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M C Mihm

Publications and source records attributed to M C Mihm.

At least 73 records · Page 4Linked to original sources
PubMed1996

Cytokine, cell adhesion receptor, and tumor suppressor gene expression in vulvar squamous carcinoma: correlation with prominent fibromyxoid stromal response.

In a previous report, we observed by light microscopy the extracellular matrix in 51 vulvar squamous carcinomas and found that some tumors has a prominent stromal response in the form of a regional or diffuse zone of extracellular myxoid matrix containing immature collagen and fibroblasts at the tumor-stromal junction. These tumors were associated with clitoral involvement, ulcerative nonexophytic growth pattern, older age groups, poorer survival rate, and more extensive lymph node metastases than when prominent fibromyxoid stromal response (PFSR) was absent. This behavior was demonstrated despite the fact that these tumors were not larger, more deeply invasive, or of higher grade than when PFSR was absent. In the current immunohistochemical study, we examined cytokine, cell adhesion receptor, and tumor suppressor gene expression in 50 vulvar squamous carcinomas using a panel of antibodies to identify any potential role of these proteins in the development of a PFSR. Semiquantification of expression into none, focal (< 25% of cells showing expression), regional (25-50%), and diffuse (> 50%) patterns revealed PFSR to be statistically associated with high CD44, transforming growth factor (TGF) beta 3, and p53 protein expression, but not with fibroblast growth factor, epidermal growth factor, epidermal growth factor receptor, or E-cadherin expression. When expression of CD44 and either stromal or tumor TGF-beta 3 expression was high, i.e., regional or diffuse in distribution, 15 (50%) of 30 cases were associated with PFSR. In contrast, only 1 (7%) of 14 cases was associated with PFSR when expression was high for only one of these two proteins and none of 3 cases was associated with response when expression was low for both proteins (p = 0.005). Furthermore, in cases showing high expression for both TGF-beta 3 and CD44, PFSR was found in 13 (72%) of 18 cases when p53 expression was diffuse compared with 2 (17%) of 12 cases when expression was less (p = 0.01). Since TGF-beta acts mitogenically for fibroblasts and has been shown to be an inhibitor of epithelial cell growth, its high expression in a carcinoma with PFSR would suggest loss of effect on the epithelial component but an intact effect on the stroma. Since CD44 is known to act as a receptor for hyaluronic acid, which is a prominent stromal component and known to play an important role in cell mobility and tumor aggressiveness, its high expression in association with PFSR would suggest a role of CD44 overexpression in altered hyaluronate metabolism with accelerated tumor cell migration and subsequent distal spread. The current study demonstrates that alterations in cytokine and cell adhesion receptor status variably occur in vulvar squamous carcinoma and that such alterations may affect tumor morphology and behavior.

Carcinoma, Squamous Cell↗
PubMed1996

Biological activity and clinical efficacy of intravenous high-dose thymopentin in metastatic melanoma patients.

Eight patients with cutaneous metastatic melanoma were submitted to high-dose intravenous thymopentin (TP5) treatment for 5 weeks: three patients received 1 g three times a week, three received 1 g daily and two received 2 g daily. Four out of eight patients presented a partial response of cutaneous lesions lasting for 1-7 months, and six remain alive with evidence of disease after a follow-up of 2-7 months. A remarkable histologic observation is the presence of tumour necrosis, which was seen as both single cells and large confluent areas. The majority of lymphoid cells present in the tumour are CD45RO+ and CD4+. The CD4+ cells might play an important role in the anti-tumour immune local response by secreting cytokines and inducing apoptotic and necrotic cell death. This hypothesis seems to be confirmed by the presence of a high number of CD4+ cells around intratumoral vessels, while the presence of endovascular micro-thrombosis provides indirect evidence of cytokine activity. Cellular lysis may be produced by the activity of both CD8+ and CD4+ lymphoid cells. The role of TP5 may be an activation of CD4+ and CD8+ lymphoid cells. Clinical and pathological data indicate that TP5 is able to produce consistent clinical and immunological effects in melanoma patients with cutaneous metastases.

