Thickness of malignant melanoma: global analysis of related factors.
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Publications and source records attributed to S L Gumport.
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Stage I cutaneous malignant melanomas between 0.76 and 1.69 mm thick (Breslow measurement) in BANS (upper part of the back, posterior aspects of the arms, posterior and lateral aspects of the neck, posterior aspect of the scalp) areas have been reported to portend a relatively poor prognosis compared to non-BANS sites. We were unable to confirm the 15% poorer survival for BANS area lesions (84% BANS, 99% non-BANS) originally reported. In this report of 211 patients, malignant melanomas in BANS sites had a 4.6% poorer 5-year cumulative survival rate (88.9% BANS, 93.5% non-BANS; p = 0.35). Although many more patients need to be studied, we believe this small difference in survival is insufficient to influence therapeutic management strategies.
In summary, we believe that in the following situations elective regional lymph node dissection should not usually be performed: Patients whose primary malignant melanomas are in situ or have a maximal thickness of less than 1.0 mm. The incidence of regional node metastases in the latter group is so low that regional lymph node dissection is not justified. Patients whose primary malignant melanomas are in the midline of the head and neck or the trunk. Bilateral nodal dissections in these two regions of the body in the absence of a clearly demonstrable therapeutic advantage are not justified. Whether radioisotopic localizing studies will add greater definition to this group remains to be seen. Elderly patients or those with serious intercurrent disease. They should not undergo elective nodal dissection unless the primary malignant melanoma is very thick and lies directly over its nodal group. Patients with systemic metastases. For all remaining patients, the therapeutic or at very least prognostic advantages of elective regional lymph node dissections have been outlined. Conversely, an adverse effect on the course of the disease has never been demonstrated. We adhere to a policy that includes these procedures as primary therapy, provided they are performed with minimal morbidity. Should a surgeon elect not to perform such a procedure in the absence of clinically suspicious lymphadenopathy, careful clinical evaluation at 2-month intervals for the first 2 to 3 years following primary excision, with more prolonged intervals thereafter, would appear prudent. Until such time as effective means of eradicating systemic metastatic malignant melanoma exist, surgery remains the treatment of choice for this potentially fatal neoplasm. Efforts to develop effective adjuvant treatment based on the precise means of delineating prognosis that have thus far been developed has eluded investigators. A reasoned surgical approach is still required in our judgment until the identification and treatment of premalignant precursor lesions are universal or effective systemic therapy is available.
The prognostic relevance of the extent of nodal metastases, lesion thickness, level of invasion, site of lesion, satellitosis, age, sex, and year of diagnosis and treatment were assessed in 213 consecutive patients with pathologic Stage II malignant melanoma (157 with clinical Stage I disease and 56 with clinical Stage II disease). Of these factors, only three were significant: 1) clinical status of the lymph nodes (p less than 0.0001); 2) thickness of the primary lesion in the ranges of less than 2.0 mm, 2.0 to 4.9 mm, and 5.0 mm or greater (p = 0.002); and 3) level of invasion (p = 0.0002). The extent of nodal metastases in those patients with clinical Stage I disease was not significant. The difference in survival between patients with clinically negative/histologically positive nodes (clinical Stage I) and clinically positive/histologically positive nodes (clinical Stage II) was apparent throughout the follow-up period. The 5- and 10-year survival rates for the clinical Stage I patients were 44% and 28%, respectively, and for the clinical Stage II patients 21% and 12%, respectively (p less than 0.0001). A 5-year cumulative survival rate of 65% was achieved for clinical Stage I patients having primary lesions of less than 2.0 mm in thickness, while it was 19% for patients having primary lesions of 5.0 mm or more in thickness. For pathologic Stage II malignant melanoma patients, prognosis is most dependent on the clinical status of the lymph nodes, not on the number of lymph nodes with micrometastases.
