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5-Fluorouracil (5-FU) is an antineoplastic agent that is used topically to treat actinic keratoses. Although topical 5-FU frequently causes irritant contact dermatitis at the site of application, distant skin reactions are rare and could relate to accidental transfer or systemic absorption of the drug. We present a patient who developed a painful scrotal dermatitis after applying the topical cream to actinic keratoses on his chest. Upon discontinuation of topical 5-FU, the reaction resolved over a four-week period with oral prednisone and topical betamethasone ointment. The patient was re-challenged with topical 5-FU one year later and again developed scrotal pain and erythema similar to the initial reaction. Scrotal dermatitis is a rare adverse effect of topical 5-FU therapy that can be associated with significant distress and disruption of daily activities.

Background: Artificial intelligence (AI) has recently surfaced as a research topic in dermatology and dermatopathology. In a recent survey, dermatologists were overall positive toward a development with an increased use of AI, but little is known about the corresponding attitudes among pathologists working with dermatopathology. The objective of this investigation was to make an inventory of these attitudes. Participants and Methods: An anonymous and voluntary online survey was prepared and distributed to pathologists who regularly analyzed dermatopathology slides/images. The survey consisted of 39 question divided in five sections; (1) AI as a topic in pathology; (2) previous exposure to AI as a topic in general; (3) applications for AI in dermatopathology; (4) feelings and attitudes toward AI and (5) self-reported tech-savviness and demographics. The survey opened on March 13, 2020 and closed on May 5, 2020. Results: Overall, 718 responders (64.1% females) representing 91 countries were analyzed. While 81.5% of responders were aware of AI as an emerging topic in pathology, only 18.8% had either good or excellent knowledge about AI. In terms of diagnosis classification, 42.6% saw strong or very strong potential for automated suggestion of skin tumor diagnoses. The corresponding figure for inflammatory skin diseases was 23.0% (P adj < 0.0001). For specific applications, the highest potential was considered for automated detection of mitosis (79.2%), automated suggestion of tumor margins (62.1%) and immunostaining evaluation (62.7%). The potential for automated suggestion of immunostaining (37.6%) and genetic panels (48.3%) were lower. Age did not impact the overall attitudes toward AI. Only 6.0% of the responders agreed or strongly agreed that the human pathologist will be replaced by AI in the foreseeable future. For the entire group, 72.3% agreed or strongly agreed that AI will improve dermatopathology and 84.1% thought that AI should be a part of medical training. Conclusions: Pathologists are generally optimistic about the impact and potential benefit of AI in dermatopathology. The highest potential is expected for narrow specified tasks rather than a global automated suggestion of diagnoses. There is a strong need for education about AI and its use within dermatopathology., (Copyright © 2020 Polesie, McKee, Gardner, Gillstedt, Siarov, Neittaanmäki and Paoli.)

Endocrine mucin-producing sweat gland carcinoma (EMPSGC) and primary cutaneous mucinous carcinoma (PCMC) are both uncommon low-grade cutaneous adnexal tumors with predilection for the eyelids of elderly women. Their clinical appearance is nonspecific, typically presenting as a slowly growing poorly circumscribed papule, nodule, plaque, or swelling. Histological features of EMPSGC include a lobulated dermal neoplasm with bland cytology and an invasive mucinous component in up to half of the cases. PCMC exhibits tumor nests suspended in abundant pools of mucin with focal strands or nests of tumor cells infiltrating the dermis. Because of their rarity and banal cytological features, both entities pose a risk for misdiagnosis with other benign/malignant cutaneous adnexal neoplasms. Histomorphological features can suggest a diagnosis of EMPSGC or PCMC, but immunohistochemistry is necessary for confirmation. A review of the literature showed variable results of antigens present in EMPSGC, and many of the positive markers only show sparse or focal immunoreactivity of tumor cells. As a result, diffusely positive markers play a crucial role in identification of these tumors, particularly with initial superficial biopsies. We present 9 cases of EMPSGC and 5 cases of PCMC with strong and diffuse immunoreactivity to renal cell carcinoma antigen. This novel finding can be useful in the diagnosis of EMPSGC and PCMC in combination with other known positive markers to differentiate them from other cutaneous neoplasms. In addition, it provides further evidence that EMPSGC could be a precursor lesion to PCMC with both existing on a spectrum.

This review, based on a lecture given at the 2009 Update in Dermatopathology meeting held at the Institute of Dermatology (London, UK), discusses the problem of misdiagnosing atypical benign melanocytic lesions as melanoma and the alternative problem of interpreting naevoid melanoma as a banal naevus. Consequences are considered. Brief consideration of a range of other melanoma variants that may be a source of diagnostic difficulty is also included.

Cutaneous sebaceous neoplasia is known to exhibit a high degree of DNA mismatch repair (MMR) deficiency leading to microsatellite instability and these tumors can be markers of the Muir-Torre syndrome and internal malignancy. Other tumors, such as colonic carcinoma, show tendencies toward particular histologic features and sites of involvement correlating with MMR deficiency. There are few comprehensive studies of unselected cutaneous sebaceous neoplasms. To address this gap in knowledge, we examined 94 sebaceous neoplasms from 92 patients and 17 sebaceous hyperplasia controls using immunohistochemistry for MLH1, MSH2, and MSH6. Our results indicate that MMR deficiency is significantly associated with anatomic location (more frequently in the trunk and extremities as compared with head and neck), tumor type (more often in adenoma compared with carcinoma within the head and neck region), and architecture (keratoacanthomalike). No correlation between cystic change and MMR deficiency was noted. Cutaneous sebaceous neoplasia has tendencies toward certain tumor types and anatomic distribution based on MMR status analogous to that seen in colonic carcinomas and other tumors. These may be helpful indicators for further workup for the Muir-Torre syndrome.

