Melanoma of the Head and Neck MATTHEW N. HARRIS, M.D., DANIEL F. ROSES, M.D., ALFRED T. CULLIFORD, M.D., STEPHEN L. GUMPORT, M.D.
A series of 94 patients with cutaneous malignant melanoma of the head and neck region has been studied. Fifty-three of the patients had regional lymph node dissections performed and the results in 37 performed more than 5 years ago are presented. The policy of elective lymph node dissection for invasive melanoma of the head and neck is strongly endorsed, although not proven by the data presented in this limited series. Whenever possible, a total excisional biopsy should be performed to establish the diagnosis. It is recommended that all melanomas be classified by the method of Clark and Mihm and that the level of invasion also be determined. There is an appreciable error in the clinical evaluation of lymph nodes for metastases. In general, it is suggested that elective regional lymph node dissections be performed for invasive melanoma (levels III, IV and V). The literature pertaining to cutaneous melanoma of the head and neck has been reviewed and surgical and pathological problems peculiar to lesions of this region are emphasized.
HE HEAD and neck region has been reported to be the most common anatomic site for cutaneous malignant melanoma.19 It would seem that lesions in an area so readily visible would be detected at an early stage and therefore have a more favorable prognosis. However, melanomas of the head and neck remain as difficult to treat as those found at other sites. Five year survival figures have ranged between 30% and 45% according to several collected series. 1'3'49'32'34 A rationale for effective treatment has eluded most investigators to the present time. The recent interest in uniform clinical and histologic classification maiy offer criteria for delineating appropriate therapy in individual cases. We have reviewed our experience with cutaneous melanoma of the head and neck with particular reference to such clinical and histologic classification and have reviewed the experience of others. Submitted for publication February 12, 1975. This study was supported by the Sylvia and Mortimer Hyams Memorial Fund. Reprint requests: Matthew N. Harris, M.D., New York University Medical Center, 566 First Avenue, New York, N.Y., 10016.
From the Tumor Service, Department of Surgery, New York University Medical Center, New York, New York
Methods In 1949 a study of malignant melanoma was initiated on the Tumor Service of the Department of Surgery at the New York University Medical Center. From 1949 to August, 1974 the authors have personally treated 94 patients with cutaneous melanoma of the head and neck. Lesions of the eye and mucous membranes were not included in this review. Patients with lentigo maligna (freckle of Hutchinson) were excluded as well. Only patients whose therapy was instituted for potential cure were included. All patients were followed by the operating surgeon, after surgical therapy. Forty-nine of these patients have been treated in the last 5 years and are not entered in 5-year survival statistics, but are included in the total series. The following general principles were used for therapy: 1) A total excisional biopsy of the melanoma was done wherever feasible. Larger lesions, particularly those clinically suspicious for lentigo maligna and lentigo maligna melanoma were diagnosed by a representative incisional biopsy.8'15 2) After the diagnosis of melanoma was confirmed, a wide and deep re-excision of the biopsy site was performed. In most instances, closure of the site of reexcision was achieved with the use of a split thickness or full thickness skin graft. 3) Regional lymph node dissections, "in continuity" with the primary lesion when possible, were done for invasive melanoma. Dissections were done not only when the nodes appeared to be positive by clinical evaluation, but for clinically uninvolved nodes as well. The contra-indications to elective regional lymph node dissection in this series of patients were: 1) The melanoma which was classified as superficial
86
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MELANOMA OF THE HEAD AND NECK
(now defined as levels I & II). 2) The melanoma arising in a lentigo maligna (Freckle of Hutchinson) unless the lymph nodes were clinically positive. 3) A primary site so situated that the lymphatic drainage might be to several different groups of regional lymph nodes. 4) The presence of serious intercurrent disease. 5) The elderly patient (70 years of age or over). 6) The presence of distant metastases. Fifty-three patients had regional lymph nodes dissections performed. Thirty-eight patients had elective operations (clinically negative nodes) and 15 had therapeutic procedures (clinically positive nodes). There were no
ing type
87
at level II invasion, produces metastases in about 8% of patients, while malignant melanoma of the nodular type at level V invasion probably causes death in greater than 80o of the patients.35 We perform radical neck dissection for invasive melanoma (level III, IV, and V) whether or not regional nodes are clinically involved. Microscopic deposits of metastatic disease in regional lymph nodes are not palpable. When the pathologist reports the nodes to be negative on random study of a so-called "prophylactic or elective lymph node dissection", serial sections may still find the nodes to be positive.23 operative mortalities. Excisions in the head and neck region must be conIn developing guidelines for the surgical treatment of sidered differently than those on the trunk or extremities. melanoma, we are now using the clinical and histologic In areas other than the head and neck we usually recomclassification of the disease as described by Clark, Mihm mend a 3-5 cm margin from the tumor site for excision and associates.62627 Statistics regarding the success of with inclusion of the underlying muscle fascia. On the various therapeutic approaches would be meaningless face, there are several additional factors to be considwithout a standard reference for pathologic classifica- ered: 1) Disfigurement with wide excision. 2) The prestion. When considering melanoma of the head and neck ence of the facial nerve on deeper dissection. 3) The particularly, an increase in the frequency of lentigo lymphatic drainage, especially in the parotid region. 4) maligna melanoma in any series will alter the results The rich lymphatic and vascular network on the scalp favorably. and forehead. 5) The necessity for grafting on periosteum Clark has defined three types of malignant melanoma: or even bare bone. In general, for wide excisions on the 1) Lentigo maligna melanoma (LMM) 2) Superficial face a margin of 2-3 cm is used except on the scalp where spreading melanoma (SSM) 3) Nodular melanoma a margin of 5-6 cm is suggested.4 There is no one standard (NMM). Lentigo maligna melanoma and superficial operation for melanoma of the head and neck. The spreading melanoma evolve through a long, relatively technique for radical neck dissection has been well desuperficial phase which has been referred to as the cen- scribed in the literature.24'25'30 In addition, the surgeon trifugal growth phase. During this phase, which can vary must be thoroughly familiar with the lymphatic drainage from one to 40 years, the tumors have a distinctive clini- of the head and neck to adapt the operation for each cal appearance and, if removed at this time, a greater individual location. Careful followup is essential to detect than 95% cure of affected patients may result. Nodular possible reappearance of the melanoma, occurrence of a melanoma has no such radial growth phase but starts its second primary and the possibility of another, but differgrowth directly in a vertical fashion. ent, neoplasm. Results Clinical and pathologic studies have indicated that malignant melanoma can be further classified according During the study a total of 94 patients with cutaneous to levels of invasion. Five levels of invasion have been malignant melanoma of the head and neck were treated described, ranging from level I where all the tumor cells surgically. Fifty-three of these patients had a radical neck are above the base membrane (in situ melanoma) to level dissection for invasive melanoma. Thirty-seven of the V where the subcutaneous tissues are invaded. Experi- neck dissections were performed more than 5 years ago. ence has shown a very low incidence of metastatic dis- There was a 90% followup of these patients and all paease in lentigo maligna melanoma and melanoma con- tients dead from causes other than melanoma or lost to fined to the dermal-epidermal junction or papillary dermis followup were counted as if they died from melanoma. (level I and level II).37 We have used levels of depth of An analysis of radical neck dissection for invasive invasion as one of our indications as to whether elective melanoma performed on 37 patients more than 5 years regional lymph node dissections are performed. We do ago is presented in Table 1. The following results are not do elective lymph node dissections for level I or level emphasized: II lesions but favor them for level III or deeper 1) When the surgeon believed the regional lymph lesions. 11,13,14 nodes to be negative clinically and after removal they Combination of classification type and level of inva- were reported by the pathologist on random sections to sion permits some precision in predicting the subsequent be negative as well, 61% of these patients were alive and behavior of a given group of malignant melanomas. For well 5 years or more after their treatment. example: malignant melanoma of the superficial spread2) Death of two patients in the category where the
Ann. Surg.