Although thin malignant melanomas, i.e., those less than 0.76 mm in thickness, of the skin generally do not metastasize, it has been recently reported that when histologic regression is present, such lesions may then have a greater propensity for dissemination. However, this was not apparent in this study in which only one melanoma metastasized in a consecutive series of 41 thin lesions which were step-sectioned and had evidence of regression histologically. Possible explanations for this discrepancy are the failure of other authors to include only step-sectioned specimens of the primary melanomas in their material and/or geographic differences in the biologic behavior of this malignant neoplasm.
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In a clinicohistopathologic study of 557 patients with primary cutaneous malignant melanoma, there were fewer metastases and/or deaths from melanoma when histologic evidence of a coexisting acquired melanocytic nevus was found. A total of 130 patients with melanocytic nevus and 427 cases of melanoma without histologic evidence of a nevus (denovo) were studied. Clinical follow-up evaluation for evidence of metastases and/or death was obtained. Only ten of the patients (7.7%) with nevus-associated melanoma had metastases and/or death v 78 (18.3%) with de novo melanoma. When stratified by lesion thickness, the logrank test for survival revealed a statistically significant difference between the two groups. An overall favorable outcome seen in patients with malignant melanomas associated with acquired melanocytic nevi was found, therefore, to be independent of lesion thickness as well as six other variables reported to be related to the biologic behavior of malignant melanoma. Thus, the presence of nevus cells in a specimen of malignant melanoma portends a better prognosis and may have important implications in the biology of this neoplasm.
Fourteen variables were tested for their prognostic usefulness in 203 patients with clinical Stage I melanoma and primary tumor 0.76-169 mm thick. Only two variables, primary tumor location and level of invasion, were useful in predicting death from melanoma for these patients. Of the 12 deaths from melanoma, 11 occurred in patients with primary tumors located on the upper back, posterior arm, posterior neck, and posterior scalp (=BANS). There has been only one death from melanoma in 136 patients with melanoma located at other sites (11/67 vs 1/136, p less than 0.0001 Fisher's Exact Test). Of the 67 BANS patients, 51 had level II or level III lesions and five (10%0 died of melanoma. This compared with six deaths from melanoma in 16 patients (37.5%) with level IV BANS lesions (5/51 vs 6/16, p = 0.01 Fisher's Exact Test). The relatively high incidence of both melanoma deaths and regional node metastases for the BANS group merits consideration for testing the efficacy of elective regional node dissection for these patients.
Fourteen variables were tested for their ability to predict visceral or bony metastases in 177 patients with clinical Stage I melanoma of intermediate thickness (1.51 - 3.39 mm). A Cox multivariate analysis yielded a combination of four variables that best predicted bony or visceral metastases for these patients: 1) mitoses greater than 6/min 2 (p = 0.0007), 2) location other than the forearm of leg) p = 0.009, 3) ulceration width greater than 3 mm (p = 0.04), 4) microscopic satellites (p = 0.05). The overall prognostic model chi square was 32.40 with 4 degrees of freedom (p less than 10 (-5). Combinations of the above variables were used to separate these patients into at least two risk groups. The high risk patients had at least a 35% or greater chance of developing visceral metastases within five years, while the low risk group had greater than an 85% chance of being disease free at five years. Criteria for the high risk group were as follows: 1) mitoses greater than 6/mm 2 in at least one area of the tumor, irrespective of primary tumor location, or 2) a melanoma located at some site other than the forearm or leg and histologic evidence in the primary tumor of either ulceration greater than 3 mm wide or microscopic satellites. The low risk group was defined as follows: 1) mitoses less than or equal to 6/mm 2 and a location on the leg or forearm, or 2) mitoses less than or equal to 6/mm 2 and the absence in histologic sections of the primary tumor of both microscopic satellites and ulceration greater then 3 mm wide. The number of patients in this series who did not undergo elective regional node dissection (N = 47) was probably too small to detect any benefit from this procedure. Based on survival rates from this and other studies, it is estimated that approximately 1500 patients with clinical Stage I melanoma of intermediate thickness in each arm of a randomized clinical trial would be needed to detect an increase in survival rates from elective regional node dissection.
