Lymph node metastases of renal cell carcinoma (RCC).

Kidney cancers (including the renal pelvis) account for approximately 3% of all adult malignancies. In the United States, the estimates for 2007 were 51,190 new cases and 12,890 deaths from kidney cancer (1). Most of these cancers are RCCs that arise in adults. A number of types of RCCs are recognized, including clear cell (conventional) carcinoma (CCC), papillary carcinoma, chromophobe carcinoma, collecting duct carcinoma, and RCC, unclassified (2,3). Other uncommon or rare RCCs also may arise in adults as a component of familial syndromes (4). Von Hippel-Lindau syndrome is associated with CCC in 50% of affected patients, usually as bilateral and multiple tumors. Other familial syndromes associated with RCC include hereditary papillary RCC (types 1 and 2), hereditary leiomyomatosis and renal cell carcinoma syndrome, and Birt-Hogg-Dube syndrome (4,5). Rarely, RCCs arise in children, and these neoplasms also are distinctive (6).

In adults, CCC, also known as the conventional type of RCC, is most common, representing more than 70% of all tumors (7). Clear cell carcinoma is also the type of carcinoma most likely to metastasize. Clinical evidence of metastasis is found in a substantial subset of patients at the time of first presentation (8). Clear cell carcinoma of the kidney also can present as a metastasis to lymph nodes of an occult primary tumor. For these reasons, most of the remainder of this chapter focuses on CCC.

RCCs are tumors of adults, with a peak incidence in the sixth decade of life. Males are more frequently affected, with a male-to-female ratio of 1.7 to 1(1). The right and left kidneys are equally affected. The clinical findings in all types of RCC are similar. The triad of hematuria, flank pain, and abdominal mass is usually seen with advanced tumors. In earlier stages, one of these signs or symptoms is more often encountered, in addition to fever, anemia, and weight loss. Paraneoplastic syndromes with vascular hypertension, hepatic dysfunction, and hypercalcemia resulting from the ectopic production of various hormones can occur. Erythrocytosis occurs in approximately 5% of patients, caused by the production of erythropoietin by the neoplastic cells. Thrombocytosis also can occur.

In a third of patients, RCC presents with metastatic disease, which may be a solitary metastases. More than half of the cases of RCC apparent at autopsy are clinically unrecognized, and 24% of cases are associated with unrecognized metastases (8). Tumor stage is the most important prognostic feature, particularly in the first 3 years after diagnosis, and both the Robson and tumor-node-metastasis (TNM) systems of staging have been used (9). In both systems, involvement of regional lymph nodes negatively impacts survival. Cases of RCC may be understaged because a limited number of lymph nodes are removed with the kidney at time of surgical excision. After stage, tumor grade best predicts frequency of metastases and survival (10,11).

Renal cell carcinomas metastasize to regional lymph nodes, but beyond that, patterns of metastasis are variable, which probably indicates that the tumor has entered a phase of systemic spread. Therefore, when metastases in lymph nodes are identified, an extended lymphadenectomy is unlikely to increase survival and is not recommended. However, not all lymph nodes that appear enlarged as assessed by imaging studies are involved by metastases. In a study of 163 patients with RCC, more than half of the patients with regional lymph nodes more than 1 cm in greatest dimension on computed tomography had tumor-reactive lymphadenopathy. By contrast, in patients with urologic carcinomas, such as those arising in the prostate and bladder, 90% of lymph nodes 1 cm or larger harbor metastases (12).

Grossly, the cut surface of CCC is typically variegated with yellow-orange areas of abundant lipid, red-black areas of hemorrhage, gray areas with little lipid content and fibrosis, and foci of cystic degeneration and dystrophic calcification. This appearance also can be observed in large lymph node metastases. Histologically, CCC are richly vascular and exhibit a variety of histologic patterns (e.g., trabecular, alveolar, papillary, solid) in different combinations (Figs. 91.1 and 91.2). The most common pattern is one of clear cells arranged in a tubuloalveolar configuration. The tumor cells in CCC are bland, uniform, and polygonal, with abundant clear cytoplasm (Fig. 91.2). In low-grade tumors, the tumor nuclei are small, hyperchromatic, and centrally located. By contrast, in high-grade tumors, the nuclei are much larger, with prominent nucleoli and very large, multinucleated or bizarre nuclei. Mitotic figures correlate with increasing nuclear grade. Admixed with the clear cell areas may be foci of cells with eosinophilic or granular cytoplasm and, in a small subset of CCC, most of the neoplastic cells can appear granular. The four-tier Fuhrman scheme most often has been used for grading CCC and other types of RCC (13). However, others have suggested two- and three-tier systems as alternatives (14,15). Grade can be appreciated in lymph node metastases but its prognostic value is uncertain. Usually, metastases are not graded.

Other types of RCC can metastasize to lymph nodes, although much less frequently than CCC. In papillary carcinoma (Fig. 91.3), the neoplasm is often circumscribed and composed of papillae with fibrous connective cores containing foamy macrophages. Ischemic necrosis is common and psammoma bodies may be associated with the neoplasm. Chromophobe carcinoma (Fig. 91.4) is composed of large polygonal cells with abundant, light-staining, flocculent cytoplasm with peripheral
accentuation of cytoplasmic granularity and sharply defined cytoplasmic membranes. Collecting duct carcinomas are centrally located and usually are composed of cytologically highly atypical cells arranged in cords that induce a desmoplastic reaction and inflammation. Sarcomatoid carcinomas are high-grade tumors composed of spindled cells. These neoplasms are transformed from other types of RCC, most often CCC (16). Lymph node metastases generally resemble the histologic appearance of the kidney tumor.