Primary cutaneous apocrine carcinoma is a rare malignancy. This study of 24 examples suggests that the prognosis is not always poor and that grading criteria devised for breast carcinoma may have utility in this group of malignancies. Furthermore, steroid receptor expression should be investigated in these tumors, particularly if a tumor is unlikely to be controlled by surgery alone.

Atypical genital nevi are rare melanocytic lesions that most commonly arise on the vulva of young women. They are currently regarded as nevi of special sites, in that despite histologically worrisome features, their clinical behavior is reportedly benign. However, only few studies with limited follow-up data are available. To better characterize the clinical presentation and behavior of these lesions and to further delineate their histologic features, we retrieved 56 atypical genital nevi arising in the lower female genital tract from our departmental and consultation files. The 56 lesions arose in 55 female patients with a median age of 26 years (range, 6 to 54 y). The dominant histologic feature was a lentiginous and nested junctional component composed of prominent round or fusiform nests, which often showed retraction artifact and/or cellular dyscohesion. Cytologic atypia was mild in 11 cases (20%), moderate in 34 (60%), and severe in 11 (20%). Ten cases (18%) showed focal pagetoid spread, with extension to the granular layer and stratum corneum in 1 case. The atypical junctional melanocytic proliferation was associated with a large common dermal nevus component that dominated the lesion in 26 cases (46%). Adnexal spread (46%) and nuclear atypia of melanocytes situated in the superficial dermis (39%) were relatively common, but dermal mitoses (7%) were uncommon and maturation was present in all cases. A broad zone of dense eosinophilic fibrosis within the superficial dermis was a frequent finding (41%). Clinical follow-up was available in 45 cases (80%) with a median follow-up period of 3.5 years (range, 1 to 16 y). Only 1 lesion recurred, 1.5 years after the initial excision. The original nevus in this patient had only mild cytologic atypia and was present at the margins of excision. The recurrent/persistent nevus was reexcised, and there was no further clinical recurrence in 11.5 additional years of follow-up. Our data support the hypothesis that atypical genital nevi have a benign clinical course despite their occasionally striking cytologic and architectural atypia. Awareness and recognition of this group of melanocytic lesions is important to avoid over diagnosis as melanoma with subsequent wide excision and possibly sentinel lymph node biopsy.

Amplification of the 12q13-15 region is a common event in several human tumors including liposarcomas, gliomas, and osteosarcomas. We have demonstrated high-level amplification of 12q14 in a subset of uncultured malignant melanomas (3 of 53). High-resolution mapping of the amplicon using quantitative PCR revealed a bipartite amplicon consisting of a primary 50-kb amplicon centered on CDK4 and a secondary amplicon centered on MDM2, without amplification of the intervening 11 Mb of genomic DNA. Analysis of mRNA and protein levels in melanomas with 12q14 amplification demonstrated overexpression of target genes CDK4 and MDM2 without loss of CDKN2A-P16 (P16INK4A) or CDKN2A-P14ARF (P14ARF) expression, important regulators of the RB1 and TP53 pathways, which are commonly lost or mutated in melanoma. These results suggest that coamplification of CDK4 and MDM2 may substitute for loss of P16INK4A and P14ARF function in a subset of melanomas., (2006 Wiley-Liss, Inc)

Matrical differentiation in basal cell carcinoma (BCC) is rare. Only nine cases have been described that showed typical diagnostic features of BCC, in addition to shadow cells indicating hair-matrix differentiation. These cases often present a diagnostic challenge due to confusion with pilomatrixoma or pilomatrix carcinoma. We present a case of BCC with matrical differentiation in a 78-year-old man. Immunohistochemical and molecular methods are used to differentiate this lesion from benign or malignant forms of pilomatrixoma. differentiation: a case study with analysis of beta-catenin.

Mutations in beta-catenin are present in benign pilomatrixomas. beta-catenin is a downstream effector in the WNT-signalling pathway, acting as a signal for differentiation and proliferation. Mutations in CTNNB1, the gene encoding beta-catenin, are present in a wide variety of benign and malignant neoplasms. We examined beta-catenin in a series of pilomatrix carcinomas (15 cases) by using immunohistochemistry and DNA sequencing of exon 3 from CTNNB1, and compared these to a series of benign pilomatrixomas (13 cases). All 11 pilomatrix carcinomas available for examination showed nuclear localization of beta-catenin and mutations in exon 3 similar to those demonstrated in benign pilomatrixomas. Two of 11 pilomatrix carcinomas showed significant nuclear accumulation of p53, whereas this was absent in all 13 benign pilomatrixomas. Expression of nuclear cyclin D1 was similar in both benign pilomatrixomas and pilomatrix carcinomas. Clinical follow-up from the 15 malignant cases reported in this study and by others indicates that wide excision offers superior control of local recurrence, compared to simple excision. Immunohistochemical and molecular analysis of beta-catenin reveals that both pilomatrix carcinomas and benign pilomatrixomas harbour mutations in beta-catenin. This implies a common initial pathogenesis and is compatible with the proposition that pilomatrix carcinomas may at least on occasion arise from their benign counterparts.

