Atypical Spitz nevi/tumors: lack of consensus for diagnosis, discrimination from melanoma, and prediction of outcome.

The biological nature of Spitz nevi/tumors and their diagnostic distinction from, or relationship to, melanoma remain unresolved issues. In this report, a series of 30 melanocytic lesions removed from 28 patients, including atypical Spitz nevi/tumors and metastasizing Spitzoid tumors/melanomas, were evaluated by a panel of dermatopathologists to evaluate interobserver diagnostic concordance and to assess the prognostic power of histological criteria. For inclusion in the study, each lesion had to display some criteria for the Spitz nevus, and in addition one of the following was required: (1) definitive clinical outcome such as metastasis or death of disease, or (2) long-term follow-up if the patient remained disease free. Each lesion was reviewed independently and blinded as to the clinical data by 10 pathologists, who categorized them as (1) typical Spitz nevus/tumor, (2) atypical Spitz nevus/tumor, (3) melanoma, (4) tumor with unknown biological potential, or (5) other melanocytic lesion. There was limited discussion of criteria before the review. Evaluation of 17 Spitzoid lesions yielded no clear consensus as to diagnosis; in only one case did six or more pathologists agree on a single category, regardless of clinical outcome. Notably, however, some lesions that proved fatal were categorized by most observers as either Spitz nevi or atypical Spitz tumors. Conversely, seven or more pathologists scored 13 lesions as melanoma. These results illustrate (1) substantial diagnostic difficulties posed by many Spitz tumors, especially those with atypical features, even among experts, and (2) the lack of objective criteria for their distinction from melanoma and for gauging their malignant potential. Nevertheless, our observations do suggest that a biological relationship exists between the Spitz nevus/tumor and melanoma.

Molecular prognostic markers in intermediate-thickness cutaneous malignant melanoma.

BACKGROUND: The limitations of morphologic criteria alone in determining the prognosis for a patient with a particular intermediate-thickness primary melanoma have prompted efforts to identify other markers. METHODS: In this study, the authors analyzed expression of p53, beta1 integrin, and beta3 integrin in primary tumors from 111 patients with intermediate-thickness malignant melanoma. RESULTS: Eighty-nine (80%) had detectable p53 protein, 58 (52%) expressed beta1 integrin, and 71 (64%) expressed beta3 integrin. Patients with beta3 positive melanomas were more likely to die of their disease (32 of 71 patients, 45%) than those with beta3 negative tumors (3 of 40 patients, 8%) (P < 0.0001). The number of involved lymph nodes, Clark's level, beta1 integrin expression, thickness, and mitotic rate also had prognostic significance. beta3 integrin was associated with subsequent lung metastases and beta1 integrin with lymph node involvement. CONCLUSIONS: Integrin expression, along with histopathologic criteria, is a prognostic marker for intermediate-thickness malignant melanoma and may indicate the site of subsequent metastasis. These observations may have clinical utility and suggest areas for future investigation.

Molecular analysis of 1p36 breakpoints in two Merkel cell carcinomas.

Merkel cell carcinoma (MCC) is a rare aggressive neuroendocrine tumor of the skin. Only little information is available on the genetic alterations occurring in this tumor. Cytogenetic studies thus far have not shown recurrent chromosomal changes, although various structural chromosome 1 rearrangements, including deletions, often leading to loss of distal 1p material appear to be frequent. We report on fluorescence in situ hybridization and loss of heterozygosity analyses of an MCC tumor and MCC cell line UISO. The present study has shown that two distinct regions in the most distal band 1p36 on the short arm of chromosome 1 can be implicated in MCC. One region at 1p36.3 was delineated by a distal deletion in the MCC tumor as a result of an unbalanced translocation, resulting in loss of all markers distal to ENO1. This region was previously shown to be deleted in different tumor types including neuroblastoma. In cell line UISO an insertion in 1p36.2 was identified. The insertion breakpoint indicates a second, more proximal, region on 1p involved in MCC. The insertion breakpoint was mapped within a cluster of repetitive tRNA and snRNA genes and thus could coincide with the constitutional 1p36 breakpoint previously reported in a patient with neuroblastoma.

Beta 1 integrin expression: a marker of lymphatic metastases in cutaneous malignant melanoma.

