16. PATTERNS OF METASTASIS IN HUMAN SOLID CANCERS STANLEY P. L. LEONG1, BLAKE CADY2, DAVID M. JABLONS1, JULIO GARCIA-AGUILAR1, DOUGLAS REINTGEN3, J. A. WERNER4, AND YUKO KITAGAWA5 1Department of Surgery, University of California San Francisco, California, USA, 2Comprehensive Breast Center, Rhode Island Hospital, Providence, Rhode Island, USA, 3Lakeland Regional Cancer Center, Lakeland, Florida, USA, 4Dept of Otolaryngology, Head & Neck Surgery, Philipps-University Marburg, Germany, 5Department of Surgery, Keio University School of Medicine,Tokyo, Japan INTRODUCTION To date, lymph node status is the most important predictor for clinical outcome. Clinical models of cancer metastasis have evolved from Halsted’s lymphatic domi- nant model in which the regional lymph nodes served as filters for cancer cells. When the filter was filled, the cancer cells would move to the other lymph nodes and distant sites. The Halsted’s model (1) was then replaced by Fisher’s model in which all breast cancers were considered to be systemic from their onset (2). Recently, the Fisher’s model has been supplemented by the spectrum model of Hellman, in which early cancer is locally aggressive. In the process of progression, cancer cells acquire the ability to metastasize to the lymph nodes and then to the systemic sites (3, 4). Recent advances in the sentinel lymph node (SLN) concept and technology have allowed us to further study the clinical significance of micrometastasis in the SLNs and the mechanism of cancer metastasis through the lymphovascular system. Evidence from the SLN era indicate that most solid cancers 210 Cancer Metastasis and the Lymphovascular System progress in an orderly fashion from the primary sites to the regional lymph nodes or the SLNs in the majority of cases with subsequent dissemination to the systemic sites. PATTERNS OF METASTASIS IN SOLID CANCER IN THE PRE-SLN ERA Melanoma Melanoma frequently starts from an in situ to a radial growth phase. Then it expands into a vertical growth phase, which is associated with increased risk of metastasis. Nodal status is the most reliable predictor of clinical outcome (5, 6). In the pre-SLN era, several retrospective studies noted that the regional nodal basin was the most frequent site of metastasis. Incidence of nodal metastasis is increased with thicker Breslow lesions, which may also be associated with higher frequency of systemic metastasis (7). In general, during the early phase of melanoma proliferation, the pattern of metastasis to the regional nodal basin is the predominant one in about 60% in patients with primary melanoma of 1.5–4 mm, but a minority of the patients will develop systemic disease, about 15%. From an autopsy series of 216 melanoma patients, the lymph nodes and lungs were the most frequent sites of metastasis (8). In the late stages of the disease, dis- semination was widespread with involvement of multiple organs. Survival for patients with extensive dissemination was usually short.When dissemination was limited, survival was longer. Such isolated metastases could potentially be resected, resulting in longer survival. Breast Cancer Based on autopsy studies, women dying of breast cancer suggest that widespread metastatic disease with bones (70%), lungs (66%), and liver (61%) are the most common sites of spread. On the other hand, with early-stage, the most common site for metastatic involvement is the regional nodal basin (9). Based on an analy- sis of an extensive breast cancer database, Nemoto et al. demonstrated that the nodal involvement with breast cancer was the most important predictor of the clinical outcome (10). On the other hand, in early breast cancer, the appropri- ate treatment results in excellent outcome (11, 12). The recent decrease in mortality rate for breast cancer (13) while the incidence of breast cancer has increased by 0.5% per year between 1987 and 1998 may be explained by treat- ment of early breast cancer detected by screening mammography (14). Most of the early breast cancers (>75%) are in occurrence with the spectrum model in which metastatic potential increases as the tumor grows in size. Early small can- cers with few exceptions have little ability to develop clinical metastases (11, 12). Survival was significantly decreased in patients with systemic dissemination of breast cancer. Overall, in stage I to II patients the 5-year survival was at least over 70% with regional lymph node involvement (Stage III) the survival dropped to 20–60%.When systemic disease was found (Stage IV) the survival dropped down to 5% (15). 