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Background The expression of TRPM1 (melastatin) mRNA is an independent marker, as measured by radioactive in situ hybridization (RISH), of disease-free survival in primary cutaneous melanoma (PM). The aim of the study was to determine if chromogenic in situ hybridization (CISH) can reproduce results examining diagnostic and prognostic utility of TRPM1 mRNA expression in melanocytic proliferations as measured by RISH. Methods The expression of TRPM1 mRNA was detected by CISH in melanocytic nevi (MN, n = 61), PM (n = 145) and metastatic melanomas (MMs, n = 15). Results A progressive loss of TRPM1 was found moving from MN to PM to MM. The histologic stepwise model of melanoma progression revealed that loss of TRPM1 occurred at the transition of RGP PM to VGP PM. As a diagnostic marker, TRPM1 gradient loss showed 93.8% sensitivity and 52.4% specificity for PM. Loss of TRPM1 mRNA correlated with melanoma aggressiveness markers and was independent predictor of disease-free and overall survival. The corresponding survival curves for degree of melanoma pigmentation matched those for degree of loss of TPRM1 mRNA. Conclusion Loss of TRPM1 mRNA expression appears to be a crucial event in the progression of melanoma to a more malignant, metastatic phenotype.

We report a case of an extra nuchal-type fibroma in a 51-year-old male suspected to have attenuated familial adenomatous polyposis (Gardner's syndrome), who presented with a longstanding buttock mass excised due to enlargement and pain. Histopathologically, lobules of haphazard, hypocellular, hyalinized collagen bundles replaced the dermis and subcutis and entrapped nerve bundles, mimicking Morton neuroma. Ramifying nerve twigs found around larger nerve fascicles showed the co-existence of traumatic neuroma. Elastic tissue stain revealed elastosis characterized by large, arborizing fibers lying between and within the hyalinized collagen bundles. Modified Masson's trichrome stain showed light blue staining of collagen bundles producing the hyalinized nodules with irregular, light red staining of collagen bundles at their periphery and within tumor collagen. Compression and/or degeneration of collagen and secondary elastosis with later entrapment by tumor collagen could explain this microscopic phenotype. By immunohistochemistry, tumor spindle cells expressed nuclear β-catenin and cyclin D1, mostly within regions of fibrosis implicating activation of the adenomatous polyposis coli (APC)-Wnt pathway. Genetic analysis showed a missense mutation in APC gene (c.7504G>A, p.G2502S in exon 15) and a functional homozygous polymorphism in the MUTYH gene (c.36+325G>C, (IVS1+5G/C)). Nuchal-type fibroma has been associated with Gardner's syndrome and trauma. In this patient, genetic predisposition coupled with repetitive, localized trauma and collagen degeneration may have provided the stimulus for the development of extra nuchal-type fibroma.

Background: Patterned hair loss, follicular miniaturization, and increased telogen hair counts characterize androgenic alopecia (AGA). Follicular inflammation in AGA has been associated with treatment resistance and progressive hair loss. Case report: Brothers, 15 and 18 years old, presented with frontal and mid-scalp hair loss with an intact frontal hairline noted over a 1-year period. The elder reported past use of androgenic steroids. Laboratory assessment for metabolic and hormonal abnormalities was unrevealing, and hair pull test was negative. Scalp biopsies revealed decreased terminal hairs, marked diameter variation of anagen hairs, decreased terminal to vellus hair ratios (3.7:1/3.4:1, older/younger), and increased telogen counts (23%/21%). Infrabulbar and peri-isthmic (follicular bulge region) lymphocytic infiltrates were present. Hair loss has progressed, unabated by daily topical 0.5% clobetasol (for 6 months), daily 5% minoxidil (1 year), and latter, daily oral finasteride (2 years – older brother only). Discussion: Based on patterned hair loss and miniaturized hairs, these brothers have AGA. The female pattern of hair loss (diffuse hair loss affecting the central scalp with preservation of frontal hair line) coupled with follicular isthmic lymphocytic inflammation represents an unusual presentation, possibly a treatment resistant, inflammatory variant of AGA. The differential diagnosis includes exogenous androgen-mediated hair loss, cicatricial pattern hair loss, or the superimposition of alopecia areata.

