BRAF V599E mutation occurs in Spitz and Reed naevi.
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DNA Mutational Analysis↗
Biomedical subjects
M C Mihm
Publications and source records attributed to M C Mihm.
Dermal dendritic melanocytic proliferations: an update.
Dermal dendritic melanocytic proliferations are a broad group of congenital and acquired melanocytic lesions characterized by the presence of dermal spindled and dendritic cells resembling melanocytes migrating from the neural crest to the epidermis. Historically, they were subdivided into dermal melanocytoses (naevus of Ota, Ito, Mongolian spot and related conditions), blue naevi and malignant blue naevi. The purpose of this review is to provide an update on recent developments in the field with emphasis on new entities and their differential diagnosis.
Animals↗
[Laser and intense pulsed light in the treatment of infantile haemangiomas and vascular malformations].
The use of the indications of the laser in treating vascular malformations and infantile haemangiomas is based on the theory of selective photothermolysis, in which the oxyhaemoglobin is the target chromophore on which the light of the laser acts, thus avoiding damage to neighbouring tissues. The pulsed dye laser is the most employed and at present is the treatment of choice in capillary malformations (port-wine stains). A variable response is obtained, with a substantial clearing of the colour of the lesion after several sessions. Application at early ages seems to improve the results. Venous malformations, especially those localised in the mucosa, respond better to the Nd:YAG laser; lymphatic malformations to the CO2 laser. Arteriovenous malformations rarely respond. Use of the pulsed dye laser in the phase of proliferation of the haemangiomas is subject to controversy, except where there is ulceration. A rapid re-epithelialization is obtained in these cases following its use. In the involution phase, patients with residual vascular lesions can benefit from other lasers such as KTP or Nd:YAG. If they show an atrophic surface and scars these complications improve with the CO2 laser or Er:YAG. New treatment modalities are emerging, such as photodynamic therapy, whose efficacy and safety, both in the treatment of haemangiomas and vascular malformations, have yet to be confirmed.
Blood Vessels↗
The use of selective lymphadenectomy in malignant blue naevus of the scalp.
Malignant blue naevus (MBN) is a rare cutaneous tumour with a close biological resemblance to malignant melanoma. MBN spreads to regional lymph nodes, creating a dilemma in managing patients with clinically negative nodal basins. Sentinel lymph node (SLN) biopsy has evolved as a powerful staging tool by identifying occult metastatic nodal disease in patients with cutaneous malignancies. Here, we report a patient with MBN of the occipital scalp who underwent wide local excision together with preoperative lymphoscintigraphy and intraoperative radiolymphoscintigraphy and vital dye injection to identify all draining SLNs. No occult nodal disease was identified. This report adds to the growing body of literature supporting the role of SLN biopsy in staging individuals with cutaneous malignancies, including MBN.
Adult↗
Reply to the article "The AJCC staging proposal for cutaneous melanoma: comments by the EORTC Melanoma Group", by D. J. Ruiter et al. (Ann Oncol 2001; 12: 9-11). American Joint Committee on Cancer.
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Humans↗
Congenital nonprogressive hemangioma: a distinct clinicopathologic entity unlike infantile hemangioma.
BACKGROUND: Infantile hemangiomas are common tumors, distinctive for their perinatal presentation, rapid growth during the first year of life, and subsequent involution-and for their expression of a unique immunophenotype shared by placental microvessels. Occasional "hemangiomas" differ from the classic form in presenting fully formed at birth, then following a static or rapidly involuting course. These congenitally fully developed lesions have generally been assumed to be clinical variants of more typical, postnatally developing hemangiomas. This assumption has not been tested by rigorous histologic and immunophenotypic comparisons. OBJECTIVE: To compare the histologic and immunohistochemical features of congenital nonprogressive hemangiomas with those of typical, postnatally proliferating, hemangiomas. DESIGN: All cellular vascular tumors resected from infants younger than 4 months at Arkansas Children's Hospital, Little Rock, over the past 20 years (43 lesions from 36 patients) were first characterized histologically and immunohistochemically, then clinically by chart review. SETTING: A university-affiliated pediatric hospital. MAIN OUTCOME MEASURES: Histologic appearance, immunoreactivity for the infantile hemangioma-associated antigens GLUT1 and LeY, and clinical behavior. RESULTS: Congenital nonprogressive hemangiomas differed from postnatally proliferating infantile hemangiomas in histologic appearance and immunohistochemical profile. Distinguishing pathologic features of these tumors were lobules of capillaries set within densely fibrotic stroma containing hemosiderin deposits; focal lobular thrombosis and sclerosis; frequent association with multiple thin-walled vessels; absence of "intermingling" of the neovasculature with normal tissue elements; and lack of immunoreactivity for GLUT1 and LeY. CONCLUSION: Congenital nonprogressive hemangiomas are histologically and immunophenotypically distinct from classically presenting hemangiomas of infancy, unlikely to be related to the latter in pathogenesis.