16. Patterns of Metastasis in Human Solid Cancers 211 Head and Neck Cancer The lymphatic drainage pattern of the head and neck is complicated (16–20), draining to about 300 regional cervical lymph nodes, which are clarified by Robbins (21) into nine lymph node levels (level I–VI). As regional lymph node status is a significant predictor for clinical outcome in squamous cell carcinoma of the upper aerodigestive tract, detection of clinically occult lymph node metastases is an integral step in the management of the clinical N0 neck. Nodal metastasis depends on the location of the primary tumor, ranging from 12 to over 50% (median, 33%) (22–24). Numerous authors favor elective neck dissection if occult lymph node metastasis carries a probability of 20% or more.Although some authors prefer a “wait and see” strategy, this approach requires both great patient compli- ance and expertise on the part of the responsible physician to detect metastasis early. Another argument in favor of elective neck dissection against a “wait-and-see” approach is that the survival rate drops significantly when neck dissection is per- formed after clinical disease is discovered (25–27). Elective neck dissection is preferred to the “wait and see” approach.The nodal basin can be electively treated either by neck dissection or radiotherapy.An advantage of the former over the latter is that histological examination of the neck dissection specimen may provide impor- tant information for deciding adjuvant therapy, as well as about the prognosis (28). Upper GI Cancer Although distant metastasis is associated with hematogenous dissemination, some organ metastases are due to lymphatic spread. Lymphatic skip metastases were found in 50–60% of esophageal cancers and 20–30% of gastric cancers in a retrospective analysis of the location of solitary metastases (29, 30). Based on a retrospective analysis of gastric cancer with solitary metastasis, Sano et al. (31) reported that the perigastric nodal area close to the primary tumor was the first site of metastasis in 62% of the cases. Therefore, extended radical procedures such as esophagectomy with three-field lymph node dissection and gastrectomy with D2 lymphadenec- tomy have been developed to become standard procedures in Japan, even for clinically node negative cases (32, 33).The disadvantage is that such extensive dis- section is associated with significant morbidity and mortality as being reported in randomized trials (34, 35). It is interesting to note that lymphatic spread from Barrett’s cancer is different than that from squamous cell carcinoma in the same location with relatively lower incidence of anatomical skip metastases (36).Autopsy reports showed that both hematogenous and lymphatic metastasis is common in esophogeal carcinoma (37, 38). Intramural metastasis is characteristic of esophageal squamous cell carcinoma and is associated with poor prognosis (39). Other poor prognostic features include gastric metastasis, location of the primary lesion (mid- dle thoracic location), size of tumor (>7 cm), histologic type (undifferentiated), and depth of invasion (T4) (40). Hematogenous spread from esophageal cancer is related to the location of primary lesions as lung metastases are associated with 212 Cancer Metastasis and the Lymphovascular System cervical nodal metastases from upper esophageal cancer, and liver metastases are associated with thoracic metastases from lower esophageal cancer (41). These findings suggest that the lymphatic metastasis exists in some of the patients with esophageal cancer. Lymphogenous liver metastasis by lymphaticovenous communi- cation has been described in an animal model (42). This phenomenon was clini- cally supported by Kumagai et al.’s demonstration that liver metastasis was correlated with lymphatic activity in gastric cancer (43). Peritoneal dissemination is observed as an initial recurrence in 20–30% of patients undergoing curative surgery for gastric adenocaricinoma and is related to the diffuse type of the distal tumors (44). Distant recurrence is related to the proximal tumors (44).The overall recurrence rate after curative surgery for early gastric cancer is generally low (1.9%) and differentiated tumors showed a 2.3% rate of hematogenous metastasis (45). Only node-positive patients showed a relatively high rate of recurrence (10.7%). Colorectal Cancer Almost 50% of patients with colorectal cancer have metastasis at the time of their diagnosis with the most common sites consisting of the regional lymph nodes, the liver, the lung, and the peritoneal cavity (46). Again, like melanoma and breast cancer, nodal status is the most important prognostic factor for patients without dis- seminated disease. The incidence of nodal metastasis increases with the depth of tumor penetration in the bowel wall; 10% in the submucosa; 22% in the muscularis propria, and 56% reaching the pericolonic fat. Other high risk factors include tumor grade, lymphatic, and vascular invasion. Carcinoma of the colon and rectum shows different patterns of nodal metastasis. For colon cancer, the regional lymph nodes include four groups: the epicolic nodes, along the vasa recta in the wall of the colon and epiploic appendices; the pericolic nodes along the marginal vessels; the intermediate nodes along the vessels, such as the sigmoidal, left colic, middle colic, and ileocolic; and the central or apical nodes along the inferior mesenteric and superior mesenteric vessels. In 97% of patients, lymph node metastasis in colon cancer occurs to the pericolic nodes, 27% have metastasis to the intermediate nodes, and 11% with central nodal involvement (47, 48).