and to describe them in further detail. 14 cases of HGRCC showing emperipolesis were retrieved from our registry. Microscopic examination of filed slides was supplemented with immunohistochemical and molecular-genetic analyses using paraffin embedded tissue. 12 of 14 patients were males with a mean age of 58.6 years (range 41-72 years). Tumor size ranged from 6-16.5 cm (mean of 8.8 cm). Follow up data were available for 8/14 patients (range 0.5-10 years). Metastases were documented in 6 cases. All tumors showed solid-alveolar growth patterns with focal pseudopapillary features, and were composed of large cells with bizarre nuclei and eosinophilic rhabdoid-like cytoplasm. Emperipolesis was a constant and prominent feature in large bizarre cells. All cases were positive for OSCAR, CANH 9, vimentin, cyclin D1, INI-1, and myoD1, while negative for melanocytic markers, CK 7, myoglobin, cathepsin K, and TFE3. VHL gene abnormalities were found in 6/9 analyzable cases, of which 2 demonstrated polysomy of chromosomes 7, 17. Emperipolesis is a rare histomorphologic feature which can be seen not only in BPRCCs but also in highgrade CCRCCs. All RCC cases with prominent emperipolesis fulfilled both morphologic and immunohistochemical diagnostic criteria of high-grade CCRCC. The majority of patients with available follow up information developed metastases.

Malignant renal epithelioid angiomyolipoma (EAML) is an extremely rare disease with a poor prognosis, and currently there are no uniform criteria for its biological behavior. Here, we present a case of malignant renal EAML with TFE3 gene amplification in a 53-year-old woman. Four months after surgery, unenhanced computed tomography scans showed recurrence as well as metastasis in the abdomen and lung. The patient succumbed to rapid neoplastic progression of the disease 6 months later.

Clear cell papillary renal cell carcinoma (CCPRCC) is a newly described variant of renal cell carcinoma (RCC) which is composed mainly of cells with clear cytoplasm arranged in cystic and papillary patterns. We report the clinicopathologic features, prognosis and differential diagnosis of 6 Clear Cell Papillary Renal Cell Carcinomas. The clinical information and follow-up data were analyzed. The patients were six males with median age of 52.5 years. Case 1 revealed dense calcification and ossification. Cases 2 and 3 contain a variably prominent smooth muscle stromal component. CA-IX, CK7, PAX-8 and VIM were positive in all cases. TFE3 and AMACR were not expressed in any tumor. CD10 was negative in 5 of 6 cases .The patients were followed for 13~55 months with no local tumor recurrences and tumor metastasis. The CCPRCC was associated with a more favorable outcome. These were low-grade and low-stage renal tumors. No lymph node or distant metastasis of the six tumors.

This article reports the pathologic features and malignant biological behavior of a perivascular epithelioid cell neoplasm (PEComa) with the clinical manifestation being endometrial polyps. The case was cured with curettage in a local hospital one year ago. The postoperative diagnosis was "endometrial polyps". This time, due to "irregular bleeding", we carried out another curettage in our hospital. After the operation, 3 pieces of polyps were inspected with diameters of 0.3 cm, 0.5 cm and 0.6 cm, respectively. The tumor consisted of epithelioid cells with alveolar and nesting pattern and showed a diffuse strong expression of HMB45, Melan-A and TFE3. The patient then underwent a hysterectomy and the "polyps" were sent for pathological examination. The result showed that tumor cells infiltrated the deep muscle layer, close to the outer membrane, suggesting a malignant biologic behavior. TFE3-related PEComa is different from general PEComa. This neoplasm and Melanotic Xp11 renal carcinoma have similar clinicopathologic features, histology, immunity and molecular phenotypes, belonging to the same type of tumor. It has been suggested in the literature naming this neoplasm as 'Xp11 neoplasm with melanocytic differentiation' or 'melanotic Xp11 neoplasm'. Our case has expanded our understanding of PEComa characteristics and increased data for TFE3 translocation-related PEComa, reminding us to avoid misdiagnosis when PEComa manifests as small polyps.