Adjuvants, Immunologic↗
PubMed1996

Acral lentiginous melanoma (including in situ melanoma) arising in association with naevocellular naevi.

Acral lentiginous melanoma (ALM) occurring on the sole of the foot is the most common type of malignant melanoma in Asians, African and North American Blacks, but is relatively infrequent in Caucasians. According to the literature ALM is thought less likely to arise in a precursor naevus of any type or be associated with dysplastic naevi elsewhere on the skin. We present five cases of ALM (two invasive and three in situ cases) arising in association with pre-existing naevi on the foot in Asians and Caucasians. All patients were female, aged 35-66 years (mean = 47.8). Clinically, all five tumours demonstrated various shades of tan, brown and black, admixed with hypopigmented areas. Histologically, these melanomas showed a lentiginous character of the radial growth phase component with rare foci of pagetoid intra-epidermal spread. Invasive determal components in the form of epithelial and spindle cells were evident in two cases, with a measured depth of 1.7 and 0.85 mm, respectively. Pre-existing naevi, either dermal or junctional, were identified in all tumours. Clinical follow-up in all patients showed no evidence of recurrence or metastasis over a period of 4 months-5 years. These cases appear at variance with the general belief that ALM and ALM in situ arise de novo and rarely arise in precursor naevi. To the best of our knowledge, this is the first documented series of ALM in situ arising in association with pre-existing naevi. We conclude that ALM can arise in association with acral naevi.

Adult↗
PubMed1996

Pharmacological disruption of hair follicle pigmentation by cyclophosphamide as a model for studying the melanocyte response to and recovery from cytotoxic drug damage in situ.

Here we show that cyclophosphamide induces disruption of follicular melanogenesis, which is characterized by abnormal transfer of pigment granules to ectopic hair bulb locations, extrafollicular melanin incontinence, disordered formation of melanosomes, and inhibition of melanosome transfer into precortical keratinocytes. This is in contrast to dexamethasone-induced termination of follicle melanogenesis, which activates premature but predominantly normal catagen development. Cyclophosphamide-induced pigmentation disruption was accompanied by significant alterations of biochemical and biophysical markers of melanogenesis, compared to control mice treated either with vehicle or with topical dexamethasone. Electron paramagnetic resonance spectroscopy shows a decline in the melanin signal and predominant eumelanin production. Tyrosine hydroxylase activity of tyrosinase and dihydroxyphenylalanine oxidation drop rapidly, while DOPAchrome tautomerase activity increases and dihydroxyindole carboxylic acid conversion factor activity remains unchanged in cyclophosphamide-treated mice compared to controls. These observations emphasize the key role of tyrosinase as opposed to postdihydroxyphenylalanine oxidase steps in normal and pathological termination of melanogenesis and shows that tyrosinase is the most sensitive target of the melanogenic apparatus for pharmacological regulation. Follicle pigmentation recovers only during the subsequent hair cycle, i.e., after a new anagen hair bulb has been constructed, which points to the existence of a relatively chemoresistant melanoblast-like cell population residing in the noncycling part of the hair follicle.

Animals↗
PubMed1996

Multiple basaloid cell hamartoma with alopecia and autoimmune disease (systemic lupus erythematosus).

We report a 22-year-old Japanese woman with multiple basaloid cell hamartoma with alopecia and autoimmune disease (systemic lupus erythematosus). She presented with infiltrated large annular, brown-violet, erythematous plaques with atrophic areas in the center on her right cheek, left abdomen and left knee. She also had progressive multiple follicular keratotic papules on her scalp, face, neck, and both axilla and hair loss from her scalp, eyebrow, and axilla. Serologically, rheumatoid factor (+ + +), rheumatoid arthritis hemagglutination test (x1280), and anti-nuclear antigen (x160) were positive. Histological findings of the annular lesion showed liquefaction degeneration of basal cells, lymphocytic infiltration around hair follicles and capillaries, and panniculitis with lymphoid cell infiltration, which was diagnosed as lupus erythematosus profundus. The histological findings of multiple follicular papular lesions of the scalp and neck showed aggregations of basaloid cells, partially with hair-bulb-like structures, which was diagnosed as trichoepithelioma. Taken together, the histogenesis of multiple basaloid cell hamartoma is thought to share the same basis with autoimmune disease.

