Section 6 -

Recent Developments in the Pathology of Renal Neoplasia John Eble

Carcinoma Associated with Neuroblastoma Over the last 45 years, at least 19 children and young adults have been diagnosed with renal cell carcinoma after surviving neuroblastoma in the first two years of life. Some of these tumors appear to have been clear cell renal cell carcinomas and for others the illustrations and descriptions are not sufficient to precisely characterize the tumors. While some authors have attributed this association to radiation therapy of the neuroblastoma, some of the patients were treated with chemotherapy but not radiation and 2 patients with stage IVs neuroblastoma received neither radiation nor chemotherapy, raising the possibility that rather than a consequence of radiation, there is a specific association between neuroblastoma and renal neoplasia. In 1999, Medeiros et al published an account of 4 survivors of neuroblastoma who had histologically distinctive renal tumors which did not fit into the specific categories of the consensus classification and suggested that they constituted a distinct clinicopathologic entity. Subsequently, another series of 4 similar tumors in neuroblastoma survivors was published. Clinical Features The cases which are best documented to have the characteristic pathologic features are those of the 8 patients reported by Medeiros et al and Koyle et al. These were 6 girls and 2 boys who were diagnosed with neuroblastoma at ages ranging from 6 to 24 months. Two of the patients received neither radiation nor chemotherapy and 1 or 2 others received only chemotherapy. The patients were diagnosed with renal cell carcinoma at ages ranging from 5 to 14 years. The interval from the diagnosis of neuroblastoma to the diagnosis of renal cell carcinoma ranged from 3 years to 11.5 years (mean = 9 yr). In one of the patients the renal cell carcinoma metastasized to lymph nodes and liver. Gross Pathology Macroscopic features have been reported for 4 cases. The major tumors ranged in diameter from 35 to 80 mm; the 20 small tumors in the patient with multiple and bilateral tumors ranged from 1mm to 24 mm. That patient also had multiple cysts which were considered neoplastic. Two tumors were invasive of renal capsule, renal vascular system, or peripelvic lymphatics. No other information about the gross pathology of these tumors is available. Microscopic Pathology The best-documented post-neuroblastoma carcinomas of the kidney contain majority populations of cells with abundant eosinophilic cytoplasm which sometimes is reminiscent of the cytoplasm in oncocytomas.The cells grow in both papillary and solid patterns . Psammoma bodies are infrequently present, as are small clusters of foamy histiocytes. The nuclei often are medium-sized and have irregular contours. Nucleoli are easy to find, corresponding to nuclear grade 3. Mitotic figures are usually present in small numbers. One of the tumors described by Medeiros et al was nuclear grade 4 and infiltrated the renal parenchyma diffusely. Immunohistochemical Profile Medeiros et al studied 4 tumors from 4 patients immunohistochemically. All tumors reacted with antibody to epithelial membrane antigen, most with a luminal staining pattern. Vimentin was detected in each tumor, often in a patchy distribution. Antibody to cytokeratin Cam 5.2 decorated all 4 tumors and antibodies to cytokeratins, 8, 19, and 20 sometimes gave positive reactions. Reactions for S-100 protein, HMB-45, and cytokeratins 7 and 14 were uniformly negative. Mucinous Tubular and Spindle Cell Carcinoma Histologically distinctive renal neoplasms composed of cuboidal and spindle cells with mucinous extracellular matrix have been described in reports of single cases and in small series since 1998. Authors have offered a variety of names for these tumors, often referring to their resemblance to tubules of the lower nephron or loop of Henle and to the remarkably low nuclear grade for a carcinoma with areas of spindle cell morphology. Clinical Features Clinical information is presently available from 22 cases described individually and 7 cases for which the data were combined. All have been adults (age range 20 to 82 years, mean 55 yr, median 58 yr). There is a 3:1 predominance of women over men (22 women and 7 men). Three of the 11 patients reported by Hes et al. also had nephrolithiasis. Approximately 50% of the tumors have been large (stage pT2); in one patient the tumor invaded perirenal fat and in 2 others there was metastasis to a lymph node. All of the tumors have been solitary except in one case in which three tumors arose and were resected over a span of 22 years. The patients have all been treated solely with surgery. With limited periods of clinical follow up, no recurrence has been reported. Gross