Female↗
Long-term results of a prospective surgical trial comparing 2 cm vs. 4 cm excision margins for 740 patients with 1-4 mm melanomas.
BACKGROUND: The Intergroup Melanoma Surgical Trial began in 1983 to examine the optimal surgical margins of excision for primary melanomas of intermediate thickness (i.e., 1-4 mm). There is now a median 10-year follow-up. METHODS: There were two cohorts entered into a prospective multi-institutional trial: (1) 468 patients with melanomas on the trunk or proximal extremity who randomly received a 2 cm or 4 cm radial excision margin and (2) 272 patients with melanomas on the head, neck, or distal extremities who received a 2 cm radial excision margin. RESULTS: A local recurrence (LR) was associated with a high mortality rate, with a 5-year survival rate of only 9% (as a first relapse) or 11% (anytime) compared with an 86% survival for those patients who did not have a LR (P < .0001). The 10-year survival for all patients with a LR was 5%. The 10-year survival rates were not significantly different when comparing 2 cm vs. 4 cm margins of excision (70% vs. 77%) or comparing the management of the regional lymph nodes (observation vs. elective node dissection). The incidences of LR were the same for patients having a 2 cm vs. 4 cm excision margin regardless of whether the comparisons were made as first relapse (0.4% vs. 0.9%) or at anytime (2.1% vs. 2.6%). When analyzed by anatomic site, the LR rates were 1.1% for melanomas arising on the proximal extremity, 3.1% for the trunk, 5.3% for the distal extremities, and 9.4% for the head and neck. The most profound influence on LR rates was the presence or absence of ulceration; it was 6.6% vs. 1.1% in the randomized group involving the trunk and proximal extremity and was 16.2% vs. 2.1% in the non-randomized group involving the distal extremity and head and neck (P < .001). A multivariate (Cox) regression analysis showed that ulceration was an adverse and independent factor (P = .0001) as was head and neck melanoma site (P = .01), while the remaining factors were not significant (all with P > .12). CONCLUSION: For this group of melanoma patients, a local recurrence is associated with a high mortality rate, a 2-cm margin of excision is safe and ulceration of the primary melanoma is the most significant prognostic factor heralding an increased risk for a local recurrence.
Humans↗
Automatic differentiation of melanoma from melanocytic nevi with multispectral digital dermoscopy: a feasibility study.
BACKGROUND: Differentiation of melanoma from melanocytic nevi is difficult even for skin cancer specialists. This motivates interest in computer-assisted analysis of lesion images. OBJECTIVE: Our purpose was to offer fully automatic differentiation of melanoma from dysplastic and other melanocytic nevi through multispectral digital dermoscopy. METHOD: At 4 clinical centers, images were taken of pigmented lesions suspected of being melanoma before biopsy. Ten gray-level (MelaFind) images of each lesion were acquired, each in a different portion of the visible and near-infrared spectrum. The images of 63 melanomas (33 invasive, 30 in situ) and 183 melanocytic nevi (of which 111 were dysplastic) were processed automatically through a computer expert system to separate melanomas from nevi. The expert system used either a linear or a nonlinear classifier. The "gold standard" for training and testing these classifiers was concordant diagnosis by two dermatopathologists. RESULTS: On resubstitution, 100% sensitivity was achieved at 85% specificity with a 13-parameter linear classifier and 100%/73% with a 12-parameter nonlinear classifier. Under leave-one-out cross-validation, the linear classifier gave 100%/84% (sensitivity/specificity), whereas the nonlinear classifier gave 95%/68%. Infrared image features were significant, as were features based on wavelet analysis. CONCLUSION: Automatic differentiation of invasive and in situ melanomas from melanocytic nevi is feasible, through multispectral digital dermoscopy.
