Localization of human BRCA1 and its loss in high-grade, non-inherited breast carcinomas.

Although the link between the BRCA1 tumour-suppressor gene and hereditary breast and ovarian cancer is established, the role, if any, of BRCA1 in non-familial cancers is unclear. BRCA1 mutations are rare in sporadic cancers, but loss of BRCA1 resulting from reduced expression or incorrect subcellular localization is postulated to be important in non-familial breast and ovarian cancers. Epigenetic loss, however, has not received general acceptance due to controversy regarding the subcellular localization of BRCA1 proteins, reports of which have ranged from exclusively nuclear, to conditionally nuclear, to the ER/golgi, to cytoplasmic invaginations into the nucleus. In an attempt to resolve this issue, we have comprehensively characterized 19 anti-BRCA1 antibodies. These reagents detect a 220-kD protein localized in discrete nuclear foci in all epithelial cell lines, including those derived from breast malignancies. Immunohistochemical staining of human breast specimens also revealed BRCA1 nuclear foci in benign breast, invasive lobular cancers and low-grade ductal carcinomas. Conversely, BRCA1 expression was reduced or undetectable in the majority of high-grade, ductal carcinomas, suggesting that absence of BRCA1 may contribute to the pathogenesis of a significant percentage of sporadic breast cancers.

Lymphomatoid granulomatosis and malignant lymphoma of the central nervous system in the acquired immunodeficiency syndrome.

While primary and secondary malignant lymphomas have been well-documented in the CNS of patients with the acquired immunodeficiency syndrome (AIDS), only one case of lymphomatoid granulomatosis (LG) involving the CNS has been reported. We present three AIDS patients with multiple grossly evident foci of necrosis in the cerebral hemispheres which, on histologic evaluation, were seen to contain angiocentric mixed chronic inflammatory infiltrates with atypical mononuclear cells, luminal thrombosis, and infarction, which is typical of LG. LG was also identified in sections of the lung in one case. Lymphoma was found in other regions of the brain in two cases, suggesting the evolution of LG into cerebral lymphoma. In addition, widespread perivascular multinucleate syncytial giant cells, associated with human immunodeficiency virus (HIV) infection of the CNS, were identified in all patients. The features of LG, its relationship to lymphoma, and the possible etiologic role of an immunodeficiency state or the HIV virus in the pathogenesis of LG are discussed.

Multifocal necrotizing leukoencephalopathy with pontine predilection in immunosuppressed patients: a clinicopathologic review of 16 cases.

Multifocal necrotizing leukoencephalopathy (MNL) is characterized by multiple, usually microscopic, foci of necrosis confined primarily to the white matter of the basis pontis, but sometimes found elsewhere in the central nervous system. All 16 patients in whom we identified MNL had underlying immunosuppression, either naturally occurring or iatrogenic, including the acquired immunodeficiency syndrome (seven patients), acute leukemias (four patients), and lymphoma (one patient). One patient each had severe combined immunodeficiency, orthotopic liver transplantation, Shwachman-Diamond syndrome, and idiopathic thrombocytopenic purpura treated with high-dose steroids. Histologically, lesions of MNL show demyelination, spongiosis, axonal swelling, minimal histiocytic infiltrates, and frequent axonal calcification. Multifocal necrotizing leukoencephalopathy lesions were found in the pons of all patients, most commonly in the crossing pontocerebellar fibers, but often in the descending white matter tracts and rarely in the tegmentum. Three cases also showed nonpontine foci of MNL involving the white matter of the medulla, cerebellum, and cerebral hemispheres. Multifocal necrotizing leukoencephalopathy is a distinct entity usually localized to the basis pontis and is most consistently associated with immunosuppression, but as yet lacks other clearly defined clinical correlates.

Giant cell arteritis in association with cerebral amyloid angiopathy: immunohistochemical and molecular studies.

Giant cell arteritis (GCA) usually manifests as a transmural vascular infiltrate of mononuclear and multinucleated giant cells (MNGC). We describe six patients with GCA associated with severe cerebral amyloid angiopathy (CAA), all with cerebral hemorrhage or varying degrees of cerebral infarct, and histological evidence of Alzheimer's disease (cortical CAA often predominating over senile plaques and neurofibrillary tangles). One case showed mostly cortical involvement (with old microhemorrhages), and the others were primarily leptomeningeal (with involvement of the underlying cortex and extensive encephalomalacia of adjacent brain). Many vessels with CAA exhibited a pronounced adventitial and perivascular infiltrate of lymphocytes, histiocytes, and MNGC. Immunohistochemical staining showed deposition of beta/A4 peptide primarily in the thickened media of CAA vessels, and within the cytoplasm of MNGC--suggesting phagocytosis of insoluble peptide. Cystatin C antibody stained vascular amyloid and diffusely highlighted astrocytic and MNGC cytoplasm. HAM56-positive macrophages were frequently seen around amyloid-laden vessels. Anti-smooth muscle actin immunohistochemistry suggests the occurrence of medial destruction by amyloid, with relative preservation of intimal cells. Ultrastructural studies performed in one case confirmed the presence of intracytoplasmic amyloid in MNGC. The GCA seen in these cases of CAA most likely represents a foreign body response to amyloid proteins, causing secondary destruction of the vessel wall. DNA from brain tissues of five affected patients was examined to assess whether mutations were present in exon 17 of the APP gene or exon 2 of the cystatin C gene, a finding that might explain the foreign body giant cell response to amyloid proteins in these cases. However, restriction fragment mapping of amplified gene segments showed that previously described mutations were not present in these cases.

