Clear cell carcinoid tumor of the gallbladder: another distinctive manifestation of von Hippel-Lindau disease.

We describe a morphologically distinctive carcinoid tumor of the gallbladder that occurred in a 38-year-old man with von Hippel-Lindau (VHL) disease. The carcinoid tumor was composed predominantly of lipid-containing clear cells arranged in nests and tubules with pagetoid spread into the biliary epithelium and was interpreted as metastatic renal cell carcinoma. The neoplastic cells showed diffuse immunoreactivity for chromogranin, synaptophysin, cytokeratins (cytokeratin 7 and AE1/AE3) and, unexpectedly, for inhibin, but were negative for monoclonal carcinoembryonic antigen, serotonin and a variety of peptide hormones. This clear cell carcinoid tumor of the gallbladder was histologically similar to the recently described clear cell endocrine pancreatic tumor associated with VHL. Four cases of the latter tumor, which were also inhibin positive showed, in addition, focal and variable reactivity for the pancreatic hormones. Two classical carcinoid tumors of the gallbladder, two renal cell carcinomas associated with VHL and 11 of 13 sporadic endocrine pancreatic tumors (not associated with VHL) did not show immunoreactivity for inhibin. Inhibin appears to be an immunohistochemical marker for gallbladder clear cell carcinoid and clear cell endocrine pancreatic tumors associated with VHL and is a useful tool to distinguish these tumors from metastatic renal cell carcinoma. However, the basis for the inhibin positivity in these endocrine tumors is unknown.

Expression of protein gene product 9.5 in epithelioid and conventional malignant peripheral nerve sheath tumors.

CONTEXT: Due to the frequent lack of S100 protein expression in malignant peripheral nerve sheath tumors (MPNSTs), especially the epithelioid variant, these tumors are difficult to diagnose without the aid of electron microscopy or a clinical history of neurofibromatosis. METHODS: Protein gene product 9.5 (PGP9.5), a broad neural marker, is expressed in nerve fibers and neurons of both the peripheral and central nervous systems. We compared its expression to that of S100 protein in 16 cases of MPNST. As controls, 6 monophasic synovial sarcomas, 9 leiomyosarcomas, and 5 dermatofibrosarcoma protuberans were included. RESULTS: Expression of PGP9.5 was seen in 15 MPNSTs, with 3 to 4+ positivity in the majority of the cases. Ten cases, 2 epithelioid and 8 conventional MPNSTs, were reactive with PGP9.5, but were negative for S100 protein. Five cases were immunoreactive for both S100 protein and PGP9.5. One case was negative for PGP9.5 but demonstrated focal S100 protein positivity. Expression of PGP9.5 was seen in 4 of 6 synovial sarcomas, 3 of 9 leiomyosarcomas, and none of 5 dermatofibrosarcoma protuberans. CONCLUSION: Although PGP9.5 is not a specific marker for MPNST, it is a more sensitive marker than S100 protein (94% vs 38%). When there is a lack of S100 protein expression and a broad panel of immunostains, such as cytokeratin, epithelial membrane antigen, and smooth muscle actin, yields only focal or equivocal staining, PGP9.5 is a useful diagnostic adjunct in confirming the neural origin of a spindle cell sarcoma.

Nasopharyngeal gangliocytic paraganglioma.

Gangliocytic paraganglioma (GP) is a rare neoplasm described almost exclusively in the gastrointestinal tract, especially the periampullary region. However, several examples have been reported at various sites, including the stomach, jejunum, and appendix. Herein we report a case of GP involving the nasopharynx. To our knowledge, this is the first report of GP at this site. A 44-year-old woman presented with headaches and symptoms of fullness and pressure related to mass effect. An initial endoscopic biopsy was followed by surgical excision of the nasopharyngeal mass. The triphasic tumor fulfilled the morphologic and immunohistochemical criteria for GP. The histogenesis of GP is uncertain, and the current belief is that it arises from the embryonic ventral pancreas. This concept is based largely on the location of most cases, which is along the embryologic migration route of the ventral pancreas, as well as the expression of pancreatic polypeptide by the tumor. The nasopharyngeal location of our case clearly refutes the pancreatic origin of GP. We propose that the tumor probably arises from totipotential adult stem cells, which in the right microenvironment differentiate along nonnative cell lineages.

Atypical bile duct adenoma, clear cell type: a previously undescribed tumor of the liver.

