Henry G. Skelton

Merkel cell carcinoma: Analysis of clinical, histologic, and immunohistologic features of 132 cases with relation to survival

BACKGROUND Merkel cell carcinoma (MCC) is an uncommon malignancy of the skin and has a high rate of recurrence and metastasis. There have been few large studies of the biologic behavior of MCC. OBJECTIVE Our purpose was to determine whether there were clinical or histologic features of MCC that predict its biologic behavior. METHODS We reviewed 132 cases of MCC. Clinical and histologic features were correlated with follow-up information to determine whether any of these were associated with prognosis. RESULTS Clinical information was available on 126 patients; 57 were alive, 1 was alive with tumor, 28 died of tumor, 27 died from other causes, and 14 were lost to follow-up. MCC on the buttock/thigh area or trunk had the worst prognosis, and those on the distal extremities had the best prognosis; however, the difference was not statistically significant. Sex and age were not significant factors. Small cell size, high mitotic rate, and large tumor size were associated with a low survival rate. When cell size was excluded, male sex and depth of invasion were associated with a worse survival, although these were not statistically significant. CONCLUSION Cell size, mitotic rate, and tumor size are significant factors in relation to the biologic behavior of MCC.

Spindle Cell and Epithelioid Cell Nevi with Atypia and Metastasis (malignant Spitz Nevus)

We report on the clinical and pathologic features of 32 lesions diagnosed as malignant spindle cell and epithelioid cell nevus (S&E nevus). Because of the clinical or initial histopathologic diagnosis of malignant melanoma, six patients had lymph node dissection. Three of these patients also had an enlarged lymph node. In all six cases, metastatic spindle or epithelioid cells were found in at least one of the resected lymph nodes. Of the 30 patients with follow-up information, including all six patients with lymph node metastases, all are alive and well. No recurrences or further metastases have been found. On histopathologic reevaluation, all the lesions had features of S&E nevi. Study of these cases suggests that although some lesions with features of S&E nevi may involve local lymph nodes, widespread metastases do not result.

Desmoplastic malignant melanoma

BACKGROUND Desmoplastic malignant melanoma (DMM) is an uncommon variant of malignant melanoma and often is difficult to diagnose. Because of the relative rarity of this tumor, it has not been well studied and controversy remains concerning its biologic potential. OBJECTIVE We compared survival rates of DMM with those of other malignant melanomas and determined what clinical and/or histologic features, if any, correlated with survival. METHODS The files of the Armed Forces Institute of Pathology were searched for cases of DMM or related tumors with adequate material for further histologic and immunohistochemical evaluation. Follow-up on each patient was requested from the pathologist, clinician, and/or the patient. The follow-up was correlated with the histologic findings in each case. The relationship of histologic features to disease-free survival was evaluated. RESULTS Adequate material for evaluation was available in 128 cases. The overall histologic features were similar to those previously reported. Immunohistochemical studies showed that all lesions were negative for HMB-45, a marker for premelanosomes. Factors that correlated with survival included tumor location, sex, tumor depth, and the presence of stromal mucin. The 5-year disease-free survival rate was 68% for all cases and 61% for lesions more than 4 mm deep. CONCLUSION With a 5-year disease-free survival rate of 61%, DMM has a significantly better prognosis than other melanomas that have a 5-year disease-free survival rates of 40% to 41%. This may be related to neural differentiation of these tumors.

