Small cell carcinoma of the bladder: a contemporary clinicopathological study of 51 cases.

AIMS: We present 51 cases of primary small cell carcinoma of the bladder in a clinicopathological study with emphasis on features that aid in the initial recognition and diagnosis of small cell carcinoma of the bladder. METHODS AND RESULTS: The patients were 40 men and 11 women between the ages of 39 and 87 years (mean age 67 years). Clinical data were available in 41 cases. The most common symptomatology was haematuria in 63% of the patients while dysuria was present in 12%. Thirty-eight patients were caucasians; seven patients were Hispanics; two patients were Asian; one patient was African-American; in the three additional patients no racial information was obtained. Biopsy material was obtained in all of the patients. Cystectomy was performed in 20 patients. At diagnosis, clinical stage was as follows: stage I in two (5%), stage II in 18 (44%), stage III in 10 (24%), and stage IV in 11 (27%). Histologically, urothelial carcinoma was present in 70% of the cases, adenocarcinoma in 8%, and squamous cell carcinoma in 10% of the cases. Small cell carcinoma was the only histology present in only 12% of the cases studied. Immunohistochemical studies using chromogranin, synaptophysin and chromogranin were positive in 30-70% of the cases. CONCLUSIONS: The present study highlights the unusual phenomenon of pure small cell carcinoma of the bladder and its association with other non-small cell carcinomas in that anatomical location. In addition, the study highlights the different modalities employed to treat patients in whom there is a component of small cell carcinoma of the bladder.

Incidence of primary neoplasms in explanted lungs: long-term follow-up from 214 lung transplant patients.

BACKGROUND: Undetected neoplasms in explanted lungs at transplantation are an unusual occurrence that may significantly complicate both the short- and long-term outcome of these patients. The incidence and survival of undetected primary neoplasms in explanted lungs with clinical and radiologic correlation have not been studied in a large cohort of patients. METHODS: We reviewed the files of 214 consecutive lung transplants from the Transplant Center at the Cleveland Clinic Foundation from 1991 to 2000. Data collected included age, gender, pathology of explanted lung, and survival. Retrospective review of all imaging studies was performed in those cases where a primary neoplasm was detected after transplant. RESULTS: One hundred thirteen males and 101 females underwent lung transplantation for the following diagnoses: emphysema, 118; cystic fibrosis, 35; primary pulmonary hypertension, 27; usual interstitial pneumonia, 26; lymphangioleiomyomatosis, 4; sarcoidosis, 2; and pneumoconiosis, 2. Four neoplasms were found in the explanted lungs, representing a 2% incidence. All four neoplasms were bronchogenic carcinomas, including three adenocarcinomas and one squamous cell carcinoma. Three of four neoplasms were found in the setting of emphysema and were detected at an early stage (stage I), and the fourth presented as stage IV in the setting of usual interstitial fibrosis. No recurrence of tumor was seen in the stage I cases. The stage IV case died in the perioperative period. Retrospective review of the imaging studies showed that, in all four cases, a portable chest radiograph performed immediately before transplant failed to identify the lesions. A chest computerized tomogram was performed in all four cases from 3 to 27 months prior to transplantation and revealed a suspicious lesion in one of the four. CONCLUSIONS: Undetected neoplasms in explanted lungs at transplantation are uncommon, with an incidence of 2% at our institution. Adenocarcinoma was the most common cell type. In long-term survivors, no recurrences were found. The 3-year survival was 50% and this approaches the 3-year survival of transplant recipients without lung tumors (58.8%) at our institution. Chest radiographs appear to have a very low sensitivity for the detection of small lesions suspicious for a neoplasm. Chest computerized tomograms performed immediately prior to transplantation may be of benefit in detecting these neoplasms.

Chromophobe renal cell carcinoma: a comparative study of histological, immunohistochemical and ultrastructural features using high throughput tissue microarray.

