Ruta Gupta

Tubulocystic carcinoma of the kidney: Clinicopathologic analysis of 31 cases of a distinctive rare subtype of renal cell carcinoma

A distinctive tumor described under the terms Bellini duct carcinoma and low-grade collecting duct carcinoma has been referred to by us and others as tubulocystic carcinoma. This renal cell carcinoma subtype is not recognized in the World Health Organization 2004 classification. Herein, we present a detailed study of 31 cases to further characterize this rare subtype of renal cell carcinoma. The tumor occurred in adults (mean age, 54 years) with a strong male predominance (7:1). Grossly, the tumors ranged from 0.7 to 17 cm, and exhibited a spongy or “bubble wrap” appearance reflecting the microscopic presence of variably sized cystically dilated tubules lined by a single layer of epithelium. The lining varied with a cuboidal, flat, and hobnail cell appearance, and the neoplastic cells had abundant eosinophilic cytoplasm and enlarged nuclei with prominent nucleoli. The cysts were closely spaced with an intervening variably fibrotic stroma. Immunohistochemistry and ultrastructural examination showed features of proximal convoluted tubules (Pax 2 immunoreactivity and short microvilli with brush border organization) and distal nephron (kidney-specific cadherin immunoreactivity and cytoplasmic interdigitation). Gene expression profiling showed that tubulocystic carcinoma displayed a unique molecular signature. Twenty-four tumors were stage pT1, 4 stage pT2, and 3 stage pT3. Disease progression (median follow-up of 56 months) occurred in 3 patients; 1 with local recurrence, and 2 with distant metastasis to bone and liver. In light of the distinctive clinicopathologic features and a low but definite metastatic potential, this unique subtype of renal cell carcinoma deserves formal recognition in the contemporary classification of renal neoplasms.

Pure epithelioid PEComas (so-called epithelioid angiomyolipoma) of the kidney: A clinicopathologic study of 41 cases: detailed assessment of morphology and risk stratification.

Epithelioid angiomyolipomas (perivascular epithelioid cell tumors) of the kidney are defined as potentially malignant mesenchymal lesions that are closely related to classic angiomyolipoma. Although approximately 120 cases are published, mostly as case reports with variably used diagnostic criteria, the pathologic prognostic predictors of outcome are unknown. We analyzed the clinicopathologic parameters in a large series of 41 cases of pure epithelioid angiomyolipomas of the kidney, which we designate as pure (monotypic) epithelioid PEComas to contrast them from classic angiomyolipomas that are regarded by some as PEComas. We use the terminology “pure” to separate these cases from those that may have variable epithelioid components. The mean age of the patients was 40.7 years (range, 14 to 68 y). The male-to-female ratio was 1:1. Seventy-nine percent of patients were symptomatic at presentation with metastatic disease at onset in 12 cases. Follow-up and/or disease progression information were available for 33 of 41 cases (mean, 44.5 mo and median, 24.5 mo; range, 4 to 240); 9 patients had a history of associated tuberous sclerosis. Recurrence and metastasis were seen in 17% and 49% of patients; 33% of patients died of disease. Lymph node involvement was seen in 24% of patients; the liver (63%), lung (25%), and mesentery (18.8%) were the most common metastatic sites. Clinicopathologic parameters associated with disease progression (recurrence, metastasis, or death due to disease) in univariate analysis included associated tuberous sclerosis complex or concurrent angiomyolipoma (any metastasis, P=0.046), necrosis (metastasis at diagnosis, P=0.012), tumor size >7 cm (progression, P=0.021), extrarenal extension and/or renal vein involvement (progression, P=0.023), and carcinoma-like growth pattern (progression, P=0.040) (the 5 adverse prognostic parameters for pure epithelioid PEComas). Tumors with <2 adverse prognostic parameters (13 cases) were considered to be low risk for progression tumor, with 15% having disease progression. Tumors with 2 to 3 adverse prognostic parameters (14 cases) were considered to be “intermediate risk,” with 64% having disease progression. Tumors with more than 4 or more adverse prognostic parameters (6 cases) were considered to be high risk, with all patients having disease progression. Of tumors with 3 or more adverse prognostic parameters, 80% had disease progression. An exact logistic regression analytic model showed that only carcinoma-like growth pattern and extrarenal extension and/or renal vein involvement were significant predictors of outcome (P=0.009 and 0.033, respectively). Our data of a large series with uniform definitional criteria confirm the malignant potential for pure epithelioid PEComas and provide adverse prognostic parameters for risk stratification in these patients.