BACKGROUND: Experimental evidence suggests that integrins are key regulators of the development of melanoma metastases, influencing both the likelihood and site of metastases. Whereas effective treatment of cutaneous melanoma remains surgical, elective lymph node dissection (ELND) is controversial. The present study was designed to investigate the relationship between integrin expression by a given primary melanoma and occult regional lymph node metastases. MATERIALS AND METHODS: We studied beta 1 integrin expression, by quantitative immunohistochemistry using an image analyzer, in the primary melanomas of 90 ELND patients. RESULTS: beta 1 integrin was expressed in > or = 10% of the primary tumor in 92% of cases eith lymph node involvement versus 9% of node negative cases (p < 0.001). CONCLUSIONS: Our data demonstrate that quantitative immunohistochemistry for beta 1 integrin expression in primary melanomas can identify patients likely to have occult lymph node metastases. This suggests that beta 1 integrins play a role in the lymphatic dissemination of cutaneous melanoma.

Beta3 integrin expression in melanoma predicts subsequent metastasis.

Previous studies have suggested that differential expression and/or activation of integrins facilitates metastatic progression in murine and human melanoma. While recent data show that the integrin alphavbeta3 is involved in tumor angiogenesis and that tumor growth may be abrogated by alphavbeta3 inhibitors in vitro, the clinical significance of beta3 integrin expression in human malignant melanoma is not known. To assess the prognostic value of beta3 integrin expression, we examined primary cutaneous melanomas from 160 patients followed for a mean of 98 months or until death. We quantified the percentage of tumor area stained with beta3 integrin Ab CD-61 using an image analyzer. beta3 integrin expression was detected in 107/160 primary melanomas (69%). beta3-integrin-positive (beta3+) tumors were thicker (mean 2.98 +/- 0.3 mm) than beta3-integrin-negative (beta3-) melanomas (mean 1.64 +/- 0.2 mm) (P = 0.002). Patients with beta3+ melanomas were more likely to relapse (57/107, 53%) and to die from disease (45/107, 42%) than those with beta3- tumors (6/53, 11%; and 4/53, 8%, respectively) (P < 0.001). Overall survival was greater for beta3- than for beta3+ patients (mean 102 +/- 9 vs 69 +/- 6 months) (P = 0.001). These data show that beta3 integrin expression in primary cutaneous melanoma predicts subsequent metastatic progression. Further study of beta3 integrins in the development of melanoma metastases may yield new therapeutic strategies, as well as prognostic information, for the treatment of this cancer.

Beta 1 integrin expression in malignant melanoma predicts occult lymph node metastases.

BACKGROUND: Elective lymph node dissection for malignant melanoma is still controversial. Experimental studies suggest that differential expression, activation, or both of beta1 integrins facilitate melanoma metastases. However, the clinical significance of beta1 integrin expression in human melanoma is unclear. METHODS: We examined primary cutaneous melanomas from 76 patients undergoing elective lymph mode dissection. We quantified the percentage of tumor area stained by beta1 integrin antibody with an image analyzer. RESULTS: beta1 integrin was expressed in all 23 primary tumors from patients with pathologically positive lymph nodes (LNs) but in only 14 (26%) of 53 cases with pathologically negative nodes (p < 0.001). No patients with beta1 integrin-negative tumors had LN involvement, whereas 23 (62%) of 37 patients with beta1 integrin-positive tumors had LN metastases (p < 0.001). Furthermore, 21 (91%) of 23 cases with LN metastases but only 4 (8%) of 53 cases without had beta1 integrin staining of 10% or more of tumor area (p < 0.001). CONCLUSIONS: Our study is the first to show a correlation between expression of a molecular marker in the primary cutaneous melanoma and likelihood of regional LN metastases. beta1 immunostaining of 10% or more of tumor area reliably predicts patients most likely to harbor occult LN metastases and likely to benefit from ELND.

Acral lentiginous melanoma.