HARRIS AND OTHERS
88
LaW NODES MICROSCOPICALLY NEGATIVE
NODES
CLIN. E)
L WITH RECUR. LOST
14 (61 %)
CLIN. 0 0
CLIN. e o
-
July 1975
DEAD TOTAL
1( 4%)
2 ( 9%)
6 (26%)
23
0
1 (50%)
1 (50%)
2
0
0
6 (100%)
6
0
0
5 (83%)
6
TABLE 1. Results of Radical Neck Dissection for Invasive Melanoma (Operations Over 5 Years Ago)
MICROSCOPICALLY
POSITIVE
CLIN.
@
DEATH FROM ALL CAUSES
1
(17%)
40% OVER-ALL LaW
37
surgeon believed the regional lymph nodes to be positive clinically, but after removal they were reported to be negative microscopically. 3) There were 6 patients in the group in which the surgeon believed the regional lymph nodes to be negative clinically but were reported as being microscopically positive. All are dead. 4) In the group in which the surgeon believed the regional nodes to be clinically positive and were reported as being microscopically positive as well, 17% of this small series were alive and well 5 years or more after the definitive surgery. Of the total number of patients who had a radical neck dissection done more than 5 years ago, 40% are alive and well. It is much too early to properly include the results in the 16 additional patients who had this procedure performed more recently. Table 2 presents our errors in clinically assessing the involvement of lymph nodes in the neck with metastatic melanoma. Of 34 patients in whom the nodes were nicroscopically negative, two were considered positive clinically, an error of 6%. Of 32 patients in whom the nodes were clinically negative, 6 were microscopically positive, an error of 19%.
Kragh and Erich reporting on the Mayo Clinic experience22 in 1960 found that of the 63 patients who had wide local excisions without neck dissection, 11 developed local lymphatic metastases. Conley and Pack4 in 1963 reported an over-all 5-year cure rate of 42%. Twenty-five per cent of their patients had evidence of local recurrence because of inadequate primary excision; 9.5% of the patients developed satellitosis. On admission 48% had evidence of regional metastases on physical examination. The authors noted that primary melanomas of the scalp area had the highest incidence of regional metastases (76%). Local recurrence was highest in lesions of the scalp. The authors, therefore, recommended a 5-6 cm margin for adequate primary excision in this area and stressed that all primary excisions should be accompanied by skin grafts. Eighteen per cent of the patients developed systemic metastasis without evidence of regional involvement. A total of 74 radical neck dissections were done. Forty-eight patients underwent radical neck dissection for Stage II disease; the survival for this group of patients was 14 to 25%. Southwick and associates34 in 1963 reviewed the experience at the University of Illinois with cutaneous melanoma of the head and neck. No patient who had a recurrent lesion and clinical evidence of regional node Discussion disease was without tumor for 5 years. Four of 9 patients with metastatic disease and primary control survived. Although we believe that a wide and deep excision of a The prognosis for this group of patients was not signifimelanoma of the head and neck combined with radical cantly different from those who had an elective neck dislymph node dissection may control local disease and TABLE 2. Evaluation of Nodes in 53 Radical Neck Dissections lymphatic spread there is no known control for the hematogenous spread of melanoma that has proven effective. In this regard, one might speculate that local control using a rather extensive operative procedure in the head and neck region is not justified. It must be kept in mind that recurrent disease in this area is particularly disabling + and disfiguring. Several of our patients developed distant
NODES-CLINICAL IMPRESSION
metastases without evidence of local reappearance. The
quality of survival may be markedly improved if an adequate local operation has been performed. We have reviewed the recent literature concerning the treatment of melanoma of the head and neck region and our results are not dissimilar to those of others (Table 3).
NODESMICROSCOPIC
l9o of clinically negative nodes
were
13
6
2
32t
microscopically positive.
89
MELANOMA OF THE HEAD AND NECK
Vol. 182 No. I
AL/THOR ANSTITUTICN DATE CONLEY a PACK
MEMORIAL
5 YR %5YR %5YR TOTAL # PATIENTS NUMBER %WHIST Rx SURIRY FOR RACVCAL AECK NODES, CL/N. OVER-ALL SURVHIST. S-/V HISI SURVIVAL 0 NODES 6) NODES. CUT. MM DISSECT/ON NEG.
116
74
32
42
12.3
76.5
40
26
12
39.5
-
-
MEMORAL3
171
103
5
34
25
53
MAYO
201
98
10
42
-
80
348
207
11
-
29.9
76.9
295
115
11
45
29
72
79
23
-
30
12
48
87
42
11.9
33
25.8
'1963
SOUTHWICK
UMV. ILL. 196 3
CATLIN
1963 SIMONS
TABLE 3. Review of Literature
BALLANTYNE
M.D. ANDERSON 1970 SIMONS
MAYO 1970
FITZPATRICK
TORONTO
1972 KNUTSON
1972OURI-E.S.C.H 1972
HARRISa GUMPORT NYU 1974
40 (TEN YR.)
94
53
19
40
8
61
(RND)* *Radical Neck Dissection
section. Evidence of metastasis subsequently developed in only one patient who was without evidence of regional node disease and who theoretically might have benefited by an elective neck dissection. These findings were in distinct contrast to the original series where 40% of a similar group of patients with originally clinically negative regional node areas required therapeutic node dissections. The primary treatment suggested is adequate local excision if the neck is clinically negative. Elective neck dissections are reserved for patients in whom such dissection can be performed in valid continuity or when the primary tumor is recurrent. Catlin,3 in 1966, reviewing his experience at Memorial Hospital with melanomas of the head and neck, concluded that the five year survival rate was better in patients who underwent prophylactic neck dissection. Simons32 reviewed the experience at the Mayo Cliiiic from 1950 to 1967 in the treatment of patients with melanoma of the skin of the head and neck. The over-all 3 and 5-year cure rate was 44% and 42% respectively. The author reported 5 methods of treatment in these patients: 1) One hundred twenty-five patients had wide and deep resection of the primary site and had no evidence of metastatic disease in the neck. Of this group 46% were alive and well at the end of 5 years. 2) Thirty-four patients had a wide and deep excision of the primary melanoma and radical neck dissection for involved nodes. Thirty-two per cent of this group of patients was
alive and well at the end of 5 years. 3) Twenty-two patients had only radical neck dissection with a healed primary lesion or a primary lesion which was not located in the immediate vicinity. The 5-year cure rate was 14% for these patients. 4) Fifteen patients had a wide and deep resection of the melanoma and a prophylactic radical neck dissection yielding a 80% 5-year cure rate. 5) Twenty-seven patients had a wide and deep resection of the primary melanoma and were later treated with a radical neck dissection when nodes became clinically enlarged. Only l9o of this group survived 5 years. It is interesting to note that in 20% of the patients who initially had negative nodes clinically, the nodes became clinically positive at a later date. In this group of patients subsequently treated with a radical neck dissection, the 5-year survival rate was 19%o. In a more recent review, the same author33 concluded that when the nodes were clinically negative and histologically positive, the survival rate was 29%; when clinically negative and histologically negative nodes were present, the 5 year survival rate was 72%. Ballantyne,1 in a review of 480 patients with melanoma of the head and neck treated at the M. D. Anderson Hospital, found that there was a 5.5% incidence of local recurrence in patients undergoing elective neck dissection as opposed to a 9.5% incidence of local recurrence in those patients not undergoing an elective neck dissection.