Acute eosinophilic pulmonary disease associated with the ingestion of L-tryptophan-containing products.

A series of four patients with pulmonary infiltrates, pleural effusions, hypoxemia, peripheral eosinophilia, and symptoms of dyspnea, fatigue, and weakness is reported. Lung tissue obtained in three patients revealed interstitial pneumonitis, small-to-medium-vessel mixed-cell vasculitis, and alveolar exudate of histiocytes and eosinophils. All patients reported ingestion of L-tryptophan-containing products at a time when an association between L-tryptophan and the eosinophilia-myalgia syndrome was established. This clinical pattern of pulmonary involvement may be part of the continuum of the eosinophilia-myalgia syndrome. The pathophysiology of this syndrome and the relationship with the ingestion of L-tryptophan-containing products have not yet been identified.

Benign melanocytic nevus cells in axillary lymph nodes. A prospective incidence and immunohistochemical study with literature review.

Benign nevus cell aggregates (NCAs) in lymph nodes usually present as intracapsular or trabecular collections of small, uniform melanocytes that resemble those seen in intradermal melanocytic nevi. The surgical pathologist must be aware of nodal NCAs because they can mimic micrometastasis of carcinoma. Although not uncommon, the frequency with which NCAs occur is controversial. Two previous studies attempted to determine the case incidence of NCAs in axillary lymphadenectomies; widely different results were reported, ranging from .33% to 6.2%. In this study, the authors examined prospectively 300 axillary lymph node dissections containing 5186 lymph nodes, using S-100 protein immunohistochemistry as a supplemental evaluation measure, to determine the incidence of NCAs. Twenty-eight NCA-positive lymph nodes from 22 cases were found, for a 7.3% case incidence and a .54% nodal incidence; these figures were higher than those previously reported. The possible pathogenesis of this phenomenon is discussed, with a review of the literature.

Neurilemoma of the kidney.

Neurilemomas are neoplasms that originate from Schwann cells of the central and peripheral nervous systems. Thirteen case reports of neurilemomas involving the kidney have been described in the English literature. We report the fifth case of a neurilemoma within the renal sinus and review the previous cases of renal neurilemoma. This neoplasm is usually found incidentally. Presenting signs are nonspecific and radiographic features are highly variable. These factors make a preoperative diagnosis extremely difficult. Accurate identification relies heavily on detailed pathologic evaluation. Wide local excision is the treatment of choice, since malignancy is found in up to 30% of cases and there is a tendency for local recurrence and distant metastasis.

Aspergillosis of the testis in a renal transplant recipient.

Aspergillus is ubiquitous worldwide. It is found primarily in soil, dust, vegetation, and decaying matter. While disseminated aspergillosis affects the testis only 1% of the time, testicular aspergillosis in the absence of disseminated disease is exceedingly rare, as demonstrated in the present case report.

Testicular plasmacytoma. A case report with immunohistochemical studies and literature review.

Plasmacytomas of the testes are extremely rare tumors, especially when occurring in the absence of a previous or concurrent diagnosis of multiple myeloma. We present a case of solitary testicular plasmacytoma in a 71-year-old man who had no clinical evidence of myeloma. Immunohistochemical stains showed monoclonal cytoplasmic production of IgA-kappa within tumor cells. A summary of the other reported cases of testicular plasmacytoma is presented. Plasmacytoma of the testes, while occasionally manifesting as a solitary, primary lesion, most likely is a precocious, highly unusual manifestation of systemic multiple myeloma.

Focal pontine leukoencephalopathy in immunosuppressed patients.

In three patients who died of immunodeficiency syndromes, including two patients with acquired immunodeficiency syndrome (AIDS), foci of necrotizing leukoencephalopathy were found in the basis pontis. The lesions were identical in location and morphology to those previously described in patients who received chemotherapy and central nervous system radiotherapy for various malignancies, and (except for their restricted anatomic location) resembled the disseminated necrotizing leukoencephalopathy that complicates central nervous system leukemia and lymphoma. The lesions are to be distinguished from central pontine myelinolysis, are confined to pontocerebellar tracts, and are not specific for the immunodeficient state, but may reflect preterminal metabolic derangements, since they seem unrelated in this clinical setting to malignancy and/or its treatment. Alternatively, they may be a consequence of the immunosuppressed state. The presence of this morphologic abnormality in two AIDS patients is especially intriguing, in view of the frequency with which white matter lesions are seen in the AIDS population.

