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M C Mihm

Publications and source records attributed to M C Mihm.

At least 109 records · Page 6Linked to original sources
PubMed1993

Perinodular injection of thymopentin (TP5) in cutaneous and subcutaneous metastases of melanoma.

The potential therapeutic efficacy of TP5 in patients with cutaneous and subcutaneous metastases of melanoma was tested in a double-blind study comparing the drug and placebo injected perinodularly. Of the 47 nodules present in the 16 patients treated with TP5, 24 showed a measurable response, whereas only one out of 15 nodules in patients treated with a placebo showed a minor response (P = 0.02). In two patients treated with TP5 a response of two nodules not perinodularly injected was also observed. Sclerosis, CD45RO+ cells and MIB 1- cells were more frequently observed in nodules treated with TP5 than with placebo. (P = 8 x 10(-4); 0.03 and 0.01, respectively). Evaluating the trends of these findings in nodules treated with placebo; with TP5-treated, non-responding nodules; or with TP5-treated, responding, a positive trend was observed for sclerosis and CD45RO+ cells (P = 5 x 10(-4) and 2 x 10(-3), respectively) and a negative one for MIB 1 cells (P = 2 x 10(-3)). These preliminary data suggest that lymphoid cells associated with nodules regression are activated large lymphocytes (CD45RO+ and CD3-). Sclerosis might be interpreted as the final morphologic event, and reduction of proliferative activity (MIB 1- cells) as the consequence of cytolytic action.

CD3 Complex↗
PubMed1993

Migration of human melanoma cells on hyaluronate is related to CD44 expression.

Phenotypic and functional aspects of melanoma-hyaluronate interactions were investigated by studying the expression of CD44, cell migration, and transmembrane penetration of human melanoma cell lines on hyaluronate-coated substrates. Expression of CD44 was tested by flow cytometry on seven human melanoma cell lines. Strong reactivity with anti-CD44 monoclonal antibody was observed in four of seven of the cell lines. Migration studies of CD44(+) cell lines on hyaluronic acid- and chondroitin-6-sulfate-coated substrates, using time-lapse video-microscopy, showed a dramatic dose-dependent increase in migration rate on hyaluronate but not on chondroitin-6-sulfate. Moreover, CD44(-) cell lines showed no modification in migration rate on either substrate. Addition of soluble hyaluronate produced a dose-dependent inhibition of acceleration of CD44(+)cells on hyaluronate-coated substrates, whereas addition of chondroitin-6-sulfate had no effect. Migration inhibition experiments with soluble CD44 (CD44 receptor globulin) also showed specific blocking of the migration of CD44(+) cells on hyaluronate. Haptotactic invasion was increased in CD44(+) cell lines through hyaluronate-coated polycarbonate membranes, whereas no change was detected on chondroitin-6-sulfate-coated membranes. CD44(-) cell lines showed no response to either type of coating. In the melanoma cell lines tested, the expression of CD44 correlated with in vitro migration and invasiveness on hyaluronate substrates. Taken together, our data are consistent with the suggestion that CD44 may play a role in stimulating in vivo aggressiveness of tumors through hyaluronate-rich stroma.

Cell Movement↗
PubMed1993

Histopathologic recognition and grading of dysplastic melanocytic nevi: an interobserver agreement study.

Before the controversies surrounding dysplastic melanocytic nevi are resolved, dermatopathologists must be able to reliably distinguish dysplastic nevi from common acquired nevi and malignant melanoma. To establish whether grading of melanocytic dysplasia has any biologic relevance, dermatopathologists must be able to consistently recognize two or more grades of atypia. We studied the concordance among five dermatopathologists for recognition and grading of 60 nevomelanocytic lesions. Ten cases from each of the following categories of melanocytic proliferation were retrieved from the Massachusetts General Hospital files: 1) common melanocytic nevi, 2) melanocytic nevi with features of dysplastic nevi, 3) dysplastic nevi with slight cytologic atypia, 4) dysplastic nevi with moderate cytologic atypia, 5) dysplastic nevi with severe cytologic atypia, and 6) primary malignant melanoma. The slides were reviewed independently; no discussion of diagnostic criteria preceded the review. Overall concordance for diagnosing dysplastic nevi was 77%, with a kappa statistic of 0.55-0.84. Furthermore, in grading dysplastic nevi, experienced dermatopathologists had a concordance ranging from 35% to 58% (kappa value 0.38-0.47). Those with less experience in grading dysplastic nevi had a concordance of 16-65% (kappa value 0.05-0.24). The five observers in this study reliably distinguished dysplastic nevi from common acquired nevi and malignant melanoma. Further refinement of the criteria for grading of nevo-melanocytic dysplasia and experience in grading are critical for accuracy in subcategorization of dysplastic nevi. Consistent, reproducible subcategorization of dysplastic nevi is a requisite before the issue of biologic or prognostic relevance of grading (dysplastic nevi) can be addressed. This study supports the validity of existing criteria for the diagnosis of dysplastic nevi because the problems in diagnosis were at the limits of the spectrum, namely, discrimination of slightly atypical dysplastic nevi from common nevi and severely atypical dysplastic nevi from radial growth phase melanoma.

