Michele Bisceglia

Oncogenic osteomalacia (OO) is a rare paraneoplastic syndrome of osteomalacia due to phosphate wasting. The phosphaturic mesenchymal tumor (mixed connective tissue variant) (PMTMCT) is an extremely rare, distinctive tumor that is frequently associated with OO. Despite its association with OO, many PMTMCTs go unrecognized because they are erroneously diagnosed as other mesenchymal tumors. Expression of fibroblast growth factor-23 (FGF-23), a recently described protein putatively implicated in renal tubular phosphate loss, has been shown in a small number of mesenchymal tumors with known OO. The clinicopathological features of 32 mesenchymal tumors either with known OO (29) or with features suggestive of PMTMCT (3) were studied. Immunohistochemistry for cytokeratin, S-100, actin, desmin, CD34, and FGF-23 was performed. The patients (13 male, 19 female) ranged from 9 to 80 years in age (median 53 years). A long history of OO was common. The cases had been originally diagnosed as PMTMCT (15), hemangiopericytoma (HPC) (3), osteosarcoma (3), giant cell tumor (2), and other (9). The tumors occurred in a variety of soft tissue (21) and bone sites (11) and ranged from 1.7 to 14 cm. Twenty-four cases were classic PMTMCT with low cellularity, myxoid change, bland spindled cells, distinctive "grungy" calcified matrix, fat, HPC-like vessels, microcysts, hemorrhage, osteoclasts, and an incomplete rim of membranous ossification. Four of these benign-appearing PMTMCTs contained osteoid-like matrix. Three other PMTMCTs were hypercellular and cytologically atypical and were considered malignant. The 3 cases without known OO were histologically identical to the typical PMTMCT. Four cases did not resemble PMTMCT: 2 sinonasal HPC, 1 conventional HPC, and 1 sclerosing osteosarcoma. Three cases expressed actin; all other markers were negative. Expression of FGF-23 was seen in 17 of 21 cases by immunohistochemistry and in 2 of 2 cases by RT-PCR. Follow-up (25 cases, 6-348 months) indicated the following: 21 alive with no evidence of disease and with normal serum chemistry, 4 alive with disease (1 malignant PMTMCT with lung metastases). We conclude that most cases of mesenchymal tumor-associated OO, both in the present series and in the reported literature, are due to PMTMCT. Improved recognition of their histologic spectrum, including the presence of bone or osteoid-like matrix in otherwise typical cases and the existence of malignant forms, should allow distinction from other mesenchymal tumors. Recognition of PMTMCT is critical, as complete resection cures intractable OO. Immunohistochemistry and RT-PCR for FGF-23 confirm the role of this protein in PMTMCT-associated OO.

Ten additional adrenocortical oncocytic tumors are presented: 2 benign oncocytomas, 4 borderline oncocytomas of uncertain malignant potential, and 4 oncocytic carcinomas. Histologically all tumors were entirely or predominantly composed of oncocytes. Immunohistochemically all tumors were immunoreactive for mitochondrial antigen mES-13. Electron microscopy was performed in 8 cases and was confirmatory of the oncocytic cell change. The morphologic parameters of the Weiss system, considered to be predictive of the biologic behavior of conventional (nononcocytic) adrenocortical tumors, are reviewed in the context of their possible application to the oncocytic tumor variant. Proposed major criteria (high mitotic rate, atypical mitoses, venous invasion) and minor criteria (large size and huge weight, necrosis, capsular invasion, sinusoidal invasion) in distinguishing malignant tumors are discussed, and definitional criteria (predominantly cells with eosinophilic and granular cytoplasm, high nuclear grade, diffuse architectural pattern) in common with all types of oncocytic tumors are outlined. The authors' proposed working rules for diagnostic categorization of oncocytic adrenocortical tumors are defined, with the presence of 1 major criterion indicating malignancy, 1 to 4 minor criteria indicating uncertain malignant potential (borderline), and the absence of all major and minor criteria indicative of benignancy. Using these criteria, the diagnosis of malignancy was straightforward in 3 of the 4 cases designated as oncocytic carcinoma (presence of at least 2 major criteria and all the minor criteria), while in 1 case the original diagnosis of benign oncocytoma was reversed to malignant following critical review of the original pathologic material after local tumor recurrence. Tumor recurrence occurred in 2 carcinomas at 8 and 20 months, respectively, and was followed in 1 case by the patient's death. The third patient expired at 6 months from unrelated causes, and the fourth patient is free of disease at the relatively short follow-up interval of 6 months. Regarding the 4 patients with borderline tumors, all are alive with no evidence of disease, with follow-up ranging from 10 to 61 months (mean 38.7 months). The 2 benign tumors have a follow-up of 25 and 30 months, respectively. Diagnostic difficulties are delineated and a complete review of the literature on this topic has also been performed.

This review aims to assist in the categorization of inherited, developmental, and acquired cystic disease of the kidney as well as to provide a pertinent, up-to-date bibliography. The conditions included are autosomal-dominant polycystic kidney disease, autosomal-recessive polycystic kidney disease, unilateral renal cystic disease (localized cystic disease), renal simple cysts, multicystic dysplastic kidney, pluricystic kidney of the multiple malformation syndromes, juvenile nephronophthisis and medullary cystic disease, medullary sponge kidney, primary glomerulocystic kidney disease, and glomerulocystic kidney associated with several systemic disorders mainly of genetic or chromosomal etiology, cystic kidney in tuberous sclerosis, and in von Hippel-Lindau syndrome, cystic nephroma, cystic variant of congenital mesoblastic nephroma, mixed epithelial stromal tumor of the kidney, renal lymphangioma, pyelocalyceal cyst, peripylic cyst and perinephric pseudocyst, acquired renal cystic disease of long-term dialysis, and cystic renal cell carcinoma and sarcoma. Whereas the gross and histologic appearance of some of these conditions may be diagnostic, clinical and sometimes molecular studies may be necessary to define other types.