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Ann. Surg. July 1975
Fitzpatrick and associates,9 in 1972, reported their ex- entity when a surgeon is confronted with a patient with a perience in treating 79 patients with melanoma of the stubbornly recurrent "fibroma" or "fibromatosis" head and neck. The authors found that survival corre- which is associated with an antecedant inconspicuous lated well with level of penetration, intensity of lym- pigmented lesion of the overlying skin. Use of electronphocytic reaction and presence or absence of marginal microscopy is suggested for accurate diagnosis. We have spread. The authors felt that except for well-lateralized had 5 such cases in our experience and confirm the findtumors, prophylactic neck dissection is unlikely to be ings of Conley. Pack and associates28 in 1970 reviewed 42 cases of rewarding. Knutson and associates,20 in 1972, reviewed their ex- melanoma of the external ear comprising 14% of the perience treating 87 patients with melanoma of the head melanomas of the head and neck area in their series. and neck at the Ellis Fischel State Cancer Hospital. The Thirty-three per cent had regional lymph node metasauthors felt that by statistical analysis there was a 40% tases when first seen. chance that differences observed in survival at 5 years Ward and Acquarelly of Los Angeles36 also reviewed among patients undergoing elective radical neck dissec- their experience in treating malignant melanoma of the tion would not be reproducible and would be caused by external ear. They reported that the ear is the site of chance. The propensity for superficial and invasive malignant melanoma in approximately 1-10% of the remelanomas to recur following local excision was ported cases of melanoma of the head and neck. The analyzed and the authors noted that the mean duration 5-year survival for melanoma of the external ear is apbetween diagnosis and recurrence for the superficial proximately 22%. Melanomas in this site, as in other sites melanomas was 33 months as compared to 12.3 months in of the body, cannot be diagnosed by their appearance. the invasive group. Expert dermatologists were screened in this regard and Wayte and Helwig37 reviewed the Armed Forces Insti- their diagnostic accuracy was only 48% in 169 cases. The tute of Pathology experience with 85 patients with a authors felt that 10% disseminate by the hematogenous melanotic freckle of Hutchinson. Most of these lesions route and an additional 17% disseminate by lymphatic were between 1 and 3 cm in size and the authors corre- and hematogenous routes in combination. They believed lated larger lesions with the higher likelihood of discover- that a 3-5 cm margin must be removed for adequate ing malignant melanoma (when the lesions were over 5 excision in this location. It should be noted that in their cm in size there was a 75% chance of discovering four cases, the external auricle was totally removed to melanoma in the lesion). The chance of a melanotic treat the primary lesion. They cited their preference for freckle containing malignant melanoma is greatest when routine treatment of melanomas in this location by radithe lesion is located on the torso and least when it is cal neck dissection because of the frequent involvement located in the head and neck region. Metastases do occur of regional lymph nodes and the fact that while correlawith melanomas arising from such freckles and 4 patients tion between clinically palpable nodes and histologic eviof 85 did develop metastatic disease. This low incidence dence of melanoma in the lymphatics is high, 16 to 50% of of metastatic disease with lentigo maligna melanoma ap- clinically negative nodes contain microscopic malignanpears to justify our conservative attitude in treating these cies. In addition, the true incidence of microscopically lesions. In their series, fifty-three per cent of the melan- positive nodes may be underestimated since few speciotic freckles did contain malignant melanoma. In those mens are submitted for thorough serial sections. patients with melanoma arising from such freckles, the Huvos and associates18 in 1973 reported on prognostic 2-year survival was 85.7% and the 5-year survival was factors in a retrospective study of 119 patients seen at the 73% when adequate followup was possible. Memorial Cancer Center with cutaneous malignant Conley and associates,5 in 1971, described a variant of melanoma of the head and neck. The authors emphasized malignant melanoma, the desmoplastic type. They de- that ulceration of the surface of malignant melanoma is scribed the initial lesion as an inconspicuous superficial an ominous sign indicating that the melanoma cells have pigmented lesion usually located in the head and neck actively penetrated the underlying dermis. Cellular types region. This was followed by a deep infiltrating tumefac- showed no prognostic significance in this study. Emtion of fibrous consistency. The appearance of the infil- phasis was given to the need for establishing the depth of trating mass from the pigmented skin lesion was usually invasion of the lesion into the dermis and subcutaneous between 6 months and 2 years. In most instances this tissue in determining prognosis. infiltrating tumefaction was initially thought to represent A recent paper by Hanson and McCarten16 suggests fibromatosis or fibrosarcoma histologically. The true na- that the prognosis in malignant melanoma correlates well ture of the lesion was frequently revealed by examining with the thickness of the lesion and the degree of lymthe regional lymph nodes which were taken in a coinci- phocytic infiltration. The authors feel that for all Stage I dental biopsy. Recurrent disease was usually manifested lesions less than 1.5 mm in vertical thickness, the most by a local appearance of a large subcutaneous firm mass. effective treatment could be local excision. For Stage I The author stressed the importance of awareness of this lesions 1.5 mm or greater in thickness, the addition of
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MELANOMA OF THE HEAD AND NECK
elective node dissection offers significantly improved survival; however, the most dramatic improvement occurred in those cases with minimal lymphocytic infiltration. Conclusions The results of the surgical management of cutaneous melanoma of the head and neck are far from satisfactory. The first line of defense is the detection and adequate treatment of early lesions. In general, physicians, ancillary help and the public at large are unaware of the characteristic appearance of these tumors during the early curable phase of the disease. It is believed that education of physicians and of the public could result in a marked reduction of mortality due to malignant melanoma. Criteria for clinical and histologic classification are now available to help the surgeon select an appropriate operation for each individual patient so as to achieve the maximum benefit with the least amount of "radical" surgery. The policy of elective lymph node dissection for invasive superficial spreading and nodular melanoma of the head and neck (levels III, IV and V) is strongly endorsed, although not proven by the data presented in this limited series. However, our previous analysis of the results of regional lymph node dissection for melanoma of all regions suggests that there is benefit to be obtained from elective regional lymph node dissections performed
selectively."1
In the years to come, surgery may evolve as a method for the prevention of local recurrence and the reduction of total tumor volume so that other agents may be employed effectively as definitive therapy. Certainly the problem of hematogenous dissemination is not solved. Reports concerning the use of immunotherapy2 7.1O021,29,31 and chemotherapyl21 7 are encouraging. Adjuvant therapy or postoperative therapy using one or both of these modalities in patients with "high-risk primaries" and Stage II disease may prove to be particularly important. Cooperative effort is needed since the treatment of melanoma may serve as a model for the treatment of many other neoplastic diseases. References 1. Ballantyne, A. J.: Malignant Melanoma of the Skin of the Head and Neck. Am. J. Surg., 120:425, 1970. 2. Bast, R. C. Jr., Zbar, B., Borsos, T., and Rapp, H. J.: BCG and Cancer. N. Engl. J. Med., 290:1413 and 1458, 1974. 3. Catlin, D.: Cutaneous Melanoma of the Head and Neck. Am. J. Surg., 112:512, 1966. 4. Clark. W. H., Jr., Lynn, F., Bernardino, E. A., and Mihm. M. C.: The Histogenesis and Biologic Behavior of Primary Human Malignant Melanomas of the Skin. Canc. Res., 29:705, 1969. 5. Conley, J. and Pack, G. T.: Melanoma of the Head and Neck. Surg. Gynecol. Obstet., 116:15, 1963. 6. Conley, J., Lattes, R. and Orr, W.: Desmoplastic Malignant Melanoma (A Rare Variant of Spindle Cell Melanoma). Cancer,
28:914, 1971.