Adult↗
PubMed1996

Tumor infiltrating lymphocytes in lymph node melanoma metastases: a histopathologic prognostic indicator and an expression of local immune response.

In lymph node melanoma metastases, the expansive proliferation of tumor cells may be compared, structurally and cytologically, to the vertical growth phase (VGP) observed in primary melanoma. Both in VGP and in nodal metastases, tumor infiltrating lymphocytes (TILs) may be present with different patterns. In the evaluation of the primary tumor, these patterns have been defined as brisk, non-brisk, and absent. The histologic slides of regional lymph node metastases, the site of first recurrence in 99 consecutive melanoma patients, were reviewed. Disease-free survival of these cases and whether or not they were treated with rIFN alpha-2A was recorded to identify any relationship among different patterns of TILs, therapy, and prognosis. Of 99 cases, 16 were classified as brisk, 37 as non-brisk, and 46 as absent. At 30 months of follow-up the disease-free survival was 81.3% for brisk cases, 46.8% for non-brisk cases, and 29.3% for absent groups (p = .007). Multivariate analysis confirmed the prognostic value of TILs in predicting disease-free survival in patients with regional node metastases. The difference according to the presence or absence of relapse is particularly evident when comparison is made between treated and untreated patients. In conclusion the evaluation of first-recurrence regional node melanoma metastases for TILs, using the same histopathologic criteria as in VGP of primary melanoma, subdivides the cases in brisk, non-brisk, and absent groups. Also, the presence of these patterns in metastatic node melanoma deposits is correlatable to disease-free survival. Our results further stress the difference of prognosis patients treated with rIFN alpha-2A compared to the untreated group. The TILs evaluation may prove useful in selecting those melanoma stage II patients who will best respond to therapy with biologic response modifiers, because the TILs may be the local immune effector cell targets of rIFN alpha-2A or of other biologic agents.

Humans↗
PubMed1996

Cutaneous lymphocytic vasculitis: a definition, a review, and a proposed classification.

Lymphocytic vasculitis is not widely accepted as a pathologic mechanism by dermatopathologists, and a comprehensive list of its causes cannot be found in the literature. This state of affairs stems largely from the lack of a rigorous definition. In this report, the authors review past efforts at coming to terms with lymphocytic vasculitis and why those efforts have fallen short. The authors propose that lymphocytic vasculitis can be separated from the ubiquitous perivascular dermatitides in routinely processed specimens by requiring the presence of either acute or chronic damage to the walls of small vessels (eg, fibrin deposition, lamination by pericytes). In the case of muscular vessels, the presence of lymphocytes within the vessel walls is sufficient, because diapedesis of lymphocytes does not occur in arteries or veins. Although lymphocytic infiltrates meeting this definition are uncommon, there are a number of conditions, with both typical and atypical lymphocytes, in which damage to vessels occurs. The authors review these conditions, outline possible pathogenetic mechanisms, ranging from delayed hypersensitivity reactions directed against endothelial cells to direct infection of these cells, and present classifications based on morphological changes and pathogenesis respectively.

Humans↗
PubMed1996

In situ distribution of integrin alpha 2 beta 1 and alpha-actinin in melanocytic proliferations.

Integrin alpha 2 beta 1 is a transmembrane protein receptor for collagen and laminin previously reported as a melanoma tumor progression antigen. alpha-Actinin is an actin-binding protein reported to interact with the cytoplasmic domain of the beta 1-integrin chain of alpha 2 beta 1. In vitro, both alpha 2 beta 1 and alpha-actinin play a role in melanoma cell motility. In turn, increased melanoma cell line motility (measured as mean migration rates), correlates with metastasis. To determine the in situ distribution of these proteins, we used monoclonal antibodies directed against the alpha 2-integrin subunit of alpha 2 beta 1 and alpha-actinin on frozen sections of 33 melanocytic proliferations, which included dermal nevi, primary melanomas, and metastatic melanomas. We found that the superficial portion of all of the melanocytic proliferations tested stained for alpha-actinin. In benign nevi and superficial spreading melanoma, there was a notable loss of staining for alpha-actinin in the cells in the deep reticular dermis. In contrast, alpha-actinin was present on almost all of the tumor cells in the nodular melanomas and the melanoma metastases. Tumors stained either uniformly positive or uniformly negative for alpha 2 beta 1; the expression of this protein correlated with the later stages of melanoma progression. Our findings suggest that alpha-actinin protein levels initially decrease and then increase during melanocytic tumor progression, whereas the alpha 2 subunit protein appears in the later stages of melanoma progression. The variable distribution of these proteins is evidence for the differential adhesive and motile properties of subpopulations of cells in melanocytic proliferations.

