Serial reconstruction of the characteristic granule of the Langerhans cell.

Three-dimensional models of individual granules in the same Langerhans cell were made after analyzing serial sections of human epidermis in the electron microscope. These models revealed that the granule is made up of a flattened or curved orthogonal net of particles which is bounded externally by a limiting membrane and which may be disc-shaped, cup-shaped, or combinations of both shapes. This variety of shapes accounts for the many configurations of the granule seen in individual electron micrographs. Usually, the granule has a vesicular portion at, or near one margin. This demonstration of the three-dimensional structure of the granule establishes the inaccuracy of previously used descriptive terms, the granule should be called simply the "Langerhans cell granule."

Melanocytic nevi in histologic association with primary cutaneous melanoma of superficial spreading and nodular types: effect of tumor thickness.

The histologic presence of benign dermal nevus cells in contiguity with primary cutaneous melanoma, as a distinct population separate from malignant melanocytes, was evaluated in a large referral data base. The melanomas were limited to superficial spreading melanoma (SSM) and nodular melanoma (NM). Overall, dermal melanocytic nevi were found associated with 1126 of 1954 primary SSM/NM (57.6%). When the melanomas were stratified by tumor thickness, an inverse relationship between the presence of benign nevus cells and tumor thickness was found: 64.9% of tumors less than 0.76 mm and 64.5% of those between 0.76 and 1.69 mm were associated with dermal nevi, whereas in the thickness range 1.70-3.60 mm, there were 45.6% associated nevi, and in melanomas greater than 3.60 mm, there were only 32.0% noted to have nevus cells. When melanomas were separated by nevus type, it was found that 41% were associated with an acquired pattern nevus, 38% with congenital pattern nevus, and 21% with dysplastic nevus. It may be concluded that 1) the histologic presence of nevus cells is a common event in SSM/NM; 2) the association of melanocytic nevus and melanoma is more easily demonstrated in thinner tumors; and 3) acquired pattern nevi, congenital pattern nevi, and dysplastic nevi are all potential precursors of melanoma.

Epidermolytic hyperkeratosis: ultrastructure and biochemistry of skin and amniotic fluid cells from two affected fetuses and a newborn infant.

Skin biopsy samples and amniotic fluid cells obtained in utero from two fetuses at risk for epidermolytic hyperkeratosis were examined by light and electron microscopy. Both fetuses were affected; the second was carried to term. Epidermal extracts were prepared from blisters of the newborn for analysis of keratin and filaggrin proteins. Abnormal clumps of keratin filaments were present in all layers of the prekeratinized fetal epidermis except the periderm and stratum germinativum. A significant population of amniotic fluid cells also contained the filament aggregations. Prenatal diagnosis of the disease should be possible using cells obtained at amniocentesis, thus avoiding fetal skin biopsy. Biochemical studies showed abnormalities in keratin and filaggrin proteins. The structural alterations in the tissue might be a consequence of altered interaction between these two abnormal epidermal proteins.

Cutaneous melanoma in women: anatomic distribution in relation to sun exposure and phenotype.

An analysis of the relationship between the anatomic site of cutaneous melanoma, sun exposure, and phenotype was conducted in 355 women with histologically confirmed superficial-spreading melanoma and in 935 control subjects. The most frequent site for superficial-spreading melanoma was the leg. However, when major sun-related and phenotype risk factors were examined by site, risk ratios were lowest for melanomas that occurred on the leg. A history of frequent sunburns during elementary or high school, increased number of self-assessed large nevi, and blond hair were more strongly associated with melanoma sites other than the leg. Tumors on the trunk were more likely than tumors at other sites to be associated with histological evidence of a preexisting nevus. Results of this work indicate that associations between melanoma phenotypic factors may differ by anatomic site.

Unusual variants of melanoma: fact or fiction?