Diagnosis, Differential↗
Microphthalmia transcription factor expression in cutaneous benign, malignant melanocytic, and nonmelanocytic tumors.
The protein encoded by the microphthalmia (mi) gene is a transcription factor essential for the development and survival of melanocytes. Using a monoclonal antibody generated against human Mi transcription factor protein (Mitf) the authors previously demonstrated that Mitf expression is conserved in primary and metastatic malignant melanomas, and appears to be a highly sensitive and specific melanocytic marker. Mitf expression in various cutaneous nevi and cutaneous nonmelanocytic tumors has not been documented systematically. The authors evaluated Mitf immunostaining in 62 benign nevi, 58 primary cutaneous melanomas, and 53 nonmelanocytic tumors. Mitf immunostaining was conserved in all benign nevi, with Spitz nevi and neurotized nevi demonstrating decreased staining intensity. With the exception of desmoplastic melanomas, all primary cutaneous melanomas were immunopositive regardless of the cell type. Only one of 14 desmoplastic melanomas was Mitf positive. None of the nonmelanocytic tumors was immunopositive, including those lesions that may resemble melanoma histologically (spindle cell carcinomas, atypical fibroxanthomas, and leiomyosarcomas). The results demonstrate that Mitf antibody expression is conserved in the majority of benign and malignant melanocytic lesions, and that it may be helpful in the diagnosis of primary melanocytic skin lesions. Its use in desmoplastic melanomas is limited and is reflective of other melanocyte-associated antigens. Mitf discriminates between spindle cell nonmelanocytic tumors and melanomas with a spindle cell morphology, and is useful in a panel with other appropriate antibodies.
Antigens, Neoplasm↗
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.
Adolescent↗
Malignant melanoma.
CONTEXT: The rapidly developing fields of melanoma research are revolutionizing the current concepts on melanoma etiology and pathogenesis and are introducing newer diagnostic techniques and potential therapeutic approaches. OBJECTIVES: To present the most current concepts on the etiology and pathogenesis of melanoma and to introduce the recent diagnostic techniques and the potential therapeutic approaches. METHODS: Data sources were reports on melanoma published in the English language literature and observations made using specimens available at Harvard University, Johns Hopkins Medical Center, Albany Medical College, Loyola University Medical Center, and University of Tennessee Health Science Center. RESULTS: Studies on melanoma containing chromosomal or genetic evaluation were selected for further analysis. Current clinical and pathologic categories with the reported genetic abnormalities were related to the latest information on pigment biology. The data extracted were used to develop a conceptual framework on the pathogenesis of melanoma; the generated model was then evaluated and used to suggest potential therapeutic approaches. CONCLUSIONS: (1) Melanoma is not genetically homogeneous, and the existing differences between the pathologic categories, particularly in areas such as type of growth phase (radial vs vertical growth), total vertical dimension, ulceration of primary tumor, and metastatic process, have profound prognostic and therapeutic implications. (2) Chromosomal aberrations and gene mutations are found in sporadic and familial melanomas; among the most important are those affecting the 9p21, which contains the p16 locus, a site known to be critical for normal progression of the cell cycle. Aberrant p16 expression is associated with more aggressive behavior. (3) Melanoma cells possess a remarkable repertoire of biosynthetic capacities represented by the production of hormones, growth factors, and their receptors that may sustain and accelerate tumor development and progression. For example, expression of the tumoral products alpha-melanocyte-stimulating hormone and adrenocorticotropic hormone is regulated in vitro by ultraviolet light, a known carcinogen. (4) Melanomas differ from other tumors in their intrinsic capability to express melanogenic enzymes with the corresponding structural proteins to actually synthesize melanin. Melanogenesis-related proteins are rapidly entering the clinical arena, being used not only as diagnostic markers, but also as potential targets for melanoma therapy.
Chromosome Aberrations↗
A unique microvascular phenotype shared by juvenile hemangiomas and human placenta.
