Chisato Ohe

Renal angiomyoadenomatous tumor: morphologic, immunohistochemical, and molecular genetic study of a distinct entity

We present a series of a distinct tumorous entity named renal angiomyoadenomatous tumor (RAT). Five cases were retrieved from the consultation files of the authors. Histologic and immunohistochemical features were evaluated. Sequencing analysis of coding region of the VHL gene was carried out in all cases. The tumors were composed of admixture of an epithelial clear cell component and prominent leiomyomatous stroma. Epithelial cells formed adenomatous tubular formations endowed with blister-like apical snouts. All tubular/glandular structures were lined by a fine capillary network. The epithelial component was positive for epithelial membrane antigen, CK7, CK20, AE1-AE3, CAM5.2, and vimentin in all cases. In all analyzed samples, no mutation of the VHL gene was found. RAT is a distinct morphologic entity, being different morphologically, immunohistochemically, and genetically from all renal tumors including conventional clear cell carcinoma and mixed epithelial and stromal tumor of kidney.

Tubulocystic carcinoma of the kidney with poorly differentiated foci

An emerging group of high-grade renal cell carcinomas (RCCs), particularly carcinomas arising in the hereditary leiomyomatosis renal cell carcinoma syndrome (HLRCC), show fumarate hydratase (FH) gene mutation and loss of function. On the basis of similar cytomorphology and clinicopathologic features between these tumors and cases described as tubulocystic carcinomas with poorly differentiated foci (TC-PD) of infiltrative adenocarcinoma, we hypothesized a relationship between these entities. First, 29 RCCs with morphology of TC-PD were identified retrospectively and assessed for FH expression and aberrant succination (2SC) by immunohistochemistry (IHC), with targeted next-generation sequencing of 409 genes—including FH—performed on a subset. The 29 TC-PD RCCs included 21 males and 8 females, aged 16 to 86 years (median, 46), with tumors measuring 3 to 21 cm (median, 9) arising in the right (n=16) and left (n=13) kidneys. Family history or stigmata of HLRCC were identifiable only retrospectively in 3 (12%). These tumors were aggressive, with 79% showing perinephric extension, nodal involvement in 41%, and metastasis in 86%. Of these, 16 (55%) demonstrated loss of FH by IHC (14/14 with positive 2SC). In contrast, 5 (17%) showed a wild-type immunoprofile of FH+/2SC−. An intriguing group of 8 (28%) showed variable FH± positivity, but with strong/diffuse 2SC+. Next-generation sequencing revealed 8 cases with FH mutations, including 5 FH−/2SC+ and 3 FH±/2SC+ cases, but none in FH+/2SC− cases. Secondly, we retrospectively reviewed the morphology of 2 well-characterized cohorts of RCCs with FH-deficiency determined by IHC or sequencing (n=23 and n=9), unselected for TC-PD pattern, identifying the TC-PD morphology in 10 (31%). We conclude that RCCs with TC-PD morphology are enriched for FH deficiency, and we recommend additional workup, including referral to genetic counseling, for prospective cases. In addition, based on these and other observations, we propose the term “FH-deficient RCC” as a provisional term for tumors with a combination of suggestive morphology and immunophenotype but where genetic confirmation is unavailable upon diagnosis. This term will serve as a provisional nomenclature that will enable triage of individual cases for genetic counseling and testing, while designating these cases for prospective studies of their relationship to HLRCC.

Neo-adjuvant Chemoradiation Therapy Using S-1 Followed by Surgical Resection in Patients with Pancreatic Cancer

ObjectiveThe aim of this study was to compare short-term surgical results in pancreatic cancer patients who underwent surgical resection after neo-adjuvant chemoradiation therapy (NACRT) using S-1.MethodsThe study population comprised 77 patients with pancreatic cancer between 2006 and 2010. Out of 34 patients who underwent staging laparoscopy between 2008 and 2010, 31 patients without occult distant organ metastasis underwent chemoradiation and of whom 30 underwent pancreatectomy (NACRT group). Of the other 43 patients, 36 underwent surgical resection in 2006–2008, followed by adjuvant therapy (adjuvant group). The primary endpoint was frequency of pathological curative resection (R0).ResultsThe new regimen of NACRT was feasible and safe. Twenty-eight of 30 (93%) patients in the NACRT group had R0 resection, which was significantly higher than in the adjuvant group (21 of 36 patients, 58%, p = 0.005). The number and extent of metastatic lymph nodes in the NACRT group (1 (0–25), N0/1; 18 of 38) was significantly lower than in the adjuvant group (2 (0–19), N0/1; 23 of 30), p = 0.0363). The frequency of intractable ascites in the NACRT group (eight of 30) was significantly higher than in the adjuvant group (two of 36, p = 0.035).ConclusionNeo-adjuvant chemoradiation therapy using S-1 followed by pancreatectomy can improve the rate of pathologically curative resection and reduces the number and extent of lymph node metastasis.

