Gary W. Mierau

Hepatic Angiomyolipoma with Striated Granules and Positivity with Melanoma-Specific Antibody (HMB-45): A Report of Two Cases

Angiomyolipoma occurs rarely in the liver, with only 25 previous cases being reported in the English literature. The article describes two additional cases, one of which was multicentric, with results of ultrastructural and immunocytochemical studies. Many of the tumor cells contained numerous electron-dense granules, some with transverse striations like those found in melanosomes. Both tumors stained positively for S-100 protein and melanoma-specific antibody HMB-45. One case also expressed vimentin and neuron-specific enolase. Both were negative for cytokeratin, carcinoembryonic antigen, alpha-fetoprotein, desmin, muscle-specific actin, factor VIII antigen, and chromogranin. Comparison of our ultrastructural findings with those of classic renal angiomyolipoma raises the possibility that the melanosomelike structures may represent renin granules rather than melanosomes, although the latter are not excluded. Expression of HMB-45 in angiomyolipoma has important biologic and diagnostic implications, whether or not it reflects melanocytic differentiation.

Renal neoplasms mimicking rhabdoid tumor of kidney: A report from the National Wilms' Tumor Study Pathology Center

Fifty-six renal neoplasms reviewed by the National Wilms Tumor Study Pathology Center presented with histologic features that resulted in confusion with rhabdoid tumor of kidney, a usually lethal childhood renal tumor; all were eventually diagnosed as other entities. Conspicuous filamentous cytoplasmic inclusions or large nucleoli, typical findings in rhabdoid renal tumors, were the usual source of diagnostic difficulty. Most, but not all, tumors occurred in pediatric patients. Sixteen were examples of Favorable Histology Wilms tumor, which invited confusion with rhabdoid tumors either on the basis of filamentous cytoplasmic inclusions (15 cases) or ma-cronucleoli (one case). In most cases, foci of typical Wilms tumor blastemal aggregation or evidence of definitive nephrogenic differentiation facilitated the correct diagnosis. All 10 patients for whom information about outcome was available were alive at last follow-up. The other 40 renal lesions mimicking rhabdoid tumor of kidney consisted of a clinically and histogenetically diverse group of neoplasms, including anaplastic Wilms tumor, congenital mesoblastic nephroma, renal cell carcinoma, transitional cell carcinoma, collecting-duct carcinoma, oncocytoma, rhabdomyosarcoma, malignant neuroepithelial tumors, and lymphoma. Most of these lesions could be separated from renal rhabdoid tumors and correctly classified on the basis of careful attention to light microscopic details, but in several cases electron microscopy or immunocytochemical studies were helpful or essential.

Primary Leiomyosarcoma of Brain in an Adolescent with Common Variable Immunodeficiency Syndrome

A 14-year-old girl with common variable immunodeficiency syndrome was found to have a low-grade malignant neoplasm arising in the left temporal lobe of the brain. Ultrastructural and immunohistochemical studies established a diagnosis of leiomyosarcoma, despite the rarity of this tumor in children. In situ hybridization with the EBER probe revealed essentially all of the neoplastic cells to be infected with Epstein-Barr virus (EBV). Children with the acquired immunodeficiency syndrome (AIDS) are known to exhibit an increased incidence of smooth muscle tumors associated with EBV. Similar tumors have been reported in EBV-infected patients undergoing therapeutic immunosuppression. This appears to be the first reported case of childhood leiomyosarcoma where the cause of the underlying immunodeficiency was a genetic rather than acquired disorder. The authors conclude that electron microscopy, immunohistochemistry, and other ancillary techniques are essential in the evaluation of unusual tumors in immunocompromised children, whether the cause is hereditary or acquired.

Ependymoma with signet-ring cells.

Two patients presented with unusual primary brain tumors having abundant signet-ring cells, for which electron microscopic study was necessary to establish the diagnosis of ependymoma. The light and electron microscopic features of these tumors are discussed, with brief comments on the differential diagnosis.

HMB-45 Staining in Angiomyolipoma, Cardiac Rhabdomyoma, Other Mesenchymal Processes, and Tuberous Sclerosis-associated Brain Lesions

HMB-45 monoclonal antibody is thought to be highly specific for melanocytic prolifer ations. In a recent study of two cases of hepatic and one case of renal angiomyolipoma, strong staining of lesional cells with this antibody was unexpectedly encountered. In follow-up evaluation, the authors studied 51 additional soft tissue, renal, and brain tumors and tumor-like processes, with emphasis on those with prominent vascular, myogenous, and fatty components or those known to be associated with tuberous sclerosis. Varying degrees of staining with HMB-45 were seen in 17 of the lesions tested. Strong staining with HMB-45 was demonstrated in four renal angiomyolipo mas. Clearly positive results were also obtained in three other processes associated with the tuberous sclerosis complex, including two cardiac rhabdomyomas and one tuberous lesion of the brain. Weak staining of several other mesenchymal and neural lesions was also observed. Electron microscopic studies showed a spectrum of granules within angiomyolipoma, some of which resembled melanosomes and others renin granules. Similar granules were observed in cardiac rhabdomyoma, cerebral tuberous lesions, and in subependymal giant cell astrocytoma. We propose that tuberous scleros is-associated tumors and tumor-like processes are interrelated, and that these and perhaps other mesenchymal proliferations may share components previously believed to be unique to melanocytic lesions. Int J Surg Pathol 1 (3):191-198, 1994