BACKGROUND: Juvenile hemangiomas are common, benign tumors, distinctive for their perinatal presentation, rapid growth during the first year of life, and subsequent involution. We recently reported that endothelia of hemangiomas highly express GLUT1, a glucose transporter normally restricted to endothelia with blood-tissue barrier function, as in brain and placenta. OBJECTIVE: To investigate possible further similarities between hemangioma and placental vessels. DESIGN: In a retrospective study of a variety of vascular tumors and anomalies, we assessed lesional immunoreactivities for the placenta-associated vascular antigens FcgammaRII, Lewis Y antigen (LeY), merosin, and GLUT1. SETTING: A university-affiliated pediatric hospital. MAIN OUTCOME MEASURE: Immunoreactivities scored for each antigen were summarized according to lesional type, compared with those of normal skin, brain, and placenta, and correlated with patient age, sex, and lesional location. RESULTS: All of 66 hemangiomas (patients aged 22 days to 7 years) showed intense immunoreactivity for FcgammaRII, merosin, LeY, and GLUT1. No immunoreactivities for these markers were seen in any of 26 vascular malformations, 4 granulation tissue specimens, 13 pyogenic granulomas, or in the tumor vasculature of 6 malignant tumors of nonvascular origin. Microvascular immunoreactivity for all 4 markers was observed in placental chorionic villi, but was absent in microvessels of normal skin and subcutis. Brain microvessels expressed only GLUT1 and merosin. CONCLUSIONS: A distinct constellation of tissue-specific markers is uniquely coexpressed by hemangiomas and placental microvessels. These findings imply a unique relationship between hemangioma and the placenta and suggest new hypotheses concerning the origin of these tumors.
Blood Vessels↗
Long-term results of a multi-institutional randomized trial comparing prognostic factors and surgical results for intermediate thickness melanomas (1.0 to 4.0 mm). Intergroup Melanoma Surgical Trial.
BACKGROUND: Ten- to 15-year survival results were analyzed from a prospective multi-institutional randomized surgical trial that involved 740 stages I and II melanoma patients with intermediate thickness melanomas (1.0 to 4.0 mm) and compared elective (immediate) lymph node dissection (ELND) with clinical observation of the lymph nodes as well as prognostic factors that independently predict outcomes. METHODS: Eligible patients were stratified according to tumor thickness, anatomical site, and ulceration, and then prerandomized to either ELND or nodal observation. By using Cox stepwise multivariate regression analysis, the independent predictors of outcome were tumor thickness (P < .001), the presence of tumor ulceration (P < .001), trunk site (P = .003), and patient age more than 60 years (P = .01). RESULTS: Overall 10-year survival was not significantly different for patients who received ELND or nodal observation (77% vs. 73%; P = .12). Among the prospectively stratified subgroups of patients, 10-year survival rates favored those patients with ELND, with a 30% reduction in mortality rate for the 543 patients with nonulcerated melanomas (84% vs. 77%; P = .03), a 30% reduction in mortality rate for the 446 patients with tumor thickness of 1.0 to 2.0 mm (86% vs. 80%; P = .03), and a 27% reduction in mortality rate for 385 patients with limb melanomas (84% vs. 78%; P = .05). Of these subgroups, the presence or absence of ulceration should be the key factor for making treatment recommendations with regard to ELND for patients with intermediate thickness melanomas. CONCLUSIONS: These long-term survival rates from patients treated at 77 institutions demonstrate that ulceration and tumor thickness are dominant predictive factors that should be used in the staging of stages I and II melanomas, and confer a survival advantage for these subgroups of prospectively defined melanoma patients.
Extremities↗
GLUT1: a newly discovered immunohistochemical marker for juvenile hemangiomas.
Juvenile hemangiomas are common, benign vascular tumors of infancy. These lesions enlarge rapidly through cellular hyperplasia during the first year of life and then involute over several years. Distinctive histopathologic features of hemangiomas diminish during this evolution, and differentiation from vascular malformations becomes increasingly difficult. This distinction has important therapeutic implications, as juvenile hemangiomas differ from malformations in natural history and in potential for recurrence. We report here that high endothelial immunoreactivity for the erythrocyte-type glucose transporter protein GLUT1 is a specific feature of juvenile hemangiomas during all phases of these lesions. In a retrospective study, we found intense endothelial GLUT1 immunoreactivity, involving more than 50% of lesional microvessels, in 97% (139 of 143) of juvenile hemangiomas from patients aged 1 month to 11 years. No endothelial GLUT1 immunoreactivity was found in any of 66 vascular malformations (17 arteriovenous, 33 venous, 11 lymphatic, and 5 port-wine) from patients aged 5 days to 75 years, or in any of 20 pyogenic granulomas or 7 granulation tissue specimens. Abundant Ki-67 positivity in these latter lesions established that GLUT1 expression does not simply reflect mitotically active endothelium. Focal GLUT1 immunoreactivity was found in 3 of 12 angiosarcomas, but not in any of 5 hemangioendotheliomas (epithelioid or infantile kaposiform). These findings establish GLUT1 immunoreactivity as a highly selective and diagnostically useful marker for juvenile hemangiomas. Because high levels of endothelial GLUT1 expression in normal tissue are restricted to microvessels with blood-tissue barrier function, these findings also have implications for the molecular and developmental pathogenic mechanisms of juvenile hemangiomas.