Background: S-phase kinase associated protein-2 (Skp2) ubiquitin ligase p45SKP2 is important in the degradation of p27kip1 (a cyclin dependent kinase inhibitor) and progression through the G1-S cell-cycle checkpoint. Low levels of p27 and high levels of Skp2 are related to poor prognosis in some cancers. Methods: Clinicopathologic features and immunohistochemical expression of Skp2 and p27kip1 were investigated in 198 melanocytic proliferations: 21 melanocytic nevi, 23 melanoma in situ, 119 primary melanoma, and 35 metastatic melanoma samples. Comparative and survival analyses were performed. Results: Progressive and significant increases and decreases in the nuclear expression of Skp2 and p27kip1, respectively, was identified moving from melanocytic nevi (0.05 ± 0.2/85 ± 15) to melanoma in situ (3 ± 2/45 ± 20) to primary cutaneous melanoma (12 ± 9/30 ± 25) to metastatic melanoma (25 ± 15/15 ± 20) (p ≤ 0.006). Expression of these proteins also significantly correlated with increasing American Joint Committee on Cancer (AJCC) T (tumor) classification and AJCC stage (p ≤ 0.01). Moreover, the level of these two proteins exhibited a significant inverse relationship (r = −0.4, p = 0.0001). Skp2 cytoplasmic labeling index of >20% predicted worse 10-year overall survival (38% vs. 86%, p = 0.04) in primary melanoma. Neither p27 nor Skp2 nuclear expression impacted significantly on prognosis. Conclusions: Gain of Skp2 and loss of p27kip1 protein expression are implicated in melanoma progression where the level of p27kip1 may be regulated by targeted proteolysis via Skp2. Cytoplasmic expression of Skp2 defines a subset of aggressive melanomas and could represent another pathway of deregulation of the cell cycle.

Background: Intratumor hypoxia has been shown to promote more aggressive and metastatic cancer phenotypes that are associated with treatment resistance and poor prognosis. Cellular proliferation and its control are known to be important components of tumor progression. Hypoxia induces cell-cycle arrest in cultured cell lines, possibly via up-regulation of the cyclin-dependent kinase inhibitor p27. The effect of hypoxia on cell-cycle regulation in excised human tumors has not been investigated. Methods: We performed immunohistochemistry for p27 and Ki-67 on 10 formalin-fixed paraffin-embedded metastatic melanomas, selected on the basis of histological evidence of zonal/geographic necrosis, adjacent to areas with viable perivascular tumor cells. Results: In the majority of cases, there was a significant increase in p27 staining in cells adjacent to necrotic areas compared to perivascular zones. An inverse staining pattern between Ki-67 and p27 was identified in these tumors. Tumors with no zonal increase in p27 staining demonstrated a diffuse pattern of staining for Ki-67 within tumor nests. Conclusions: While increased cellular proliferation is a characteristic of cancer, subsets of human melanomas may retain the ability to regulate their rate of proliferation in response to changes in the tumor microenvironment. The hypoxia-mediated cell-cycle arrest (decreased Ki-67) in these tumors may be mediated by p27 up-regulation.

Drug reactions are well-known complications of antidepressant therapy, often related to photosensitization. Herein is reported a singular case of antidepressant (amoxapine and citalopram) and anxiolytic related (perphenazine) photo-distributed neutrophilic dermatosis and adult respiratory distress syndrome (ARDS). The clinicopathologic findings displayed overlapping features with drug-induced Sweet's syndrome, acute generalized exanthematous pustulosis (AGEP), and so-called sterile neutrophilic folliculitis with perifollicular vasculopathy. Of the three medications, only amoxapine has been associated with AGEP. Treatment with high-dose systemic corticosteroids and cessation of drug therapy was followed by rapid resolution of the cutaneous eruption and respiratory distress. The possibility that neutrophil infiltration of the lung and/or accumulation of neutrophils in the skin and blood served as a source for reactive oxygen species, leading to lung injury and subsequent ARDS, is discussed.