7. Einhorn, L. H., Burgess, M. A., Vallejos, C., et al.: Prognostic Correlations and Response to Treatment in Advanced Metastatic Malignant Melanoma. Canc. Res., 34:1995, 1974. 8. Epstein, E., Bragg, K. and Linden, G.: Biopsy and Prognosis of Malignant Melanoma. JAMA, 208:1369, 1969.
91
9. Fitzpatrick, P. J., Brown, T. C. and Reid, J.: Malignant Melanoma of the Head and Neck: a Clinicopathological Study. Can. J. Surg., 15:90, 1972. 10. Fudenberg, H. H., Levin, A. S., Spitler, L. E., et al.: The Therapeutic Uses of Transfer Factor. Hosp. Prac., Jan: 95, 1974. 11. Gumport, S. L. and Harris, M. N.: Results of Regional Lymph Node Dissection for Melanoma. Ann. Surg., 179:105, 1974. 12. Gutterman, J. V., Mavligit, G., Gottlieb, J. A., et al.: Chemoimmunotherapy of Disseminated Malignant Melanoma with Dimethyl Triazeno Imidazole Carboxamide and Bacillus Calmette-Guerin. N. Engl. J. Med., 291:592, 1974. 13. Harris, M. N., Gumport, S. L. and Maiwandi, H.: Axillary Lymph Node Dissection for Melanoma. Surg. Gynecol. Obstet., 135:936, 1972. 14. Harris, M. N., Gumport, S. L., Berman, I. R. and Bernard, R. W.: Ilioinguinal Lymph Node Dissection for Melanoma. Surg. Gynecol. Obstet., 136:33, 1973. 15. Harris, M. N. and Gumport, S. L.: Total Excision Biopsy for Primary Malignant Melanoma. JAMA, 226:354, 1973. 16. Hansen, Mulloy G., McCarten and Alan D.: Tumor Thickness and Lymphocytic Infiltration in Malignant Melanoma of the Head and Neck. Am. J. Surg., 128:557, 1974. 17. Hill, G. J., Ruess, R., Berris, R., et al.: Chemotherapy of Malignant Melanoma with DTIC and Nitrosurea Derivatives (BCNU, CCNU). Ann. Surg., 180:167, 1974. 18. Huvos, A. G., Mike, V., Donnellan, M. J., Seemayer, J., Strong, E. W.: Prognostic Factors in Cutaneous Melanoma of the Head and Neck. Am. J. Pathol., 71:33, 1973. 19. Knutson, C. O., Hori, J. M., Spratt, J. S., Jr.: Melanoma. Current Problems in Surgery, Year Book Medical Publishers, Inc., 1971. 20. Knutson, C. O., Hori, J. M. and Watson, F. R.: Melanoma of the Head and Neck. Am. J. Surg., 124:543, 1972. 21. Kragh, L. V. and Erich, J. B.: Malignant Melanomas of the Head and Neck. Ann'. Surg., 151:91, t960. 22. Krementz, E. T., Mansell, P. W. A., Horning, M. D., et al.: Immunotherapy of Malignant Disease: The Use of Viable Sensitized Lymphocytes or Transfer Factor Prepared from Sensitized Lymphocytes. Cancer, 33:394, 1974. 23. Lane, N., Lattes, R. and Malm, J.: Clinicopathological Correlation in a Series of One Hundred Seventeen Malignant Melanomas of the Skin of- Adults. Cancer, 11: 1025, 1958. 24. MacFee, W. F.: Transverse Incisions for Neck Dissection. Ann. Surg., 151:280, 1960. 25. Martin, H., DelValle, B., Ehrlich, H. and Cahan, W. G.: Neck Dissection. Cancer, 4:441, 1951. 26. McGovern, V. J., Mihm, M. C. Jr., Bailly, C., et al.: The Classification of Malignant Melanoma and Its Histologic Reporting. Cancer, 32:1446, 1973. 27. Mihm, M. C., Clark, W. H., Jr. and From, L.: This Clinical Diagnosis Classifications and Histogenic Concept of the Early Status of Cutaneous Malignant Melanomas. N. EngI. J. Med., 284:1078, 1971. 28. Pack, G. T., Conley, J. and Oropeza, R.: Melanoma of the External Ear. Arch. Otolaryng., 92:106, 1970. 29. Roenigk, H. H.: Immunotherapy of Malignant Melanoma. Derm. Digest, July 9, 1974. 30. Rush, B. F., Jr.: A Standard Technique for in Continuity Incisions of the Head and Neck. Surg. Gynecol Obstet., 121:353, 1965. 31. Seigler, H. F., Shingleton, W. W., Metzgar, R. S., et al.: Immunotherapy in Patients with Melanoma. Ann. Surg., 178:352, 1973. 32. Simons, J. N.: Malignant Melanoma of the Head and Neck. Am. J. Surg., 116:494, 1968. 33. Simons, J. N.: Malignant Melanoma of the Head and Neck. Am. J. Surg., 124:485, 1972. 34. Southwick, H. W., Slaughter, D. P. and Hinkamp, J. F.: Malignant Melanomas of the Skin of the Head and Neck. Am. J. Surg., 106:852, 1963. 35. Unpublished data, Malignant Melanoma Cooperative Group, August, 1974. 36. Ward, N. 0. and Acquarelli, M. J.: Malignant Melanoma of the External Ear. Cancer, 21:226, 1968. 37. Wayte, D. M. and Helwig, E. B.: Melanotic Freckle of Hutchinson. Cancer. 21:893, 1968.