Dysplastic Nevus Syndrome↗
PubMed1993

Role of integrin alpha 2 beta 1 (VLA-2) in the migration of human melanoma cells on laminin and type IV collagen.

The random cell migration of four human melanoma cell lines on laminin and type IV collagen-coated substrates was studied by video time-lapse image analysis and compared to the expression of a number of beta 1 integrins including alpha 1 beta 1, alpha 2 beta 1, alpha 3 beta 1, and alpha 6 beta 1 using flow cytometry. These integrins were heterogeneously expressed in the four cell lines tested with three of four lines expressing alpha 2 beta 1. The melanoma cell line that did not express alpha 2 beta 1 exhibited weak attachment and low cell migration rate on both laminin and type IV collagen, whereas the other melanoma cell lines showed an increase in attachment and mean cell migration rate in a dose-dependent manner on the matrix molecules (p < 0.001). The enhanced migration seen in the three cell lines could be specifically inhibited by function blocking anti-beta 1 and anti-alpha 2 monoclonal antibodies (p < 0.001) but not by function blocking anti-alpha 3 and anti-alpha 6 monoclonal antibodies. Image analysis of the cells before and after treatment with anti-beta 1 and anti-alpha 2 MoAb indicated that the inhibition of migration did not result in detectable cell detachment, retraction of cell processes, or other significant cell-shape change. Taken together, the findings suggest that the observable enhanced migration on laminin and type IV collagen of a number of human melanoma cell lines is largely mediated by integrin alpha 2 beta 1.

Antibodies, Monoclonal↗
PubMed1993

Benign trichogenic tumours: a report of two cases supporting a simplified nomenclature.

We report two cases of a rare benign tumour of hair germ. Clinically, both were solitary, well-circumscribed, subcutaneous nodules located in the extremities. Histologically, the tumours were characterized by nests and thin cords of basaloid epithelial cells intimately associated with a cellular stroma. The basaloid cells exhibited peripheral palisading, keratinization in the form of keratotic cysts and squamoid transformation, and pilar differentiation. An unusual, but distinctive, cribriform pattern of growth was observed. There was no communication with the overlying epidermis. Abundant primitive hair germinal buds and rare more advanced abortive hair follicles were identified. These histological appearances encompass features of both trichoblastic fibroma and trichogenic trichoblastoma, thus distinguishing these neoplasms from other skin tumours and reinforcing the hypothesis that these tumours are closely related from a histogenetic point of view. The presence of overlapping histological features can be problematic for practising histopathologists who rarely encounter these conditions. With this in mind, the term benign trichogenic tumour may be more appropriate to encompass these two tumours and related neoplasms that appear to lie within the spectrum of hair follicle development.

Adult↗
PubMed1993

Common acquired melanocytic nevi, dysplastic melanocytic nevi and malignant melanomas: an image analysis cytometric study.

We used computerized image analysis cytometry to analyze 10 melanocytic lesions from each of the following categories: common acquired nevi, melanocytic nevi with architectural features of dysplasia, dysplastic melanocytic nevi (DMN) with slight atypia, DMN with moderate atypia, DMN with severe atypia, and superficial spreading melanomas. The nuclei of at least 50 consecutive nevomelanocytes in the most atypical zones were digitized at x 1000 under oil immersion, without knowledge of diagnosis by one observer. Grading of atypia was based on current practices as described in the literature. The results showed significant differences (p < 0.05) in nuclear area and standard deviation of nuclear area between melanoma and DMN with severe atypia, and between DMN with severe atypia and all other categories of nevi. There were no differences among any lesions with respect to nuclear shape. No differences in nuclear area were found among DMN with moderate, or slight atypia, nevi with features of dysplasia, and typical nevi. These results show for the first time objective distinction of low-grade (slight-moderate atypia), and high-grade or severe atypia in pre-malignant nevomelanocytic lesions of the skin.