Background: Lichen aureus is localized variant of persistent pigmented purpuric dermatitis that typically affects the legs and can be associated with delayed hypersensitivity reactions or vascular abnormalities. Plasma cell vulvitis (Zoon's vulvitis) is a rare condition that frequently contains hemosiderin deposits and is suspected to be a mucosal reaction pattern due to variety of insults, most often local irritation or trauma. Case Report: A 50-year-old female with longstanding complaints of spotting, vulvar dryness, irritation, and dyspareunia presented with circumscribed, purpuric, erythematous vulvar patches. Past estrogen cream treatment evoked symptoms of discomfort. On biopsy, siderophages and extravasated red blood cells were found in conjunction with a lichenoid, lymphocyte and plasma cell infiltrate, and dilated dermal and intraepithelial vessels. Conclusions: Reported herein is an unusual vulvar dermatosis that is best classified as a localized variant of persistent pigmented dermatosis (lichen aureus) but overlaps clinically and histologically with Zoon's vulvitis. This constellation of findings may represent a site-specific mucosal reaction to an erosive process that could either be inflammatory (hypersensitivity reaction) and/or traumatic in nature.

Background: Neuroectodermal differentiation or melanocytic colonization are the opposing theories of histogenesis for the Bednar tumor or pigmented dermatofibrosarcoma protuberans (DFSP). Observation: A 31-year-old African-American woman presented with a 2-cm blue-black shoulder nodule of 1-year duration. Punch biopsy revealed a CD34+, Factor XIIIa-DFSP, harboring numerous, pigmented spindle S100+, Mart-1+ and HMB-45+ cells. Subsequent wide excision demonstrated pigmented dendritic and spindled cells widely scattered throughout the dermis of the 3-cm excisional margins and punch biopsy specimens of normal skin from both shoulders. This latter process was interpreted as dermal melanocytosis (nevus of Ito). The dermal pigmented spindle cells were Mart-1+ and CD34−, and were associated with non-pigmented CD34+, cytologically banal spindle cells, which were more numerous in the excisional margins than the contralateral shoulder. Conclusion: Reported herein is a singular case of Bednar tumor associated with dermal melanocytosis. Although the coexistence of these processes implicates colonization of the DFSP by constituent dermal melanocytes, the mixed immunophenotype (CD34+ or Mart-1+ cells) of dispersed dermal spindle cells hints at the possibility of a common cell of origin: the putative neuromesenchymal cell. In effect, the Bednar tumor could represent one part of a spectrum of neural crest-derived dermal tumors that includes dermal melanocytosis, cellular blue nevus and conventional DFSP.

Background: Fascin containing actin bundles provide mechanical support to cellular protrusions and stress fibers. In cancers, some malignant cells (e.g. subsets of breast and ovarian carcinomas) express fascin. In skin cancer, the role of fascin is unknown. Methods: Cases of 61 keratocytic neoplasms, 35 melanocytic neoplasms, nine extramammary Paget's disease (four with adenocarcinoma) and five sarcomas (angiosarcoma and atypical fibroxanthoma) were examined by immunohistochemistry, using monoclonal antihuman fascin antibody, clone 55 k-2 (Dako Corporation, Carpinteria, CA, USA). Results: Fascin labeled all sarcomas and all keratinocytic neoplasms except for pagetoid pattern Bowen's disease. The regions of most intense fascin labeling were seen in the basal cells of infiltrative tumor margins. A minority of Merkel cell carcinomas exhibited weak or absent immunoreactivity. All melanocytic nevi except for some junctional nests of dysplastic melanocytic nevi expressed fascin. However, pagetoid cells of melanoma in situ and epithelioid cells of invasive melanoma weakly expressed or did not express fascin, whereas melanoma cells exhibiting spindle cell morphologies labeled intensely with fascin. Lastly, all cells of extramammary Paget's disease and most associated adenocarcinomas cells did not or were faintly labeled by fascin antibodies. Decreased or absent fascin expression was significantly associated with skin cancers with a high risk for metastasis (e.g. melanoma) vs. those with a low risk (e.g. basal cell carcinoma) (24% vs. 100% with > 50% immunoreactivity; p = 0.0001, chi-squared test). Conclusion: Fascin is expressed by skin tumors that locally infiltrate and replace surrounding tissues indicating a role for fascin in cell adhesion, cell motility and invasiveness. No or weak fascin expression is exhibited by cancers with pagetoid intraepidermal spread and by invasive tumors with a high risk of metastasis. Downregulation or loss of fascin's actin-bundling properties, probably associated with disorganization of cell–cell and cell–matrix contacts, may be a crucial step in the progression from locally invasive to widely disseminating cancers.