Histological assessment of melanocytic naevi constitutes a substantial proportion of a dermatopathologist's daily workload. Although they may be excised for cosmetic reasons, most lesions encountered are clinically atypical and are biopsied or excised to exclude melanoma. Although dysplastic naevi are most often encountered, cytological atypia may be a feature of several other melanocytic lesions, including genital type naevi, acral naevi, recurrent naevi, and neonatal or childhood naevi. With greater emphasis being given to cosmetic results, and because of an ever increasing workload, several "quicker and less traumatising" techniques have been introduced in the treatment and diagnosis of atypical naevi including punch, shave, and scoop shave biopsies. A major limitation to all of these alternatives is that often only part of the lesion is available for histological assessment and therefore all too frequently the pathologist's report includes a recommendation for complete excision so that the residual lesion can be studied. Complete or large excision of all clinically atypical naevi permits histological assessment of the entire lesion, and in most cases spares the patient the need for further surgical intervention.

Graft-versus-host disease (GvHD) is a frequent and serious complication of bone-marrow transplantation (BMT), and carries a high morbidity and mortality if not promptly recognized and treated. The rash of acute GvHD is often difficult to distinguish clinically from a drug eruption, and skin biopsies are often performed in an attempt to render a diagnosis. Histologically, eosinophils are classically associated with hypersensitivity reactions, and their presence in inflamed tissue is considered suggestive of a drug-induced dermatitis. We present 3 cases of acute exanthema in BMT recipients in whom the presence of eosinophils on skin biopsy specimen led to an initial diagnosis of drug eruption over GvHD. As a result, these patients experienced delays in the institution of definitive immunosuppressive therapy for GvHD. We review the growing literature suggesting that no single or combined histologic feature, including tissue eosinophils, is useful in differentiating GvHD from drug eruptions in BMT recipients. Indeed, in most cases, the cause of a new-onset blanchable erythematous rash in a BMT recipient is most accurately determined by close examination and follow-up of the clinical features without a skin biopsy.

Background: Review of the literature reveals that congenital malignant melanoma is an exceptionally rare occurrence and has a generally poor prognosis when it does occur. However, benign proliferative melanocytic lesions are known to occur within giant congenital nevi (GCN). This entity is not well recognized and can be confused clinically and histologically with malignant change., Observations: We report 2 cases of GCN in neonates demonstrating benign proliferating nodules present at birth. An initial diagnosis of malignant melanoma was assumed in both cases. Careful histologic analysis, however, revealed these lesions to be benign, as did long-term follow-up of 3.5 years, with both patients remaining well with no evidence of melanoma. Review of the literature suggests that there are 2 clinical patterns of these benign nodules arising within GCNs: small (<1 cm) and large (>1 cm) dermal nodules with varying histologic patterns that we have attempted to categorize., Conclusions: Our cases illustrate the difficulty in accurate diagnosis of melanocytic lesions in the neonate. We recommend caution in making a diagnosis of malignant melanoma and highlight the possibility that benign lesions can be mistaken for melanoma in this age group. We encourage the acquisition of fixed histologic specimens for accurate diagnosis of melanocytic lesions.

Aims: To examine a series of deep penetrating naevus (DPN) and discuss the differential diagnosis of pigmented, deep penetrating melanocytic lesions and their biological potential. DPN has been described as a variant of common acquired intradermal melanocytic naevus. DPN remains poorly recognized by pathologists, partly attributable to its relatively rare occurrence., Methods and Results: Thirty-one cases of deeply pigmented lesions were studied. The patients included 17 females and 14 males with an age range between 3 and 56 years (mean 25.8, median 23). The common clinical sites were face (n = 10) back (n = 6) and lower extremity (n = 7). The clinical diagnoses included various benign melanocytic naevi, and malignant melanoma, as well as non-melanocytic lesions. Histologically, all cases presented as wedge-shaped lesions composed of fusiform cells but also epithelioid melanocytes, with pale cytoplasm and oval nuclei. Pigment was identified in melanophages but also within lesional melanocytic cells. Nine cases contained mitotic figures. Nine cases showed the coexistence of 'ordinary' common acquired naevocytes, and seven lesions showed overlapping features with either ordinary blue naevus or Spitz naevus. In 13 lesions there was at least one feature that may cause concern as to the biological nature of the tumour. These include asymmetry, cytological atypia, inflammation, or an 'expansile' advancing margin. Each tumour was treated by simple excision; one lesion recurred after 1 year. No tumour metastasized., Conclusions: DPN is a distinct variant of melanocytic naevus. In some cases the histological features overlap with other benign melanocytic lesions. Criteria for recognizing malignant examples remain unclear, but cytological atypia and low mitotic activity do not necessarily portend a sinister outcome.