Fourteen prognostic factors were examined in 79 patients with clinical Stage I melanoma greater than or equal to 3.65 mm in thickness. All nine patients with melanoma of the hands or feet died of melanoma. A Cox proportional hazards (multivariate) analysis of the remaining 70 patients showed that a combination of the following four variables best predicted bony or visceral metastases: 1) a nearly absent or minimal lymphocyte response at the base of the tumor, 2) histologic type other than superficial spreading melanoma, 3) location on the trunk, and 4) positive nodes or no initial node dissection. Ulceration and/or ulceration width were not useful in predicting outcome either singly or in combination with other variables. Patients with negative lymph nodes and primary tumors of the trunk, hands, and feet did not do better than patients with positive nodes at those sites. Conversely, non of 16 patients with negative lymph nodes and extremity melanomas (excluding the hands and feet) or head and neck melanomas developed visceral or bony metastases (i.e., five-year disease-free survival rate 100%).
Fifteen variables were tested for their value in predicting recurrent disease in 46 clinical Stage I melanoma patients with metastases to regional nodes. A stepwise proportional hazards general linear model (Cox multivariate analysis) separated these melanoma patients with regional node metastases into at least two risk groups. Twenty patients in the relatively low-risk group had a five-year disease-free survival of 80% (in spite of having nodal metastases). This compares to a five-year disease-free survival of 17.5% for 26 patients in the high-risk group (P less than 0.001, Lee-Desu Statistic). Criteria for the high-risk group required that a patient have only one of the following two values: (1) The number of regional lymph nodes that contained tumor divided by the total number of nodes removed x 100% (percentage of positive nodes) greater than or equal to 20%; or (2) a primary tumor thickness of greater than 3.5 mm (regardless of node percentage). Conversely, patients in the low-risk group had neither of the above features. The high-risk group could further be stratified by the lymphocytic response at the base of the tumor. These findings have direct immediate application to the elective regional node dissection controversy and to adjuvant therapy studies containing these patients.
A group of 525 patients with primary cutaneous malignant melanoma of the trunk was treated by a uniform surgical approach that included regional lymph node dissection for selected patients; 266 (50.6%) had regional lymph node dissections in addition to wide and deep excision, all with primary lesions extending below the superficial papillary dermis. Of 171 patients treated over five years ago, 130 had histologically negative nodes; 94 (72%) are alive with no evidence of disease (NED). Of 41 with histologically positive nodes, 12 (29%) are alive with NED. A comparison of the 21 patients with clinically occult micrometastases shows eight (38%) alive with NED, whereas four of 20 (20%) with clinically demonstrable as well as histologically proven nodal metastases are alive with NED. Though there may be a modest benefit to lymph node dissection for microscopic rather than gross nodal metastases for invasive melanoma of the trunk, for most such patients melanoma in regional nodes indicates the presence of systemic metastatic disease.
Fifteen variables were studied for their usefulness in predicting recurrent disease in 254 patients with clinical stage I melanoma of the trunk. Thickness of the primary tumor correctly predicted outcome with an accuracy of 90 percent or greater in 176 patients with melanoma primaries with a thickness of less than 1.70 mm or 5.5 mm or greater. No other variables significantly increased predictive accuracy over these ranges of thickness. A Cox proportional hazards analysis of the remaining 78 patients with primary tumors 1.70 to 5.49 mm thick demonstrated that the following four variables functioned as independent risk factors for recurrent disease: (1) thickness of the primary tumor (p = 0.0005), (2) mitoses/mm2 greater than 6 (p = 0.006), (3) a nearly absent or minimal lymphocyte response at the base of the tumor (p = 0.009), and (4) location on the upper trunk (p = 0.03). Trunk lesions located near the midline did not have a worse prognosis than more lateral melanomas of similar thickness.
