Belur S. Bhagavan

Ectopic ACTH, prostatic oat cell carcinoma, and marked hypernatremia

Locally recurrent, poorly differentiated carcinoma of the prostate was associated with hypokalemic alkalosis, marked hypernatremia, diabetes mellitus of recent onset,and hyperosmolar syndrome. These findings, with mild hypertension, in the absence of clinical features of Cushings syndrome, suggested an ectopic ACTH syndrome. Plasma ACTH and cortisol levels were markedly elevated, and failed to suppress in response to either low or high‐dose dexamethazone administration. The patients condition deteriorated rapidly. Autopsy findings included carcinoma extensively infiltrating the prostate with extension to the urinary bladder, and metastases confined to the pelvic nodes and soft tissues. The adrenal glands weighed 23 g and showed diffuse hyperplasia. Extract of the prostatic tumor was analyzed for ACTH and showed approximately 40 times normal plasma levels (or about 4,010 pg/g of tissue); ultrastructural features showed secretory granules consistent with ACTH content of the tumor cells. Such cells were positive when stained for ACTH by peroxidase‐tagged immunochemical methods. The case fulfills all established criteria for relating excess corticosteroid production and nonpituitary tumors. Cancer 40:773–778, 1977.

Upper gastrointestinal tract injury in patients receiving kayexalate (sodium polystyrene sulfonate) in sorbitol: clinical, endoscopic, and histopathologic findings.

Kayexalate (sodium polystyrene sulfonate) in sorbitol has been demonstrated to cause colonic necrosis in a subset of uremic patients who are administered the cation exchange resin for treatment of hyperkalemia. Upper gastrointestinal damage associated with Kayexalate in sorbitol is reported far less frequently, and the clinicopathologic spectrum of disease in cases with upper gastrointestinal damage has not been investigated previously. The authors studied the clinical, endoscopic, and histologic features of 11 patients with Kayexalate crystals in biopsies from the esophagus (n = 7), stomach (n = 6), and duodenum (n = 2). The endoscopic appearance was markedly abnormal in all 11 patients. The effects of the medication closely mimicked other endoscopic and radiologic diagnoses in three cases, including esophageal carcinoma, Candidal esophagitis, and gastric bezoar. Histologic and/or endoscopic evidence of mucosal injury in the form of an ulcer or erosion was present in nine patients (82%). In four patients with mucosal injury, no other etiology apart from Kayexalate in sorbitol could be identified. In comparison with a cohort of patients with Kayexalate crystals in lower gastrointestinal specimens identified during the same period (11 patients) the frequency of associated mucosal damage was not significantly different (55%, p = 0.19), but no patient with upper gastrointestinal Kayexalate required surgical resection or died as a result of Kayexalate-induced mucosal injury. The results of this study provide evidence that Kayexalate in sorbitol can induce damage to the upper gastrointestinal tract. Recognition of Kayexalate crystals in histologic sections as a marker for sorbitol-induced mucosal damage may aid in establishing the correct diagnosis for clinically or endoscopically misleading lesions.

Intravascular bronchiolo-alveolar tumor (IVBAT). A low-grade sclerosing epithelioid angiosarcoma of lung

Intravascular bronchiole-alveolar tumor (IVBAT) is a rare and highly distinctive pulmonary tumor of disputed cellular nature. Both epithelial and endothclial differentiation of this neoplasm have been suggested. We have studied multiple nodules of IVBATs from three patients by light and electron microscopy and by immunohistochemical methods for Factor VIII-related antigen (FVIII RAG). Our light and ultrastructural studies are in essential agreement with the previous suggestion of the cndothelial nature of the neoplasm and our demonstration of the presence of FVIII RAG in many of the tumor cells offers new evidence strongly supportive of their endothelial differentiation. We believe that IVBAT and a group of cxtrapulmonary tumors described as epithelioid hcmangiocndothclioma and endovascular papillary angioendothelioma are similar biologically indolent neoplasms of epithelioid and dendritic cndothelial cells characterized by stromal sclerosis, intravascular spread, a low incidence of metastases and slow clinical evolution. Thus, we regard IVBAT as a low-grade sclerosing angiosarcoma of the lung.