The high frequency of mutation, deletion, and promoter silencing of the gene encoding p16(INK4A) (p16) in premalignant dysplasias and squamous cell carcinomas (SCC) of epidermis and oral epithelium classifies p16 as a tumor suppressor. However, the point during neoplastic progression at which this protein is expressed and presumably impedes formation of an SCC is unknown. Induction of p16 has been found to be responsible for the senescence arrest of normal human keratinocytes in culture, suggesting the possibility that excessive or spatially abnormal cell growth in vivo triggers p16 expression. We examined 73 skin and oral mucosal biopsy specimens immunohistochemically to test this hypothesis. p16 was not detectable in benign hyperplastic lesions, but instead was expressed heterogeneously in some dysplastic and carcinoma in situ lesions and consistently at areas of microinvasion and at superficial margins of advanced SCCs. p16-positive cells in these regions coexpressed the gamma2 chain of laminin 5, identified previously as a marker of invasion in some carcinomas. Normal keratinocytes undergoing senescence arrest in culture proved to coordinately express p16 and gamma2 and this was frequently associated with increased directional motility. Keratinocytes at the edges of wounds made in confluent early passage cultures also coexpressed p16 and gamma2, accompanying migration to fill the wound. These results have identified the point during neoplastic progression in stratified squamous epithelial at which the tumor suppressor p16 is expressed and suggest that normal epithelia may use the same mechanism to generate non-dividing, motile cells for wound repair.

Leukemia cutis may clinically mimic many inflammatory dermatoses. A patient with myelodysplastic syndrome presented with an acute eruption of bilateral, lower-extremity, tender, indurated, brown plaques that clinically resembled chronic stasis dermatitis. Histologic study revealed a dermal myeloblastic leukemic infiltrate.

Bullous pemphigoid (BP) is an acquired bullous disorder that predominantly affects the elderly. It is rare in children but when it occurs, there is considerable clinical and histologic overlap with other acquired or congenital blistering disorders. A definitive diagnosis of childhood BP requires direct immunofluorescence and, in some cases, characterization of the target antigen. Three cases of childhood BP are presented, with their histologic and immunofluorescence findings. The first was a 5-month-old male infant who presented with erythema and bullae of the palms and soles and was found to have linear deposition of IgG and C3 along the dermoepidermal junction on direct immunofluorescence (DIF). Histopathologic examination revealed a subepidermal blister containing eosinophils. Type IV collagen was demonstrated along the floor of the blister cavity by a direct immunoperoxidase technique. The second case was an 8-month-old female infant who presented with a blistering eruption of her palms and soles that then became widespread. Direct immunofluorescence showed linear IgG and C3 at the dermoepidermal junction, with laminin deposition at the base of the blister. The third case was a 7-year-old female with bullae and erosions on the vulva and vaginal mucosa. A subepidermal blister was seen on microscopic examination whereas immunofluorescence demonstrated linear IgG and C3 deposition at the basement membrane zone (BMZ). A literature review uncovered 50 cases of childhood BP confirmed by direct or indirect immunofluorescence, or both, and often with evidence of autoantibodies against either the 180 kD or the 230 kD human bullous pemphigoid antigens (BP180 or BP230). This review was used to delineate characteristics of childhood BP, including the newly proposed subtypes: infantile BP and childhood localized vulval BP. Infantile BP presents within the first year of life and is characterized by BP-like lesions on erythematous or normal acral skin. Localized vulval BP is a self-limited, nonscarring BP-like process that involves only the vulva. Both subtypes are normally self-limited and respond well to either topical or systemic steroids, if treatment is initiated before the disease becomes widespread.

Blue nevus and its variants typically present as pigmented lesions. Dermal melanin is responsible for coloration and is an expected histologic finding. Herein, we report 20 cases of an unusual amelanotic variant of cellular blue nevus. Our series showed clinical demographics similar to pigmented counterparts. Thus, there was a predilection for young individuals with a mean age of 24 years (range 6-74 years). Both sexes were affected, with a female-to-male ratio of approximately 2:1. The lower back, distal extremities, and scalp were the most common sites of occurrence. Importantly, the lack of pigmentation resulted in an atypical clinical appearance. A diagnosis of blue nevus by the attending physician was not considered in any of the reported lesions. All of the tumors extended deep into the reticular dermis or subcutaneous fat with a mean thickness of 5.5 mm (range 1.7-11 mm). Ulceration was present in two lesions. Mild cytologic atypia and pleomorphism were present in five cases. Mitotic activity (up to 3 mitoses/mm ) was observed in 11 lesions. A brisk lymphocytic host response was present in only one lesion. Tumor necrosis was not observed. Most, but not all, tumors showed reactivity for S-100 and HMB-45. Clinical follow-up (mean 32 months) was consistent with a benign course. Local recurrence was not observed after complete excision. None of the cases was associated with clinical evidence of lymph node or distant metastases. Recognition of amelanotic cellular blue nevus is important because the lack of expected pigmentation may result in clinical and pathologic diagnostic difficulty. In particular, amelanotic cellular blue nevus must be distinguished from malignant cellular blue nevus and other variants of melanoma.