Evidence is reviewed separating unusual variants of melanoma from the large group of superficial spreading and nodular (SSM/NOD) histogenetic types. These include (1) the relationship of moles to melanoma of the SSM/ NOD types not found in melanoma arising in lentigo maligna (LMM), desmoplastic neurotrophic melanoma (DNM), mucosal lentiginous melanoma (MLM), or acral lentiginous melanoma (ALM); (2) the strong sunlight association in lentigo maligna (LM) and LMM not always present in SSM/NOD and not likely at all in acral or mucosal lesions (ALM, MLM); (3) epidemiological differences of age, race, and prognosis among the various subtypes; and (4) analogies to neoplasms in other organ systems. These data justify the following conclusions: (1) Variants of melanoma exist as in other neoplasms. (2) They are of epidemiological and therapeutic importance. (3) Until further data are available or networked, data base analysis should use microstage measurements in the common forms of SSM and NOD only, and approach the unusual variants separately and cautiously.

Pigmented spindle cell nevus. Clinical and histologic review of 90 cases.

A clinical and histologic review of 90 patients with melanocytic lesions termed pigmented spindle cell nevi (PSCN) is reported. The lesions are small in surface diameter, sharply confined both clinically and histologically, and often occur on the proximal extremities of young adults. They are generally of recent onset, moderately to heavily pigmented, and made up of nests of spindled cells confined to the epidermis and papillary dermis. There were 30 male and 60 female patients. Their average age was 25.3 years (ranging from 2.5 to 56 years). Lesions were located on the extremities in 61 cases (67%). Follow-up was possible in 38 cases seen more than 6 months after histologic diagnosis and ranged up to 40 months (average 14 months). No local recurrence or distant spread was found. The importance of recognizing this lesion lies in differentiating it from malignant melanoma. Conservative but complete excision has resulted in no recorded instances of local recurrence or distant spread.

Inter-observer variability among pathologists' evaluation of malignant melanoma: effects upon an analytic study.

This study examined whether inter-observer variability in rating tumor characteristics affected results of an investigation of surveillance bias and malignant melanoma at the Lawrence Livermore National Laboratory. The 20 cases from the Laboratory and their 36 non-Laboratory controls belonged to the same pre-paid health plan and were diagnosed with melanoma between 1970 and 1984. Tumors were independently and then jointly rated by three dermatopathologists blind to the subjects' Laboratory status. The mean difference between the reviewers and the consensus reading for tumor thickness was small, ranging from -0.06 mm (95% confidence interval [CI]--0.12, 0.00) to 0.00 mm (95% CI--0.07, 0.07). Agreement was much lower for histologic type (kappa = 0.48, 95% CI 0.37, 0.58). Because the inter-observer variability, the study's hypothesis was rejected by analyses based on data from the consensus reading and two reviewers, but not on data from the third reviewer. These findings suggest that epidemiologists using data subject to inter-observer variability may want to employ consensus instead of individual ratings.

Optimal selective sentinel lymph node dissection in primary malignant melanoma.

OBJECTIVE: To determine the optimal approach of selective sentinel lymph node (SLN) dissection in primary malignant melanoma. DESIGN: Consecutive patient study. Prior to selective SLN dissection and wide local excision of the primary melanoma biopsy site, technetium Tc 99m sulfur colloid was injected intradermally around the primary melanoma or biopsy site to mark the SLN. Isosulfan blue (Lymphazurin, Hirsch Industries Inc, Richmond, Va) was injected at the primary biopsy site immediately before the surgical procedure. SETTING: Teaching hospital tertiary care referral center. MAIN OUTCOME MEASURES: Successful identification of SLNs being defined as positive for microscopic metastatic melanoma by blue dye staining, radioisotope uptake, or both. RESULTS: Selective intraoperative mapping by gamma probe and visualization of blue dye-stained SLN(s) resulted in a 98% (160/163) successful identification rate. Thirty patients (18.4%) had microscopic metastatic melanoma of the SLN(s), 22 of whom had subsequently completed lymphadenectomy. In 4 (18.2%) of these 22 patients, further microscopic metastatic disease was found in 1 of 8 nodes, 1 of 8 nodes, 1 of 28 nodes, and 1 of 9 nodes. No notable complications were encountered. Five recurrent cases from patients with SLNs without microscopic metastatic melanoma (3.8%) and 2 from patients with SLNs with microscopic metastatic melanoma (6%) were found during a median follow-up period of 463 days. A second primary melanoma developed in 2 patients; neither had no local recurrence. CONCLUSIONS: Sequential combination of preoperative lymphoscintigraphy and intraoperative mapping is a reliable way to identify regional SLN. The frequency of microscopic metastatic melanoma of the SLN(s) is 18.4%. Gamma-probe--guided resection minimizes the extent of lymph node dissection. Further follow-up is needed to assess the outcome of this group of patients for regional and systemic recurrences.