OBJECTIVE: To analyze whether the histologic subtype acral lentiginous melanoma confers independent prognostic significance. DESIGN: Case series retrospective review. SETTING: Academic surgical practice. PATIENTS OR OTHER PARTICIPANTS: Fifty-six patients with histologically confirmed acral lentiginous melanoma identified from patients with malignant melanoma consecutively treated by the faculty of the Department of Surgical Oncology at the University of Illinois at Chicago. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Lymph node metastases, disease-free survival, and overall concurrent or subsequent survival. RESULTS: The average age of our patients with acral lentiginous melanoma was 61.1 years. Thirty-four (61%) were white, and the remaining 22 (39%) were African-American, Hispanic, or Asian. Thirty (54%) were male and 26 (46%) were female. The primary tumor occurred on the lower extremity in 46 (82%) of the cases and on the upper extremity in the remaining 10 (18%). Twenty-four primary tumors (43%) were greater than 4.00 mm thick. Analyzed by means of a logistic regression model, the rate of lymph node metastases did not significantly differ among patients with acral lentiginous melanoma, superficial spreading melanoma, and nodular malignant melanoma. Furthermore, when corrected for tumor thickness, disease-free and overall survival were the same for the three histologic groups. Multifactorial analysis identified only thickness as a prognostic variable for disease-free survival and overall survival. CONCLUSIONS: Despite the greater age, diverse ethnic background, and distinctive tumor characteristics of our patients with acral lentiginous melanoma, this histologic subtype does not, in itself, affect the outcome of these patients.

Prognostic significance of nucleolar organizer regions (NORS) in malignant melanoma.

Nucleolar organizer regions (NORs) are loops of ribosomal DNA (rDNA) in the nucleolus and are associated with acidic proteins. They are seen in routinely processed paraffin sections by using a one-step colloidal silver (Ag) staining method; they appear as black dots termed "AgNORs". The quantitative assay of AgNORs has been used to differentiate benign from malignant neoplasms. Melanocytic lesions differ significantly in AgNOR counts between malignant melanoma and nevi. However, conflicting results have been reported as to AgNORs' prognostic value in melanoma. A recent study showed AgNOR counts to be a more accurate prognostic indicator than Breslow's thickness. In this study, we counted the AgNORs in 26 patients with primary cutaneous melanomas (CMM) between 2.0 mm and 2.5 mm thick. Of these, 14 are alive without disease (AN) at 5 years after diagnosis (group 1) and 12 are dead of disease (DD) in less than 5 years (group 2). The AgNORs were scored in 30 nuclei per tumor, and the means were calculated. For group 1, the mean number of AgNORs per nucleus was 6.88, ranging from 3.73 to 12.70. For group 2, the mean number was 6.97, ranging from 3.63 to 11.67. Statistical analysis using analysis of variance (ANOVA) showed no significant difference between the groups (p = 0.33). In our study, AgNOR counts did not prove to be of prognostic value in malignant melanoma.

Merkel cell carcinoma: in vitro and in vivo characteristics of a new cell line.

BACKGROUND: Few studies exist that describe Merkel cell carcinoma (MCC) growth characteristics in vitro, in vivo, or both. OBJECTIVE: Our purpose was to evaluate the pathologic features of MCC implanted into athymic mice and to determine cytogenetic abnormalities in the established cell line. METHODS: Tumor tissues from a patient with MCC were grown in culture. Cultured cells were karyotyped and inoculated subcutaneously into athymic mice. Nude mouse tumors were re-implanted into other athymic mice. Tissues from the primary skin tumor and the nude mouse tumor were processed for light and electron microscopy and immunocytochemistry. RESULTS: The cell line showed a doubling time of 64.8 hours. Xenografts of 4 x 10(6) cells produced tumors in athymic mice with a doubling time of 16.1 days. The nude mouse tumors showed pathologic features similar to those of the primary skin tumor. Cytogenetic studies showed a t(1;17) (p36;q21) translocation in 100% of the cells. CONCLUSION: MCC implanted into athymic mice retained the pathologic features of the primary skin tumor and behaved aggressively. The t(1;17) (p36;q21) translocation may be a marker of an aggressive phenotype.

Primary cutaneous phaeohyphomycosis: report of seven cases.

We report seven cases of primary cutaneous phaeohyphomycosis. There were five males and two females, ranging in age from 42-65 years (mean 57.7 years). Two patients were otherwise healthy, but five were immunocompromised. One patient had rheumatoid arthritis and was on oral prednisone; two were renal transplant recipients, one was a heart transplant recipient, and the fifth had dermatomyositis. No history of trauma was elicited from any of the patients, but in two cases, foreign material was seen in the tissue sections. All lesions were on the extremities. In two cases, tissues were cultured, and these grew Exophiala jeanselmei. The others were not cultured because fungal infection was not clinically suspected. No systemic disease developed in any of the cases, and all were cured by the simple, complete excision of the lesions.

