Lymph node metastases of prostatic adenocarcinoma.

In the United States, prostatic carcinoma is the most commonly diagnosed internal malignant neoplasm in men. For the year 2007, 218,890 new cases of prostate cancer were estimated, with approximately 27,000 deaths (1). Prostate cancer is the second leading cause of cancer death in men after lung cancer (1). The incidence of prostate cancer dramatically increased in the United States between 1984 and 1994 as a result of improved screening methods, in particular, monitoring prostate specific antigen (PSA) levels in serum (2). The incidence has leveled off and stabilized since 1994 (2). The rate of prostate cancer is 1.5 to 2 times higher in African Americans than whites (3).

In the remainder of the world, marked variation occurs in the frequency of prostate cancer, probably also attributable to PSA serum screening. A similar high incidence of prostate cancer occurs in Western Europe, with an annual incidence rate of approximately 55 per 100,000 (2). In Eastern Europe, the incidence is lower, 19 per 100,000 (2). Presumably, these differences in incidence between developed and underdeveloped countries correspond to a greater number of latent asymptomatic prostate cancers in elderly men in underdeveloped countries without PSA serum testing (4).

The frequency of prostate cancer increases with age, with as many as 75% of men over 65 years of age having the disease in autopsy studies (5). The annual incidence rate of prostate cancer in men under 45 years of age is very low, 0.4 per 100,000. This rate increase to 6 per 100,000 in men 45 to 54 years of age, 60 per 100,000 in men 55 to 64 years of age, and 270 per 100,000 in men older than 65 years of age (2).

Hormonal, environmental, and genetic factors appear to be involved in the etiology of prostate carcinoma, although these are currently poorly understood. In eunuchs castrated before puberty, the incidence of prostate carcinoma is low. Similarly, in men with increased serum estrogen as a result of liver cirrhosis, the frequency of prostate carcinoma is lowered. These patient groups argue for a role for androgens in prostate carcinoma onset or growth. Diet is loosely linked to prostate carcinoma frequency, with high meat intake correlating with increased risk (2). Evidence also suggests a genetic basis for prostate carcinoma, in approximately 5% to 10% of cases. Brothers or sons of an affected man have a two to three times increased risk of also developing prostate carcinoma (6). The disease is more common in African Americans, also suggesting a role for genetics (3,6).

Frequency of lymph nodes metastases correlates with pathologic stage and histologic grade of the primary neoplasm. Prostatic carcinoma can be staged using either the A–D or the tumor, node, metastases (TNM) systems. Using the A–D system, stage A indicates latent nonpalpable tumors confined within the prostate, stage B indicates clinically detectable tumors confined by the prostatic capsule, stage C indicates tumors that have spread beyond the prostatic capsule, and stage D indicates tumors with metastases. Each of these groups can be further broken down. For example, D1 designates the presence of regional lymph node metastases, and D2 designates distant metastases. The TNM system, which is more detailed, is currently recommended by the College of American Pathologists and is described elsewhere (7). The grading system almost universally used for prostatic carcinoma is the Gleason score, recently reviewed elsewhere (8). Lymph node metastases occur on average in 12% of patients with prostatic carcinoma and Gleason scores of 2 to 4, in 35% of those with Gleason scores of 5 to 7, and in 61% of those with Gleason scores of 8 to 10 (9,10).

Isolated tumor cells (ITCs) can be identified in regional lymph nodes of patients with prostate carcinoma. Isolated tumor cells are single metastatic cells or small clusters of metastatic cells 2 mm or less in greatest dimension. If these are the only evidence of metastatic disease in lymph nodes, it is recommended that the designation N0 i+ be used (7). The “i+” indicates that micrometastases are not identified histologically, but ITCs are identified either by examination of hematoxylin-eosin or immunohistochemically stained slides.

Similarly, molecular methods such as reverse transcriptase polymerase chain reaction (RT-PCR) have been used to assess lymph nodes for metastases by detecting PSA or prostate-specific membrane antigen (PSMA) mRNA. These studies have detected high levels of PSA or PSMA mRNA supporting the presence of metastatic carcinoma in lymph nodes morphologically negative for tumor (11,12). As above, it is recommended that the designation N0 mol+ be used (7). The “mol+” indicates that micrometastases are not identified histologically, but evidence of metastatic carcinoma is present by molecular methods. The prognostic significance of detecting ITCs morphologically (by routine or immunohistochemical staining), or the significance of detecting molecular evidence of metastases, in patients with prostate carcinoma is currently unknown.

In the era of PSA screening, the overall clinical stage of men with prostatic carcinoma has decreased in the United States because elevated serum PSA levels allow detection of small, localized carcinomas that are associated with a low risk of metastases. Prostate-specific antigen serum testing has high sensitivity and specificity, and is rapid, inexpensive, and easy to perform (13). Mildly elevated PSA levels can occur with either benign or malignant prostate disease, but very high PSA levels or serial, progressively rising PSA levels support the presence of prostate carcinoma. In a subset of men, prostatic carcinoma is first detected by digital rectal examination, but this method is not sensitive or specific (14). Many low-stage prostatic carcinomas are not palpable and some benign diseases, most
commonly focal nodular hyperplasia, are palpable and can mimic carcinoma.

Some patients who initially present with advanced disease, however, will have urologic symptoms or metastases, of which the most common sites are lymph nodes and bones (15,16). The most common sites of bone metastases are the lumbar spine, sacrum, and pelvis, presumably through lymphatic spread via the Batson vertebral venous system (15). The most common sites of lymph node metastases are the pelvic lymph nodes.

In older literature, lymph node metastases were reported in approximately 40% of patients with prostatic carcinoma (17). This frequency is now substantially lower (18,19), presumably corresponding to the detection of smaller and lower-stage primary neoplasms allowed by PSA serum screening that are infrequently associated with lymph node metastases (20). In patients with smaller, localized tumors, when lymph node metastases occur, they almost always are on the same side as the primary neoplasm (21). Nevertheless, the presence of lymph node metastases indicates a poor prognosis, whether unilateral or bilateral lymph nodes, or single versus multiple lymph nodes are involved. In one study of patients with lymph node metastases detected radiologically, the lymph node groups most commonly involved were the medial external iliac (obturator), followed by para-aortic and lateral external iliac, in 75%, 24%, and 18% of patients, respectively (22).