A series of 94 patients with cutaneous malignant melanoma of the head and neck region has been studied. Fifty-three of the patients had regional lymph node dissections performed and the results in 37 performed more than 5 years ago are presented. The policy of elective lymph node dissection for invasive melanoma of the head and neck is strongly endorsed, although not proven by the data presented in this limited series. Whenever possible, a total excisional biopsy should be performed to establish the diagnosis. It is recommended that all melanomas be classified by the method of Clark and Mihm and that the level of invasion also be determined. There is an appreciable error in the clinical evaluation of lymph nodes for metastases. In general, it is suggested that elective regional lymph node dissections be performed for invasive melanoma (levels III, IV and V). The literature pertaining to cutaneous melanoma of the head and neck has been reviewed and surgical and pathological problems peculiar to lesions of this region are emphasized.
HE HEAD and neck region has been reported to be the most common anatomic site for cutaneous malignant melanoma.19 It would seem that lesions in an area so readily visible would be detected at an early stage and therefore have a more favorable prognosis. However, melanomas of the head and neck remain as difficult to treat as those found at other sites. Five year survival figures have ranged between 30% and 45% according to several collected series. 1'3'49'32'34 A rationale for effective treatment has eluded most investigators to the present time. The recent interest in uniform clinical and histologic classification maiy offer criteria for delineating appropriate therapy in individual cases. We have reviewed our experience with cutaneous melanoma of the head and neck with particular reference to such clinical and histologic classification and have reviewed the experience of others. Submitted for publication February 12, 1975. This study was supported by the Sylvia and Mortimer Hyams Memorial Fund. Reprint requests: Matthew N. Harris, M.D., New York University Medical Center, 566 First Avenue, New York, N.Y., 10016.
From the Tumor Service, Department of Surgery, New York University Medical Center, New York, New York
Methods In 1949 a study of malignant melanoma was initiated on the Tumor Service of the Department of Surgery at the New York University Medical Center. From 1949 to August, 1974 the authors have personally treated 94 patients with cutaneous melanoma of the head and neck. Lesions of the eye and mucous membranes were not included in this review. Patients with lentigo maligna (freckle of Hutchinson) were excluded as well. Only patients whose therapy was instituted for potential cure were included. All patients were followed by the operating surgeon, after surgical therapy. Forty-nine of these patients have been treated in the last 5 years and are not entered in 5-year survival statistics, but are included in the total series. The following general principles were used for therapy: 1) A total excisional biopsy of the melanoma was done wherever feasible. Larger lesions, particularly those clinically suspicious for lentigo maligna and lentigo maligna melanoma were diagnosed by a representative incisional biopsy.8'15 2) After the diagnosis of melanoma was confirmed, a wide and deep re-excision of the biopsy site was performed. In most instances, closure of the site of reexcision was achieved with the use of a split thickness or full thickness skin graft. 3) Regional lymph node dissections, "in continuity" with the primary lesion when possible, were done for invasive melanoma. Dissections were done not only when the nodes appeared to be positive by clinical evaluation, but for clinically uninvolved nodes as well. The contra-indications to elective regional lymph node dissection in this series of patients were: 1) The melanoma which was classified as superficial
86
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MELANOMA OF THE HEAD AND NECK
(now defined as levels I & II). 2) The melanoma arising in a lentigo maligna (Freckle of Hutchinson) unless the lymph nodes were clinically positive. 3) A primary site so situated that the lymphatic drainage might be to several different groups of regional lymph nodes. 4) The presence of serious intercurrent disease. 5) The elderly patient (70 years of age or over). 6) The presence of distant metastases. Fifty-three patients had regional lymph nodes dissections performed. Thirty-eight patients had elective operations (clinically negative nodes) and 15 had therapeutic procedures (clinically positive nodes). There were no
ing type
87
at level II invasion, produces metastases in about 8% of patients, while malignant melanoma of the nodular type at level V invasion probably causes death in greater than 80o of the patients.35 We perform radical neck dissection for invasive melanoma (level III, IV, and V) whether or not regional nodes are clinically involved. Microscopic deposits of metastatic disease in regional lymph nodes are not palpable. When the pathologist reports the nodes to be negative on random study of a so-called "prophylactic or elective lymph node dissection", serial sections may still find the nodes to be positive.23 operative mortalities. Excisions in the head and neck region must be conIn developing guidelines for the surgical treatment of sidered differently than those on the trunk or extremities. melanoma, we are now using the clinical and histologic In areas other than the head and neck we usually recomclassification of the disease as described by Clark, Mihm mend a 3-5 cm margin from the tumor site for excision and associates.62627 Statistics regarding the success of with inclusion of the underlying muscle fascia. On the various therapeutic approaches would be meaningless face, there are several additional factors to be considwithout a standard reference for pathologic classifica- ered: 1) Disfigurement with wide excision. 2) The prestion. When considering melanoma of the head and neck ence of the facial nerve on deeper dissection. 3) The particularly, an increase in the frequency of lentigo lymphatic drainage, especially in the parotid region. 4) maligna melanoma in any series will alter the results The rich lymphatic and vascular network on the scalp favorably. and forehead. 5) The necessity for grafting on periosteum Clark has defined three types of malignant melanoma: or even bare bone. In general, for wide excisions on the 1) Lentigo maligna melanoma (LMM) 2) Superficial face a margin of 2-3 cm is used except on the scalp where spreading melanoma (SSM) 3) Nodular melanoma a margin of 5-6 cm is suggested.4 There is no one standard (NMM). Lentigo maligna melanoma and superficial operation for melanoma of the head and neck. The spreading melanoma evolve through a long, relatively technique for radical neck dissection has been well desuperficial phase which has been referred to as the cen- scribed in the literature.24'25'30 In addition, the surgeon trifugal growth phase. During this phase, which can vary must be thoroughly familiar with the lymphatic drainage from one to 40 years, the tumors have a distinctive clini- of the head and neck to adapt the operation for each cal appearance and, if removed at this time, a greater individual location. Careful followup is essential to detect than 95% cure of affected patients may result. Nodular possible reappearance of the melanoma, occurrence of a melanoma has no such radial growth phase but starts its second primary and the possibility of another, but differgrowth directly in a vertical fashion. ent, neoplasm. Results Clinical and pathologic studies have indicated that malignant melanoma can be further classified according During the study a total of 94 patients with cutaneous to levels of invasion. Five levels of invasion have been malignant melanoma of the head and neck were treated described, ranging from level I where all the tumor cells surgically. Fifty-three of these patients had a radical neck are above the base membrane (in situ melanoma) to level dissection for invasive melanoma. Thirty-seven of the V where the subcutaneous tissues are invaded. Experi- neck dissections were performed more than 5 years ago. ence has shown a very low incidence of metastatic dis- There was a 90% followup of these patients and all paease in lentigo maligna melanoma and melanoma con- tients dead from causes other than melanoma or lost to fined to the dermal-epidermal junction or papillary dermis followup were counted as if they died from melanoma. (level I and level II).37 We have used levels of depth of An analysis of radical neck dissection for invasive invasion as one of our indications as to whether elective melanoma performed on 37 patients more than 5 years regional lymph node dissections are performed. We do ago is presented in Table 1. The following results are not do elective lymph node dissections for level I or level emphasized: II lesions but favor them for level III or deeper 1) When the surgeon believed the regional lymph lesions. 11,13,14 nodes to be negative clinically and after removal they Combination of classification type and level of inva- were reported by the pathologist on random sections to sion permits some precision in predicting the subsequent be negative as well, 61% of these patients were alive and behavior of a given group of malignant melanomas. For well 5 years or more after their treatment. example: malignant melanoma of the superficial spread2) Death of two patients in the category where the
Ann. Surg.
