Skin biopsy utilization and melanoma incidence among Medicare beneficiaries.

BACKGROUND: Melanoma incidence has increased in recent decades in the U.S.A. Uncertainty remains regarding how much of this increase is attributable to greater melanoma screening activities, potential detection bias and overdiagnosis. OBJECTIVES: To use a cross-sectional ecological analysis to evaluate the relationship between skin biopsy and melanoma incidence rates over a more recent time period than prior reports. METHODS: Examination of the association of biopsy rates and melanoma incidence (invasive and in situ) in SEER-Medicare data (including 10 states) for 2002-2009. RESULTS: The skin biopsy rate increased by approximately 50% (6% per year) throughout this 8-year period, from 7012 biopsies per 100 000 persons in 2002 to 10 528 biopsies per 100 000 persons in 2009. The overall melanoma incidence rate increased approximately 4% (< 1% per year) over the same time period. The incidence of melanoma in situ increased approximately 10% (1% per year), while the incidence of invasive melanoma increased from 2002 to 2005 then decreased from 2006 to 2009. Regression models estimated that, on average, for every 1000 skin biopsies performed, an additional 5·2 (95% confidence interval 4·1-6·3) cases of melanoma in situ were diagnosed and 8·1 (95% confidence interval 6·7-9·5) cases of invasive melanoma were diagnosed. When considering individual states, some demonstrated a positive association between biopsy rate and invasive melanoma incidence, others an inverse association, and still others a more complex pattern. CONCLUSIONS: Increased skin biopsies over time are associated with increased diagnosis of in situ melanoma, but the association with invasive melanoma is more complex.

Screening for cutaneous melanoma by skin self-examination.

BACKGROUND: Although some evidence indicates that early detection protects against the development of lethal melanoma, no randomized clinical trials have been conducted to measure the efficacy of early detection (or screening) in preventing death from this disease. Since melanoma incidence in the United States is relatively rare, a randomized clinical trial to test the efficacy of screening would be extremely expensive. PURPOSE: As an alternative to a randomized clinical trial, we conducted a population-based, case-control study to investigate whether early detection through skin self-examination (SSE) is associated with a decreased risk of lethal melanoma (includes the presence of advanced disease with distant metastases in addition to death from melanoma). METHODS: SSE (conducting a careful, deliberate, and purposeful examination of the skin) was assessed in all subjects by use of a structured questionnaire and personal interviews. The major exposure variable, SSE, was defined following focus-group interviews with melanoma patients and healthy control subjects. The final study population consisted of 1199 Caucasian residents of the state of Connecticut enrolled from January 15, 1987, through May 15, 1989; 650 individuals were newly diagnosed with cutaneous melanoma, and the remaining 549 individuals were age- and sex-frequency matched control subjects from the general population. During the study interviews, nevi on the arms and backs of subjects were counted. In 5 years of follow-up (through March 1994), 110 lethal cases of melanoma were identified. The study design allowed separate estimation of the impact of SSE on reduced melanoma incidence (primary prevention) and survival among incident cases (secondary prevention). Odds ratios (ORs) were used to measure the associations between SSE and melanoma and between SSE and lethal melanoma. RESULTS: SSE, practiced by only 15% of all subjects, was associated with a reduced risk of melanoma incidence (adjusted OR = 0.66; 95% confidence interval [CI] = 0.44-0.99; comparing case patients with control subjects). The data indicated further that SSE may reduce the risk of advanced disease among melanoma patients (unadjusted risk ratio = 0.58; 95% CI = 0.31-1.11); however, longer follow-up is required to confirm this latter estimate. If both estimates are correct, they suggest, in combination, that SSE may reduce mortality from melanoma by 63% (adjusted OR = 0.37; 95% CI = 0.16-0.84; comparing lethal cases with general population controls). CONCLUSIONS AND IMPLICATIONS: SSE may provide a useful and inexpensive screening method to reduce the incidence of melanoma. SSE may also reduce the development of advanced disease. The results of this study need to be replicated before strategies to increase the practice of SSE are further developed and promoted.

Dysplastic nevi in association with multiple primary melanoma.