Background: An animal model for the study of basal cell carcinoma (BCC) is required to better understand its biology. Several attempts to grow BCC in immuno-incompetent animals have been only modestly successful. Methods: To test the ability of BCC to grow in a mouse with complete and severe immuno-incompetence, 14 individual BCC were transplanted into the subcutaneous tissue of 18 SCID-beige mice (T, B and natural killer cell deficient). Light microscopy and immunophenotypic analyses were performed on primary BCC and first and seventh passage tumors. Results: Transplantation of three BCC yielded rapidly growing anaplastic tumors for a tumor take of 18% (3/18). SCID-beige mice without tumor growth had mostly scars or epidermoid cysts at the transplant sites. The three patients whose BCC gave rise to the anaplastic tumors were significantly older than those without tumor growth (87 vs. 64, p = 0.001), but they did not differ with respect to BCC type or general health. These three anaplastic tumors were histologically and immunophenotypically similar, being composed of dyscohesive, pleomorphic cells that expressed vimentin and smooth muscle actin. In the first passage mice these tumors were locally invasive, tumor-forming nodules associated with an expansion of donor inflammatory cells (T and B lymphocytes and plasma cells), rare remnants of BCC epithelium and epidermoid cysts. By the seventh passage, the tumors were homogenous and metastasized widely throughout the mice. Changing transplantation location to the dermis to wound environment or supplementing the tumor with BCC-derived fibroblasts did not alter the phenotype or growth rate in SCID-beige mice. Anaplastic tumors also grew easily in SCID mice (T and B cell deficient). However, transplantation of the anaplastic tumors into normal mice (CB-17) or less severely immunodeficient mice (NCr and Balb/c: T and natural killer cell deficient) did not allow for growth. Furthermore, tumor growth could not be maintained in vitro. Conclusion: Empirically, these data suggest that BCC has the potential to become an aggressive metastatic neoplasm, given the right immune and stromal environment. Moreover, a functional B lymphocyte system appears to prevent this growth. As human lymphocytes also engraft in SCID-beige mice, the original host immune response could be responsible for the lack of tumor growth in the majority of xenografts. Furthermore, the anaplastic and metastatic phenotype of these BCC derived neoplasms may be the experimental equivalent of metastatic BCC and BCC associated with carcinosarcoma.