HARRIS AND OTHERS
88
LaW NODES MICROSCOPICALLY NEGATIVE
NODES
CLIN. E)
L WITH RECUR. LOST
14 (61 %)
CLIN. 0 0
CLIN. e o
-
July 1975
DEAD TOTAL
1( 4%)
2 ( 9%)
6 (26%)
23
0
1 (50%)
1 (50%)
2
0
0
6 (100%)
6
0
0
5 (83%)
6
TABLE 1. Results of Radical Neck Dissection for Invasive Melanoma (Operations Over 5 Years Ago)
MICROSCOPICALLY
POSITIVE
CLIN.
@
DEATH FROM ALL CAUSES
1
(17%)
40% OVER-ALL LaW
37
surgeon believed the regional lymph nodes to be positive clinically, but after removal they were reported to be negative microscopically. 3) There were 6 patients in the group in which the surgeon believed the regional lymph nodes to be negative clinically but were reported as being microscopically positive. All are dead. 4) In the group in which the surgeon believed the regional nodes to be clinically positive and were reported as being microscopically positive as well, 17% of this small series were alive and well 5 years or more after the definitive surgery. Of the total number of patients who had a radical neck dissection done more than 5 years ago, 40% are alive and well. It is much too early to properly include the results in the 16 additional patients who had this procedure performed more recently. Table 2 presents our errors in clinically assessing the involvement of lymph nodes in the neck with metastatic melanoma. Of 34 patients in whom the nodes were nicroscopically negative, two were considered positive clinically, an error of 6%. Of 32 patients in whom the nodes were clinically negative, 6 were microscopically positive, an error of 19%.
Kragh and Erich reporting on the Mayo Clinic experience22 in 1960 found that of the 63 patients who had wide local excisions without neck dissection, 11 developed local lymphatic metastases. Conley and Pack4 in 1963 reported an over-all 5-year cure rate of 42%. Twenty-five per cent of their patients had evidence of local recurrence because of inadequate primary excision; 9.5% of the patients developed satellitosis. On admission 48% had evidence of regional metastases on physical examination. The authors noted that primary melanomas of the scalp area had the highest incidence of regional metastases (76%). Local recurrence was highest in lesions of the scalp. The authors, therefore, recommended a 5-6 cm margin for adequate primary excision in this area and stressed that all primary excisions should be accompanied by skin grafts. Eighteen per cent of the patients developed systemic metastasis without evidence of regional involvement. A total of 74 radical neck dissections were done. Forty-eight patients underwent radical neck dissection for Stage II disease; the survival for this group of patients was 14 to 25%. Southwick and associates34 in 1963 reviewed the experience at the University of Illinois with cutaneous melanoma of the head and neck. No patient who had a recurrent lesion and clinical evidence of regional node Discussion disease was without tumor for 5 years. Four of 9 patients with metastatic disease and primary control survived. Although we believe that a wide and deep excision of a The prognosis for this group of patients was not signifimelanoma of the head and neck combined with radical cantly different from those who had an elective neck dislymph node dissection may control local disease and TABLE 2. Evaluation of Nodes in 53 Radical Neck Dissections lymphatic spread there is no known control for the hematogenous spread of melanoma that has proven effective. In this regard, one might speculate that local control using a rather extensive operative procedure in the head and neck region is not justified. It must be kept in mind that recurrent disease in this area is particularly disabling + and disfiguring. Several of our patients developed distant
NODES-CLINICAL IMPRESSION
metastases without evidence of local reappearance. The
quality of survival may be markedly improved if an adequate local operation has been performed. We have reviewed the recent literature concerning the treatment of melanoma of the head and neck region and our results are not dissimilar to those of others (Table 3).
NODESMICROSCOPIC
l9o of clinically negative nodes
were
13
6
2
32t
microscopically positive.
89
MELANOMA OF THE HEAD AND NECK
Vol. 182 No. I
AL/THOR ANSTITUTICN DATE CONLEY a PACK
MEMORIAL
5 YR %5YR %5YR TOTAL # PATIENTS NUMBER %WHIST Rx SURIRY FOR RACVCAL AECK NODES, CL/N. OVER-ALL SURVHIST. S-/V HISI SURVIVAL 0 NODES 6) NODES. CUT. MM DISSECT/ON NEG.
116
74
32
42
12.3
76.5
40
26
12
39.5
-
-
MEMORAL3
171
103
5
34
25
53
MAYO
201
98
10
42
-
80
348
207
11
-
29.9
76.9
295
115
11
45
29
72
79
23
-
30
12
48
87
42
11.9
33
25.8
'1963
SOUTHWICK
UMV. ILL. 196 3
CATLIN
1963 SIMONS
TABLE 3. Review of Literature
BALLANTYNE
M.D. ANDERSON 1970 SIMONS
MAYO 1970
FITZPATRICK
TORONTO
1972 KNUTSON
1972OURI-E.S.C.H 1972
HARRISa GUMPORT NYU 1974
40 (TEN YR.)
94
53
19
40
8
61
(RND)* *Radical Neck Dissection
section. Evidence of metastasis subsequently developed in only one patient who was without evidence of regional node disease and who theoretically might have benefited by an elective neck dissection. These findings were in distinct contrast to the original series where 40% of a similar group of patients with originally clinically negative regional node areas required therapeutic node dissections. The primary treatment suggested is adequate local excision if the neck is clinically negative. Elective neck dissections are reserved for patients in whom such dissection can be performed in valid continuity or when the primary tumor is recurrent. Catlin,3 in 1966, reviewing his experience at Memorial Hospital with melanomas of the head and neck, concluded that the five year survival rate was better in patients who underwent prophylactic neck dissection. Simons32 reviewed the experience at the Mayo Cliiiic from 1950 to 1967 in the treatment of patients with melanoma of the skin of the head and neck. The over-all 3 and 5-year cure rate was 44% and 42% respectively. The author reported 5 methods of treatment in these patients: 1) One hundred twenty-five patients had wide and deep resection of the primary site and had no evidence of metastatic disease in the neck. Of this group 46% were alive and well at the end of 5 years. 2) Thirty-four patients had a wide and deep excision of the primary melanoma and radical neck dissection for involved nodes. Thirty-two per cent of this group of patients was
alive and well at the end of 5 years. 3) Twenty-two patients had only radical neck dissection with a healed primary lesion or a primary lesion which was not located in the immediate vicinity. The 5-year cure rate was 14% for these patients. 4) Fifteen patients had a wide and deep resection of the melanoma and a prophylactic radical neck dissection yielding a 80% 5-year cure rate. 5) Twenty-seven patients had a wide and deep resection of the primary melanoma and were later treated with a radical neck dissection when nodes became clinically enlarged. Only l9o of this group survived 5 years. It is interesting to note that in 20% of the patients who initially had negative nodes clinically, the nodes became clinically positive at a later date. In this group of patients subsequently treated with a radical neck dissection, the 5-year survival rate was 19%o. In a more recent review, the same author33 concluded that when the nodes were clinically negative and histologically positive, the survival rate was 29%; when clinically negative and histologically negative nodes were present, the 5 year survival rate was 72%. Ballantyne,1 in a review of 480 patients with melanoma of the head and neck treated at the M. D. Anderson Hospital, found that there was a 5.5% incidence of local recurrence in patients undergoing elective neck dissection as opposed to a 9.5% incidence of local recurrence in those patients not undergoing an elective neck dissection.