Pathology Mucinous tubular and spindle cell carcinomas have ranged in size from 22 mm to 130 mm in diameter. The cut surfaces are solid and tan brown to pinkish. Some authors have variously described the cut surfaces as gray to white, tan, and yellow to pinkish. Foci of hemorrhage or necrosis have been found in a few of the tumors. One small tumor appeared to be centered on the renal medulla. All but one of the tumors has been well-circumscribed and contained within the renal capsule. Microscopic Pathology Mucinous tubular and spindle cell carcinomas have a distinctive histologic appearance, consisting of cuboidal cells arranged in long cords and tubules and making abrupt transitions to spindle cell morphology. These epithelial structures are arrayed against a background of lightly basophilic mucinous or myxoid material. The nuclei usually are spherical or oval, have a few small chromatin clumps and small nucleoli Mitotic figures are uncommon. The spindle cell component may form sheets. The mucinous background material may focally dominate and the epithelial elements form small cords in lakes of mucinous material. The mucinous background material has little affinity for mucicarmine but reacts strongly with alcian blue. Plasma cells, mast cells, and clusters of foamy histiocytes are sometimes present. The degree of morphologic variability which occurs in mucinous tubular and spindle cell carcinoma is not clear. One of the tumors reported by Hes et al contained areas of typical clear cell renal cell carcinoma. Two other reports include tumors with some similarities to mucinous tubular and spindle cell carcinoma. Ordóñez et al. reported a tumor composed predominantly of long cords of cuboidal cells separated by clefts. However, they did not describe a spindle cell component or mucinous background material and the tumor contained an area of papillary carcinoma. Lloreta et al described a tumor composed entirely of uniform spindle cells with bland ovoid nuclei with small nucleoli, similar to the spindle cell component of mucinous tubular and spindle cell carcinoma. This tumor had no component of cuboidal cells forming cords or tubules and lacked mucinous background material. Parwani et al excluded 2 tumors which appeared to be mucinous tubular and spindle cell carcinomas in H&E sections from their series on the grounds of immunohistochemical differences. Immunohistochemical Profile The immunohistochemical results obtained in different series have been variable. Positive reactions with antibodies to vimentin and epithelial membrane antigen have been the most frequent findings. Reaction with the cytokeratin cocktail AE1/3 was positive in 10 of 14 tumors in two studies. The lectin Ulex europaeus, which binds to collecting duct epithelium, has consistently failed to bind to the cells of mucinous tubular and spindle cell carcinoma. The immunohistochemical case for lower nephron differentiation is mixed and inconclusive. The positive reactions with antibodies to high molecular weight cytokeratins reported by some authors appear to favor this and the negative reactions for CD15 (which marks proximal tubules) also support the idea. Rakozy et al. found that the lectins soybean agglutinin and peanut agglutinin (which bind to the epithelium of the distal tubule and collecting duct) bound to mucinous tubular and spindle cell carcinoma but antibody to THP (a marker of the ascending loop of Henle and distal convoluted tubules) and Ulex europaeus failed to bind, weighing against the idea of collecting duct origin. Acquired Cystic Disease-Associated Carcinoma Long-term renal dialysis has long been known to predispose to the development of acquired cystic disease and renal cell neoplasms; 3 to 7% of patients with acquired cystic disease develop renal cell carcinoma, indicating a risk 2 orders of magnitude greater than that of the general population. Many of these appear to be typical clear cell, papillary, and chromophobe renal cell carcinomas. Recently, a morphologically distinctive carcinoma has been discovered in patients with acquired cystic disease. Some appear to be unique to end-stage renal disease and acquired cystic disease. Clinical Features Males predominate in a ratio of 2:1. The patients have had end-stage renal disease of varied etiology and have been treated with dialysis for a median duration of 8 years. In the study by Tickoo et al 1 patient died of widespread metastases and 2 other patients had lymph node metastases at the time of nephrectomy. The metastases showed the morphology of acquired cystic disease-associated carcinoma. Sarcomatoid change was present in both the primary and the metastases of of the patient who died of disease. Sarcomatoid change was present in a second acquired cystic disease-associated carcinoma who