Melanoma in childhood and adolescence: clinical and pathological features of 48 cases.

Forty-eight cases of melanoma occurring in patients under 20 years of age were reviewed from a 23-year period at a single center. Fourteen of the patients were preadolescent children and 44 were Caucasian. Histological review of 44 available primary tumors showed only superficial spreading and nodular types. Thickness ranged from 0.23 mm to 8.50 mm, with a median of 1.03 mm. Ulceration was present in 7%, necrosis in 35%, evidence of regression in 16%, and antecedent nevus in 49% of the cases. The overall 5-year survival is 77%, with a median follow-up of 48 months. There is no detectable survival difference between preadolescent children and adolescents. Several treatment failures occurred after improper biopsy and/or inaccurate original diagnosis of Spitz's nevus. Of 38 stage I and II patients given definitive surgical treatment by the authors, the 5-year survival is 90%. Although histological confusion with Spitz's nevi occasionally occurs, melanoma in this age group can be treated with good results.

Malignant melanoma in a child with oculocutaneous albinism.

Malignant melanoma is extremely rare in patients with albinism. To date, in the English language literature, there have been only sixteen documented cases of malignant melanoma in albino patients. These cases include thirteen cutaneous, one oral, one ocular, and one anal; only one of these was in a child. Here, we present the case of the youngest known albino patient to have cutaneous malignant melanoma.

Lipoid proteinosis: case report.

A 20-month-old Kuwaiti girl had manifestations of lipoid proteinosis, a rare autosomal recessive disorder seen more commonly in Caucasians. This condition is diagnosed based on clinical, histopathologic, and ultrastructural criteria. Its biochemical and genetic aspects are still poorly understood.

Role of technetium 99m-labeled monoclonal antibody in the management of melanoma patients.

PURPOSE: A study was performed to assess the usefulness of a radiolabeled monoclonal antibody (MoAb; technetium 99m NR-ML-05 Fab) as a detecting agent, as well as to evaluate its role in the overall decision-making process in the management of cutaneous malignant melanoma. PATIENTS AND METHODS: Twelve patients with histologically confirmed primary cutaneous melanoma and palpable regional nodes were injected with MoAb NR-ML-05 Fab, radiolabeled with 20 to 30 mCi of 99mTc. Whole-body anterior and posterior images were obtained. Left and right lateral views of the head and anterior and posterior views of the chest, abdomen, pelvis, and extremities were obtained, as were selected single-photon emission computed tomographic (SPECT) views of regional lymph nodes and areas of known or suspected lesions. RESULTS: In nine of 12 patients, clinical and/or MoAb evolution identified 30 discrete sites of suspected melanoma. The remaining three patients showed no positive sites, and there was no evidence of metastatic melanoma. All 30 sites were examined microscopically, and melanoma was confirmed histologically in 23. The remaining seven were negative. MoAb imaging detected 21 (true-positive) but failed to detect two (false-negative) lesions. Sensitivity was 91% (21 of 23); positive predictive value was 95% (21 to 22). CONCLUSIONS: MoAb imaging seems to provide an excellent way to obtain information with regard to the metastatic status of melanoma patients. Immunocytochemistry showed that MoAb (NR-ML-05) is as sensitive as the S-100 antibody and probably more sensitive than the commercially available antimelanoma antibody HMB-45.

Invasive cutaneous melanoma in elderly patients.

Clinical and pathologic variables were compared between "older" (greater than or equal to 70 years) and "younger" (30 to 39 years) patients with primary invasive cutaneous melanoma. Older patients had more nodular melanomas and acral lentiginous melanomas (58%); superficial spreading melanomas predominated in younger patients (74%). Mean tumor thickness was greater in the older patients (3.95 vs 2.02 mm). Invasive levels 2 and 3 occurred more often in younger patients (41.1% vs 13%); level 5 occurred more often in older patients (30.4% vs 5.3%). Microscopic ulceration occurred more often in older (46.4%) than in younger patients (19.4%). Older patients classified as clinical stage I at presentation or with primary lesions 1.50- to 3.00-mm thick had poorer survival. Younger women survived longer than younger men; this was not true of older patients. The elderly patients with cutaneous melanoma were more likely to have poor prognostic features and thus more likely to die from melanoma than the younger patients.

Interrelationship between histopathologic characteristics of melanoma and estrogen receptor status.