90
HARRIS AND OTHERS
Ann. Surg. July 1975
Fitzpatrick and associates,9 in 1972, reported their ex- entity when a surgeon is confronted with a patient with a perience in treating 79 patients with melanoma of the stubbornly recurrent "fibroma" or "fibromatosis" head and neck. The authors found that survival corre- which is associated with an antecedant inconspicuous lated well with level of penetration, intensity of lym- pigmented lesion of the overlying skin. Use of electronphocytic reaction and presence or absence of marginal microscopy is suggested for accurate diagnosis. We have spread. The authors felt that except for well-lateralized had 5 such cases in our experience and confirm the findtumors, prophylactic neck dissection is unlikely to be ings of Conley. Pack and associates28 in 1970 reviewed 42 cases of rewarding. Knutson and associates,20 in 1972, reviewed their ex- melanoma of the external ear comprising 14% of the perience treating 87 patients with melanoma of the head melanomas of the head and neck area in their series. and neck at the Ellis Fischel State Cancer Hospital. The Thirty-three per cent had regional lymph node metasauthors felt that by statistical analysis there was a 40% tases when first seen. chance that differences observed in survival at 5 years Ward and Acquarelly of Los Angeles36 also reviewed among patients undergoing elective radical neck dissec- their experience in treating malignant melanoma of the tion would not be reproducible and would be caused by external ear. They reported that the ear is the site of chance. The propensity for superficial and invasive malignant melanoma in approximately 1-10% of the remelanomas to recur following local excision was ported cases of melanoma of the head and neck. The analyzed and the authors noted that the mean duration 5-year survival for melanoma of the external ear is apbetween diagnosis and recurrence for the superficial proximately 22%. Melanomas in this site, as in other sites melanomas was 33 months as compared to 12.3 months in of the body, cannot be diagnosed by their appearance. the invasive group. Expert dermatologists were screened in this regard and Wayte and Helwig37 reviewed the Armed Forces Insti- their diagnostic accuracy was only 48% in 169 cases. The tute of Pathology experience with 85 patients with a authors felt that 10% disseminate by the hematogenous melanotic freckle of Hutchinson. Most of these lesions route and an additional 17% disseminate by lymphatic were between 1 and 3 cm in size and the authors corre- and hematogenous routes in combination. They believed lated larger lesions with the higher likelihood of discover- that a 3-5 cm margin must be removed for adequate ing malignant melanoma (when the lesions were over 5 excision in this location. It should be noted that in their cm in size there was a 75% chance of discovering four cases, the external auricle was totally removed to melanoma in the lesion). The chance of a melanotic treat the primary lesion. They cited their preference for freckle containing malignant melanoma is greatest when routine treatment of melanomas in this location by radithe lesion is located on the torso and least when it is cal neck dissection because of the frequent involvement located in the head and neck region. Metastases do occur of regional lymph nodes and the fact that while correlawith melanomas arising from such freckles and 4 patients tion between clinically palpable nodes and histologic eviof 85 did develop metastatic disease. This low incidence dence of melanoma in the lymphatics is high, 16 to 50% of of metastatic disease with lentigo maligna melanoma ap- clinically negative nodes contain microscopic malignanpears to justify our conservative attitude in treating these cies. In addition, the true incidence of microscopically lesions. In their series, fifty-three per cent of the melan- positive nodes may be underestimated since few speciotic freckles did contain malignant melanoma. In those mens are submitted for thorough serial sections. patients with melanoma arising from such freckles, the Huvos and associates18 in 1973 reported on prognostic 2-year survival was 85.7% and the 5-year survival was factors in a retrospective study of 119 patients seen at the 73% when adequate followup was possible. Memorial Cancer Center with cutaneous malignant Conley and associates,5 in 1971, described a variant of melanoma of the head and neck. The authors emphasized malignant melanoma, the desmoplastic type. They de- that ulceration of the surface of malignant melanoma is scribed the initial lesion as an inconspicuous superficial an ominous sign indicating that the melanoma cells have pigmented lesion usually located in the head and neck actively penetrated the underlying dermis. Cellular types region. This was followed by a deep infiltrating tumefac- showed no prognostic significance in this study. Emtion of fibrous consistency. The appearance of the infil- phasis was given to the need for establishing the depth of trating mass from the pigmented skin lesion was usually invasion of the lesion into the dermis and subcutaneous between 6 months and 2 years. In most instances this tissue in determining prognosis. infiltrating tumefaction was initially thought to represent A recent paper by Hanson and McCarten16 suggests fibromatosis or fibrosarcoma histologically. The true na- that the prognosis in malignant melanoma correlates well ture of the lesion was frequently revealed by examining with the thickness of the lesion and the degree of lymthe regional lymph nodes which were taken in a coinci- phocytic infiltration. The authors feel that for all Stage I dental biopsy. Recurrent disease was usually manifested lesions less than 1.5 mm in vertical thickness, the most by a local appearance of a large subcutaneous firm mass. effective treatment could be local excision. For Stage I The author stressed the importance of awareness of this lesions 1.5 mm or greater in thickness, the addition of
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MELANOMA OF THE HEAD AND NECK
elective node dissection offers significantly improved survival; however, the most dramatic improvement occurred in those cases with minimal lymphocytic infiltration. Conclusions The results of the surgical management of cutaneous melanoma of the head and neck are far from satisfactory. The first line of defense is the detection and adequate treatment of early lesions. In general, physicians, ancillary help and the public at large are unaware of the characteristic appearance of these tumors during the early curable phase of the disease. It is believed that education of physicians and of the public could result in a marked reduction of mortality due to malignant melanoma. Criteria for clinical and histologic classification are now available to help the surgeon select an appropriate operation for each individual patient so as to achieve the maximum benefit with the least amount of "radical" surgery. The policy of elective lymph node dissection for invasive superficial spreading and nodular melanoma of the head and neck (levels III, IV and V) is strongly endorsed, although not proven by the data presented in this limited series. However, our previous analysis of the results of regional lymph node dissection for melanoma of all regions suggests that there is benefit to be obtained from elective regional lymph node dissections performed
selectively."1
In the years to come, surgery may evolve as a method for the prevention of local recurrence and the reduction of total tumor volume so that other agents may be employed effectively as definitive therapy. Certainly the problem of hematogenous dissemination is not solved. Reports concerning the use of immunotherapy2 7.1O021,29,31 and chemotherapyl21 7 are encouraging. Adjuvant therapy or postoperative therapy using one or both of these modalities in patients with "high-risk primaries" and Stage II disease may prove to be particularly important. Cooperative effort is needed since the treatment of melanoma may serve as a model for the treatment of many other neoplastic diseases. References 1. Ballantyne, A. J.: Malignant Melanoma of the Skin of the Head and Neck. Am. J. Surg., 120:425, 1970. 2. Bast, R. C. Jr., Zbar, B., Borsos, T., and Rapp, H. J.: BCG and Cancer. N. Engl. J. Med., 290:1413 and 1458, 1974. 3. Catlin, D.: Cutaneous Melanoma of the Head and Neck. Am. J. Surg., 112:512, 1966. 4. Clark. W. H., Jr., Lynn, F., Bernardino, E. A., and Mihm. M. C.: The Histogenesis and Biologic Behavior of Primary Human Malignant Melanomas of the Skin. Canc. Res., 29:705, 1969. 5. Conley, J. and Pack, G. T.: Melanoma of the Head and Neck. Surg. Gynecol. Obstet., 116:15, 1963. 6. Conley, J., Lattes, R. and Orr, W.: Desmoplastic Malignant Melanoma (A Rare Variant of Spindle Cell Melanoma). Cancer,
28:914, 1971.