Rosai-Dorfman disease (RDD) is a rare but distinctive clinicopathologic entity of unknown etiology affecting lymph nodes as well as extranodal sites. Although cutaneous involvement in RDD is common, purely cutaneous disease is rare and not well documented. We report 22 patients with cutaneous and superficial subcutaneous RDD. The lesions presented as papules and nodules, often with discoloration (9/22) and frequent multifocality (13/22), without predilection for a specific site of the body. Age distribution was wide and ranged from 15 to 68 years, with a median of 43.5 years. Of the 17 patients for whom information on racial background was available, 7 were Asian, 8 were white, and 2 were black, with a marked female predominance (2:1). The lesions resolved in 6 of 13 patients for whom follow-up data were available, regardless of the treatment given. Lesions persisted or recurred in 7 patients. Histologically, the lesions are invariably characterized by a proliferation of polygonal S100-positive histiocytes showing emperipolesis and a mixed inflammatory infiltrate. This study characterizes the histologic spectrum of cutaneous RDD in regard to variation in the numbers of typical S100-positive histiocytes and emperipolesis, variation in the quality and quantity of the inflammatory response, and the degree of stromal fibrosis, which resulted in a strikingly storiform growth pattern in six lesions and a lobulated pattern in two lesions. Whereas the clinical as well as histologic appearance of the cutaneous and subcutaneous lesions in the purely extranodal forms of RDD is indistinguishable from that of systemic RDD, this study emphasizes that purely cutaneous RDD is a distinct clinical entity in regard to its epidemiology and remains localized to the skin even with long-term follow-up. Patients with purely cutaneous RDD are of an older age at onset of disease (median = 43.5 years), with a reversed male/female ratio. There are no significant systemic extracutaneous or serologic manifestations. Whereas systemic RDD is commonly seen in blacks and only rarely reported in Orientals, the majority of the patients in this series with purely cutaneous RDD are Asians and whites.

Cutaneous T-cell lymphoproliferative disorders (CTCLs) remain a subject of confusion and controversy. In this review, the authors discuss diagnostic criteria and classification, including the role of immunohistochemistry and gene rearrangement studies. In addition, cutaneous T-cell pseudolymphomas, the current status of parapsoriasis and other premalignant syndromes, and the clinicopathological variants of mycosis fungoides are discussed. CD30-positive lymphoproliferative disorders and a number of rare variants of CTCL including granulamatous slack skin, subcutaneous (panniculitic) T-cell lymphoma, gamma-delta cutaneous lymphoma, NK/NK-like T-cell lymphoma, and primary cutaneous CD8-positive epidermotropic cytotoxic T-cell lymphoma are also considered.

Nevoid melanoma is a rare variant of melanoma characterized by deceptive morphologic features reminiscent of a benign melanocytic nevus. Twenty (13 nodular, 7 verrucous) nevoid melanomas were reviewed with the goal of identifying the predominant architectural patterns, cytologic features, and prognostic indicators. Although at scanning magnification, many lesions showed a strong resemblance to banal compound or dermal nevi, careful inspection in all cases demonstrated subtle pleomorphism and impaired maturation with depth, invariably accompanied by multiple dermal mitoses. Four tumors recurred and three metastasized, with subsequent death of the patients. Follow-up information for a period of at least 3 years was available in eight cases. In this group, mortality was 37.5%, the metastasis rate was 37.5%, and the local recurrence rate was 75%, with an average tumor thickness of 2.5 mm. We conclude that nevoid melanoma may be distinguished from a benign melanocytic nevus by a high index of suspicion, a careful analysis of architecture, and attention to cytologic features. Our data and a review of the literature do not support the notion that nevoid melanoma has a better prognosis than ordinary melanoma.

The clinicopathologic characteristics of 69 cases of eccrine porocarcinoma (EP) have been studied. Seven cases of purely in situ disease are included. Forty patients were female, 29 male with ages ranging from 29 to 91 years (mean 73 years). The lower extremity represented the single most common site (44%). Other common sites were the trunk (15 cases, 24%) and head (11 cases, 18%). The histologic diagnosis of EP was predicated on the basis of an irregular tumor at least partly formed of characteristic poromatous basaloid epithelial cells displaying ductal differentiation, and significant cytologic atypia. Forty-seven tumors (68%) contained mature well-formed eccrine ducts having an eosinophilic luminal cuticle, with the remaining tumors containing small ill-formed ducts and/or intracytoplasmic lumina. All ducts were discernible via light microscopy and in 49 cases were highlighted with DPAS stain and/or CEA/EMA immunocytochemistry. A variant with a broad pushing tumor margin and marked nuclear pleomorphism showed some resemblance to proliferative bowenoid dysplasia. In 11 cases (18%) the tumors appeared to arise in continuity with a benign preexistent poroma. A variety of histologic patterns were displayed including clear, squamous, and spindle cell differentiation, mucus cell metaplasia, and colonization by melanocytes. Lymphovascular invasion was present in 9 cases (15%). Three cases showed pagetoid extension of malignant cells (epidermotropism) and appeared to be multifocal. Follow-up was available in 54 patients (78%) with 9 (17%) experiencing local recurrence, 10 developing lymph node metastases (19%), and 6 (11%) experiencing distant metastases or death. Mitoses, the presence of lymphovascular invasion, and tumor depth >7 mm were associated with a poorer prognosis. Dividing tumors into those with a "pushing" or "infiltrating" advancing margin was also predictive of outcome with the latter having an increased risk of local recurrence. This report, the largest series of EP to date, suggests that the incidence of aggressive behavior is less than popularly believed. Furthermore, EP can display a wide variety of histologic patterns that may lead to diagnostic error in the unwary. The large number of cases in this series enables a reliable evaluation of prognostic parameters. A more aggressive clinical course may be indicated by more than 14 mitoses per high power field (hazard ratio [HR] for death 17.0, 95% confidence interval [CI] 2.71-107), lymphovascular invasion by tumor (HR 4.41, CI 1.13-17.2), and depth >7 mm (HR 5.49, CI 1.0-30.3). Thus, mitoses, lymphovascular invasion, and tumor depth should be evaluated in these tumors. We also suggest that tumors presenting an "infiltrative" advancing margin are particularly prone to local recurrence and require wide excision with close attention to the surgical margins by the reporting pathologist.