Early diagnosis of cutaneous malignant melanoma at Lawrence Livermore National Laboratory.

The Lawrence Livermore (Calif) National Laboratory (LLNL) has observed a threefold increase in incidence of cutaneous malignant melanoma (CMM) since 1972. A consultant pathologist reviewed 49 of 50 cases of CMM diagnosed from 1969 to 1984 and reclassified 4 cases; this did not significantly affect the elevated rate. A comparison of the thicknesses of CMM at LLNL from 1976 to 1984 with those from a nearby community histopathology laboratory showed that 74% of the LLNL cases were Clark level I or II, compared with 40% of the comparison laboratory cases. A matched-pair comparison controlling for age, sex, and year of diagnosis showed the LLNL cases were thinner in 58% of the pairs. The median thickness of CMMs at LLNL decreased faster than those from the comparison laboratory.

Risk factors for melanoma incidence in prospective follow-up. The importance of atypical (dysplastic) nevi.

BACKGROUND AND DESIGN: Assessment of melanoma risk factors can help identify individuals at greatest risk for melanoma. Previous studies were retrospective case-control or prospective without control groups. A prospective group of 3889 employees without previous melanoma or family history of multiple melanoma at the Lawrence Livermore (Calif) National Laboratory were examined as part of a melanoma screening program. Their subsequent incidence of melanoma in relationship to potential melanoma risk factors, which were recorded at the first examination, was determined. RESULTS: Nine invasive melanomas developed after initial examination among the studied population over an 8-year period with an average follow-up of 5 years. The presence of an easily recognized pattern of definite clinically atypical (dysplastic) nevi was present in 7% of employees and was associated with a cumulative melanoma risk of 1.9%. It was the strongest risk factor, with a relative risk of 47 compared with the 0.04% cumulative melanoma risk in the 64% of employees with no atypical (dysplastic) moles (chi 2 for equal risk, P = 7 x 10(-8). Significant, but less marked associations with melanoma risk were found for the total number of moles and for a history of many moles in other family members, with a maximal relative risk of 11.6 and 10.4, respectively. CONCLUSION: A small subgroup of the population with easily recognizable definite atypical (dysplastic) nevi have a marked increased risk of melanoma. Smaller significant melanoma risks were found for a total number of moles and a family history of many moles.

Vascular involvement in the prognosis of primary cutaneous melanoma.

OBJECTIVE: To examine the role of vascular invasion as a prognostic factor in melanoma. DESIGN: Retrospective survival analysis. SETTING: Academic medical center. PATIENTS: A total of 526 patients with primary cutaneous melanoma from the University of California, San Francisco, Melanoma Center database with 2 years of follow-up or documented relapse. MAIN OUTCOME MEASURES: (1) Presence of vascular involvement defined as vascular invasion with tumor cells within blood or lymphatic vessels; or uncertain vascular invasion, with melanoma cells immediately adjacent to the endothelium. (2) Percentage with metastasis or death and relapse-free and overall survival. RESULTS: The presence of either type of vascular involvement significantly increased the risk of relapse and death and reduced the survival associated with melanoma. The impact of vascular involvement on these outcomes was similar to that of ulceration. In a multivariate analysis, vascular involvement was the second most important factor (after tumor thickness) in the primary tumor in predicting survival. CONCLUSIONS: Vascular involvement is an important independent predictor of metastasis and survival in melanoma. The phenomenon of uncertain vascular invasion describes an earlier step than definite vascular invasion in tumor progression.