Risk factors for multiple primary cutaneous melanoma were evaluated in a case-control study. Eight cases of multiple primary melanoma were matched on sex, age, and education to 24 first primary melanoma controls. Risk factors examined in the analysis included pigmentary characteristics, history of sun exposure, and nevi. The importance of histologically dysplastic nevi (DN) and clinically atypical nevi was of particular interest. Single-factor conditional logistic regression analysis showed that first primary melanoma patients with histological DN are at increased risk for a second primary (odds ratio, 6.2; 95% confidence interval, 1.2-33.4). Patients with two or more clinically atypical nevi also have elevated risk for a second primary (odds ratio, 8.8; 95% confidence interval, 1.0-80.7). Two-factor logistic models were used to evaluate the effect of histological DN while controlling singly for all other variables as potential confounders. Odds ratios for the association of histological DN varied from 6.1 to 10.4 when adjusting singly for pigmentary and sun exposure variables. In the two-factor model that included histological and clinical DN, both variables retained marginally significant statistical association with multiple primary melanoma. These results suggest that DN is a marker of increased risk for multiple primary melanoma and suggest that melanoma patients with evidence of DN should be followed closely for the development of additional primaries.

Loss of the p16INK4a and p15INK4b genes, as well as neighboring 9p21 markers, in sporadic melanoma.

Although homozygous deletions of the cyclin-dependent kinase inhibitor 2 gene p16INK4a on 9p21 have been reported frequently in metastatic melanoma cell lines, and intragenic mutations within the p16INK4a gene have been detected in familial melanoma kindreds, specific targeting of this gene in the development of sporadic melanoma in vivo remains controversial. Southern analyses were performed in this study to initially assess the frequency of hemi- or homozygous losses of p16INK4a, as well as its neighboring family member, p15INK4b, and other candidate regions within 9p21, in sporadic melanoma. Overall, 22 of 40 (55%) uncultured sporadic melanoma DNAs were determined to harbor deletions of 1-11 markers/genes located on 9p21. This included 10 tumors (25%; 10 of 40) with homozygous deletions limited to either the p16INK4a gene only (20%; 2 of 10), both the p16INK4a and p15INK4b genes (10%; 1 of 10), another novel 9p21 gene, FB19 (10%; 1 of 10), or all three of these genes plus surrounding markers (60%; 6 of 10). In subsequent single-strand conformation polymorphism and sequencing analyses, intragenic mutations in the p16INK4a gene were also revealed in two (10%; 2 of 21) melanoma DNAs that retained one copy of this locus. By comparison, the frequency of pl6INK4a and p15INK4b homozygous deletions, as well as p16INK4a mutations, in melanoma cell lines (analyzed in parallel) was 2-3-fold higher at 61 (23 of 38) and 24% (9 of 38), respectively. These findings indicate that (a) p16INK4a is inactivated in vivo in over one-fourth (27.5%; 11 of 40) of sporadic melanomas; (b) mutation/deletion of p16INK4a may confer a selective growth advantage in vitro; and (c) other 9p21 tumor suppressor genes could be targeted during the development of melanoma.

Biochemical modulation of angiogenesis in the chorioallantoic membrane of the chick embryo.

A variety of substances potentially having effects on angiogenesis in the skin were assayed on the chorioallantoic membrane of the chicken embryo (CAM). Millipore filter discs alone and saturated with saline 0.9% (controls), keratinocyte-conditioned medium, lactic acid 10(-1) M, adenosine 10(-4) M, sodium fluoride 10(-4) M, dinitrophenol 10(-4) M, histamine 10(-4) M, 5-hydroxytryptamine 10(-4) M, acetylcholine 10(-4) M, prostaglandin E2 3 X 10(-4) M, prostaglandin F2 alpha 3 X 10(-4) M, arachidonic acid 10(-4) M, epidermal growth factor 5 X 10(-5) g/ml, human plasma fibronectin 10(-4) g/ml, acetylsalicylic acid 10(-3) M, and arachis oil were applied to the CAM and the vascular responses quantitated 4 days later. None of the agents with the exception of keratinocyte-conditioned medium stimulated new vessel growth as compared to the controls. However, arachis oil (p less than 0.001) and ADP (p less than 0.01) were associated with significantly decreased vascular responses relative to controls. The specimens incubated with saline, fibronectin, ADP, and arachis oil were examined histologically; with the exception of arachis oil all displayed ectodermal epithelial and mesenchymal hyperplasia of the membrane in association with increased vascularity. Almost no perceptible change was noted histologically with arachis oil.