A variable proportion of bile duct adenomas of the liver are still confused with metastatic well-differentiated adenocarcinoma by surgeons and pathologists. We present here three examples of previously undescribed primary hepatic bile duct tumors that were composed almost entirely of clear cells that closely mimicked metastatic renal cell carcinoma. They were interpreted as atypical bile duct adenomas and occurred in two males and one female whose ages ranged from 25 to 64 years. All three tumors were incidental findings and measured from 0.8 to 1.1 cm. The clear neoplastic cells showed mild nuclear atypia and no mitotic activity. They were arranged in tubules and nests that focally infiltrated the hepatic parenchyma. For comparison, a case of clear cell cholangiocarcinoma and 13 conventional bile duct adenomas were examined. The clear cell cholangiocarcinoma was larger (6.0 cm) and had the tubular pattern of conventional cholangiocarcinoma and an abundant desmoplastic stroma. The clear cells of this tumor exhibited greater nuclear atypia and increased mitotic activity. All three atypical bile duct adenomas expressed cytokeratin (CK) 7, p53 protein, epithelial membrane antigen (EMA), and carcinoembryonic antigen (CEA); they were negative for CK20, vimentin, Hep Par 1, chromogranin, and prostatic specific antigen (PSA) and exhibited less than 10% of Ki-67-positive nuclei. One atypical bile duct adenoma displayed luminal immunoreactivity for villin. With the exception of Ki-67 reactivity, the 13 conventional bile duct adenomas and the clear cell cholangiocarcinoma had essentially a similar immunohistochemical profile as that of the atypical clear cell bile duct adenomas. The absence of an extrahepatic primary tumor, the histologic features, the immunohistochemical profile, and the fact that all patients are symptom-free 2 months to 18 years after wedge liver biopsy support the interpretation of atypical clear cell bile duct adenoma. The differential diagnosis with clear cell hepatocellular carcinoma and metastatic clear cell carcinomas is discussed.

Deletion of the NF2 region in both meningioma and juxtaposed meningioangiomatosis: case report supporting a neoplastic relationship.

We report a case of juxtaposed atypical meningioma and meningioangiomatosis (MA) in an 8-year-old boy with no clinical stigmata or family history of neurofibromatosis. We studied the proliferative activity and genetic changes in the two lesions in an attempt to define their biologic and pathogenetic relationships. The MIB-1 index was 11% in the meningioma and <1% in the MA, indicating increased proliferative activity in the meningioma. Fluorescence in situ hybridization was done for two chromosomal regions commonly deleted in meningiomas. There was loss of the neurofibromatosis 2 locus (22q12) in both the meningioma and MA. Conversely, the region of 1p32 was not deleted. Our results indicate that both the meningioma and MA arose from the same clonal process, with the meningioma probably undergoing additional, but undefined, genetic alterations that confer upon it a more proliferative potential. This loss of 22q12 in the MA raises doubt about the presumed hamartomatous nature of MA.

Adenomyofibroma of the endometrium with skeletal muscle differentiation.

A case of adenomyofibroma with skeletal muscle differentiation is described. A 55-year-old asymptomatic woman had atypical glandular cells of undetermined significance on a routine Papanicolaou smear. The endometrial biopsy revealed fragments composed of benign endometrial glands and myofibromatous stroma with foci of skeletal muscle differentiation. The stroma exhibited focal mild cytologic atypia and hypercellularity without periglandular cuffing or mitoses. Electron microscopy and immunohistochemical staining for myoglobin confirmed the skeletal muscle differentiation. A diagnosis of low-grade adenosarcoma with heterologous differentiation was made in the biopsy specimen based on the atypical stroma, the skeletal muscle differentiation, and previous observations that adenosarcomas may contain bland areas indistinguishable from an adenofibroma. The patient underwent hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymphadenectomy. The hysterectomy specimen revealed small foci of residual tumor. In light of these findings the diagnosis was revised to adenomyofibroma with skeletal muscle differentiation. Uterine adenomyofibroma with skeletal muscle differentiation should be distinguished from a low-grade adenosarcoma in an endometrial biopsy.

Endometrial endometrioid carcinomas associated with Ewing sarcoma/peripheral primitive neuroectodermal tumor.

Three uterine tumors, each consisting of endometrioid carcinoma and Ewing's sarcoma/peripheral primitive neuroectodermal tumor (ES/pPNET) are described. The diagnosis of ES/pPNET in each case was first established in the hysterectomy specimen because each ES/pPNET was misinterpreted on the endometrial biopsy specimens as a high-grade homologous sarcoma. The ES/pPNET element in each case consisted of solid masses of small- to medium-sized round cells without Homer-Wright pseudorosettes, glial or ganglion cells, true rosettes with central lumens, or medulloepithelial tubules. Each ES/pPNET exhibited focal positive immunostaining for neuron-specific enolase, diffuse staining for vimentin, and strong cell membrane immunoreactivity for O13 (CD99), the last finding providing the first clue to the diagnosis of ES/pPNET in each case. The diagnosis in each case was confirmed by detection of EWS/FLI-1 fusion transcript through reverse transcription polymerase chain reaction. We also examined O13 immunoreactivity retrospectively in 40 cases of malignant mixed mullerian tumors (MMMT) with homologous or heterologous elements. O13 immunoreactivity was not observed in the malignant epithelium or in the homologous or heterologous sarcomas. The immunoreactivity of O13 in round cell endometrial sarcomas provides a clue to the diagnosis of ES/pPNET.