Actinin↗
PubMed1995

Nevoid melanoma: a clinicopathological study of seven cases of malignant melanoma mimicking spindle and epithelioid cell nevus and verrucous dermal nevus.

We report seven cases of a distinctive type of malignant melanoma characterized by a deceptively benign histological appearance with an architecture resembling that of benign melanocytic nevi on scanning magnification. Two predominant architectural patterns were observed: a dome-shaped pattern (two specimens) and a verrucoid pattern (five specimens). The specimens with a dome-shaped pattern of growth were characterized by a smooth epidermal surface and a proliferation of epithelioid melanoma cells with an inconspicuous intraepidermal component resembling spindle and epithelioid cell nevi (Spitz nevi). Gradual diminution in the size of dermal nests toward the bases of the lesions simulating the maturation phenomenon of benign nevi was observed; however, the dermal organization in cords and strands of melanoma cells and the persistence of cellular atypia extending to the bases of the tumors allowed their recognition as malignant melanomas. On the other hand, the specimens with a verrucoid growth pattern consisted of broad, exophytic tumors with a verrucous epidermal surface resembling that of papillomatous dermal nevi but distinguished from them by the presence of a continuous proliferation of melanocytes along the dermal-epidermal junction and by confluent sheets of melanoma cells in the dermis without evidence of true maturation. Clinical follow-up showed local recurrence in three patients after intervals ranging from 5 months to 5 years and regional metastasis in one patient after 2 years. The lesions described here may constitute a serious pitfall for diagnosis because of their innocent silhouette on scanning magnification and their superficial resemblance to spindle and/or epithelioid cell nevi and benign verrucous melanocytic nevi. Proper attention to cytological detail and subtle architectural features will aid in recognizing this unusual variant of malignant melanoma.

Adult↗
PubMed1995

Cutaneous melanoma: pathology, relevant prognostic indicators and progression.

Malignant melanoma, one of the most rapidly increasing malignancies in man, has recently received substantial attention in the world literature concerning application of traditional morphologic and newer immunologic and molecular biologic methods of predicting progression and ultimate clinical outcome. Although clinical features of patient sex, age and anatomic site of the lesion are important, classic morphologic variables defining prognosis remain the cornerstone of predicting disease outcome. Extent of radial growth phase and the two microstaging methods of measuring tumor thickness and determining level of invasion remain the critical disease progression predictors. Assessment of mitotic rate, number of tumor infiltrating lymphocytes, and determining the presence of regression, ulceration, and epithelioid cell component, microscopic satellites and vascular invasion are also important. More recently a variety of molecular and biochemical prognostic markers have been cited for prediction of disease recurrence and metastasis. Both overexpression and down regulation of a variety of cell adhesion molecules have been implicated in disease progression as has alterations in the plasminogen activation system. A series of growth factors, growth factor receptors, oncogenes and tumor suppressor genes have also been considered. Structural and numerical genomic DNA abnormalities, cell proliferation markers and DNA ploidy status have also been considered. Recently a variety of serum and blood markers indicating disease persistence or progression have been studied including melanin synthesis precursors and intermediate compounds of melanogenesis. Molecular detection by PCR of melanogenesis specific mRNA may become the most sensitive prognostic marker of the future. At present histopathologic and clinical criteria remain the cornerstones of predicting prognosis in malignant melanoma.

Disease Progression↗
PubMed1995

Focal adhesion kinase (p125FAK) expression correlates with motility of human melanoma cell lines.

