William A. Maddox

A multifactorial analysis of melanoma: prognostic histopathological features comparing Clark's and Breslow's staging methods.

A multifactorial analysis was used to identify the dominant prognostic variables affecting survival from a computerized data base of 339 melanoma patients treated at this institution during the past 17 years. Five of the 13 parameters examined simultaneously were found to independently influence five year survival rates: 1) pathological stage (I vs II, p = 0.0014), 2) lesion ulceration (present vs absent, p = 0.006), 3) surgical treatment (wide excision vs wide excision plus lymphadenectomy, p = 0.024), 4) melanoma thickness (p = 0.032), and 5) location (upper extremity vs lower extremity vs trunk vs head and neck, p = 0.038). Additional factors considered that had either indirect or no influence on survival rates were clinical stage of disease, age, sex, level of invasion, pigmentation, lymphocyte infiltration, growth pattern, and regression. Most of these latter variables derived their prognostic value from correlation with melanoma thickness, except sex which correlated with location (extremity lesions were more frequent on females, trunk lesions on males). This statistical analysis enabled us to derive a mathematical equation for predicting an individual patients probability of five year survival. Three categories of risk were delineated by measuring tumor thickness (Breslow microstaging) in Stage I patients: 1) thin melanomas (<0.76 mm) were associated with localized disease and a 100% cure rate: 2) intermediate thickness melanomas (0.76–4.00 mm) had an increasing risk (up to 80%) of harboring regional and/or distant metastases and 3) thick melanomas (≤4.00 mm) had a 80% risk of occult distant metastases at the time of initial presentation. The level of invasion (Clarks microstaging) correlated with survival, but was less predictive than measuring tumor thickness. Within each of Clarks Level II, III and IV groups, there were gradations of thickness with statistically different survival rates. Both microstaging methods (Breslow and Clark) were less predictive factors in patients with lymph node or distant metastases. Clinical trials evaluating alternative surgical treatments or adjunctive therapy modalities for melanoma patients should incorporate these parameters into their assessment, especially in Stage I (localized) disease where tumor thickness and the anatomical site of the primary melanoma are dominant prognostic factors.

A multifactorial analysis of melanoma. III. Prognostic factors in melanoma patients with lymph node metastases (stage II)

Twelve prognostic features of melanoma were examined in a series of 185 patients with nodal metastases (Stage II), who underwent surgical treatment at our institution during the past 20 years. Forty-four per cent of the patients presented with synchronous nodal metastases (substage IIA), 44% of the patients had delayed nodal metastases (substage IIB), and 12% of the patients had nodal metastases from an unknown primary site (substage IIC). The patients with IIB (delayed) metastases had a better overall survival rate than patients with IIA (synchronous) metastases, when calculated from the time of diagnosis. These differences could be explained on the basis of tumor burden at the time of initial diagnosis (microscopic for IIB patients versus macroscopic for IIA patients). Once nodal metastases became evident in IIB patients, their survival rates were the same as for substage IIA patients, when calculated from the onset of nodal metastases. The survival rates for both subgroups was 28% at five years and 15% for ten years. Substage IIC patients (unknown 1st site) had better five-year survival rates (39%), but the sample size was small and the differences were not statistically significant. A multifactorial analysis was used to identify the dominant prognostic variables from among 12 clinical and pathologic parameters. Only two factors were found to independently influence survival rates: 1) the number of metastatic nodes (p = 0.005), and the presence or absence of ulceration (p = 0.0019). Additional factors considered that had either indirect or no influence on survival rates (p > 0.10) were: anatomic location, age, sex, remission duration, substage of disease, tumor thickness, level of invasion, pigmentation, and lymphocyte infiltration. All combinations of nodal metastases were analyzed from survival differences. The combination that showed the greatest differences was one versus two to four versus more than four nodes. Their five-year survival rates were 58%, 27% and 10%, respectively (p < 0.001). Ulceration of the primary cutaneous melanoma was associated with a <15% five-year survival rate, while nonulcerative melanomas had a 30% five-year survival rate (p < 0.001). The combination of ulceration and multiple metastatic nodes had a profound adverse effect on survival rates. While tumor thickness was the most important factor in predicting the risk of nodal metastases in Stage I patients (p < 10-8), it had no predictive value on the patients clinical course once nodal metastases had occurred (p = 0.507). The number of metastatic nodes and the presence of ulceration are important factors to account for when comparing surgical results, and when analyzing the efficacy of adjunctive systemic treatments.