Background: ‘Human papillomavirus (HPV) vulvitis’ is a disputed entity where most studies examining for genital-mucosal (GM) HPV have been negative. Methods: Using degenerate and type specific primers for cutaneous (CU), GM and epidermodysplasia verruciformis (EV) HPV types, the prevalence of specific HPV types was investigated in biopsy specimens from 19 women with ‘HPV vulvitis’, seven with asymptomatic vulvar squamous papillomatosis (ASxVSP), and controls of vulvar fibroepithelial polyps (FEP) (15), vulvar condyloma (10) and normal vulva (NV) (10). Results: HPV DNA/EV HPV/GM HPV/CU HPV were detected in 84/74/47/5% of vulvitis patients, 78/71/0/28% of ASxVSP, 47/20/20/7% of FEP, 10/10%/0/0 of NV and 100/0/100/10% of condyloma. Fourteen putatively novel HPV genotypes were detected in vulvitis and ASxVSP patients, but not in controls. The two most frequent novel EV HPV, Alb-4 and DL285, were detected in 9/19 (47%) and 5/19 (26%) of vulvitis cases and were persistently identified in serial biopsies. HPV co-infection and Alb-4 infection occurred significantly more frequently in vulvitis patients, particularly those complaining of ‘burning’ (62/62% vs. 17/7%, p ≤ 0.004). Koilocytosis was identified significantly more frequently in vulvitis compared with non-condyloma controls (81% vs. 40%, p = 0.0001), and its presence correlated with detection of HPV DNA (r = 0.3, p = 0.002). Conclusion: The high frequency of novel EV HPV in HPV vulvitis and correlation of clinicopathologic findings with HPV DNA suggests that HPV vulvitis may indeed exist.

Six years after kidney-pancreas transplant, a 47-year-old white man developed multiple subcutaneous and tenosynovial nodules of hands and wrists, limiting mobility. Biopsy of multiple nodules showed fibrosing, sarcoidal granulomas, some of which contained pigmented material. Microbiology, immunohistochemistry, scanning electron microscopy with backscattered electron imaging and energy dispersive X-ray analysis and polymerase chain reaction assays failed to show any infectious agents or foreign material. There was no historical, clinical or laboratory evidence of systemic sarcoidosis. It is not known whether the donor had sarcoidosis. Despite empiric antimycobacterial therapy and ongoing immunosuppressive therapy (corticosteroids, mycophenolate, cyclosporine), the man has progressively developed more nodules, limiting hand function. Sarcoidosis occurring in non-donor tisssue post-transplantation is an exceedingly rare complication of transplantation. We discuss this case and review the literature on sarcoidal tenosynovitis and sarcoidosis occurring post-transplantation.

S-phase kinase associated protein-2 (Skp2) ubiquitin ligase p45(SKP2) is important in the degradation of p27kip1 (a cyclin dependent kinase inhibitor) and progression through the G1-S cell-cycle checkpoint. Low levels of p27 and high levels of Skp2 are related to poor prognosis in some cancers.Clinicopathologic features and immunohistochemical expression of Skp2 and p27kip1 were investigated in 198 melanocytic proliferations: 21 melanocytic nevi, 23 melanoma in situ, 119 primary melanoma, and 35 metastatic melanoma samples. Comparative and survival analyses were performed.Progressive and significant increases and decreases in the nuclear expression of Skp2 and p27kip1, respectively, was identified moving from melanocytic nevi (0.05 +/- 0.2/85 +/- 15) to melanoma in situ (3 +/- 2/45 +/- 20) to primary cutaneous melanoma (12 +/- 9/30 +/- 25) to metastatic melanoma (25 +/- 15/15 +/- 20) (por = 0.006). Expression of these proteins also significantly correlated with increasing American Joint Committee on Cancer (AJCC) T (tumor) classification and AJCC stage (por = 0.01). Moreover, the level of these two proteins exhibited a significant inverse relationship (r = -0.4, p = 0.0001). Skp2 cytoplasmic labeling index of20% predicted worse 10-year overall survival (38% vs. 86%, p = 0.04) in primary melanoma. Neither p27 nor Skp2 nuclear expression impacted significantly on prognosis.Gain of Skp2 and loss of p27kip1 protein expression are implicated in melanoma progression where the level of p27kip1 may be regulated by targeted proteolysis via Skp2. Cytoplasmic expression of Skp2 defines a subset of aggressive melanomas and could represent another pathway of deregulation of the cell cycle.