Prediction of sentinel lymph node micrometastasis by histological features in primary cutaneous malignant melanoma.

OBJECTIVE: To develop a prognostic model, based on clinical and pathological data, to estimate the probability of micrometastasis in the sentinel lymph node in patients with malignant melanoma. DESIGN: Retrospective analytical study. SETTING: University medical center. PATIENTS: Two hundred fifteen patients with American Joint Committee on Cancer stages I and II cutaneous malignant melanoma underwent sentinel lymph node biopsy. MEASUREMENTS: Presence of microscopic melanoma in the sentinel lymph node(s). Clinical attributes recorded included age, sex, and location of the primary melanoma. Pathological attributes recorded before lymph node evaluation included ulceration, microsatellites, angiolymphatic invasion, mitotic rate, tumor infiltrating lymphocytes, and regression. RESULTS: Forty-six patients (21.4%) overall had a positive sentinel lymph node. Patients with tumor thickness ranging from 3.0 to 3.9 mm had the highest incidence (50%) of nodal involvement, followed by those with tumors 4.0 to 4.9 mm thick (41%). Patients with melanomas measuring greater than 4.9 mm thick and those between 1.0 and 2.9 mm had a similar rate of nodal involvement (16%-17%). Clinical characteristics had minimal correlation with nodal status in multivariate analysis. The total number of histological high-risk features was significantly correlated with sentinel lymph node involvement. Important pathological risk factors included ulceration, high mitotic rate, angiolymphatic invasion, and microsatellites. Patients with tumor thickness greater than 1.0 mm but lacking these features had a 14% risk of occult metastases. CONCLUSION: Among patients with clinically node-negative primary melanoma, the presence of 1 or more high-risk histological features significantly increases the incidence of microscopic nodal involvement and can be used to predict the likelihood of a positive sentinel lymph node biopsy.

The inheritance pattern of dysplastic naevi in families of dysplastic naevus patients.

Dysplastic naevi (DN) are the major precursor lesions of malignant melanoma, yet the presumed mode of inheritance or genetic aetiology of DN remains controversial. The inheritance pattern of DN in families from a randomly selected population of 26 dysplastic naevus patients was investigated by estimating the segregation ratio in families ascertained through an offspring with DN (incomplete ascertainment). For families ascertained through a parent with DN (complete ascertainment) the transmission pattern was examined by comparing the observed number of affected offspring to the expected number using a chi 2 goodness-of-fit test. Results from the chi 2 tests and the estimated segregation ratio of 0.52 (95% confidence interval: 0.31, 0.73) suggest that the inheritance pattern for dysplastic naevi in these families is consistent with autosomal dominant transmission, although the present study was limited because of a small sample size. The findings, therefore, need to be confirmed by a much larger study that is able to test more rigorously specific genetic hypotheses.

Diagnosis and management of premalignant melanocytic proliferations.

The histopathology of melanocytic proliferations in human skin can be defined in a way which allows a rational approach to their management. Early and/or premalignant lesions such as melanocytic hypertrophy, hyperplasia, dysplasia, and atypical hyperplasias are correlated with clinical lesions such as lentigo, compound nevoid lentigo, changes in nevi during pregnancy, and unusual moles seen in patients with the dysplastic nevus syndrome. Clinical management of such lesions may be determined from the pathological process. Hypertrophic and hyperplastic lesions need not be re-excised, although partially removed moles showing junctional hyperplasia may recur clinically. The mildly and moderately dysplastic nevus need only be narrowly removed. Severe dysplasia and melanoma in situ may recur locally as invasive melanoma, and consideration for conservative reexcision is warranted. Dysplastic nevi should be considered to be markers of patients who may develop melanoma. Patients with dysplastic nevi or a family history of unusual moles or melanoma should have continued follow-up, preferably with standardized clinical photographs.