To evaluate whether the increase in disease-free survival and survival previously reported for women with melanomas with estrogen receptors (ER) was a reflection of the histopathology of the primary melanoma, the interrelationship of histopathologic characteristics of 143 patients with such tumors was examined. The ER was assayed in the primary tumor from 44 patients and in 99 metastatic deposits from the other patients. Tumor thickness, level of invasion, prognostic index, mitoses/mm2, ulceration, vascular invasion, necrosis, histologic grade, preexisting nevus, and predominant malignant cell type were examined. There was no relationship between ER presence and any histopathologic characteristic examined, irrespective of the tumor source (primary or metastatic). Examination of histopathologic characteristics as a function of sex and receptor status showed a slight but insignificant predominance of more well-differentiated, thinner tumors in women whose lesions were positive for the ER. These results suggest that the increased disease-free survival in patients with ER-positive lesions is not attributable to the pathologic characteristics of the primary tumor examined during this study.

Estrogens influence the natural history of Sinclair swine cutaneous melanoma.

Initial results (Cancer Res., 48: 1708-1711, 1988) suggest that ovariectomy alters the proliferation of congenital exophytic melanoma in Sinclair swine. In order to provide a phenotypic basis for this effect, histopathological staging of 375 exophytic melanomas from 236 intact male and female Sinclair swine was compared with 114 lesions from 51 gonadectomized (6 weeks of age) and 90 lesions from castrated swine receiving s.c. silastic implants of estradiol during the first year of life. A rapid progression from actively proliferating tumor cells (Stages I-III) to regressive lesions (Stages IV-V) was virtually complete by 16 weeks of age in intact swine of both sexes. Bilateral ovariectomy reduced (P less than 0.02) tumor volume over time compared with intact animals. Replacement of estradiol in gilts increased tumor volume to that in intact animals. In contrast, neither bilateral orchidectomy nor estradiol replacement altered tumor volume in boars. Ovariectomy significantly reduced the tumor macrophage, keratinocyte, and fibroblast invasion that normally replaces tumor cells and expands tumor volume (Stages IV and V) with increasing age. Chronic exposure to estradiol reversed this process. Orchidectomy and estradiol replacement did not significantly affect histopathological stage in boars with increasing age. A significant number (20 of 41; 49%) of Stage III lesions (greater than 75% tumor cells) in swine of both sexes contained low but reproducibly measurable amounts of receptor for estrogen determined radiometrically and by enzyme-linked immunosorbent assay. These results suggest that reproductive steroids influence the natural history of these heritable lesions, and that the effect may be via alteration of host immune status.

Pigmented Bowen's disease arising from pigmented seborrheic keratoses.

We report three cases of pigmented Bowen's disease that clinically and histologically had features of seborrheic keratoses. We speculate about the mechanism of pigmentation in these lesions and suggest that they arise from pigmented seborrheic keratoses.

Malignant melanoma of the female genitalia.

Fifteen women with genital malignant melanoma were studied. Their ages ranged from 19 to 66 years (mean 49.1 years); 12 were white, and three were black. The sites of involvement were the mons pubis (one patient), perineal body (one), labium majus (three), labium minus (three), and vagina (seven). Ten patients (66.6%) died of their disease, one is alive with disease, and four are alive without evidence of disease. For the living patients the duration of follow-up was 20 to 118 months (mean 63.6 months). Of those who died, survival ranged from 3 to 76 months (mean 25.1 months). The predominant type of malignancy was superficial spreading melanoma 50%. Nodular melanoma represented 22%, and the nodular polypoidal variant 14%. Melanoma of the squamous mucosa, also referred to as lentiginous melanoma, constituted 14%. By using Chung's method of determining levels of invasion, we found that no lesion was in situ (level I), two were level II (less than 1.0 mm thick), one was level III (between 1.0 and 2.0 mm) and the remaining 11 patients had lesions that were greater than 2.0 mm (levels IV and V). Because the subcutaneous fat is not consistently present in all sites of the female genitalia, all tumors thicker than 2.0 mm were included in level IV, and no level V tumors were classified in our study. Using Breslow's microstaging method, we found the thickness to range from 0.65 to 9.5 mm (mean 4.75 mm). When we correlated survival with level and thickness of tumor in nine patients who died, one tumor was level III and eight were level IV; thickness ranged from 1.65 to 9.0 mm (mean 5.64 mm).(ABSTRACT TRUNCATED AT 250 WORDS)