Focal adhesion kinase (p125FAK), a recently characterized protein localized within focal adhesion plaques, is believed to play a role in extracellular matrix-integrin-mediated signal transduction involving cytoskeletal proteins. We studied p125FAK expression, distribution, and relation to cell migration in six human melanoma cell lines. Western blot analysis detected differential expression of p125FAK among these lines that was directly proportional to the amount of phosphorylated p125FAK. Time-lapse image analysis of the cell lines exhibited 10-fold differences in the mean migration rates on fibronectin-coated substrates. Regression analysis revealed that p125FAK expression correlated significantly with mean migration rate in the six melanoma lines tested. Double immunofluorescent labeling for p125FAK and actin in these lines demonstrated p125FAK plaques that were localized to actin stress-fiber termination sites in the periphery of cells. The number of p125FAK plaques in the melanoma cell lines was heterogeneous, but the cell lines with more p125FAK plaques per cell exhibited significantly higher mean migration rates on fibronectin as compared with cell lines with fewer p125FAK plaques per cell. The findings support the hypothesis that focal adhesion tyrosine kinase modulates cytoskeletal function during melanoma cell migration on fibronectin.

Cell Adhesion Molecules↗
PubMed1995

Increased thickness of pregnancy-associated melanoma.

The effects of pregnancy on the pathophysiology of melanoma remain unclear. Although a gender-specific advantage for women vs. men is seen for characteristics such as stage at presentation, site of primary tumour, and survival time, an adverse effect of pregnancy on melanoma development and progression has been reported. In a retrospective study, we investigated the tumour characteristics of women who developed pregnancy-associated melanoma, and compared them with melanomas arising in non-pregnant women of child-bearing age. The patient records of the Massachusetts General Hospital Pigmented Lesion Clinic were reviewed, and 465 women of reproductive age (16-45 years) who developed melanoma were identified. Of these, in 45 women (age 21-42 years) there was a close temporal relationship between diagnosis of the tumour and pregnancy. Clinical and histological characteristics of the primary tumours were recorded. Differences in tumour thickness, site and histological type were analysed. The mean thickness of pregnancy-associated melanomas was significantly greater than that of non-pregnancy-associated tumours (2.28 vs. 1.22 mm, respectively; P < 0.007). No differences in histological type (P = 0.64) or site (P = 0.74) of the primary tumours were found between the two patient groups. Not surprisingly, multivariate analysis revealed that tumour thickness was a statistically significant variable in determining prognosis (P = 0.001). An unexpected finding, on multivariate analysis, was a possible pregnancy-associated prognostic advantage (P = 0.08). Melanomas arising during pregnancy are thicker, but are not necessarily associated with a less favourable prognosis than tumours arising in non-pregnant women of child-bearing age.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Histologic spectrum of cutaneous involvement in patients with myelogenous leukemia including the neutrophilic dermatoses.

BACKGROUND: Cutaneous manifestations of myeloid leukemia can be specific or nonspecific. The study was designed to determine the prevalence and histologic appearance of cutaneous lesions in patients with myeloid leukemia and various myeloproliferative disorders. METHODS: The histologic changes of cutaneous lesions in 52 patients with myelodysplastic syndrome, polycythemia vera, and myeloid, myelomonocytic, or monocytic leukemia are presented in this study. RESULTS: Two types of cellular infiltrates were identified. In the first group, the most common pattern was a diffuse involvement by the leukemic cells through the entire dermis with preservation of a "grenz zone" in the superficial dermis. Two cases exhibited a Kaposi's sarcoma-like pattern, with prominent slit-like blood-filled spaces lined by myeloblasts against a fibrocellular stroma. The second group of lesions was characterized by dense, neutrophilic dermal infiltrates resembling acute neutrophilic dermatosis (Sweet's syndrome) or pyoderma gangrenosum. In two of these cases, scattered immature blast cells admixed with the mature neutrophilic elements were identified. CONCLUSIONS: Awareness of these different morphologic features and application of special stains are of value in the evaluation of suspicious cutaneous infiltrates in patients with myeloid leukemia and various myeloproliferative disorders.

Adult↗