The term "malignant blue nevus" refers to a rare and heterogeneous group of melanomas that arise in several clinical settings. This includes melanomas arising in association with a common or cellular blue nevus and those arising de novo and resembling cellular blue nevi. We reviewed the clinicopathologic features of 10 cases of malignant blue nevi. Six cases proved to be de novo melanoma mimicking cellular blue nevus, but lacking a clear-cut benign component. Two melanomas arose in association with a common blue nevus, and two with a cellular blue nevus. The patients' (5 males, 5 females) ages ranged from 11 to 77 years (average age, 48.1 years). The head and neck was the most common location (6 of 10 patients), with five scalp tumors. Four tumors were located on the trunk; none was located on the extremities. Tumor size ranged from 0.5 to 2.2 cm (average size, 1.1cm). Most lesions had been present for many years before surgical removal. Pigmented dendritic cells were observed in 9 of 10 cases. The malignant and benign components were easily distinguished in the four cases that arose in association with a common or cellular blue nevus. Abrupt transition between a benign blue nevus and melanoma was readily recognized at scanning magnification as distinctive nodules of epithelioid to spindled cells with a sheet-like growth pattern. In all cases, malignancy was evidenced by increased mitotic rate, necrosis, nuclear atypia, pleomorphism, hyperchromasia, and prominent nucleoli. All 7 patients with follow-up information experienced recurrence (3 patients) or metastasis (4 patients). Three patients died of disease. Malignant blue nevus is a heterogeneous group of melanomas that are highly aggressive and often lethal, with a propensity for metastasis to the lymph nodes and lungs.

Background: Vulval carcinoma is a relatively rare disorder that may have various aetiologies. Objectives To document the features and outcome in a series of patients with this disorder., Methods: Retrospective analysis of patients presenting to a vulval clinic over a 5-year period., Results: Twenty-one women presented with a squamous cell carcinoma (SCC) and two with a verrucous carcinoma (VC). The age range was 43-83 years. Twenty-one had well-established (1-30 years) vulval symptoms prior to developing their tumour. Specific tumour-related symptoms ranged from 3 weeks to 11 months. Eight had had a prior diagnosis of lichen sclerosus (LS) or lichen planus (LP), only two of whom were on regular treatment and follow-up. At presentation, 12 patients had clinical signs of LS, three of LP, and five had some changes of both LS and LP. Two patients had multifocal vulval intraepithelial neoplasia (VIN3). Only one had no evidence of any background vulval skin disease. The commonest histological changes noted in the epithelium either adjacent to or distant from the SCC were those of atrophic LS (n = 8), LS with squamous cell hyperplasia (n = 3), LS with hyperplastic foci and lichenoid infiltrate (n = 4), and LS with differentiated VIN3 (n = 1). Four cases demonstrated the changes of LP, and three showed VIN3. All patients were treated surgically and, in those who had lymphadenectomy, four had positive nodes. There have been two deaths due to metastatic disease, and one further patient has developed a second primary SCC at a different site., Conclusions: An underlying skin disorder prior to the development of their carcinoma was found in 22 of 23 patients with vulval SCC and is therefore an important risk factor.

Malignant eccrine spiradenoma is a very rare tumor. The clinicopathologic features of 12 cases are reported herein. Six patients were men, six were women, and the average patient age was 62 years. Seven tumors were located on the trunk, three on the extremities, and two in the head and neck region. All tumors were large (average size-7.5 cm). Lesions had been present from 7 months to 30 years before surgical removal. In all cases, continuity between benign eccrine spiradenoma and areas with malignant change was observed. Malignancy was evidenced by increased mitotic rate, necrosis, nuclear atypia, pleomorphism, and hyperchromasia, loss of nested and trabecular growth patterns, and absence of a dual cell population. In most cases (8 of 12), the malignant component comprised the bulk of the lesion. Two distinctive histologic patterns were observed. Five of 12 tumors exhibited abrupt transition between a benign eccrine spiradenoma and a high-grade carcinoma component. The others lacked a clear-cut transition between benign and malignant components and were diagnostically challenging. Diagnosis in such cases was established based on the loss of two cell populations, increased nuclear to cytoplasmic ratio, hyperchromasia, and marked mitotic activity. Two tumors showed focal squamous differentiation. Five of seven patients on whom there was follow-up information were free of disease (average duration of follow-up = 3.4 years). One patient developed metastases to local lymph nodes 5 years after the primary tumor was resected. This patient had no evidence of disease 16 months after resection of her lymph node metastases.

Background: The differentiation of soft tissue sarcoma (STS) from benign masses is difficult owing to their clinical and radiological similarities. Accurate staging is hindered by the large number of sites at which metastases may be found. This study examined the value of whole-body [18F]2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) in patients presenting with soft tissue masses., Methods: Thirty patients with a soft tissue mass suspected to be malignant were evaluated with FDG PET. The images were evaluated qualitatively and quantitatively for uptake of FDG to determine whether benign lesions could be differentiated from malignant tumours, and for the presence of metastases., Results: Thirty-one masses were removed from 30 patients; 12 were benign and 19 were malignant STSs. Using qualitative assessment of the FDG PET images, all the high-grade STSs (n = 12) were correctly identified, but low-grade STS (n = 7) could not be differentiated from a benign lesion. Using a quantification assessment, there was a 95 per cent sensitivity and a 75 per cent specificity in diagnosing STS. Three patients had metastases at presentation; two were correctly identified by FDG PET., Conclusion: FDG PET has a role in distinguishing high-grade STS from low-grade or benign STS and may have a role in staging malignant tumours.