Intratumor hypoxia has been shown to promote more aggressive and metastatic cancer phenotypes that are associated with treatment resistance and poor prognosis. Cellular proliferation and its control are known to be important components of tumor progression. Hypoxia induces cell-cycle arrest in cultured cell lines, possibly via up-regulation of the cyclin-dependent kinase inhibitor p27. The effect of hypoxia on cell-cycle regulation in excised human tumors has not been investigated.We performed immunohistochemistry for p27 and Ki-67 on 10 formalin-fixed paraffin-embedded metastatic melanomas, selected on the basis of histological evidence of zonal/geographic necrosis, adjacent to areas with viable perivascular tumor cells.In the majority of cases, there was a significant increase in p27 staining in cells adjacent to necrotic areas compared to perivascular zones. An inverse staining pattern between Ki-67 and p27 was identified in these tumors. Tumors with no zonal increase in p27 staining demonstrated a diffuse pattern of staining for Ki-67 within tumor nests.While increased cellular proliferation is a characteristic of cancer, subsets of human melanomas may retain the ability to regulate their rate of proliferation in response to changes in the tumor microenvironment. The hypoxia-mediated cell-cycle arrest (decreased Ki-67) in these tumors may be mediated by p27 up-regulation.

Drug reactions are well-known complications of antidepressant therapy, often related to photosensitization. Herein is reported a singular case of antidepressant (amoxapine and citalopram) and anxiolytic related (perphenazine) photo-distributed neutrophilic dermatosis and adult respiratory distress syndrome (ARDS). The clinicopathologic findings displayed overlapping features with drug-induced Sweet's syndrome, acute generalized exanthematous pustulosis (AGEP), and so-called sterile neutrophilic folliculitis with perifollicular vasculopathy. Of the three medications, only amoxapine has been associated with AGEP. Treatment with high-dose systemic corticosteroids and cessation of drug therapy was followed by rapid resolution of the cutaneous eruption and respiratory distress. The possibility that neutrophil infiltration of the lung and/or accumulation of neutrophils in the skin and blood served as a source for reactive oxygen species, leading to lung injury and subsequent ARDS, is discussed.

Neuroectodermal differentiation or melanocytic colonization are the opposing theories of histogenesis for the Bednár tumor or pigmented dermatofibrosarcoma protuberans (DFSP).A 31-year-old African-American woman presented with a 2-cm blue-black shoulder nodule of 1-year duration. Punch biopsy revealed a CD34+, Factor XIIIa-DFSP, harboring numerous, pigmented spindle S100+, Mart-1+ and HMB-45+ cells. Subsequent wide excision demonstrated pigmented dendritic and spindled cells widely scattered throughout the dermis of the 3-cm excisional margins and punch biopsy specimens of normal skin from both shoulders. This latter process was interpreted as dermal melanocytosis (nevus of Ito). The dermal pigmented spindle cells were Mart-1+ and CD34-, and were associated with non-pigmented CD34+, cytologically banal spindle cells, which were more numerous in the excisional margins than the contralateral shoulder.Reported herein is a singular case of Bednár tumor associated with dermal melanocytosis. Although the coexistence of these processes implicates colonization of the DFSP by constituent dermal melanocytes, the mixed immunophenotype (CD34+ or Mart-1+ cells) of dispersed dermal spindle cells hints at the possibility of a common cell of origin: the putative neuromesenchymal cell. In effect, the Bednár tumor could represent one part of a spectrum of neural crest-derived dermal tumors that includes dermal melanocytosis, cellular blue nevus and conventional DFSP.