Uterine metastasis from a heterologous metaplastic breast carcinoma simulating a primary uterine malignancy.

OBJECTIVE: To describe the first distant metastasis of a heterologous metaplastic breast carcinoma in the uterus and discuss its differential diagnosis. METHODS: Light microscopy, immunohistochemistry, and flow cytometry were used to evaluate the tumor. RESULTS: A 58-year-old woman underwent mastectomy for metaplastic breast carcinoma confined to the breast. She presented 4 years later with vaginal bleeding. The endometrial curettage showed a poorly differentiated carcinoma. She underwent hysterectomy and bilateral salpingo-oophorectomy as well as pelvic and periaortic lymphadenectomy. Clinical and intraoperative findings favored a primary uterine malignancy. The uterus was markedly distorted with multiple gray-white, solid subserosal, and intramural tumor nodules. The tumor diffusely infiltrated the endometrium sparing benign endometrial glands. The tumor nodules were distributed full thickness of the myometrium. These nodules were composed of high-grade malignant epithelial cells with areas of chondroid metaplasia. Extrauterine microscopic tumor was present in left ovary, pelvic, and periaortic lymph nodes. The histologic features and estrogen/progesterone receptors (ER/PR) as well as DNA ploidy analysis of the uterine tumor showed striking similarity with those of the primary metaplastic breast carcinoma. A diagnosis of metastatic metaplastic breast carcinoma in the uterus was rendered. CONCLUSION: A metastatic heterologous metaplastic breast carcinoma with cartilaginous metaplasia should be considered in the differential diagnosis of heterologous uterine malignant mixed mesodermal tumor (MMMT) and high-grade endometrioid carcinoma with rare foci of cartilage.

Clinical significance of negative and equivocal urinary bladder cytology alone and in combination with DNA image analysis and cystoscopy.

BACKGROUND: We evaluated the individual and combined ability of cytology (CYT), image analysis (IA), and cystoscopy (CYSTO) to predict the presence of transitional cell carcinoma (TCC) at 6 months of follow-up in patients with or without a prior history of urothelial carcinoma and negative (NEG) or equivocal (atypical or suspicious) urinary CYT. METHODS: Fifty-one patients (43 with prior TCC) provided 57 urinary samples that were evaluated by CYT and DNA IA. Forty-nine patients were evaluated by CYSTO. Disease status was reassessed at 6 months by a combination of clinical, CYSTO, CYT, and histologic follow-up. RESULTS: At 6 months' follow-up, the incidence of recurrence for patients with diploid, broad diploid, or aneuploid DNA histograms was 38%, 73%, and 100%, respectively. In the same group of patients, 43% of patients with NEG and "atypical" CYT recurred compared with 83.3% of patients with "suspicious" CYT. The predictive value (PV) of a positive (+) CYSTO evaluation was 100%; however, a NEG CYSTO examination was correct in only 73% of cases. Sensitivities of CYT, IA, and CYSTO to predict recurrence were 54%, 59%, and 62.5%, respectively, whereas the combined sensitivity of all three modalities was 72%. The +PV of combined CYT and IA in patients with prior TCC was 90% with aneuploidy 100% specific for malignancy; the NEG PV of combined CYT, IA, and CYSTO was 70%. CYT, IA, and CYSTO were highly significant in predicting recurrence (P = 0.0017, P = 0.0026, and P = 0.0002, respectively) whereas tumor grade and degree of invasiveness as assessed on initial biopsy were not significant. However, 11% of patients recurred between 6 months to 1 year who had NEG CYT, NEG CYSTO, and NEG IA. CONCLUSIONS: Diagnostic accuracy increases in patients with NEG or equivocal CYT if supplemented by DNA IA and CYSTO. In patients with no history of TCC, equivocal urine CYT and/or abnormal DNA IA can occur after chemotherapy, radiation therapy, or viral infection. In these patients, the combined approach together with accurate history is essential for correct diagnosis. For the small subpopulation of patients who recur but demonstrate no abnormalities on combined testing, more sensitive diagnostic tests, such as chromosomal abnormalities by in situ hybridization, need to be developed.