Interobserver variability in the interpretation of epithelial ovarian cancer

The interobserver diagnostic reproducibility for epithelial ovarian neoplasia was studied. The histologic sections of 68 ovarian tumors from 34 patients were independently reviewed by two pathologists from different institutions, without knowledge of the clinical course. Each observer rendered 68 diagnoses. The interobserver agreement rate for histologic type was 60% and for histologic grade 66%. In the 23 instances in which a discrepancy in grade occurred, 5 (23%) were disagreements in the diagnosis of borderline versus malignant tumors. On analysis of the diagnostic variability with regard to histologic type, one observer (A) classified 60% of the tumors as undifferentiated, while the other observer (B) classified 59% of the tumors as serous. In an attempt to understand the reasons for the diagnostic disagreements, the observers were asked to simultaneously reexamine the material. This occurred 6 months after the initial review and they were unaware of their original diagnoses. The diagnostic differences with regard to histologic type were mainly due to (1) tumor cell heterogeneity, and (2) difficulty in discriminating between serous and undifferentiated tumors. The differences in grade were largely related to the use of different criteria. Observer A used mitotic counts while observer B used glandular pattern and its replacement by solid sheets of epithelium. Observer B consistently assigned a higher grade to the tumors. In making therapeutic decisions, clinicians should be aware of the interobserver diagnostic variability and the reasons for this variability.

Nephrogenic adenoma of the urinary bladder and urethra

The histologic and ultrastructural features of nephrogenic adenomas of the urinary bladder and urethra were studied in multiple specimens obtained from eight patients. Three of these were studied by indirect immunofluorescence for Tamm-Horsfall uromucoprotein. The lesions are uncommon benign metaplastic proliferations of urothelium, occurring most frequently in males as small cystic, papillary, or nodular masses and most often presenting with hematuria. Typically the metaplastic tubules resemble nephronic tubules. A florid atypical and pseudoinfiltrative proliferation of these tubules may led to an erroneous diagnosis of adenocarcinoma. Ultrastructural features of proximal convoluted tubules were identified in some of the tubules, but resemblance to specific segments of distal tubules was less certain. The ultrastructural features combined with the absence of Tamm-Horsfall protein in tubular lumina or cells suggest a mesonephric rather than metanephric homology. The lesions are appropriately treated by transurethral resection or fulguration, but persistent lesions were present in three patients up to 18 yeas after initial treatment.

Blue nevus of the uterine cervix

The clinical, gross pathologic, and light and electron microscopic features of three blue nevi of the endocervix were studied. Immunocytochemical studies for the localization of S-100 protein in the blue nevus cells were performed. A comprehensive review of 47 previously published cases is also presented. Blue nevi of the endocervix appear to be rare incidental lesions; they are often found in hysterectomy specimens from middle-aged women. The lesion is seldom detected clinically or colposcopically. However, it appears in most instances as a blue-black lesion in the posterior wall of the endocervix on gross pathologic examination. The demonstration of S-100 protein in the blue nevus cells before and after bleaching in the present study, along with the ultrastructural observations, supports combined melanocytic and schwannian differentiation of the blue nevus cell.

Papillary urothelial hyperplasia. A precursor to papillary neoplasms.

Precursor lesions of papillary urothelial neoplasms have not been well characterized. We reviewed the surgical pathology files of the Johns Hopkins Hospital and three regional hospitals from 1992 to present. Sixteen cases of papillary hyperplasia, defined as undulating urothelium arranged into thin mucosal papillary folds, were identified (in 11 men and five women: age range, 40-89 years). Relative to the diagnosis of papillary hyperplasia, nine patients had a history of papillary urothelial neoplasms; in one of these cases, the patient also had subsequent papillary urothelial neoplasms, and two of these patients had concurrent papillary urothelial neoplasms with papillary hyperplasia. In one of these nine cases, papillary hyperplasia arose in the scar of a prior papillary urothelial neoplasm. In two cases, the patients had concurrent, yet no prior history, of papillary urothelial neoplasms. Of these 11 cases, three had multiple resections showing papillary hyperplasia over time. In case 12, the patient had a history of moderate urothelial atypia. The remaining four patients had no history of papillary urothelial neoplasms or urothelial atypia. We describe papillary hyperplasia as a well-defined entity that is usually asymptomatic and generally found on routine follow-up cystoscopy for papillary urothelial neoplasms. Papillary hyperplasia appears to be a precursor lesion of low-grade papillary urothelial neoplasms.