A study of uniaxial tension on the superficial dermal microvasculature.

A spring-loaded apparatus was designed to apply uniaxial tension to forearm skin in 17 human subjects--10 normals, 6 psoriatics, and 1 patient with scleroderma. Simultaneously, the effects of stretching on the upper dermal vasculature were observed stereomicroscopically. Progressive changes (collapse) in the superficial microvasculature--vertical capillary loops and horizontal subpapillary plexus--with increasing tension were photographed. Force and strains were recorded at the points of disappearance of virtually all vessels. An average force of 11.9 newtons (N), accompanied by a mean strain of 10.3%, resulted in occlusion of all vessels. A much higher force (18.5 N) was necessary to occlude blood flow in the 1 patient with scleroderma. In summary, we have described a new technique for the study of mechanical forces on the blood supply of the epidermis. The data have shown that uniaxial tension has important effects on the superficial dermal microvasculature, resulting in impedance and obliteration of blood flow at relatively low magnitudes.

Histopathologic recognition and grading of dysplastic melanocytic nevi: an interobserver agreement study.

Before the controversies surrounding dysplastic melanocytic nevi are resolved, dermatopathologists must be able to reliably distinguish dysplastic nevi from common acquired nevi and malignant melanoma. To establish whether grading of melanocytic dysplasia has any biologic relevance, dermatopathologists must be able to consistently recognize two or more grades of atypia. We studied the concordance among five dermatopathologists for recognition and grading of 60 nevomelanocytic lesions. Ten cases from each of the following categories of melanocytic proliferation were retrieved from the Massachusetts General Hospital files: 1) common melanocytic nevi, 2) melanocytic nevi with features of dysplastic nevi, 3) dysplastic nevi with slight cytologic atypia, 4) dysplastic nevi with moderate cytologic atypia, 5) dysplastic nevi with severe cytologic atypia, and 6) primary malignant melanoma. The slides were reviewed independently; no discussion of diagnostic criteria preceded the review. Overall concordance for diagnosing dysplastic nevi was 77%, with a kappa statistic of 0.55-0.84. Furthermore, in grading dysplastic nevi, experienced dermatopathologists had a concordance ranging from 35% to 58% (kappa value 0.38-0.47). Those with less experience in grading dysplastic nevi had a concordance of 16-65% (kappa value 0.05-0.24). The five observers in this study reliably distinguished dysplastic nevi from common acquired nevi and malignant melanoma. Further refinement of the criteria for grading of nevo-melanocytic dysplasia and experience in grading are critical for accuracy in subcategorization of dysplastic nevi. Consistent, reproducible subcategorization of dysplastic nevi is a requisite before the issue of biologic or prognostic relevance of grading (dysplastic nevi) can be addressed. This study supports the validity of existing criteria for the diagnosis of dysplastic nevi because the problems in diagnosis were at the limits of the spectrum, namely, discrimination of slightly atypical dysplastic nevi from common nevi and severely atypical dysplastic nevi from radial growth phase melanoma.

Chromosome 17 allelic loss and NF1-GRD mutations do not play a significant role as molecular mechanisms leading to melanoma tumorigenesis.

Allelic loss in human cutaneous melanoma has been detected on chromosomes 1p, 6q, 9p, 10q, and 11q. Chromosome 17 contains important tumor suppressor genes such as p53, NM23, and neurofibromatosis type 1 (NF1), which have been implicated in melanoma tumorigenesis. The role of p53 has already been studied by a number of laboratories, showing contrasting results. In the present study, two restriction fragment length polymorphism (RFLP) probes for the NM23 and NF1 genes, together with five other RFLP and four variable number of tandem repeat chromosome 17 probes, were investigated at the loss of heterozygosity (LOH) level in a Southern blot-based assay. The NF1 gene was also tested for LOH by a polymerase chain reaction (PCR)-based approach in two different experiments, using a dinucleotide repeat polymorphic probe at locus D17S250 (17q11.2-q12), and an Alu probe intragenic to the NF1 gene (17q11.2). A PCR single-strand conformation polymorphism assay was included in the study for mutation detection at the NF1-GTPase-activating protein-related domain (GRD). A total of 68 melanocytic tumors were analyzed. LOH was detected in 9 of 87 informative cases (10%). LEW301 (17p11.2-pcen) presented the highest LOH frequency (22%). NM23 showed LOH in 17% of the informative cases, while NF1 did not show either LOH in the Southern blot- and PCR-based experiments or mutations at the NF1-GRD. These results are in concordance with those of previous smaller studies, but when compared with higher LOH frequencies obtained from other chromosomes, these findings indicate that the LOH values found in our study can most likely be attributed to background effect. Thus, chromosome 17 LOH is likely to play and unimportant role as a genetic event in melanoma tumorigenesis. Nevertheless, NF1 merits further study, since homozygous deletions have been detected at this locus in melanoma cell lines.