AIMS: In some cases distinction between chromophobe renal cell carcinoma (CRCC), oncocytoma and clear cell (conventional) renal cell carcinoma (eosinophilic variant) using routine light microscopy remains problematic. The present study investigates the level of agreement in the diagnosis of CRCC, as well as the histological features most frequently used for this diagnosis by two pathologists with a special interest in renal neoplasia. The sensitivity and specificity of immunohistochemical markers in cases with overlapping histological features in the diagnosis of CRCC were also studied. Electron microscopy was performed, as a diagnostic gold standard, on all of the cases. METHODS AND RESULTS: Thirty-two renal tumours with predominantly eosinophilic cytoplasm were reviewed in a blinded fashion by two pathologists. The diagnosis and morphological features used to render each diagnosis were tabulated. Validation of the utility of keratin 7 and 20, epithelial membrane antigen (EMA), vimentin, CD10, parvalbumin, RCC antigen, antimitochondrial antibody and Hale's colloidal iron was performed by the construction of a tissue microarray (TMA) master block. Based on histological criteria alone, overall agreement on the diagnosis of these tumours was reached in 69% of the cases, while there was total disagreement in 12%. In 59% of the cases, total agreement was reached in classifying the case as a CRCC based on histology alone. Kappa statistics for interobserver variability were calculated as only slight agreement (kappa = 0.3). The histological features most frequently associated with a diagnosis of CRCC were accentuated cell borders (87%) and a combination of hyperchromatic wrinkled nuclei (79%) and perinuclear halos (74%). The most sensitive and specific marker for CRCC was parvalbumin (sensitivity 0.91; specificity 1.0). The immunohistochemical profile of EMA+/ vimentin- was useful but had low specificity (sensitivity 0.75; specificity 0.4). CD10 had the highest sensitivity (1.0) but worst specificity (0.25) for CRCC. Keratin 7 had high sensitivity (0.83) but fairly low specificity (0.37) for CRCC. Hale's colloidal iron and the RCC antigen marker were not contributory. Finally, the antimitochondrial antibody was found to be fairly sensitive (0.83) for excluding CRCC. CONCLUSIONS: A small but significant proportion of renal tumours with cells having eosinophilic cytoplasm cannot be classified, even by experienced pathologists, based on histology alone. In these cases it is imperative to use markers with known sensitivity and specificity for the diagnosis of CRCC.

Validation of cytokeratin 5/6 as an effective substitute for keratin 903 in the differentiation of benign from malignant glands in prostate needle biopsies.

AIMS: Keratin 903 (also known as anti-cytokeratin antibody 34betaE12) is widely used to differentiate benign glands from malignant glands in prostate needle biopsies. However, it is subject to considerable staining heterogeneity. We sought to evaluate the use of cytokeratin 5/6 (CK5/6) as an effective alternative to K903 in the evaluation of prostate needle biopsies in clinical practice. METHODS AND RESULTS: Thirty Hollandes-fixed prostate needle biopsies were randomly selected over a period of 2 months from the surgical specimens accessioned over that period of time. Twelve cases had diagnosed prostatic adenocarcinoma (Gleason scores 3 + 3, 3 + 4 and 4 + 4) and the remaining cases (n = 18) were negative for carcinoma. Four sequential sections were stained with H&E (x2), K903, and CK5/6. Care was taken to preserve tissue so that matching glands were evaluated on all four sections. All cases were run routinely over a period of 3 weeks on a daily basis with matching positive controls. All slides were evaluated in a blinded fashion independently by two pathologists using a semiquantitative analysis of staining: <25%, 25-50%, 50-75%, >75% and >95% of benign glands (verified on H&E). Cases that showed no staining were repeated to ensure no false negatives. Both observers agreed with respect to percentage of staining in 96% of the cases. Twenty-nine of 30 cases (97%) showed staining in >95% of benign glands with CK5/6. In contrast, K903 staining was seen in <50% of benign glands in five of 30 (17%), 50-75% in nine of 30 (30%), and >75% in 10 of 30 (33%), with only two cases (7%) showing >95% staining for K903. In four cases (13%) the K903 failed to stain any tissue even after repeat staining. K903 was conspicuously negative in atrophic glands in three of 30 cases (10%). Neither K903 nor CK5/6 stained malignant glands. Using a cut-off of >75% staining in benign glands the sensitivity of CK5/6 and K903 was 97% and 40%, respectively. CONCLUSIONS: CK5/6 has superior sensitivity and reliability compared with that of K903 when evaluating routine prostate needle biopsies, including improved staining of atrophic prostatic glands. While K903 is traditionally used to differentiate benign glands from malignant glands, these results support the use of CK5/6 as an effective and reliable substitute for K903 in routine clinical practice.

Posttransplant lymphoproliferative disorders in lung transplant patients: the Cleveland Clinic experience.

PTLD is a well-recognized complication of organ transplantation. Large series of heart, renal, and liver transplants have been examined for the incidence and behavior of PTLD. However, reports of the incidence and characteristics of PTLDs in lung transplant (LTx) patients are few. We report our experience with PTLDs in a large series of LTx recipients at a single institution and compare them to other solid organ transplant recipient PTLDs seen at our institution. Twenty-eight patients were found to have PTLD, of whom 8 were lung transplant recipients. We evaluated nine PTLD specimens from these 8 patients for their histology, immunophenotype (CD20, CD3, EBV-LMP1), EBER status by in situ hybridization, and clinical features. The incidence of PTLD was 3.3% (8/244 patients). The time to development of PTLD, after transplant, was short (median time, 7 mo). All were of B-cell lineage. Overall, EBV was demonstrated in 77.7% (7 of 9 specimens) of PTLDs. All specimens tested for clonality were found to be monoclonal. Five patients died, with a median time to death of only 4.6 months. PTLDs in LTx patients are EBV-associated B-cell, predominantly monoclonal lymphoid lesions similar to other solid organ transplant PTLDs. Compared with other solid organ transplant recipients with PTLD at our institution, PTLDs in LTx patients have a propensity to involve the transplanted organ (P =.001, Fisher's exact test), occur earlier after transplant (P =.003, Wilcoxon test), and have a shorter survival (P =.002, log rank test). Reasons for this may include the relatively higher level of immunosuppression required in these patients and limited options in decreasing it. Although the incidence is low, careful early monitoring of lung transplantation patients is warranted because of the poor prognosis of patients developing this complication.