Cutaneous findings in HIV-1-positive patients: A 42-month prospective study

BACKGROUND Cutaneous disease is common in patients infected with HIV-1. OBJECTIVE The aim of our study was to identify cutaneous markers associated with HIV-1 infection and disease progression as measured by Walter Reed (WR) stage. METHODS For 42 months we have observed 912 HIV-1-positive patients in all WR stages. All patients had an extensive past and present medical history taken as well as a complete physical examination, periodic visits, and appropriate diagnostic procedures. RESULTS Increasing dryness of the skin and seborrheic dermatitis are early findings in a large percentage of patients in WR stage 1; the occurrence and severity of both conditions increase with disease progression. Tinea infections, condylomata acuminata, and verrucae are seen early, but with disease progression, although there is no clear increase in occurrence, these infections become more diffuse and resistant to treatment. Flares in acne vulgaris and folliculitis show a peak occurrence in early and mid-stage disease with a decreased occurrence in late-stage disease. Herpes simplex infections, oral candidiasis, molluscum contagiosum, Staphylococcus aureus infections, and oral hairy leukoplakia show a marked increase in occurrence with advanced disease. Conditions that have a statistically significant association with disease progression as measured by a change in a stage include drug eruptions, seborrheic dermatitis, oral candidiasis, oral hairy leukoplakia, molluscum contagiosum, herpes zoster, and hyperpigmentation (nail, oral, skin). CONCLUSION The most frequent and persistent cutaneous disorders were asteatosis (with or without asteatotic eczema) and seborrheic dermatitis. Conditions that were associated with a change in WR stage include drug eruptions, seborrheic dermatitis, oral candidiasis, oral hairy leukoplakia, molluscum contagiosum, herpes zoster, and hyperpigmentation. In addition to Kaposis sarcoma, patients with HIV-1 disease have an increased potential for the development of both cutaneous epithelial and probably melanocytic malignancies. Epithelial tumors were seen in patients in all stages of disease.

Sulfur mustard: Its continuing threat as a chemical warfare agent, the cutaneous lesions induced, progress in understanding its mechanism of action, its long-term health effects, and new developments for protection and therapy

Although sulfur mustard (SM) has been used as a chemical warfare agent since the early twentieth century, it has reemerged in the past decade as a major threat around the world. SM is an agent that is easily produced even in underdeveloped countries and for which there is no effective therapy. This agent is a potential threat not only on the battlefield but also to civilian populations. The skin and other epithelial surfaces are the first targets as this agent is absorbed, and reactions within the skin are the subject of active research into the mechanism of action of this alkylating agent. The depletion of glutathione, generation of reactive oxygen species, and the formation of stable DNA adducts remain theoretic and demonstrated by-products of SM exposure implicated in the disease produced. However, new findings related to the effects of SM on the basement membrane zone; interest in delayed healing of the lesions induced; the inflammatory mediators, enzymes, and cytokines that result; and cellular typing of the inflammatory infiltrate will increase our understanding of the pathophysiology of the lesions caused by SM. In addition, the recent development of a topical skin protectant for SM and for other chemical warfare agents may have broad applications within dermatology.

Hmb-45 Staining in Benign and Malignant Melanocytic Lesions: A Reflection of Cellular Activation

The antibody HMB-45 used as an immunohistochemical reagent has often been labeled as a marker for melanoma, even though some benign lesions have been noted to show positive staining reactions with this reagent. Biopsy specimens from 225 benign and malignant melanocytic lesions were examined after immunoperoxidase staining for S-100 protein and HMB-45. The lesions studied included common acquired nevi, spindle cell and epithelioid cell nevi (Spitz nevi), cellular blue nevi, deep penetrating nevi, congenital nevi, nevi from hormonally reactive areas (genital), malignant melanoma, and desmoplastic malignant melanoma. A positive reaction for HMB-45 was seen in the dermal component in a high percentage of each of these types of lesions except for the common acquired nevi and the desmoplastic malignant melanomas that were uniformly negative for HMB-45 in the dermal component. HMB-45 correlates with melanosome production and thus a melanocytic origin of HMB-45-positive cells. HMB-45 may correlate best with factors that stimulate melanocytic proliferation and production of melanosomes.

Majocchi's granuloma

Majocchis granuloma (nodular granulomatous perifolliculitis) is a well recognized but uncommon infection of dermal and subcutaneous tissue by fungal organisms (dermatophytes) usually limited to the superficial epidermis. The organism usually associated with Majocchis granuloma is Trichophylon rubrum; however, other dermatophytes including T. mentagrophytes (variety granulosum), T. epilans, T. violaceum, M. audouinii, M. gypseum, M. ferrugineum, and M. canis may be the causative agent. A review of 17 cases revealed not only the variety of possible organisms but also a marked variation from the usual hyphal forms. The morphologic variations including yeast forms, bizarre hyphae, mucinous coatings, and the Splendore‐Hoeppeli phenomenon may be factors which allow the dermatophytes to persist and grow in an abnormal location. Also, there is evidence that Majocchis granuloma may occur in two distinct groups of patients.