Humans↗
PubMed1993

Histologic regression in malignant melanoma: an interobserver concordance study.

Histologic evidence for regression as a prognostic indicator in melanoma has shown conflicting results. To assess if melanoma regression is a consistently identifiable histologic feature, an interobserver concordance study was undertaken. Fifty histologic slides of melanoma with Breslow thickness of 1 mm or less were non-randomly selected from the Massachusetts General Hospital Melanoma Registry. The selection was in favor of those with regression present in 44 of 50 slides (88%). Two dermatopathologists working independently evaluated a 2 mm wide bracketed area in each tissue section and then the remainder of the non-bracketed tissue section for regression. Before and after each slide review, the evaluators were required to read criteria for early, intermediate, and late regression explicitly outlined. The overall concordance rate for the presence and absence of regression was 96% (48/50) in the bracketed area and 90% for the outside area. When the group with regression was subdivided into three stages, interobserver agreement fell to 86% for the bracketed, and 66% for the outside area. In at least 30% of cases where regression was detected in the bracketed area, both reviewers observed two or more stages of regression in the remainder of tissue section. Therefore, subdividing the process is impractical and unrealistic. Consistent histologic identification of regression in melanoma requires a simple and systematic approach which should be applied to future studies that include melanoma regression as a prognostic factor.

Humans↗
PubMed1993

Role of beta-1 integrins in organ specific adhesion of melanoma cells in vitro.

BACKGROUND: Recent data suggest that the extracellular matrix of organs and heterogeneous integrin expression of tumor cells may influence metastasis distribution. EXPERIMENTAL DESIGN: Three human melanoma cell lines were characterized for integrin expression, in vitro binding to cryostat sections of different organs, and ability to generate experimental metastases in triple immunodeficient mice. RESULTS: The three cell lines exhibited heterogeneous expression of integrins, binding to cryostat sections, and organ colonization. A primary melanoma cell line (PM-WK) did not give rise to experimental metastases, showed scant or mild attachment to only a few organ tissue sections, and showed absent or minimal expression of alpha-integrin subunits tested (VLA 1-6) and alpha v beta 3. In contrast, two lymph node derived lines exhibited distinct patterns of organ colonization: MM-RU colonized only the lungs and expressed predominantly alpha 2 beta 1 and alpha v beta 3 integrin, whereas MM-AN colonized lung and extrapulmonary sites including pancreas and subcutaneous brown fat and expressed predominantly alpha 2 beta 1 and alpha 6 beta 1 integrin. In vitro, MM-RU exhibited marked attachment to lung, brown fat, kidney, and adrenal with no binding to liver, pancreas, brain, or muscle tissue sections, whereas MM-AN had a similar binding profile but with additional attachment to liver and pancreas. Function blocking anti-beta 1 monoclonal antibody inhibited the attachment of MM-RU and MM-AN cells to these tissues (p < 0.001), whereas function blocking anti-alpha 5 and an unrelated monoclonal antibody (HLA class I) did not. Function blocking anti-alpha 2 monoclonal antibody inhibited MM-RU cell adhesion (p < 0.001) but not MM-AN adhesion. However, the function blocking monoclonal antibody alpha 6 beta 1 significantly inhibited the binding of MM-AN to these tissues. CONCLUSIONS: These data suggest that alpha 2 beta 1 and alpha 6 beta 1 mediate differential melanoma cell attachment to organ tissue sections in vitro and that differences in integrin expression of these melanoma cells may be involved in differential organ colonization in vivo.

Animals↗
PubMed1993

Organ-specific metastases in immunodeficient mice injected with human melanoma cells: a quantitative pathological analysis.

Pathological and morphometric techniques were used to investigate the potential of two human melanoma cell lines for organ colonization in three different immunodeficient mouse strains; nude (nu/nu), NIH triple immunodeficient (TID: nu/nu, bg/bg, xid/xid) and severe combined immunodeficient (SCID) mice. The MM-RU cell line gave rise exclusively to lung metastases, whereas the MM-AN cell line gave rise to lung and extrapulmonary metastases. Although the TID mice showed more pancreatic and brown fat lesions than nude or SCID mice, the overall pattern of distribution of organ metastases among the strains was similar, suggesting that cellular properties intrinsic to the melanoma cells are important for the colonization of specific organs. The metastatic nodules were well circumscribed in all organs and exhibited peripherally located macrophages, except for brain metastases, where a more invasive pattern along vasculature was observed. The differences in cellular infiltrate and infiltrative patterns of the tumors implicate features of the host microenvironment (organ-specific factors) which are, at least in part, independent of the host's genetic background or degree of immunodeficiency. Our findings suggest that intrinsic malignant cellular properties play an important role in organ-specific colonization by haematogenously metastasizing cells.