Primary thyroid-like follicular carcinoma of the kidney: Report of 6 cases of a histologically distinctive adult renal epithelial neoplasm

Thyroidization of kidney reminiscent of thyroid follicles with accumulation of inspissated colloid-like material in renal tubules is a hallmark of chronic pyelonephritis. We identified 6 tumors in the kidney, distinct from currently known subtypes of renal cell carcinoma, with a striking histology that closely mimicked well-differentiated thyroid follicular neoplasms and raised the possibility of metastatic follicular thyroid carcinoma. Three occurred in males and 3 in females with an age range of 29 to 83 years and size range from 1.9 to 4 cm. All tumors were encapsulated and exclusively demonstrated follicular architecture comprising of microfollicles and macrofollicles containing inspissated colloid-like material. A minor component of small tightly packed follicles devoid of secretions was also noted. The follicles were lined by cells with moderate amphophilic to eosinophilic cytoplasm with round nuclei and occasional prominent nucleoli. The tumors were nonimmunoreactive with thyroglobulin and thyroid transcription factor 1 and for markers contemporarily used for renal differentiation. The tumors had a gene expression profile distinct from clear cell and chromophobe renal cell carcinoma. Comparative genetic hybridization failed to reveal cytogenetic alterations. Mean follow-up of 47.3 months (range: 7 to 84 mo) showed that 5 patients had no evidence of disease and 1 developed a metastasis to the renal hilar lymph nodes in which the follicular architecture with colloid was retained. Thyroid-like follicular renal cell carcinoma represents a unique histologic subtype of renal cell carcinoma of low malignant potential and its primary importance is to distinguish it from metastatic carcinoma from the thyroid.

Evidence-based pathology and the pathologic evaluation of thymomas: The world health organization classification can be simplified into only 3 categories other than thymic carcinoma

The clinical validity and applicability of the World Health Organization (WHO) histopathologic classification of thymomas (‘classification’) has been questioned. Evidence‐based pathology promotes the use of systematic reviews and analysis of data with meta‐analysis rather than subjective reviews of the literature.

Primary vascular tumors and tumor-like lesions of the kidney: a clinicopathologic analysis of 25 cases.

Vascular tumors of the kidney are distinctly rare, and to date no large series have been reported. We analyzed a series of primary vascular tumors of the kidney to further delineate their clinicopathologic features and identify organ-specific morphologic features, if present. Twenty-five renal cases previously coded as “arteriovenous malformation,” “hemangioma,” and “angiosarcoma” were retrieved from the archives of 4 collaborating institutions and were reevaluated histologically. Tumors were classified according to the 2002 World Health Organization classification of tumors of soft tissue and bone. There were 18 males and 7 females (M:F=2.6:1) ranging from 21 to 95 years (mean 56.7 y). Lesions ranged from “microscopic” to 30 cm (mean 6.0 cm) and were tan-brown, cystic, and hemorrhagic. On re-review, cases were classified as arteriovenous malformation (n=3), capillary hemangioma (n=14), and angiosarcoma (n=8). Arteriovenous malformations were identical to their somatic soft tissue counterparts. Renal capillary hemangiomas often lacked a well-formed lobular pattern and 5 cases showed a “sieve-like” arrangement reminiscent of splenic sinusoids, a pattern previously noted by others (anastomosing hemangioma). All hemangiomas were noninfiltrative and lacked cytologic atypia and mitotic activity. GLUT-1, D2-40, and CD8 were performed in 3 anastomosing hemangiomas and were all negative. Angiosarcomas were diffusely infiltrative with extensive parenchymal destruction; all showed at least small areas of conventional vasoformative growth, but were frequently dominated by spindled and epithelioid histology. All cases were positive for some combination of vascular tumor-associated markers (CD31, CD34, and FLI-1). Cytokeratin expression was absent in all angiosarcomas. Follow-up was available for 15 cases: all patients with arteriovenous malformation and hemangioma with follow-up were disease free after complete excision; 4 cases of angiosarcoma died of the disease at 1, 1, 6, and 11 months. Our review shows that many capillary hemangiomas of the kidney are morphologically distinctive tumors, which often show “spleen-like” or “anastomosing” features. Angiosarcomas of the kidney are highly aggressive tumors with poor outcome and may have morphologic features (spindling and epithelioid change), which could result in confusion with sarcomatoid carcinomas and other renal mesenchymal tumors.