The significance of bone and cartilage formation in malignant fibrous histiocytoma of soft tissue

Malignant fibrous histiocytoma of soft tissues (MFH), a mesenchymal tumor of varied morphologic patterns and cell types, sometimes contains bone and cartilage. Such bony and cartilaginous elements in a pleomorphic MFH may pose a difficult diagnostic challenge. An MFH with bone and cartilage can be distinguished from extraosseous osteogenic sarcoma and chondrosarcoma on the basis of qualitative and quantitative features of the osseous and chondroid elements. Five cases of soft tissue MFH containing bone and cartilage reported here showed: 1) that the bony and cartilaginous elements are mostly meta‐plastic and tend to be in the pseudo‐capsule or fibrous septa of the tumor; and 2) that the bony elements may show a zoning pattern with peripheral maturation similar to myositis ossificans. In a single case, there was a small amount of “tumor osteoid.” However, this was focal and lacked the diffuse and finely divided or ribbon‐like pattern generally associated with osteogenic sarcoma. The probability that MFH with bone and cartilage is less aggressive than soft tissue osteogenic sarcoma or chondrosarcoma underscores the importance of accurate histologic diagnosis of these tumors.

Ectopic gastrinoma and Zollinger-Ellison syndrome

In Zollinger-Ellison syndrome (ZES), the discovery of gastrinomas in unusual locations, such as a lymph node, poses a diagnostic problem centered on whether the neoplasm is primary or metastatic. The clinical, gross, microscopic, immunocytochemical, and ultrastructural features of ectopic gastrinomas were studied in four patients with ZES, and reports of 14 similar cases were reviewed. These extragastroenteropancreatic (EGEP) gastrinomas have many of the morphologic features of gastrinomas in conventional locations. However, the centrifugal expansile growth pattern, characterized by a thick fibrous capsule, hyalinized fibrous septa, and, frequently, cystic degenerative changes in EGEP gastrinomas should alert the pathologist to the probability that these neoplasms are primary. Additional evidence for the primary nature of these EGEP gastrinomas is derived from the postoperative normalization of high serum gastrin levels and the correction of the abnormal gastrin response to secretin challenge or to calcium infusion tests. Increased awareness of the occurrence and features of these EGEP gastrinomas is crucial for both pathologists and surgeons to ensure proper evaluation and treatment of patients with ZES.

Pseudoactinomycotic radiate granules in the lower female genital tract: Relationship to the splendore-hoeppli phenomenon

Splendore-Hoeppli phenomenon, the in vivo formation of eosinophilic radiate structures around microorganisms and biologically inert substances, may simulate actinomycotic sulfur granules and has been recognized in extragenital sites. In the lower female genital tract, the authors have noted these pseudoactinomycotic radiate granules (PAMRAGs) in both the presence and the absence of intrauterine contraceptive devices. To elucidate the nature and morphogenesis of PAMRAGs, the light microscopic morphologic features of PAMRAGs were studied by means of a battery of special stains. The absence of central branching filaments or diptheroid forms in PAMRAGs serves to distinguish them from true actinomycotic sulfur granules. Using the immunoperoxidase technique, the authors examined PAMRAGs for the presence of immunoglobulin, complement, and fibrin. Their studies showed that PAMRAGs contain neutral glycoproteins, lipid, and calcium with no demonstrable microorganisms, immunoglobulin, complement, or fibrin. The authors do not support the assertions of others that Splendore-Hoeppli radiate bodies are immune complexes derived from host serum proteins. They speculate that PAMRAGs of the genital tract are derived from host leukocytes that aggregate in response to the commonly present bacteria, parasites, or inert foreign bodies that initiate the Splendore-Hoeppli phenomenon and the morphogenesis of PAMRAGs.