Epithelioid hemangioendothelioma arising in the skin is extremely rare, and the majority of documented cases have developed in association with an underlying bone tumor. We report eight patients with an age range of 29-84 years (mean 53), who presented with primary cutaneous tumors at a variety of sites including the palm, shin, neck, knee, nose, back, and penis with a duration of between 6 and 12 months. Histologically, all eight cases presented as circumscribed nodules with an overlying acanthotic epidermis, three showing striking acrosyringeal proliferation, reminiscent of eccrine syringofibroadenoma. The tumors were composed of an admixture of slightly pleomorphic spindle and epithelioid cells with abundant, sharply defined eosinophilic cytoplasm and vesicular nuclei containing single nucleoli. Mitoses were generally sparse. All tumors showed intracytoplasmic lumina and intraluminal erythrocytes were occasionally apparent. The tumor cells were embedded in a myxoid or hyaline matrix. In contrast to visceral lesions, a vascular origin was not evident in any of our cases. The tumor cells variably expressed CD31, CD34, factor VIII-Rag, and smooth-muscle actin but not pankeratin or epithelial membrane antigen. Follow-up ranged from 4 months to 3 years. None of the lesions has thus far recurred and there have been no metastases.

We performed a retrospective analysis to evaluate the ability of whole-body F-fluorodeoxyglucose positron emission tomography (FDG PET) to identify local recurrence and pulmonary metastases in patients with soft-tissue tumours after treatment. We compared the results of FDG PET with those of MRI for the detection of local recurrence, and with CT of the chest for pulmonary metastases. We assessed 62 patients of mean age 51 years, who had 15 types of soft-tissue sarcoma, after a mean follow-up of 3 years 2 months. For the detection of local disease, 71 comparisons showed that the sensitivity and specificity of FDG PET were 73.7% and 94.3%, respectively; there were 14 true-positive and five false-negative results. MRI had a sensitivity and specificity of 88.2% and 96.0% respectively. For the identification of lung metastases, 70 comparisons showed that the sensitivity and specificity of FDG PET were 86.7% and 100%, with 13 true-positive results and two false-negative results. CT of the chest had a sensitivity and specificity of 100% and 96.4%. Thirteen other sites of metastases were identified by FDG PET. FDG PET can identify both local and distant recurrence of tumour as a one-step procedure and will detect other metastases. It seems that all three methods of imaging are needed to define accurately the extent of disease, both at initial staging and during follow-up.

Malignant rhabdoid tumors are morphologically characterized by the presence of sheets of large polygonal cells with abundant cytoplasm containing eosinophilic inclusions. They have vesicular nuclei, often with prominent central nucleoli. The term rhabdoid tumor was originally coined to describe a group of rare, aggressive renal neoplasms of childhood. Since then, similar lesions, so-called extrarenal malignant rhabdoid tumors have been increasingly reported. The evidence to date suggests that, at least in extrarenal locations, rhabdoid tumors do not constitute a homogeneous entity, but rather represent the shared morphological pattern of a diverse range of malignant neoplasms. Although such rhabdoid features are not uncommon in metastatic malignant melanoma, they have only once been briefly described in a primary lesion. We report three further cases of cutaneous primary malignant melanoma with rhabdoid morphology.

Metaplastic carcinoma (carcinosarcoma, sarcomatoid carcinoma, malignant mixed tumor) is a biphasic tumor comprising malignant epithelial and heterologous mesenchymal elements. Primary cutaneous cases are rare, with only seven cases documented in the English literature to date. We present four further cases, including three that developed in association with squamous cell carcinoma and one in an eccrine porocarcinoma. Heterologous malignant mesenchymal elements included malignant osteosarcoma, chondrosarcoma, leiomyosarcoma, and rhabdomyosarcomas. In contrast to metaplastic carcinomas arising in visceral sites, those primarily arising in the skin do not appear to behave in a very aggressive manner (Recurrence rate 22%, metastasis rate 22%, overall mortality 11%). However, the numbers involved are small and the follow-up period is short. In view of recent developments and progress in our understanding of the possible histogenesis of such tumors, we suggest that metaplastic carcinoma rather than carcinosarcoma is the most appropriate term with which to describe these very rare cutaneous neoplasms.

In normal skin, proliferation and differentiation are tightly coupled in order to maintain normal architecture in a continually renewing tissue. The temporal and spatial relationships between these two processes in normal, psoriatic, pre-neoplastic and neoplastic skin were investigated by a double immunolabelling technique with Ki67 as a marker of proliferation and involucrin as a marker of terminal differentiation. In normal skin, expression of the two antigens was strictly spatially segregated. In the abnormal, the proportions of cells expressing the antigens were increased with some loss of the spatial segregation, while small numbers of cells showed dual expression suggesting loss of the normal control between proliferation and differentiation. However, the quantitative ratio of proliferation to differentiation in psoriatic and pre-neoplastic skin was similar to the normal; transition to an invasive phenotype, however, was associated with a reversal of this ratio, and this correlated well with the degree of histological differentiation.