Tumor thickness as a guide to surgical management of clinical stage I melanoma patients

An analysis of failure to control locally recurrent or metastatic melanoma was used to substantiate the value of thickness as a guide to surgical management. There were no local recurrences in patients with melanomas less than 0.76 mm in thickness, regardless of the skin margins excised. The three year actuarial incidence of subsequent regional metastases in patients initially treated by wide local excision (WLE) of their melanoma was directly correlated with tumor thickness (p = <0.001); it was 0% for lesions <0.76 mm, 25% for 0.76 to 1.50 mm lesions, 51% for 1.50 to 3.99 mm lesions and 62% for lesions >4.0 mm in thickness. At five years, patients with melanomas of 1.50 to 3.99 mm thickness who had WLE plus elective regional node dissection (RND) had a calculated 15% incidence of distant metastases and an actuarial survival rate of 83%, while patients with melanomas of the same thickness who had WLE alone as their initial surgical treatment had a 78% incidence of distant metastases and a 37% survival rate (p = 0.001 and 0.01, respectively). In patients with melanomas exceeding 4.0 mm in thickness, the potential benefits of RND were less apparent because of a high risk (>70%) of distant metastases at the time of initial diagnosis. Based upon this analysis, our initial surgical management of melanomas <0.76 is a WLE using a 2.0 cm margin of skin, while thicker lesions are excised using a 3 to 5 cm skin margin. Elective RND is not indicated for lesion <0.76 mm in thickness, but it is considered for 0.76 to 1.50 mm lesions in selected patients and is employed for virtually all patients with lesions exceeding 1.5 mm in thickness. The rationale of elective RND is improved survival in patients with intermediate thickness lesions (0.76 to 3.99 mm) while it is justifiable as a staging procedure for lesions exceeding 4.0 mm thickness. Cancer 43:883–888, 1979.

A comparison of prognostic factors and surgical results in 1,786 patients with localized (stage I) melanoma treated in Alabama, USA, and New South Wales, Australia

Twelve clinical and pathologic parameters were compared in two series of Stage I melanoma patients treated at the University of Alabama in Birmingham, USA (676 patients) and at the University of Sydney in New South Wales, Australia (1,110 patients). Actuarial survival rates were virtually the same at the two institutions over a 25-year follow-up period. The incidence of thin melanomas (<0.76 mm) was also similar at both geographic locations (25% vs. 26%). Other similarities of these two patient populations included the following: 1) tumor thickness (Breslow Microstaging), 2) level of invasion (Clark Microstaging), 3) surgical results, 4) sex distribution, and 5) age distribution. The greatest differences between the two patient populations were their 1) anatomic distribution, 2) growth pattern, and 3) incidence of ulceration. The trunk was the most common site of melanoma, and occurred more frequently among Australian patients (37% vs. 28%). A multifactorial analysis (Coxs regression model) was then performed that included a comparison of the two institutions as a variable (Alabama vs. Australia). The dominant prognostic factors (p < 0.0001) were 1) ulceration, 2) tumor thickness, 3) initial surgical management (wide excision ± node dissection), 4) anatomic location, 5) pathologic stage (I vs. II), and 6) level of invasion. The benefit of elective lymph node dissection was demonstrated in both series for patients with intermediate thickness melanoma (0.76 to 3.99 mm). For melanomas ranging from 0.76 to 1.5 mm in thickness, the benefit of node dissection was primarily in male patients. Survival rates for melanoma at the two institutions were not significantly different in the multifactorial analysis, even after adjusting for all other variables. Thus, the biologic behavior of melanoma in these two different parts of the world was virtually the same, with only minor differences that did not significantly influence survival rates. Long-term follow-up exceeding eight to ten years after surgery is critical in the interpretation of these prognostic factors and the surgical results.

Conventional TRAM flap versus free microsurgical TRAM flap for immediate breast reconstruction.