Gangliocytic paraganglioma associated with duodenal adenocarcinoma. Case report with immunohistochemical evaluation.

We present the first reported case (to our knowledge) of duodenal gangliocytic paraganglioma (GPG) to be associated with an underlying invasive adenocarcinoma. The patient, a 71-year-old man, presented with epigastric tenderness and was found to have metastatic adenocarcinoma in two regional lymph nodes. Immunohistochemical evaluation of the GPG demonstrated positive staining for gastrin, glial-fibrillary acidic protein, glucagon, neuron-specific enolase, pancreatic polypeptide, S100 protein, somatostatin, and substance P. The clinical, pathologic, and immunohistochemical features of GPG are discussed, with a review of the literature.

Oat cell carcinoma of the gallbladder. A rare and highly lethal neoplasm.

Oat cell carcinomas arising in the gallbladder are an extremely rare and aggressive form of gallbladder cancer. These neoplasms are morphologically identical to their pulmonary counterparts, contain neurosecretory granules on ultramicroscopic examination, and demonstrate immunohistochemical staining for cytokeratin, neuron-specific enolase, and other neuroendocrine markers. Oat cell carcinomas typically occur in elderly women with cholelithiasis, and pursue a fulminant course with extensive metastases, especially to the liver. The mean survival is less than 7 months. We present a well-documented case of oat cell carcinoma of the gallbladder and review the literature on this unusual entity.

Fine-needle aspiration of primary soft-tissue lesions.

This study presents the cytologic findings of fine-needle aspiration (FNA) in a series of 136 primary soft-tissue tumors. The cytologic appearances of some rare mesenchymal lesions are presented, including the first (to our knowledge) published descriptions of fibrous hamartoma of infancy and myositis ossificans. Fine-needle aspiration showed high diagnostic sensitivity (95%) and specificity (95%) for the determination of malignancy, approaching that obtained with frozen-section interpretation. Problems encountered with the diagnosis of mesenchymal lesions, including nodular fasciitis, Kaposi's sarcoma, and spindle cell lipoma, are discussed. Based on these findings, recommendations for aspiration cytology of soft-tissue tumors are presented.

Fine needle aspiration cytology of primary bone lesions.

Fine needle aspiration (FNA) cytologic findings were compared with the results of conventional histology in a series of primary bone lesions to determine the diagnostic accuracy of FNA cytology. The series included 12 osteogenic sarcomas, 4 Ewing's sarcomas, 3 chordomas, 3 myelomas, 2 chondrosarcomas, 2 undifferentiated sarcomas and 1 case each of normal bone and marrow elements, lymphoma and giant-cell tumor. All aspirates yielded adequate material for smear diagnosis, and all 29 cases were correctly identified as benign or malignant by cytology. In 19 cases (66%), specific cytologic diagnoses were rendered and histologically confirmed. This series is compared with other published series of bone aspirations in terms of technique, accuracy and ability to obtain diagnostic material. The importance of technique, radiographic investigations and experience in performing the aspirations in achieving a high diagnostic yield is emphasized.

Fatal embolization of ball portion of Starr-Edwards aortic valve prosthesis.

We report an unusual case of a Starr-Edwards aortic valve malfunction with fatal dislodgment and embolization of its ball portion to the distal abdominal aorta, just above the bifurcation, leading to sudden death. This case is unusual in that it is, to date, the longest time elapsed between valve placement and ball dislodgment.

Human prion diseases.

The Council on Scientific Affairs of the California Medical Association presents the following inventory of items of progress in pathology. Each item, in the judgment of a panel of knowledgeable physicians, has recently become reasonably firmly established, both as to scientific fact and important clinical significance. The items are presented in simple epitome, and an authoritative reference, both to the item itself and to the subject as a whole, is generally given for those who may be unfamiliar with a particular item. The purpose is to assist busy practitioners, students, researchers, and scholars to stay abreast of these items of progress in pathology that have recently achieved a substantial degree of authoritative acceptance, whether in their own field of special interest or another. The items of progress listed below were selected by the Advisory Panel to the Section on Pathology of the California Medical Association, and the summaries were prepared under its direction.

The many faces and phases of borreliosis. I. Lyme disease.

Lyme disease is increasingly being reported throughout the United States and many parts of the world. Borrelia burgdorferi, the etiologic agent of Lyme disease, is a spirochete that, not unlike the treponema of syphilis, can cause a spectrum of disease from the initial skin lesion, through widely varied symptoms and signs, to chronic neurologic and arthritic disability. The borrelial spirochete and Lyme disease are the subject of this review. A subsequent article will review other definite and possible cutaneous manifestations of borreliosis.