Dysplastic nevi in relation to superficial spreading melanoma.

The aim of the present study was to evaluate the frequency with which histologically confirmed dysplastic nevi are observed among patients with superficial spreading melanoma compared to patients with nodular melanoma. A pathology review of 117 new cases of first primary nonfamilial cutaneous melanoma identified 61 patients with superficial spreading melanoma and 19 with nodular melanoma. Study participants received a physician-conducted skin examination which included enumeration of clinically benign and atypical nevi and the surgical excision of the clinically most atypical nevus. Patients' dysplastic nevus status was established by histological review of the clinically most atypical nevus. A comparison based on the tumor subtypes showed that dysplastic nevi occur nearly four times more frequently among patients with a prior diagnosis of superficial spreading melanoma relative to nodular melanoma (odds ratio = 3.6; P = 0.03).

Evaluation of factors associated with skin self-examination.

Early detection and excision of thin lesions may be important in reducing mortality from melanoma. Periodic skin self-examination may be beneficial in identifying thin lesions. The purpose of this study was to evaluate factors associated with skin self-examination. The study population was comprised of 549 Caucasian residents of Connecticut 18 years of age or older who were selected as controls as part of a population-based case-control study on skin self-examination and melanoma conducted during 1987-1989. Personal interviews were conducted to obtain information on skin self-examination, demographics, history of cancer, phenotypic characteristics, sun exposure habits, and screening and health behaviors. Nevus counts were performed by trained nurse interviewers. Logistic regression was used to model the relationship between the variables of interest and skin self-examination. Female gender was identified a priori as a predictor of skin self-examination, and thus all analyses were stratified by gender. Age, education, and marital status were also identified a priori as important predictor variables and were selected for inclusion in the final models. Skin awareness was a strong factor associated with skin self-examination for both females and males. For females, previous benign biopsy or the presence of an abnormal mole was identified as important for future skin self-examination using our criteria. A family history of cancer, physician examination, and change in diet to reduce cancer risk increased the likelihood of skin self-examination in males but not females. In women, light hair color may increase the likelihood of performing skin self-examination. Older age and college or postgraduate education was associated with a decreased likelihood of performing skin self-examination in both males and females. Identifying factors associated with skin self-examination will enable health care providers to target individuals who may not be performing skin self-examination but who are at increased risk for developing melanoma.

Interobserver reproducibility of ulceration assessment in primary cutaneous melanomas.

In the recently revised melanoma staging system proposed by the American Joint Committee on Cancer (AJCC), ulceration assessment by the pathologist is a pivotal parameter. Patients upstaged because of ulceration might be included in adjuvant trials conducted in AJCC stage II melanoma patients. Therefore, accuracy based on interobserver reproducibility for melanoma ulceration assessment is crucial for proper clinical management. In some cases, it is extremely difficult, even for an experienced pathologist, to distinguish between trauma-induced ulceration, artifact and tumoral ulceration. Whether this difficulty may be resolved by the use of a more precise definition of ulceration has not been evaluated. Therefore, we have proposed a refined definition of melanoma ulceration and we tested whether this definition might improve the interobserver interpretative reproducibility of ulceration in primary cutaneous melanomas. The results of this study support the need for a more precise definition of melanoma ulceration that rules out biopsy trauma or processing artifact and could be incorporated into a standardised pathology worksheet for reporting primary melanomas.

Pagetoid Spitz nevus. Intraepidermal Spitz tumor with prominent pagetoid spread.

A distinctive variant of melanocytic growth pattern is described, which appears to be related to Spitz nevus and is characterized by a mainly intraepidermal proliferation of large epithelioid melanocytes with a predominantly pagetoid distribution. This melanocytic lesion appears clinically as a small (< 0.4 cm) pigmented macule in young patients. Histologically, this lesion needs to be distinguished primarily from in situ or microinvasive malignant melanoma with pagetoid spread. Features favoring nevus over melanoma include small size, circumscription, symmetry, even distribution of cells, and lack of marked cytologic atypia.