Immediate breast reconstruction using the transverse abdominal myocutaneous island (TRAM) flap was performed in 54 patients over the past 3 years at our institution. This represented approximately 59 percent of patients undergoing all types of immediate breast reconstruction. In 10 patients, the abdominal island flap was transferred as a free flap based on the deep inferior epigastric pedicle. These patients were compared with the other 44 patients, in whom the flap was transferred using the conventional technique. The TRAM flap is well suited for immediate breast reconstruction because the procedure can be carried out simultaneously with mastectomy using separate operating teams and instruments. The operation is safe and relatively free of complications. The free TRAM group compared favorably with the conventional group in terms of complications, operating time, estimated blood loss, hospitalization, and return to functional baseline. The free TRAM flap appears to be as safe as the conventional technique with the advantages of a more limited rectus muscle harvest, improved medial contour of the breast due to the lack of tunneling, and perhaps a healthier flap because of the large donor vessels.

Head and neck melanoma in 534 clinical Stage I patients. A prognostic factors analysis and results of surgical treatment

Single and multifactorial analyses were used to evaluate prognosis and results of surgical treatment in 534 clinical Stage I patients with head and neck cutaneous melanoma treated at the University of Alabama in Birmingham (U.S.A.) and the University of Sydney (Australia). This computerized data base was prospectively accumulated in over 90% of cases. Melanomas were about equally distributed between men and women. They were located on the skin of the face in 47%, neck in 27%, scalp in 13%, and the ear in 13% of patients. Both the results of the prognostic factors analyses and the surgical treatment demonstrated that lentigo maligna melanoma (LMM) was distinct from the other two growth patterns, superficial spreading melanoma and nodular melanoma (SSM and NM). In a multifactorial analysis of the 453 patients with SSM and NM, the dominant prognostic variables were tumor thickness (p less than 0.00001), anatomic subsite (p = 0.0213), and ulceration (p = 0.0289). Patients with melanomas on the scalp or neck subsites fared worse than those with tumors located on the face or ear. The results differed for LMM, where thickness was not a significant predictor of survival, and the most dominant prognostic variable was ulceration (p = 0.0042). Local recurrence rates were low, being 2.4% for tumors less than 2.5 mm in thickness, but were 12.3% for tumors greater than or equal to 4.0 mm in thickness. Patients with SSM and NM lesions located on the head and neck had a lower survival rate than those with extremity melanomas in every tumor thickness category, although only those in the 0.76 to 1.49 mm thickness subgroup were significantly different (p = 0.0007). After 5 years of follow-up, patients who underwent an elective lymph node dissection for SSM and NM with a thickness range of 1.5 to 3.99 mm had a better survival (72%) than patients with melanomas of equivalent thickness whose initial treatment was wide excision alone (45%). LMM had a less aggressive biologic behavior compared to SSM or NM and was treated more conservatively. Thus, LMM lesions had an 85% 10-year survival rate with wide excision only, and there was no significant improvement in survival with ELND. Growth patterns, tumor thickness, ulceration, and anatomic subsites should be considered when evaluating risk factors and when making treatment decisions in head and neck melanoma patients.

Patient risk factors and surgical morbidity after regional lymphadenectomy in 204 melanoma patients

A series of 204 melanoma patients were studied six months or longer after regional lymph node dissection of the neck (N = 48), axilla (N = 98) and groin (N = 58) in order to determine the degree of morbidity and analyze for risk factors associated with these procedures. Only one‐quarter of the patients experienced wound‐related, short‐term complications that were common at all sites; however, these rarely resulted in long‐term functional deficits. Seromas (22%), temporary nerve dysfunction or pain (14%), and wound infections (6%) were the most frequent short‐term complications. Wound complications extended the mean hospital stay by 0.6 to 4.8 days. Residual lymphedema of the leg was measurable in 26% of groin dissection patients after six months or longer; most of the edema was confined to the thigh. Only 8% of patients had significant functional deficit from lymphedema. The risk of developing at least one complication for all patients was increased for obese patients (P = 0.05) and increasing age (P =.01). These risk factors should be considered when evaluating melanoma patients for regional lymph node dissection.