Review of juxtaglomerular cell tumor with focus on pathobiological aspect

Juxtaglomerular cell tumor (JGCT) generally affects adolescents and young adults. The patients experience symptoms related to hypertension and hypokalemia due to renin-secretion by the tumor. Grossly, the tumor is well circumscribed with fibrous capsule and the cut surface shows yellow or gray-tan color with frequent hemorrhage. Histologically, the tumor is composed of monotonous polygonal cells with entrapped normal tubules. Immunohistochemically, tumor cells exhibit a positive reactivity for renin, vimentin and CD34. Ultrastructurally, neoplastic cells contain rhomboid-shaped renin protogranules. Genetically, losses of chromosomes 9 and 11 were frequently observed. Clinically, the majority of tumors showed a benign course, but rare tumors with vascular invasion or metastasis were reported. JGCT is a curable cause of hypertensive disease if it is discovered early and surgically removed, but may cause a fatal outcome usually by a cerebrovascular attack or may cause fetal demise in pregnancy. Additionally, pathologists and urologists need to recognize that this neoplasm in most cases pursues a benign course, but aggressive forms may develop in some cases.

Recent advances of immunohistochemistry for diagnosis of renal tumors

The recent classification of renal tumors has been proposed according to genetic characteristics as well as morphological difference. In this review, we summarize the immunohistochemical characteristics of each entity of renal tumors. Regarding translocation renal cell carcinoma (RCC), TFE3, TFEB and ALK protein expression is crucial in establishing the diagnosis of Xp11.2 RCC, renal carcinoma with t(6;11)(p21;q12), and renal carcinoma with ALK rearrangement, respectively. In dialysis‐related RCC, neoplastic cells of acquired cystic disease‐associated RCC are positive for alpha‐methylacyl‐CoA racemase (AMACR), but negative for cytokeratin (CK) 7, whereas clear cell papillary RCC shows the inverse pattern. The diffuse positivity for carbonic anhydrase 9 (CA9) is diagnostic for clear cell RCC. Co‐expression of CK7 and CA9 is characteristic of multilocular cystic RCC. CK7 and AMACR are excellent markers for papillary RCC and mucinous tubular and spindle cell carcinoma. CD82 and epithelial‐related antigen (MOC31) may be helpful in the distinction between chromophobe RCC and renal oncocytoma. WT1 and CD57 highlights the diagnosis of metanephric adenoma. The combined panel of PAX2 and PAX8 may be useful in the diagnosis of metastatic RCC.

Clear cell papillary renal cell carcinoma and clear cell renal cell carcinoma arising in acquired cystic disease of the kidney: An immunohistochemical and genetic study

Clear cell papillary renal cell carcinoma (RCC) is a recently established disease entity. However, there are few reports on genetic study of this entity. We report such a case with focus on genetic study. A 57-year-old Japanese man was found to have 3 renal tumors. Histologically, two tumors showed findings of clear cell RCC; and the other tumor showed findings of clear cell papillary RCC that was characterized by papillary growth pattern of neoplastic cells in cystic space with purely clear cell cytology. Immunohistochemically, tumor cells of clear cell papillary RCC were diffusely positive for PAX2 and cytokeratin 7, but negative for CD10, RCC Ma, and AMACR. In fluorescence in situ hybridization study for one clear cell papillary RCC, we detected polysomy for chromosome 7 and monosomy for chromosomes 17, 16, and 20. In addition, we detected mutation of VHL gene in clear cell RCC, but found no VHL gene mutation in clear cell papillary RCC. Finally, our results provide further evidence that clear cell papillary RCC may be both morphologically and genetically distinct entity from clear cell RCC and papillary RCC.

Clear cell renal cell carcinoma with focal renal angiomyoadenomatous tumor-like area.

Recently, renal angiomyoadenomatous tumor (RAT) has been identified. However, there are no descriptions about clear cell renal cell carcinoma (RCC) with focal RAT-like features. A 33-year-old Japanese man was found to have a tumor in the left kidney. Macroscopically, the tumor extended into the perinephric fat tissue, and the cut surface showed the yellowish color. The histologic examination of the tumor consisted of 2 components of clear cell RCC and RAT-like area. The RAT-like area showed the admixture of epithelial cells with basophilic or clear cytoplasm and stromal component containing leiomyomatous stroma, fine capillary network, and pericytic network. Immunohistochemically, epithelial neoplastic cells in RAT-like area were diffusely positive for CD10 and RCC Ma. G-band karyotype showed the structural abnormality of chromosome 3 and both components of clear cell RCC and RAT-like area revealed the identical VHL gene mutation. Finally, pathologists should pay attention to the presence of clear cell RCC focally resembling RAT.