Background: Acquired lymphedema of the genitalia is a rare childhood presentation and is more common in elderly individuals secondary to pelvic/abdomenal malignancy or its therapy or worldwide due to filariasis. Objective: Herein, we report a case of a healthy 11-year-old boy who presented with a 1-year history of chronic, asymptomatic scrotal and penile swelling. Biopsy revealed edema, lymphangiectases and peri- and intralymphatic sarcoidal type granulomas. This histologic pattern of granulomatous lymphangitis is most commonly associated with orofacial granulomatosis (granulomatous cheilitis and Melkersson-Rosenthal syndrome) and Crohn’s disease. Treatment with topical steroids and physical support has resulted in marked improvement. No systemic disease (Crohn’s disease) is evident 1 year later. Literature review revealed 44 cases of genital lymphedema with non-infectious granulomas. The majority of these young patients had Crohn’s disease, frequently with anal involvement and a minority, both with and without Crohn’s disease, had orofacial granulomatosis. Conclusions: Granulomatous lymphangitis should be considered in the differential diagnosis of chronic idiopathic swelling of the genitalia, particularly in younger individuals. Further clinical examination, additional laboratory studies and close follow-up for co-existing or subsequent development of Crohn’s disease should be performed. The overlap between granulomatous lymphangitis of the genitalia, Crohn’s disease and orofacial granulomatosis suggest that granulomatous lymphangitis of the genitalia may represent a forme fruste of Crohn’s disease.

Malignant melanoma (MM) is considered to be a chemotherapy-refractory tumor. New anti-cancer drugs (e.g. etoposide) that target DNA topoisomerases (e.g. topoisomerase II-alpha (topo IIalpha)) show activity against a wide variety of solid tumors. In this study, we investigated the frequency and rate of labeling for topo IIalpha in 163 MMs (primary and metastatic) and 67 melanocytic nevi to determine whether topo IIalpha expression is elevated in MM. Primary MM exhibited significantly more frequent topo IIalpha expression compared to benign nevi (86% vs. 56%, p=0.0001). The rate of topo IIalpha labeling in dysplastic melanocytic nevi, radial growth phase MM, vertical growth phase MM and metastatic MM revealed significant differences amongst groups and a positive covariance with advancing stage (means: 0.3, 0.5, 5, and 8 '+' cells/hpf, respectively; r=0.3, all p < or = 0.02). Topo IIalpha labeling significantly correlated with increasing mitotic activity, depth of invasion and Clark's level, diminishing tumor infiltrating lymphocytes, and poor outcome (all p < or = 0.01) in primary MM. For metastatic MM, a minority (30%) exhibited marked elevation of topo IIalpha expression. These findings indicate topo IIalpha as a potential therapeutic target and marker for MM. Immunohistochemical analysis of disseminated MM may allow for correlation with clinical response and enable selection of candidates sensitive for specific chemotherapy.

Disruption of the cell-cycle regulation through over-expression or mutation of cyclins and cyclin-dependent kinases has been implicated in carcinogenesis. In order to determine whether keratoacanthoma (KA) is unique or a variant of squamous cell carcinoma (SCC) and whether expression of mitosis-related antigens are associated with KAs' tendency to regress, we compared the immunohistochemical expression of mitotic cyclins (cyclins A and B) and their cyclin-dependent kinase p34(cdc2) in 21 KAs, 8 regressing KAs, and 28 conventional squamous cell carcinomas. KAs showed both overlap and significant differences in expression of these mitosis-related antigens compared to SCCs. Basal and parabasal pattern of expression of cyclins A and B significantly predominated in KAs in contrast to SCCs which exhibited diffuse pattern (cyclin A 86%/cyclin B 64% vs. 25%/36%, p0.01). However, no differences in the highest mean level of expression in 'hot spot' loci of cyclins A and B were identified comparing KAs to SCCs (19%/12% vs. 25%/13%, p0.05). For the cyclin-dependent kinase p34(cdc2), no differences in pattern, distribution or mean levels of expression were found. For cyclins A and B, regressing KA showed significantly more regional tumor labeling (88%/88% vs. 57%/33%, p = 0.03) and a lower mean level of immunoreactivity (5%/4% vs. 19%/12%, p = 0.001) compared to mature KAs. These findings indicate a role for mitotic cyclins in the evolution of both SCC and KA. The overlapping patterns of expression for these mitosis-related antigens suggest that KAs represent a variant of SCC that exhibit an overwhelming but not absolute tendency to involute.