Molluscum contagiosum: its clinical, histopathologic, and immunohistochemical spectrum

Although molluscum contagiosum virus (MCV) is considered by some as an unclassified poxvirus, others consider it a member of the orthopoxvirus genus, family Poxiviridae. It is a large double-stranded DNA virus that has a worldwide distribution. With the eradication of small pox, variola virus (VAR), MCV remains by far the most common pox viral pathogen for humans.1–6 Lesions of MCV occur almost exclusively in the skin, and only rare reports have referred to mucous membrane lesions.1–3 Lesions of MCV are most commonly seen in young children, sexually active adults, and in some immune suppressed patient populations (Figs 1–5). Although MCV infections are highest in warm moist climates, and in populations where personal hygiene is difficult to maintain, they have a worldwide distribution.1–3 In children, MCV has a diffuse distribution and may occur on the face, trunk, and extremities, as well as in the genital area (Fig. 1).1–4 In young adults, sexual contact is probably the most common mode of transmission, and genital lesions are common (Fig. 2).1–4 In human immunodeficiency virus type 1-positive (HIV-11) patients, widespread lesions do occur, but head and neck lesions are most common, followed by genital involvement.1–4,7,8 Although the typical umbilicated papules occur in all patient populations, in HIV-11 patients, verrucous, warty papules, as well as giant molluscum greater than 1 cm in diameter, are also seen (Figs 3–5).1–4,7,8 In patients without severe immune suppression, lesions produced by MCV typically regress spontaneously usually within months, rarely years.1–6,9 MCV cannot be grown in tissue culture cells and does not infect animals; however, it has been replicated in human skin grafted to immune deficient mice.5,6,9 MCV is only distantly related to VAR, and lacks DNA cross-hybridization or immunologic cross-reactivity.5,6,9 Four major subtypes of MCV have been defined by recent work, including three MCV-1 variants and MCV-2, MCV-3, and MCV-4 subtypes.9 MCV-1 subtypes dominate worldwide and, in one report, MCV-1 subtypes occurred exclusively in children under the age of 15 years;2,3,10 however, there is evidence that other MCV subtypes are more common in the HIV-11 patient population.3,11 In the light of the new molecular information available on MCV, we returned to review the clinical and histologic features seen in both HIV11 and HIV-1– individuals.

Neuroendocrine (Merkel cell) carcinoma with an intraepidermal component.

We present 11 cases of primary neuroendocrine (Merkel cell) carcinoma of the skin with an intraepidermal component that were identified in a larger review of Merkel cell carcinomas. Among these is a case with a follow-up of over 11 years in which the primary lesion appeared as bowenoid dysplasia, with subsequent recurrences as intraepidermal Merkel cell carcinoma with focal tubular differentiation, and then with dermal invasion and lymph node metastasis. In addition to immunohistochemical markers commonly used in the identification of Merkel cell carcinomas (neuron-specific enolase and cytokeratin), these tumors stained with Ber-EP4, an immunohistochemical marker used to identify carcinomas. We believe that these histopathologic and immunohistochemical features further confirm that Merkel cell carcinomas represent an epithelial tumor with the potential for neuroendocrine and adnexal differentiation.

Imiquimod therapy for molluscum contagiosum

Background: Molluscum contagiosum virus (MCV) is a large double-stranded DNA virus that is a member of the family Poxviridae, and which has a worldwide distribution. As with other poxviruses, MCV does not appear to develop latency but evades the immune system through the production of viral specific proteins. Objective: To evaluate the therapeutic efficacy of imiquimod 5% cream for MCV. Methods: Thirteen children >5 and <10 years old, 19 immune-competent adults and four adults with advanced, but stable HIV-1 disease with >10 MCV lesions were treated with topical 5% imiquimod cream three times weekly for up to 16 weeks. Results: Fourteen of 19 immune-competent adults, four of four adults with HIV-1 disease, and six of 13 children had resolution of their MCV lesions in <16 weeks of imiquimod therapy. Children tended to have more pruritus and inflammatory reactions with imiquimod, although most treated lesions appeared to respond. The development of new MCV lesions resulted in a lower overall resolution of the lesions in children. Imiquimod appeared to be the most efficacious in patients with HIV-1 disease and in the genital area in immune-competent adults. Conclusion: Although topical imiquimod appears to have some efficacy in the therapy of MCV, in children the pruritus correlated relatively well with the development of new lesions. In adults, areas that would be expected to have better penetration appeared to respond more consistently. Although the HIV-1-positive patients had the largest clinical lesions at the onset of therapy, as a group they had the best overall response to therapy.