APPRAISAL OF THE COMPARATIVE UTILITY OF IMMUNOHISTOCHEMISTRY AND ELECTRON MICROSCOPY IN THE DIAGNOSIS OF CHILDHOOD ROUND CELL TUMORS

To provide an objective assessment of the comparative utility of fluorescence- and peroxidase-based immunohistochemistry and electron microscopy, an observer blinded study was conducted under realistic study conditions utilizing a large sampling of poorly differentiated pediatric round cell tumors. Working independently, using a single ancillary technique of particular expertise, each of three investigators attempted to render a specific diagnosis with regard to 50 diagnostically challenging tumors. The results were compared against the subsequent file diagnosis established by consensus with all relevant information made available. A grading scheme was applied wherein points were awarded based on the accuracy and confidence of diagnosis. A comparative efficiency rating, expressed as a percentage, was formulated by dividing the number of points awarded each technique by the total number of points theoretically available. Electron microscopy proved superior overall, with an efficiency rating of 89%. Immunoperoxidase and immunofluorescence studies yielded efficiency ratings of 71 and 61%, respectively. Used in combination, the techniques achieved an efficiency rating of 95%. Application of these ancillary techniques resulted in a revision of the provisional diagnosis in 11 of 50 cases, and left only two cases without a firm specific diagnosis.

The Role of Electron Microscopy in Evaluating Ciliary Dysfunction: Report of a Workshop

This report summarizes the proceedings of a workshop organized with the purpose of bringing together many of those with substantial experience in this troublesome area of pathology for an active interchange of ideas, opinions, problems, and solutions. Recognition was given the fact that current knowledge and technical capabilities are woefully inadequate for dealing with the diagnostic questions now being asked. Until such time as these inadequacies can be remedied, a very conservative approach to the interpretation of ultrastructural studies is advocated.

Ultrastructure of cellular congenital mesoblastic nephroma.

A detailed ultrastructural description of the cellular variant of congenital mesoblastic nephroma (CMN) is presented and compared to the classical form. Studied were 9 cases of the cellular variant, 6 mixed (cellular/classical) tumors, and 1 classical CMN. The occurrence of a broad selection of ultrastructural features was assessed using a semiquantitative scoring system. The results indicate that cellular CMNs are composed mainly of primitive mesenchymal cells, but also usually contain varying numbers of differentiating fibroblasts and myofibroblasts. This entity thus bears a closer resemblance at the ultrastructural level of organization to infantile fibrosarcoma than to conventional fibrosarcoma. Electron microscopy can be useful in distinguishing this relatively benign entity from the several malignancies with which it is sometimes confused.

Intriguing Case: Primitive Pelvic Sarcoma Resembling Clear Cell Sarcoma of Kidney

A 46-year-old man presented with a cytologically bland testicular tumor composed of spindle cells that showed both epitheliallike (ie, true desmosomes and tonofilamentlike structures) and myogenous differentiation (ie, thin filaments with focal densities and alpha-smooth muscle actin immunoreactivity). Tumor cells were immunoreactive for vimentin and S-100 protein but negative for cytokeratin and desmin. Peritubular myoid cells are present in the normal testis; contain subplasmalemmal micropinocytotic vesicles; show thin filaments with focal densities; and are reactive with desmin, vimentin, and alpha-smooth muscle actin. They have no desmosomes and lie outside the basement membrane of the seminiferous tubules; thus they are not true myoepithelial cells (a cell type not present in the testis). Paradoxically, the current tumor appeared to show bidirectional differentiation, mimicking both a peritubular myoid spindle cell and an epitheliallike cell (possibly similar to the granulosa cell or rete testis epithelial cell). Although the findings suggest myoepithelial differentiation, the cytogenesis of this tumor remains uncertain.Clear cell sarcoma of kidney (CCSK) is an aggressive childhood renal tumor of unknown histogenesis that has not been reported to occur outside the kidney. The article describes an extrarenal neoplasm arising in the pelvic soft tissues of a 13-year-old boy that was composed predominantly of uniform mesenchymal cells with optically clear cytoplasm supported by an arborizing network of small blood vessels, which was indistinguishable in appearance from CCSK. The electron microscopic findings, although nonspecific, were essentially identical to those of CCSK, with tumor cells displaying fine chromatin, electron-lucent cytoplasm, and intercellular collagen but no evidence of tissue-specific differentiation. Immunocytochemical studies showed positivity for vimentin but negative results for desmin, myoglobin, cytokeratin, epithelial membrane antigen, S-100 protein, neuron-specific enolase and factor VIII-related antigen. Tumor cells were also nonreactive with Ulex lectin. This unusual pelvic tumor and CCSK may both derive from primitive mesenchymal cells and may represent phenotypic but not necessarily histogenetic analogs.

Intranuclear rod myopathy, a rare and morphologically striking variant of nemaline rod myopathy

A 4-year-old boy with muscle weakness underwent skeletal muscle biopsies. Light microscopy showed distinct eosinophilic inclusions within the majority of muscle cell nuclei, but none in the cytoplasm. Electron microscopy revealed crystalline, round to rod-shaped inclusions in the muscle cell nuclei. The inclusions stained positively for alpha-actinin. Intranuclear inclusions identical to those seen here have been described in rare cases of nemaline rod myopathy, though almost always together with classic intracytoplasmic rods. This case illustrates the importance of electron microscopy in the diagnosis of rare myopathies and in the characterization of cellular inclusions of unknown origin.