Cellular neurothekeoma. A distinctive variant of neurothekeoma mimicking nevomelanocytic tumors.

We describe the clinical, histopathologic, and immunohistochemical characteristics of five examples of a distinctive subtype of neurothekeoma we term "cellular neurothekeoma" (CNT). These lesions are nondescript papules or nodules primarily involving the head and neck areas of young adults. Histopathologically, CNT are fairly well-defined proliferations involving the reticular dermis; they consist of fascicles of polygonal and spindle cells with eosinophilic or pale-staining cytoplasm and neuroid characteristics. Low-grade cytologic atypia and mitotic activity are common. All immunohistochemical markers--including S-100 protein, myelin basic protein, epithelial membrane antigen, and histiocytic antigens--have failed to show positivity in our laboratory. Separation from myxomatous variants of neurothekeoma is based on greater cellularity, less myxomatous change, and less pronounced plexiform compartmentalization by fibrous septae, which resemble perineurium. The differential diagnosis usually includes spindle and epithelioid cell (Spitz) nevus, malignant melanoma (particularly desmoplastic-neurotropic melanoma), cellular blue nevus, and fibrohistiocytic proliferations. The recognition of CNT and its differentiation from melanoma are important so that overly aggressive therapy is avoided.

Small cell sweat gland carcinoma in childhood.

Sweat gland carcinomas are rare skin tumors that typically occur in older patients. The spectrum of their clinical and pathologic features is broad, and many different types of sweat gland carcinomas have been described, ranging from fairly indolent to highly aggressive neoplasms. We present two cases of sweat gland carcinoma with a predominant small cell morphology. Both tumors occurred in children. One lesion developed in an 8-year-old girl as an asymptomatic papule on her left forearm, which ultimately was evaluated using biopsy because of rapid growth and change in color. The other lesion occurred on the hand of a 12-year-old boy. Both tumors were pandermal and extended into fat. They were composed of monotonous cuboidal cells with scant cytoplasm that formed tubules and grew in anastomosing cords and trabeculae. The tumor cells were immunoreactive for cytokeratins but not for cytokeratin 20. Ultrastructural analysis (available in one case only) showed that the tumor cells lacked neurosecretory granules. This variant of sweat gland carcinoma needs to be distinguished from other small cell neoplasms of the skin, especially Merkel cell carcinoma, its closest mimic.

Atypical or worrisome features in cellular neurothekeoma: a study of 10 cases.

Cellular neurothekeoma is a recently characterized benign cutaneous neoplasm arising usually on the upper trunk or head and neck of children or young adults. Typical histology is that of a lobulated dermal tumor composed of spindle and epithelioid cells, arranged in fascicles and nests, lacking immunoreactivity for S-100 protein, but usually being NK1/C3 positive. We present 10 new cases of cellular neurothekeoma with atypical histologic features that have not been described previously and that suggested the possibility of malignancy. The age range of affected patients was 1 to 44 years (median, 20.5 years); sites included the head and neck (three cases), the upper limbs (two cases), the lower limbs (two cases), and the trunk (two cases). Atypical findings in individual cases included large size (up to 6 cm), deep penetration (extending into skeletal muscle or subcutaneous fat, or both), diffusely infiltrative borders, vascular invasion, high mitotic rate, and marked cytologic pleomorphism. Clinical follow-up was available in 7 of 10 cases. Although the atypical features raised concern about the biologic potential of these lesions, preliminary follow-up (1-5 years) has shown no recurrence and suggests that complete surgical excision of these lesions is curative. These new data expand the morphologic spectrum of cellular neurothekeoma.

Expression of melan-A (MART1) in benign melanocytic nevi and primary cutaneous malignant melanoma.

