My approach to atypical melanocytic lesions.

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.

Deep penetrating naevus: clinicopathological study of 31 cases with further delineation of histological features allowing distinction from other pigmented benign melanocytic lesions and melanoma.

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.

Morphological analysis of nevoid melanoma: a study of 20 cases with a review of the literature.

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.

Eccrine porocarcinoma (malignant eccrine poroma): a clinicopathologic study of 69 cases.

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.

Melanoma associated with blue nevus and melanoma mimicking cellular blue nevus: a clinicopathologic study of 10 cases on the spectrum of so-called 'malignant blue nevus'.

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.

A clinical study of 23 cases of female anogenital carcinoma.

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 (spiradenocarcinoma): a clinicopathologic study of 12 cases.

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.

Prospective evaluation of soft tissue masses and sarcomas using fluorodeoxyglucose positron emission tomography.

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 presenting in the skin: a clinicopathologic study of eight cases.

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.

Evaluation of fluorodeoxyglucose positron emission tomography in the management of soft-tissue sarcomas.

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.

Primary malignant melanoma with rhabdoid features: a histologic and immunocytochemical study of three cases.

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.

Primary metaplastic carcinoma (carcinosarcoma) of the skin. A clinicopathologic study of four cases and review of the literature.

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.

Extraordinary case report: cutaneous anthrax.

Anthrax is a very rare disease in the United Kingdom. It is caused by the spore-forming bacterium Bacillus anthracis. Humans become infected when they come into contact with infected animals or their products. Cutaneous anthrax, the most common form of the disease, accounts for 95% of cases, and the disease usually developing on exposed sites. We present a patient who developed cutaneous disease after exposure to untreated leather. Owing to the initial clinical information, the biopsy specimen was misinterpreted as representing a severe acute insect bite reaction. The subsequent involvement by the Department of Microbiology established the correct diagnosis. Because today the disease is so rare in Europe and the United States, sporadic cases of anthrax are easily overlooked as the diagnosis often is not considered. Cutaneous anthrax should be considered in any patient with a painless ulcer with vesicles, edema, and a history of exposure to animals or animal products.

The relationship of Ki67 and involucrin expression in proliferative, pre-neoplastic and neoplastic skin.

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.

Prognostic significance of Ki-67 and p53 immunoreactivity in cutaneous squamous cell carcinomas.

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.

Vulval Crohn's disease: difficulties in diagnosis.

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.

Transforming growth factor-alpha expression in in situ epidermal neoplasia.

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.

Altered p53 expression and epidermal cell proliferation is seen in vulval lichen sclerosus.

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)