was alive without disease at 29 months. Gross Pathology The kidneys are atrophic and have numerous cysts, typical of acquired cystic disease. The carcinomas are usually well-circumscribed and the larger ones often have a thick fibrous pseudocapsule which often contains foci of calcification. More than half the tumors appear to arise in a cyst. The larger tumors also often have foci of hemorrhage and necrosis. Microscopic Pathology The architecture is complex with acinar, compact sheets, microscopic and macroscopic cysts in various combinations. Papillary structure ranging from very focal to more than 50% of the tumor, are present in roughly half the tumors. A nearly ubiquitous (present in > 94% of carcinoma) and diagnostically helpful feature is a pattern of sharply defined lumens giving a cribriform appearance. Oxalate crystals are readily visible in routine sections in about 80% of the tumors. The carcinoma cells are large and have eosinophilic cytoplasm. The nuclei often have prominent nucleoli. Immunohistochemical Profile Acquired cystic disease-associated carcinomas gave consistently positive reactions with antibodies to AMACR and vinculin and mostly gave negative reactions with antibodies to cytokeratin 7 and parvalbumin in Tickoo's series. Cossu-Rocca et al. found in three tumors positive reactions for CD10 and cytokeratin AE1/3 and negative reactions with antibodies to cytokeratin 7 and epithelial membrane antigen. References Post-neuroblastoma Carcinoma Eble JN. Mucinous tubular and spindle cell carcinoma and post-neuroblastoma carcinoma: newly recognized entities in the renal cell carcinoma family. Pathology 35:499-504, 2003 Medeiros LJ, Palmedo G, Krigman HR, Kovacs G, Beckwith JB. Oncocytoid renal cell carcinoma after neuroblastoma: a report of four cases of a distinct clinicopathologic entity. Am J Surg Pathol 1999;23:772-80. Fleitz JM, Wootton-Gorges SL, et al. Renal cell carcinoma in long-term survivors of advanced stage neuroblastoma in early childhood. Pediatr Radiol. 33:540-545, 2003. Mucinous Tubular and Spindle Cell Carcinoma Eble JN. Mucinous tubular and spindle cell carcinoma and post-neuroblastoma carcinoma: newly recognized entities in the renal cell carcinoma family. Pathology 35:499-504, 2003. Ferlicot S, Y. Allory Y, et al. Mucinous tubular and spindle cell carcinoma, a report of 15 cases with a review of the literature. Virchows Arch 447:978-983, 2005. Paner GP, SrigleyJR, et al. Immunohistochemical analysis of mucinous tubular and spindle cell carcinoma and papillary renal cell carcinoma of the kidney: significant immunophenotypic overlap warrants diagnostic caution. Am J Surg Pathol. 30:13-19, 2006. Cossu-Rocca P, Eble JN, et al. Renal mucinous tubular and spindle carcinoma lacks the gains of chromosomes 7 and 17 and losses of chromosome Y that are prevalent in papillary renal cell carcinoma. Mod Pathol 19:488-493, 2006. Parwani AV, Husain AN, Epstein JI, Beckwith JB, Argani P. Low-grade myxoid renal epithelial neoplasms with distal nephron differentiation. Hum Pathol 32:506-12, 2001. Rakozy C, Schmahl GE, Bogner S, Störkel S. Low-grade tubular-mucinous renal neoplasms: morphologic, immunohistochemical, and genetic features. Mod Pathol 15:1162-71, 2002. Hes O, Hora M, Perez-Montiel DM, et al. Spindle and cuboidal renal cell carcinoma, a tumour having frequent association with nephrolithiasis: report of 11 cases including a case with hybrid conventional renal cell carcinoma/ spindle and cuboidal renal cell carcinoma components. Histopathology 41:549-55, 2002. Acquired Cystic Disease-Associated Carcinoma Sakai N, Ogawa T, Ishibashi Y, Fukuoka H, Sakanishi S. [A case of renal adenocarcinoma with oxalate calcification on long-term hemodialysis] Hinyokika Kiyo. 1991 Jan;37:65-7, 1991. Dry SM, Renshaw AA. Extensive calcium oxalate crystal deposition in papillary renal cell carcinoma: report of two cases. Arch Pathol Lab Med 122:260-261, 1998. Rioux-Leclercq NC, Epstein JI. Renal cell carcinoma with intratumoral calcium oxalate crystal deposition in patients with acquired cystic disease of the kidney. Arch Pathol Lab Med 127:e89-e92, 2003. Sule N, Yakupoglu U, Shen SS, et al. Calcium oxalate deposition in renal cell carcinoma associated with acquired cystic kidney disease, a comprehensive study. Am J Surg Pathol 29:443-491, 2005. Tickoo SK, dePeralta-Venturina MN, Harik LR, et al. Spectrum of epithelial neoplasms in end-stage renal disease: an experience from 66 tumor-bearing kidneys with emphasis on histologic patterns distinct from those in sporadic adult renal neoplasia. Am J Surg Pathol 30:141-153, 2006. Cossu Rocca P, Eble JN, Zhang S, Martignoni G, et al. Acquired cystic disease-associated renal tumors: an immunohistochemical and fluorescence in situ hybridization study. Mod Pathol 19:780-787, 2006.