7. Einhorn, L. H., Burgess, M. A., Vallejos, C., et al.: Prognostic Correlations and Response to Treatment in Advanced Metastatic Malignant Melanoma. Canc. Res., 34:1995, 1974. 8. Epstein, E., Bragg, K. and Linden, G.: Biopsy and Prognosis of Malignant Melanoma. JAMA, 208:1369, 1969.
91
9. Fitzpatrick, P. J., Brown, T. C. and Reid, J.: Malignant Melanoma of the Head and Neck: a Clinicopathological Study. Can. J. Surg., 15:90, 1972. 10. Fudenberg, H. H., Levin, A. S., Spitler, L. E., et al.: The Therapeutic Uses of Transfer Factor. Hosp. Prac., Jan: 95, 1974. 11. Gumport, S. L. and Harris, M. N.: Results of Regional Lymph Node Dissection for Melanoma. Ann. Surg., 179:105, 1974. 12. Gutterman, J. V., Mavligit, G., Gottlieb, J. A., et al.: Chemoimmunotherapy of Disseminated Malignant Melanoma with Dimethyl Triazeno Imidazole Carboxamide and Bacillus Calmette-Guerin. N. Engl. J. Med., 291:592, 1974. 13. Harris, M. N., Gumport, S. L. and Maiwandi, H.: Axillary Lymph Node Dissection for Melanoma. Surg. Gynecol. Obstet., 135:936, 1972. 14. Harris, M. N., Gumport, S. L., Berman, I. R. and Bernard, R. W.: Ilioinguinal Lymph Node Dissection for Melanoma. Surg. Gynecol. Obstet., 136:33, 1973. 15. Harris, M. N. and Gumport, S. L.: Total Excision Biopsy for Primary Malignant Melanoma. JAMA, 226:354, 1973. 16. Hansen, Mulloy G., McCarten and Alan D.: Tumor Thickness and Lymphocytic Infiltration in Malignant Melanoma of the Head and Neck. Am. J. Surg., 128:557, 1974. 17. Hill, G. J., Ruess, R., Berris, R., et al.: Chemotherapy of Malignant Melanoma with DTIC and Nitrosurea Derivatives (BCNU, CCNU). Ann. Surg., 180:167, 1974. 18. Huvos, A. G., Mike, V., Donnellan, M. J., Seemayer, J., Strong, E. W.: Prognostic Factors in Cutaneous Melanoma of the Head and Neck. Am. J. Pathol., 71:33, 1973. 19. Knutson, C. O., Hori, J. M., Spratt, J. S., Jr.: Melanoma. Current Problems in Surgery, Year Book Medical Publishers, Inc., 1971. 20. Knutson, C. O., Hori, J. M. and Watson, F. R.: Melanoma of the Head and Neck. Am. J. Surg., 124:543, 1972. 21. Kragh, L. V. and Erich, J. B.: Malignant Melanomas of the Head and Neck. Ann'. Surg., 151:91, t960. 22. Krementz, E. T., Mansell, P. W. A., Horning, M. D., et al.: Immunotherapy of Malignant Disease: The Use of Viable Sensitized Lymphocytes or Transfer Factor Prepared from Sensitized Lymphocytes. Cancer, 33:394, 1974. 23. Lane, N., Lattes, R. and Malm, J.: Clinicopathological Correlation in a Series of One Hundred Seventeen Malignant Melanomas of the Skin of- Adults. Cancer, 11: 1025, 1958. 24. MacFee, W. F.: Transverse Incisions for Neck Dissection. Ann. Surg., 151:280, 1960. 25. Martin, H., DelValle, B., Ehrlich, H. and Cahan, W. G.: Neck Dissection. Cancer, 4:441, 1951. 26. McGovern, V. J., Mihm, M. C. Jr., Bailly, C., et al.: The Classification of Malignant Melanoma and Its Histologic Reporting. Cancer, 32:1446, 1973. 27. Mihm, M. C., Clark, W. H., Jr. and From, L.: This Clinical Diagnosis Classifications and Histogenic Concept of the Early Status of Cutaneous Malignant Melanomas. N. EngI. J. Med., 284:1078, 1971. 28. Pack, G. T., Conley, J. and Oropeza, R.: Melanoma of the External Ear. Arch. Otolaryng., 92:106, 1970. 29. Roenigk, H. H.: Immunotherapy of Malignant Melanoma. Derm. Digest, July 9, 1974. 30. Rush, B. F., Jr.: A Standard Technique for in Continuity Incisions of the Head and Neck. Surg. Gynecol Obstet., 121:353, 1965. 31. Seigler, H. F., Shingleton, W. W., Metzgar, R. S., et al.: Immunotherapy in Patients with Melanoma. Ann. Surg., 178:352, 1973. 32. Simons, J. N.: Malignant Melanoma of the Head and Neck. Am. J. Surg., 116:494, 1968. 33. Simons, J. N.: Malignant Melanoma of the Head and Neck. Am. J. Surg., 124:485, 1972. 34. Southwick, H. W., Slaughter, D. P. and Hinkamp, J. F.: Malignant Melanomas of the Skin of the Head and Neck. Am. J. Surg., 106:852, 1963. 35. Unpublished data, Malignant Melanoma Cooperative Group, August, 1974. 36. Ward, N. 0. and Acquarelli, M. J.: Malignant Melanoma of the External Ear. Cancer, 21:226, 1968. 37. Wayte, D. M. and Helwig, E. B.: Melanotic Freckle of Hutchinson. Cancer. 21:893, 1968.