Carcinoma of the collecting ducts of Bellini and renal medullary carcinoma: clinicopathologic analysis of 52 cases of rare aggressive subtypes of renal cell carcinoma with a focus on their interrelationship.

Carcinoma of the collecting ducts of Bellini and renal medullary carcinoma are rare aggressive neoplasms of putative distal nephron origin. First described in 1949, case reports and review articles constitute a major source of information on collecting duct carcinoma, whereas Davis and colleagues and the pediatric tumor registry have contributed the seminal works on renal medullary carcinoma. Here we present a detailed study of collecting duct carcinoma (n=39) and renal medullary carcinoma (n=13), characterizing these rare neoplasms and analyzing their interrelationship. Both collecting duct carcinoma and renal medullary carcinoma exhibited significant similarities, such as predilection for the right kidney, tumor mass with an epicenter in the renal medulla, and a mean size of 7 cm. Overall, both tumors exhibited a poorly differentiated adenocarcinoma histology with desmoplastic stromal response (100%), inflammatory infiltrate (100%), frequent perinephric extension (collecting duct carcinoma: 97%; renal medullary carcinoma: 83%), lymphovascular invasion (100%), intraluminal mucin (collecting duct carcinoma: 42%; renal medullary carcinoma: 73%), high nuclear grade (97%), overlapping immunoreactivity for Ulex europaeus agglutinin 1 (collecting duct carcinoma: 75%; renal medullary carcinoma:55%), CK7 (collecting duct carcinoma: 44%; renal medullary carcinoma: 71%), and high–molecular weight cytokeratin (collecting duct carcinoma: 26%; renal medullary carcinoma: 29%), and nonimmunoreactivity for Ksp-cadherin. Histologically, collecting duct carcinoma frequently had tubular, tubulopapillary, or irregular glandular architecture, whereas renal medullary carcinoma commonly demonstrated islands of anastomosing tubules and cords forming irregular microcystic spaces. Multiple metastases to the lymph nodes, lung, bone, and liver were observed in both categories at presentation (collecting duct carcinoma: 17%; renal medullary carcinoma: 36%). Only patients with organ-confined small tumors were disease free beyond the median survival time. Differential clinical features between collecting duct carcinoma and renal medullary carcinoma included proclivity for younger male individuals of African ancestry with hemoglobin abnormalities and a shorter median survival of 17 weeks (vs. 44 wk for collecting duct carcinoma) for renal medullary carcinoma. The markedly overlapping clinical features, histology, immunophenotype, metastasis patterns, and uniformly aggressive outcome in collecting duct and renal medullary carcinomas suggest that renal medullary carcinoma is a distinctive clinicopathologic subtype within the entity of collecting duct carcinoma. The extremely poor prognosis and ongoing clinical trials with specific therapeutic protocols argue for their accurate distinction from other renal cell carcinoma subtypes.

Perivascular epithelioid cell tumor (PEComa) of the urinary bladder: report of 3 cases and review of the literature.

The perivascular epithelioid cell family of tumors (PEComas) includes familiar lesions such as angiomyolipoma, lymphangioleiomyoma, and clear-cell “sugar” tumors of the lung. Less frequently, PEComas arise in various other locations throughout the body including soft tissue, bone, and visceral organs. We report 3 cases of PEComa arising in the urinary bladder in 2 men in their fourth decade, and 1 woman in her third decade. All 3 tumors showed histologic features characteristic of PEComa including spindled and epithelioid cell morphology with variable clear cell change, and all coexpressed melanocytic and smooth muscle associated markers by immunohistochemistry. Follow-up demonstrated an indolent course for 2 patients with no evidence of disease at 10 and 21 months, respectively, and the third case was recently diagnosed. We also provide a review of the 4 previously reported PEComas occurring in the bladder. PEComas of the urinary bladder should be carefully distinguished from a variety of histologically similar, but clinically dissimilar entities.