Adipose Tissue, Brown↗
PubMed1993

The histopathology of cutaneous malignant melanoma.

The vast majority of cutaneous malignant melanomas (CMM) develop from a proliferation of intraepidermal melanocytes that may progress through radial (including in situ and microinvasive stages) and vertical growth phases (VGP). The currently accepted classification of melanoma is based on the presence (eg, superficial spreading, lentigo maligna, or acral lentiginous melanoma) or absence of a radial growth phase (nodular melanoma). Although not standardized, melanoma may also be classified as to the nature of the VGP, eg, as expansile nodules composed of epithelioid cells, spindle cells, or smaller nevus-like cells supervening on one of the radial growth components previously mentioned, or developing de novo. Less common variants of the VGP include desmoplastic and neurotropic melanomas (often arising with lentiginous melanomas), and the controversial (and perhaps mainly conceptual) entity, minimal deviation melanoma. Other unusual or rare forms of melanoma are malignant blue nevus, balloon cell melanoma, and clear cell sarcoma. An extensive discussion of the differential diagnosis of the various types of melanoma is provided.

Cell Division↗
PubMed1992

Multiple primary cutaneous melanomas.

BACKGROUND: Development of multiple primary cutaneous melanomas is a well-recognized phenomenon. As with single primary melanoma, personal and family histories of melanoma and dysplastic nevi (DN) are considered important risk factors. The natural history and impact of regular follow-up evaluation of this entity were examined. METHOD: Through a search of the computerized data bank of the Pathology Department and the Melanoma Registry of the Pigmented Lesion Clinic at Massachusetts General Hospital, 41 patients with multiple cutaneous melanomas were identified. RESULTS: Mean (+/- standard error) age at first diagnosis was 49 +/- 2 years (range, 21-75 years). The male to female ratio was 2:1. The median number of primary melanomas was two (88%). Three patients had three and one had five. Melanoma types included superficial spreading (70%), nodular (8%), lentigo maligna (2%), and unclassified (10%), and in 7% the type was unknown. Nineteen (46%) patients had histologic and/or clinical evidence of DN. For the group with DN, the mean age at first diagnosis (44 +/- 3 years) was significantly less than that of patients without DN (54 +/- 3 years) (P less than 0.05). Family history of melanoma was found in 10 patients (24%). Multiple melanomas were diagnosed concurrently in 16 patients (39%), whereas in 25 (61%) diagnosis was sequential. For the latter group, the mean tumor thickness from the first (1.21 +/- 0.28 mm) to the second melanoma (0.51 +/- 0.08 mm) decreased significantly (P less than 0.05); the median time interval was 36 months (range, 2-372 months). CONCLUSION: These data confirm the need for complete skin examination for patients with newly diagnosed melanoma; and, with subsequent melanomas appearing as long as 31 years after the first melanoma, continued follow-up with complete skin examinations seems prudent.

Adult↗
PubMed1992

Integrin expression in malignant melanoma and their role in cell attachment and migration on extracellular matrix proteins.

The interaction between melanoma cells and extracellular matrix (ECM) components may be important for invasion and metastasis. The integrins belong to a family of protein heterodimers composed of alpha and beta subunits and the beta 1-integrins are especially important as ECM receptors. We investigated the expression of beta 1-integrins on four human melanoma cell lines (two primary, one from the radial growth phase (RGP) and another from the vertical growth phase (VGP), and two metastatic) and examined their attachment and migration on laminin (LN), type IV collagen (CN) and fibronectin (FN). Among LN and/or CN integrin receptors, only alpha 2 beta 1 (VLA2) was expressed at significantly higher levels in the VGP and metastatic cell lines in comparison to the RGP cell line. In addition, enhanced attachment and migration on LN and CN were significantly inhibited by anti-VLA2 monoclonal antibody (mAb). As to FN receptors, alpha 4 beta 1 and alpha 5 beta 1 expression was heterogeneous among the cell lines, however, it was directly related to enhanced attachment and migration on FN, which also could be inhibited by anti-VLA4 and anti-VLA5 mAbs. Our findings provide evidence for a role in beta 1-integrins, in particular alpha 2 beta 1, in melanoma progression and metastasis.