Angiogenic polypoid proliferation adjacent to ileal carcinoid tumors: a nonspecific finding related to mucosal prolapse.

Case reports have highlighted angiogenic polypoid proliferation in the mucosa adjacent to ileal carcinoid tumors, describing them as granulation tissue polyposis and florid angiogenesis. Some authors have proposed that the ileal carcinoid tumors themselves produce growth factors that cause the change. The purpose of this study was to determine the frequency of angiogenic polypoid proliferation in a large cohort of resected ileal carcinoid tumors compared with control groups. Search of the Cleveland Clinic and Summa Health System pathology files (1985 to 1999) yielded 65 resected ileal carcinoid tumors. Mucosal abnormalities adjacent to the ileal carcinoid tumors were graded 0 to 4+. Twenty ileal resection margins from colonic carcinoma cases served as normal controls. Ileal mucosa adjacent to 22 noncarcinoid neoplasms were also examined. The mucosa adjacent to 54/65 ileal carcinoid tumors (83%) showed mucosal abnormalities (vs. 3/20 normal controls), including mucosal edema, capillary ectasia, muscularis mucosae hypertrophy, fibrosis/smooth muscle proliferation within the lamina propria, club-shaped villi, and intramucosal capillary proliferation. Forty ileal carcinoid tumor cases (61%) showed some degree of angiogenic polypoid proliferation characterized by club-shaped villi and prominent intramucosal capillaries, with 17 (26%) graded as 3+ or 4+. Angiogenic polypoid proliferation was associated with hypertrophy of the muscularis mucosae, lamina proprial fibrosis/smooth muscle proliferation, and capillary ectasia similar to that described with gastrointestinal mucosal trauma/prolapse. This trauma/prolapse change was identified in 45 cases (69%) and was graded 3+ or 4+ in 23 (35%). Seventeen (77%) of the noncarcinoid neoplasms showed trauma/prolapse changes, with 7 (32%) graded as 3+ or 4+. Angiogenic polypoid proliferation also correlated with trauma/prolapse change in the noncarcinoid neoplasm controls. Neither APP (P =.24) nor the prolapse changes (P =.33) were found to be statistically different between the two tumor groups. Angiogenic polypoid proliferation of the adjacent ileal mucosa is common in patients with ileal carcinoid tumors and with noncarcinoid neoplasms. Angiogenic polypoid proliferation almost invariably coexists with fibromuscular change and capillary ectasia within the lamina propria, suggesting that mucosal trauma/prolapse plays a role in the histogenesis. The association of angiogenic polypoid proliferation with a variety of different neoplasms makes it unlikely that the tumors themselves secrete growth factors.

The role of histopathologic examination of intracranial blood clots removed for hemorrhage of unknown etiology: a clinical pathologic analysis of 31 cases.

Intracranial hemorrhage is a well recognized cause of morbidity and mortality. Often, the etiology of the hemorrhage is known before surgical intervention, ie, evacuation of the hematoma. In a subset of patients, however, no known cause for the hemorrhage has been found in either history (eg, trauma) or radiographic findings (eg, tumor) before surgery. We retrospectively reviewed 54 blood clot evacuation specimens received in the surgical pathology department over a 16-year period (1983-1999). Cases were excluded in which the hemorrhage was attributed to or associated with prior trauma or for which there was a prior known cause of the hemorrhage. Thirty-one cases fulfilled the study requirements and comprised the study group. Thirty-one patients (aged 7 to 79 years; mean 54 years), including 16 females and 15 males, formed the study group. In 14 cases (45%), only blood clot was identified in the tissues examined. Of the remaining 17 cases, specific pathologic diagnoses were made in nine instances including cerebral amyloid angiopathy in three cases, arteriovenous malformations in three cases, and tumors in three cases. Tumor types included metastatic non-small cell carcinoma in two cases and low-grade astrocytoma in one case. Examination of blood clot evacuation specimens can lead to a discovery of the etiology of the hemorrhage in a subset of cases, particularly if neural tissue is part of the specimen. The quantity of neural tissue submitted for histologic evaluation seems to correlate with a higher likelihood of making a diagnosis. The routine use of Congo red stain in all adult cases in which brain tissue is present proved to be of diagnostic utility in screening for amyloidosis.