The influence of surgical margins and prognostic factors predicting the risk of local recurrence in 3445 patients with primary cutaneous melanoma

Risk factors associated with local recurrences were analyzed from a series of 3445 clinical Stage I melanoma patients. In single‐factor analysis, tumor thickness, ulceration, and increasing age were highly significantly predictive of recurrence (p < 0.00001). After 5 years of follow‐up, local recurrence rates were 0.2% for tumors less than 0.76 mm thick, 2.1% for tumors 0.76 to 1.49 mm thick, 6.4% for tumors 1.5 to 3.99 mm thick, and 13.2% for tumors 4.0 mm or greater in thickness. Ulcerated melanomas recurred more often than nonulcerated lesions (11.5% versus 1.9%). When analyzed as a continuous variable, increasing age increased the risk of local failure. In multifactorial analysis, all of these three factors remained independently predictive of local recurrence. Recurrences were more common with nodular melanomas (5.6%) compared to superficial spreading (2.5%) or lentigo maligna melanoma (2.5%), but this difference did not reach statistical significance (P = 0.115). Lower extremity (4.7%) and head and neck lesions (4.4%) recurred more frequently than upper extremity (1.6%) or trunk (1.2%) melanomas (P = 0.0217). The highest recurrence rates were observed in patients with melanomas located on the foot (11.6%) and hand (11.1%). The safety of conservative margins for the excision of low‐risk melanomas was demonstrated in a review of 1151 consecutive patients with melanomas less than 1 mm thick where only one local recurrence was observed. Sixty‐two percent of these patients had resection margins of 2 cm or less. In 95 patients local recurrence developed as the first site of relapse and were treated with surgical excision. The median survival for this group was 3 years, whereas 20% of this group survived 10 years. These data demonstrate that: (1) the risk of local recurrence rises with increasing tumor thickness, presence of ulceration, and age; (2) melanomas less than 1 mm thick have a very low local recurrence rate, even when excised with margins of 2 cm or less; and (3) local recurrence is a poor prognostic sign because regional and systemic metastases subsequently develop in many patients. Cancer 55:1398‐1402, 1985.

Neck dissection with and without radiotherapy: prognostic factors, patterns of recurrence, and survival.

A group of 179 patients who had 205 neck dissections between 1979 and 1984 has been reviewed to assess the influence of adjuvant radiotherapy on survival. Lymph nodes were histologically involved in 91 of 107 radical neck dissections (85 percent) and 55 of 98 modified neck dissections (56 percent). Eighty-two patients received adjuvant radiotherapy of 5,000 rads or more. Patients with involved nodes had significantly lower survival rates than those with uninvolved nodes. Among patients with involved nodes, survival was significantly lower when two or more nodes were involved, when there was nodal involvement at multiple levels, or when extracapsular spread was present. Adjuvant radiotherapy was associated with a reduced recurrence rate in the ipsilateral neck but the incidence of distant metastases was higher. When patients with involved nodes were subgrouped according to prognostic factors, the survival of irradiated patients was improved only in the highest risk group, but this was not statistically significant. When radiotherapy is added to neck dissection for treatment of cervical metastases it can be expected to reduced ipsilateral neck recurrence and prevent relapse in the contralateral neck. Improved survival may depend on an ability to detect and treat occult distant metastases.

Squamous cell carcinoma of the buccal mucosa: Analysis of prognostic factors

Although the TNM system is the accepted standard for head and neck tumor classification, there are often discrepancies between tumor size and survival. This retrospective analysis of 89 patients with squamous cell carcinoma of the buccal mucosa was carried out to evaluate tumor thickness and depth of invasion as prognostic variables and to compare them to the standard parameters. Recurrence rates increased with tumor size, clinical stage, thickness, and depth of invasion. In univariate analysis, sex, clinical stage, thickness, and depth of invasion were significantly related to survival (p less than 0.10). Multivariate analysis revealed that only thickness was an independent variable (p less than 0.0001). Patients with tumors less than 6 mm in thickness had a significantly better survival rate compared with those patients with tumors greater than 6 mm in thickness, regardless of the tumor stage. Measurement of tumor thickness should be included in estimating prognosis, planning therapy, and comparing results in patients with squamous cell carcinoma of the buccal mucosa.