The Melan-A (MART1) gene encodes an antigen recognized by cytotoxic T cells. Although its expression in metastatic melanoma has been documented in the literature by several investigators, little is known about its distribution in primary melanomas and benign melanocytic nevi. In this study, we evaluated Melan-A expression immunohistochemically on sections from paraffin-embedded material of 50 benign nevi and 40 primary cutaneous melanomas using the monoclonal antibody A103. To evaluate a potential role of A103 in the differential diagnosis of melanocytic from nonmelanocytic tumors, we also analyzed a number of benign and malignant peripheral nerve sheath tumors, fibrohistiocytic tumors, and leiomyosarcomas. Immunoreactivity with A103 was present in all "nonneurotized" nevi and in all nondesmoplastic primary melanomas, both in the intraepidermal and the dermal component. Only two nevi that underwent prominent neurotization showed no staining with A103. Although all melanomas with epithelioid cells tended to be strongly positive with A103, only 4 of 13 spindle cell and desmoplastic melanomas (all positive with anti-S-100 and negative with HMB-45) were immunoreactive with A103 (two focally, two diffusely). None of the nonmelanocytic lesions expressed Melan-A. Our results confirm that Melan-A protein is broadly expressed in the majority of benign and malignant melanocytic lesions and suggest that A103 can be helpful diagnostically, not only for metastatic tumors, but also for primary skin lesions. Its use in distinguishing between melanocytic and peripheral nerve sheath tumors, however, is limited because of the low or absent expression of Melan-A in nevi that underwent neurotization and spindle cell and desmoplastic melanomas.

The histologic spectrum of pigmented spindle cell nevus: a review of 120 cases with emphasis on atypical variants.

The histopathologic features of 120 cases of pigmented spindled nevus (PSCN) from the years 1973 through 1988 were reviewed from a consultative practice heavily weighted with difficult nevomelanocytic lesions. The patients' mean age was 25.2 years, and females outnumbered males (68 versus 52). Extremity lesions made up 69.6% of the total, with the thigh the most common site. The lesions were categorized into one of four variants of PSCN, based on the presence or absence of various architectural and cytologic parameters and involvement of the reticular dermis. Thirteen cases (10.8%) were designated typical PSCN, and were characterized by fascicles of uniform pigmented spindle cells without cellular atypia and limited to the epidermis or papillary dermis. Ninety-five cases (79.2%) were classified as atypical PSCN (PSCN with architectural and/or cytologic atypia). Some of the latter also demonstrated substantial numbers of epithelioid cells, thus exhibiting some overlap with Spitz nevus. Eight cases showed striking features of dysplastic nevus. Ten cases had fascicles of pigmented spindle cells involving the reticular dermis ("plexiform" PSCN). Two cases were designated as combined PSCN because of the presence of banal nevus cells in addition to the spindle cell component. Clinical follow-up of a small group of patients has not suggested, to date, any aggressive behavior. Knowledge of PSCN and its atypical variants is important for discrimination from malignant melanoma.

Correlation of histologic architectural and cytoplasmic features with nuclear atypia in atypical (dysplastic) nevomelanocytic nevi.

The dysplastic nevus in nonfamilial melanoma is a clinicopathologic entity consistently demonstrating an eightfold or greater association with malignant melanoma. The present report quantifies the relationship between nuclear atypia and 16 architectural and cytoplasmic features in 153 pigmented nevi removed from a similar number of patients with newly diagnosed nonfamilial melanoma. All lesions were evaluated by one dermatopathologist, and most lesions were reviewed by a second dermatopathologist. Nuclear atypia of nevomelanocytes was defined as at least three of the following: nuclear enlargement, pleomorphism, hyperchromatism, and prominent nucleoli easily observed throughout each lesion. Seventeen percent of the total nevi had such atypia. On univariate analysis, 11 parameters (lentiginous hyperplasia of the epidermis, basal melanocytic hyperplasia, junctional nest disarray, fusion [bridging] of theques, suprabasal melanocytes, lymphoid response, prominent vascularity, fibroplasia, abundant cytoplasm, "dusty" cytoplasm, and large melanin granules) showed an association with nuclear atypia (P less than .05). However, on multivariate analysis only five parameters continued to be important: basal melanocytic hyperplasia, junctional nest disarray, melanophages (inverse correlation), prominent vascularity, and large melanin granules. These data support the idea that multiple histopathologic characteristics, correlating objectively with nuclear atypia, are important for the diagnosis of dysplastic nevi. In our view, the minimal essential histologic criteria for dysplastic nevi based on these findings include nuclear atypia and abnormal patterns of intraepidermal nevomelanocytic proliferation (ie, basal melanocytic hyperplasia and/or junctional nest disarray).

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.