In this retrospective study we have investigated the expression of Ki-67 and p53 in 175 random cases of cutaneous squamous cell carcinomas by using the monoclonal antibodies MIB-1 and DO-1, respectively. The expression of these antibodies was compared with various histological parameters of prognostic significance. The staining results were also compared with the clinical outcome of the patients. MIB-1 and DO-1 staining showed statistically significant correlation with histopathological grade of the tumor (p < 0.0001 and p = 0.0016, respectively). The degree of immunolabelling of these antibodies also showed significant correlation with tumor depth and tumor thickness (MIB-1 thickness p = 0.02 and depth p = 0.026, and DO-1 thickness p = 0.014 and depth p = 0.005). The majority of the squamous cell carcinomas in our series were Clark's level IV, which therefore did not correlate with the extent of immunoreactivity (MIB-1, p = 0.098; and DO-1, p = 0.885). Mean length of clinical follow-up was 5.2 years. Aggressive tumor behaviour was seen in 17 patients (10.6%) with 6.9% and 3.4% local recurrences and nodal metastasis respectively. A total of 89.4% patients remained disease-free following their definitive surgical treatment. Vulval skin represented the commonest site associated with unfavourable clinical outcome (five of 17 cases). A large number of squamous cell carcinomas in this poor prognosis group showed a high prevalence of immunoreactivity of the antibodies but this did not achieve any statistical significance. We conclude that Ki-67 and p53 expression in cutaneous squamous carcinoma is not an independent predictor of prognosis.

Four patients with chronic vulval inflammation are described. The histological features of non-caseating granulomata and multinucleated giant cells are compatible with Crohn's disease, but only two patients had proven gastrointestinal involvement. The clinical and histological characteristics of Crohn's disease and other granulomatous inflammations of the vulva are discussed and the literature is reviewed.

Twenty cases of solar keratosis and 15 cases of Bowen's disease were investigated for the expression of transforming growth factor alpha (TGF-alpha) by an indirect immunoperoxidase technique using monoclonal antibody TGF-alpha AB-2 in formalin-fixed wax-embedded tissue. Twelve cases (60%) of solar keratosis and 13 cases (86%) of Bowen's disease showed marked overexpression of TGF-alpha in both membranous and cytoplasmic distributions. This suggests that overexpression of TGF-alpha may play an important role in the evolution of these two neoplastic conditions.

Aberrant p53 immunoreactivity has been found in skin pre-malignancies and dysplasias such as Bowen's disease and actinic keratoses. Vulval lichen sclerosus (LS) has been reported to be pre-malignant, with an association of vulval carcinoma in 3% to 6% of patients. In contrast, non-genital LS appears to have no malignant potential. In this immunocytochemical study, we investigated p53 expression in 10 cases of histologically proven vulval LS and 9 cases of non-genital LS using the murine monoclonal antibody Do-1 raised against recombinant human p53 which reacts with both wild-type and mutant p53. None of the vulval specimens had epithelial dysplasia or malignancy. Normal vulval (7 cases) and non-genital skin (5 cases) were used as tissue controls, respectively. The cell proliferation index was also studied using the MIB 1 monoclonal antibody which detects the cell-cycle associated Ki-67 antigen. The technique of microwave irradiation for antigen unmasking was employed on formalin-fixed and paraffin-embedded tissues. There was a significant increase in p53 immunoreactivity in vulval LS (32.13 +/- 15.11 epidermal cells per 100 basal cells) compared to normal vulval skin (7.52 +/- 5.04 epidermal cells per 100 basal cells) (p < 0.001), whereas the MIB 1 labelling index was lower in vulval LS (39.45 +/- 15.88 epidermal cells per 100 basal cells) than in normal controls (86.26 +/- 32.31 epidermal cells per 100 basal cells) (0.001 < p < 0.01). In contrast, there was no significant difference in p53 immunoreactivity or MIB 1 labelling index between non-genital LS and normal controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Expression of the p53 tumor suppressor gene product was determined in keratoses and skin cancers associated with psoralen photochemotherapy (PUVA). An immunocytochemical study was employed using CM-1 (polyclonal) and Do-1 (monoclonal) antibodies to human wild-type p53. Thirty-two cutaneous lesions and 20 perilesional PUVA-irradiated skin biopsies were examined from 7 patients, all of whom had received more than 200 PUVA treatments and/or a cumulative UVA dose of greater than 1000J/cm2 as treatment for widespread plaque psoriasis. p53 immunoreactivity was seen in 7 of 15 squamous cell carcinomas (46.7%), 5 of 8 dysplastic keratoses (62.5%) and in no basal cell carcinomas or benign keratoses. The overall prevalence of p53 immunoreactivity in 46.2% of malignant or dysplastic PUVA-associated skin tumors is similar to that previously found by our group in comparable skin tumors from the general population. Most patients with lesions showing positive p53 immunoreactivity had, however, been exposed to additional risk factors before receiving PUVA therapy. p53 gene sequencing of PUVA-associated non-melanoma skin cancer (NMSC) may clarify whether p53 mutation contributes to the development of these tumors and whether this relates to PUVA therapy or prior carcinogen exposure.

A 67-year-old man presented with discrete mucinous papules on the scalp and fingers, and bilateral carpal tunnel syndrome. Both features remitted spontaneously within several months. The acral distribution, and histopathological features, were in keeping with the recently described acral persistent papular mucinosis. Involvement of the scalp, however, has not previously been described, and transient mucin deposition is unusual. The history of bilateral carpal tunnel compression raises the possibility of extracutaneous involvement, not previously reported in this group of patients.