The multidisciplinary melanoma center.

The evolution of the multidisciplinary melanoma clinics from 1965 to the present is reviewed. The University of California Melanoma Center database is presented as a model of actual visualization of the data in the care of individual melanoma patients. The basis of the ideal melanoma multidisciplinary center is given with common attributes that could be shared among all clinics, thus establishing a national network of such clinics.

The relationship of psychosocial factors to prognostic indicators in cutaneous malignant melanoma.

This study investigated the relationship between prognosis (estimated by histopathologic indicators) in cutaneous malignant melanoma and a comprehensive set of physical risk, demographic, psychosocial, and situational variables. These variables were derived from the medical examination, the pathology report, psychosocial self-report measures, and an hour-long videotaped interview with 59 patients from two melanoma clinics in San Francisco. Variables significantly correlated with tumor thickness were: darker skin/hair/eye coloring, longer patient delay in seeking medical attention, two correlated dimensions within an operationally defined 'Type C' constellation of characteristics, two character style measures, and less previous knowledge of melanoma and understanding of its treatment. Of these variables, delay was the most significant in a hierarchical multiple regression analysis in which tumor thickness was the dependent variable. Associations between tumor thickness and psychosocial measures of Type C were considerably stronger and more significant for subjects less than age 55, suggesting that the role of behavioral and psychosocial factors in the course of malignant melanoma is more potent for younger than for older subjects.

Differential diagnosis of Kaposi's sarcoma.

The biopsies of all lesions clinically thought to be suspicious for Kaposi's sarcoma (KS) were reviewed over a 15-month period. A diagnosis of KS was made in 40 of 106 biopsies (38%). The cases in which a diagnosis other than KS was made included dermatofibroma, hemangioma, and scar. This second group comprised 59 of 106 cases (56%). A third group included some lesions that had an atypical vascular proliferation, but in which the changes were insufficient for a definite diagnosis of KS. The presence of abnormally shaped vessels, especially those classified as irregular, was the best single criterion to diagnose KS in its early stages. In later stages, the neoplasm assumes a nodular configuration with typical, slitlike vascular channels. At the periphery of such nodules dilated, irregularly shaped vessels similar to those of the early lesions are often seen. The histologic features which help in the diagnosis of KS from other histologic entities are reviewed.

Kaposi's sarcoma in young homosexual men: a histopathologic study with particular reference to lymph node involvement.

Recent reports indicate an increased incidence of Kaposi's sarcoma in young homosexual men. In contrast with the form of the disease seen in the elderly, in which skin involvement is usually confined to the lower extremities, lymph node involvement is rare, and disease progression is relatively slow, Kaposi's sarcoma in young homosexual men is characterized by diffuse skin and lymph node involvement and a fulminant disease course.

Cytologic detection of recurrent vaginal melanoma.

A case of malignant melanoma of the vagina is described. Ultrastructural examination of tissue from the neoplasm showed a well-developed protein framework similar in appearance to that seen in the slowly progressive lentigo maligna form of malignant melanoma from the general body skin. The spectrum of malignancy known for most other neoplasms, from slowly and locally recurrent to highly aggressive, seems to be found similarly in vaginal malignant melanoma. The patient was treated with local excisions and followed by cytologic examination; she is without known deep or systemic spread after more than three years.

Cutaneous malignant melanoma--the party line and more--with a word on "safe sun".

Although the incidence of melanoma in adults seems to be increasing in recent decades, the survival rate has improved too, largely because of early diagnosis. Early diagnosis results in definition of a low risk primary group, for which conservative therapy is warranted. High risk primary patients still face controversial decisions regarding more radical surgery, a topic for another opinion paper. Patients with recurrences where fresh tissue can be made available should be considered for autologous tumor vaccine.