Thirteen variables were studied for their relative usefulness in predicting recurrent disease in 107 patients with clinical Stage I melanoma of the upper extremity. After a mean follow-up period of 54 months, the only patents who have had recurrent disease to date are those who primary lesions were located either on the hand or posterior upper arm. The five-year disease-free survival role for 44 patients with melanoma at these sites was 68%. None of 63 patients with melanoma located on the forearm of anterior upper arm have had recurrent disease (i.e., the five-year, disease-free survival rate was 100% (p = 0.00004), compared with the hand or posterior arm group). A Cox proportional hazards (multivariate) analysis demonstrated that two primary tumor histologic variable, thickness in millimeters and ulceration, interacted to produce the best prognostic model for those 44 patients with melanoma of the hand or posterior upper arm. Twenty-one patients with primary lesions at these sites had primary tumors less than 2.25 mm in thickness and no evidence of ulceration histologically. Their five-year, disease-free survival role was 95%. For the remaining 23 patients with primary tumors on the hand or posterior upper arm who had either histologic evidence of ulceration or primary tumors greater than or equal to 2.25 mm, the five-year disease-free survival rate was 37% (p = 0.002, compared with group nonulcerated, thin lesions). The excellent survival rate for patients with melanomas on the forearm or anterior upper arm was not completely explained by pathologic stage, by primary tumor thickness, or by histologic ulceration of the primary tumor.
A technique for total mastectomy with complete axillary dissection, which uses division of the insertion of the sternal portion of the pectoralis major muscle, preservation of its innervation, reconstruction after completion of the dissection and resection of the pectoralis minor muscle has been evaluated for 115 consecutive procedures. This modification facilitates a thorough axillary dissection, while preserving the cosmetic and functional benefits of the Patey operation.
Thirteen variables were studied to determine their usefulness in predicting recurrent disease in 158 patients with stage I melanoma of the lower extremity. A Cox proportional hazards analysis demonstrated that three variables were independent risk factors for recurrent disease in these patients: (1) thickness, in millimeters, of the primary tumor (P = 0.000009), (2) primary tumor location on the foot (P = 0.0003), and (3) the number of mitoses/mm2 (P = 0.0244). Life-table analyses of patient subgroups defined by different combinations of these three variables demonstrated that thick (greater than or equal to 3.0 mm) melanomas of the foot were associated with recurrent disease much more frequently than tumors of similar thickness located on the thigh or calf. These data provide guidelines that can be used to evaluate results of surgical and/or adjuvant therapy studies for patients with melanoma of the lower extremity.
Seven hundred thirty-nine patients with malignant melanoma of the extremities were treated with a uniform surgical approach that included wide and deep excision of the primary site and regional node dissection therapeutically and electively for invasive lesions (Clark's levels III, IV, and V). Of the 490 patients who underwent lymph node dissections, follow-up was available for 457 (93%). Life-table comparison of 362 patients with histologically negative nodes to 95 with histologically proved lymph node metastases yielded statistically significant differences in survival (P less than 0.001). Five-year cumulative survival rates were 91% in the group without and 48% in the group with nodal metastases. Among histologically positive patients, differences in life-table survival curves for the 60 clinically negative patients compared to the 35 clinically positive patients were also statistically significant (P = 0.004); 5-year cumulative survival rates were 57% for the former group and 33% for the latter. Although there appears to be an advantage to regional lymph node dissection for micrometastases as opposed to gross nodal involvement, for the majority of patients metastatic melanoma in these nodes is the major indicator of systemic disease.
A series of 206 patients with cutaneous melanoma of the head and neck has been studied. Ninety patients had a regional lymph node dissections performed. Seventeen lymph node dissections were done therapeutically and 73 were done electively. Thirty-one patients had histologically positive lymph nodes and, of these, 30 patients have been followed to the present time or death. Twenty-nine of these patients (97%) have developed systemic melanoma. Twenty-six patients have died and three are alive with disease. No patient had local recurrence alone while four had local recurrence synchronously with systemic metastases. This contrasts with 29 patients followed for greater than five years with histologically negative nodes, 27 (93.1%) of whom are alive with no evidence of recurrent disease. Regional node metastases with melanoma of the head and neck is an almost certain indication of systemic disease. A selective surgical approach to invasive melanoma in this region is proposed based on the observation in the 31 patients who had radical neck dissections with histologically positive nodes. The metastases always involved the nodal group adjacent to the primary site. This selective approach should allow optimal local control and accurate pathologic staging while limiting the extent of the surgery.