Evaluation of EGFR abnormalities in patients with pulmonary adenocarcinoma: the need to test neoplasms with more than one method

Patients with advanced pulmonary adenocarcinoma exhibiting overexpression or mutation of epidermal growth factor receptor tend to respond better to targeted therapy with tyrosine kinase inhibitors such as gefitinib and erlotinib. There is no consensus regarding how these neoplasms should be routinely tested for epidermal growth factor receptor (EGFR) and whether the results of immunohistochemistry (IHC), mutation analysis and fluorescent in situ hybridization correlate with each other or are independent predictive variables. We tested 100 pulmonary adenocarcinomas from patients with stage III or IV disease for EGFR abnormalities using IHC, PCR and fluorescent in situ hybridization (FISH) and compared the results using κ and other statistical methods. The sensitivity of each test to detect an EGFR abnormality and its negative predictive value to estimate the presence of an abnormal test result by the other two methods were calculated. Abnormal EGFR test results were found in 62, 40 and 24% by IHC, FISH and PCR, respectively. κ statistics yielded poor concordance between the results of the EGFR tests (κ=0.3, and 0.2 for IHC and PCR and for PCR and FISH, respectively). Strong membranous immunoreactivity in more than 90% of the tumor cells was found to correlate with amplification or polysomy. PCR when used as a single test is likely to underestimate the presence of EGFR abnormalities that may significantly predict response to tyrosine kinase inhibitors. The need to standardize the approach to EGFR testing in patients with advanced pulmonary adenocarcinoma is discussed.

Diagnostic use of antibody to smoothelin in the recognition of muscularis propria in transurethral resection of urinary bladder tumor (TURBT) specimens.

Accurate recognition of muscularis propria invasion by urothelial carcinoma is vital as it serves as a crossroad between conservative and aggressive clinical management. Recently, there has been attention to the hyperplastic pattern of muscularis mucosae which may mimic the muscularis propria. We have earlier shown that smoothelin, a marker of terminally differentiated smooth muscle cells, is relatively specific for muscularis propria (positive staining) and is variably negative to weak in muscularis mucosae. The earlier study was based on cystectomy specimen slides in which the bladder cancer was not present. Pathologic staging in transurethral resection of urinary bladder tumor (TURBT) specimens is complicated by limited, unoriented, or highly cauterized samples. Herein, we test the capability of smoothelin to recognize muscularis propria in TURBT specimens to further substantiate its diagnostic applicability in routine practice. Representative sections from 70 TURBTs were immunostained with smoothelin, and muscularis propria was evaluated in H&E slides and the corresponding smoothelin immunohistochemistry slides using double-blinded analysis. In 31/70 (44%) cases, muscularis propria was involved by invasive carcinoma. Cautery artifact was present in 46/70 (66%) cases, which did not seem to affect smoothelin immunohistochemistry staining of the muscularis propria. Muscularis propria was present by H&E in 48/70 (69%) cases and 48/70 (69%) cases had muscularis propria by smoothelin immunohistochemistry-based 2 (+) or 3 (+) positivity in larger muscle bundles with round regular contours. Desmoplastic response to invasive carcinoma stained negatively for smoothelin. The sensitivity, specificity, positive predictive value, and negative predictive value of smoothelin based on comparison with morphology in TURBT specimens was 98%, 95%, 98%, and 95%, respectively. This study confirms the relatively high sensitivity and specificity for smoothelin in MP, including in TURBT specimens. Immunoreactivity is retained despite the presence of thermal tissue injury, desmoplasia, or involvement by carcinoma. Our data confirm the use of smoothelin in the accurate distinction between muscularis propria and muscularis mucosae or desmoplastic reactions, thereby facilitating appropriate pathologic stage designation in often challenging TURBT specimens.

What can we learn from the errors in the frozen section diagnosis of pulmonary carcinoid tumors? An evidence-based approach

The intraoperative diagnosis of pulmonary neuroendocrine tumors can be difficult. Frozen section diagnosis was requested on 87 neuroendocrine tumors including 58 typical carcinoids, 8 atypical carcinoids, 18 large cell neuroendocrine carcinomas, and 3 small cell carcinomas from 2405 patients that underwent frozen section diagnosis at Cedars-Sinai Medical Center from 2002 to 2007. The deferral and error rate for carcinoid tumors was 4.13% and 7.5%, respectively, and resulted in 4 unnecessary lobectomies and 2 second thoracotomies. The most common errors included misdiagnoses as lymphoma, squamous carcinoma or metastasis from breast carcinoma. Thirty one pathologic features were evaluated in the 66 carcinoid tumors and 10 frozen sections each of lymphoma, squamous cell carcinoma, and metastatic breast carcinoma. Seven pathologic features were significant by chi square test at P > .05. Positive likelihood ratios identified 11 pathologic features that were useful for the diagnosis of carcinoid tumor from other neoplasms. The applicability of the 11 pathologic features was tested with a group of pathologists, resulting in significant improvement in diagnostic accuracy as measured by pre and posttests. The value of evidence-based pathology and Bayesian statistics to evaluate complex differential diagnoses in pathology is discussed.