Renal angiomyoadenomatous tumor: fluorescence in situ hybridization.

To the Editor: Renal angiomyoadenomatous tumor (RAT) is a very rare tumor and it was first described by Michal et al. 1 This tumor is histologically characterized by components including adenomatous cells endowed with bleb-like apical snouts (Fig. 1a) and surrounded by capillary network (Fig. 1b), and smooth muscle stroma focally forming abortive vessels (Fig. 1c). In this article we report on the chromosomal change of four RATS. Three of the four tumors have been previously described. Fluorescence in situ hybridization (FISH) was performed using the centromeric probe of chromosome 1 (D1Z5), chromosome 11 (D11Z1) and chromosome 16 (D16Z3; Vysis, Downers Grove, IL, USA). FISH was carried out by the Cytogenetic Testing Group, Molecular Genetic Testing Department, Clinical Testing Center, Mitsubishi Chemical Medience Corporation, Kyoto, Japan. For the results more than 400 neoplastic cells were evaluated and the percentages of one, two and three signals per cell were calculated. The cut-off for monosomy was >20%. The FISH results are summarized in Table 1. In case 1, tumorous cells had disomy for chromosome 1 and monosomy for chromosomes 11 and 16. In cases 2, 3 and 4, neoplastic cells demonstrated monosomy of all three chromosomes (Fig. 2). To date there have been no reports on chromosomal changes in RAT. We found monosomy of chromosomes 11 and 16 in all four RATS cases and monosomy of chromosome 1 in three of four RATS cases on FISH. We consider that RAT is characterized by monosomy of chromosomes 1, 11 and 16 on FISH. To the best of our knowledge, no renal tumors show the combination of abnormalities of chromosomes 1, 11 and 16 on FISH. Tumorous cells of clear cell renal cell carcinoma (RCC) often have loss of 3p including 3p13p14, 3p 21.3 and 3p24pter. In papillary RCC, neoplastic cells were generally known to show gain of chromosomes 7, 17, 12, 16 and 20, and loss of chromosome Y. Chromophobe RCC generally exhibits monosomy of chromosomes 1, 2, 6, 10, 13, 17 and 21. In collecting duct carcinoma, neoplastic cells had polysomy of chromosomes 3, 7 and 17, although the histological features were not described in that study. Neoplastic cells of mucinous tubular and spindle cell carcinoma demonstrate monosomy of chromosomes 15 and 22 and, furthermore, disomy or polysomy of chromosomes 7 and 17. Monosomy of chromosomes 1, 3, 4, 6 and 9 has also been reported. Renal oncocytoma shows loss of chromosomes Y and 1, normal chromosome or non-specific results. In metanephric adenoma, gain of chromosomes 7 and 17 and loss of sex chromosome may be seen, but some reports are inconsistent with this result. Therefore, we strongly believe that RAT is a genetically distinct entity of renal tumors. In contrast, the analysis of chromosomes 1, 11 and 16 on FISH may contribute to accurate diagnosis on histological suspicion of RAT.

Thyroid-like low-grade nasopharyngeal papillary adenocarcinoma: Report of two cases

Thyroid‐like low‐grade nasopharyngeal papillary adenocarcinoma (LGNPPA) is extremely rare; only four cases have been reported. Herein are presented the case reports of two Japanese male patients with thyroid‐like LGNPPA. Macroscopically, these tumors were pedunculated polypoid masses on the roof of the nasopharynx. Microscopically, they were characterized by papillary and glandular epithelial proliferation. The papillae were complex and tightly packed with hyalinized fibrovascular cores and lined by columnar and pseudostratified cells with intervening spindle‐shaped cells. Both cell types had round to oval vesicular nuclei with tiny nucleoli and mildly eosinophilic cytoplasm. Mitotic figures were not evident and necrosis was not observed. Psammoma bodies were seen focally in one of the patients. Transition from normal surface epithelium to tumor cells was identified in both cases. On immunohistochemistry the tumor cells were positive for cytokeratin (CK)7, CK19, thyroid transcription factor‐1 (TTF‐1) and vimentin. They were negative for CK5/6, CK20, thyroglobulin, S‐100 protein and CD15. In situ hybridization for EBV was negative. Nasopharyngeal tumors with similar morphological appearance should be examined for TTF‐1 immunoreactivity, and patients should be clinically followed to determine the course of this unusual disease and the significance of TTF‐1 expression.

A renal epithelioid angiomyolipoma/perivascular epithelioid cell tumor with TFE3 gene break visualized by FISH

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.