Cell Adhesion↗
PubMed1992

Actin organization and cell migration of melanoma cells relate to differential expression of integrins and actin-associated proteins.

We have recently described marked differences in cell migration rates and organization of actin in human melanoma cell lines isolated from various stages of tumor progression. Metastatic lines derived from lymph node metastases organized actin into stress fiber arrays and had high mean migration rates in vitro when compared to lines from other stages. Melanoma cells also reveal marked differences in localization of alpha-actinin and beta 1 integrins at stress fiber termination sites (focal contacts). Disruption of this organization is induced by antibodies against beta 1 integrins, alpha-actinin, recently postulated as having a role in linkage of actin to beta 1 integrins, is differentially expressed in melanoma cells by Northern blot analysis and a relatively high alpha-actinin to actin ratio is associated with stress fiber formation and increased cell migration. Furthermore, actin-binding protein, which cross-links actin filaments, is also significantly increased in lines exhibiting high migration rates. Control of migration and actin organization may be mediated by extracellular matrices and/or modulation of actin-associated proteins including alpha-actinin and actin binding protein. These findings provide evidence that an interaction of transmembrane adhesion molecules and elements of the cytoskeleton in melanoma cells may be responsible for differences in migration rates and capacity for metastasis.

Actinin↗
PubMed1992

Desmoplastic melanoma.

Desmoplastic melanoma is a rare tumour of which a limited number of cases have been described. The clinical and histopathological features of desmoplastic melanoma and its variants may give rise to perplexing diagnostic and therapeutic dilemmas. In the past decades, some insight has been gained into the histogenesis of these lesions and discriminating clinical and morphological features are now recognized. Review of the literature reveals an extensive list of differential diagnoses. Adequate surgical excision and close follow-up of these radioresistant, frequently-recurring tumours is strongly advocated.

Diagnosis, Differential↗
PubMed1992

Image analysis of stage 1 melanoma (1.00-2.50 mm): lymphocytic infiltrates related to metastasis and survival.

Image analysis of histologic sections of 11 patients with clinical Stage 1 melanoma, 1.00 mm-2.50 mm, who developed metastasis, was done to determine the significance of lymphocytic infiltrates relative to metastasis and survival. An age, sex, site, and thickness matched control group of non-metastasizing clinical Stage 1 melanoma revealed no significant difference in the lymphocytic infiltrate parameters from the metastasizing group with the exception of the ratio of lymphocyte infiltrate width to the tumor width (p = 0.003). Increased lymphocytic infiltrates within the tumor and subjacent to its base significantly correlated with delayed time to metastasis (p = 0.014 and p < 0.001, respectively) and longer survival period (p = 0.045 and p < 0.001, respectively). Lymphocytic infiltrate area at the tumor base in relation to tumor area was of prognostic value: the larger the ratio, the greater the time interval from metastasis to death (p = 0.008).

Humans↗
PubMed1992

Occurrence of melanoma in "dysplastic" nevus spilus: report of case and analysis by flow cytometry.

We report a case of melanoma arising in a large nevus spilus. On histologic examination, the nevus spilus had diagnostic features of melanocytic dysplasia. Further characterization by flow cytometry showed DNA-aneuploidy within the melanoma as well as in one of the darker pigmented papules within the nevus spilus. The significance of this finding and a review of melanomas originating in nevi spili are presented.

Adult↗
PubMed1992

Desmoplastic melanoma: clinicopathologic aspects of six cases.

We report 6 cases of desmoplastic melanoma. Upon removal and histologic examination, each lesion consisted of a dermal nodule of fascicles of spindle cells, many of which showed pleomorphic and hyperchromatic nuclei. Fascicles, as well as single cells, were seen infiltrating the dermal collagen. Lentiginous hyperplasia of melanocytes with varying but usually slight cellular atypia overlay the dermal proliferations in all cases. Melanophages and some pigmented cells, albeit few in number, were present in the infiltrate, whereas mitotic figures were also noted. These features are most consistent with desmoplastic melanoma, a rare tumor of which a limited number of cases has been described. The clinical and histopathologic features of the lesions presented exemplify the diagnostic and therapeutic dilemma associated with desmoplastic melanoma.

Adult↗