Adolescent↗
Progression to invasive melanoma from malignant melanoma in situ, lentigo maligna type.
We have previously hypothesized that lesions that have been termed lentigo maligna can be divided into 2 categories: 1 represents a pigmented lesion that is a precursor to melanoma, and the other melanoma in situ. We and others have hypothesized that there is a progressive acquisition of attributes in pigmented lesions that results in malignant melanoma. Based on these 2 hypotheses, we have predicted that the intraepidermal component of invasive malignant melanomas, lentigo maligna type, should be similar to those lesions that we have termed malignant melanoma in situ, lentigo maligna type rather than lentigo maligna. The intraepidermal component of 42 consecutive cases of invasive malignant melanoma, lentigo maligna type was evaluated by all of the authors. Malignant melanoma in situ, lentigo maligna type is characterized by pagetoid spread, confluence, and nesting of atypical melanocytes. All of the cases evaluated showed features diagnostic of malignant melanoma in situ, lentigo maligna type, in the epidermis overlying the invasive dermal component. We conclude that invasive lentigo maligna melanoma arises in association with those lesions that we have termed malignant melanoma in situ, lentigo maligna type, which may represent a step in the progression between atypical melanocytic hyperplasia (lentigo maligna) and invasive melanoma. This finding supports the distinction of these entities and may have therapeutic implications.
Aged↗
Warty (condylomatous) squamous cell carcinoma of the penis: a report of 11 cases and proposed classification of 'verruciform' penile tumors.
Within the spectrum of penile squamous cell carcinomas, those that we descriptively refer to collectively as the "verruciform" lesions are particularly difficult to subclassify. In a review of 50 such tumors, we found 11 distinctive neoplasms with condylomatous features conforming to the appearance of so-called "warty (condylomatous) carcinoma." The average patient age was 55 years and the average duration of disease was 19 months. The primary tumor involved multiple anatomic sites (glans, coronal sulcus, and foreskin) in seven cases and a single site (glans or foreskin) in four cases. Grossly, white to gray cauliflower-like tumors typically measuring approximately 5 cm were noted. Histologically the tumors were mainly papillomatous with acanthosis and hyperkeratosis. The papillae had prominent fibrovascular cores. The most conspicuous microscopic findings were striking nuclear atypia of koilocytotic type and clear cytoplasm. The interface between tumor and stroma was irregular in the majority of cases; deep invasion of corpus cavernosum was noted in five cases. The differential diagnosis included verrucous carcinoma, low-grade papillary squamous cell carcinoma, not otherwise specified, and giant condyloma acuminatum. Among other differences, the first two lesions show no koilocytotic changes and the last lacks malignant features and irregular stromal invasion. Metastatic spread occurred in two patients; both are alive with evidence of recurrent disease 12 and 72 months after initial diagnosis. A third patient was alive with recurrent disease 12 months after diagnosis. Five patients were free of disease 8, 12, 24, 52, and 108 months after diagnosis. Three patients were lost to follow up. Warty (condylomatous) carcinomas of the penis are morphologically distinctive verruciform neoplasms with features of human papillomavirus-related lesions and should be distinguished from other verruciform tumors so that differences in behavior, if any, between these tumors will become established.
Adult↗
Thin melanomas.
Thin melanoma refers to that grouping of melanomas that statistically have a good prognosis and survival rate. A small but significant percentage of these lesions metastasize and cause mortality. Histologically, these lesions comprise a diverse grouping of tumors of any intraepidermal growth pattern; in the radial or vertical growth phase; or in anatomic level I, II, III, or IV. Additional histologic findings may also be variably present, such as regression, tumor infiltrating lymphocytes, and mitoses. Molecular studies suggest that thin melanomas may have different properties to thicker and metastatic melanomas. The factors governing the ability of thin melanomas to metastasize and cause mortality are not known. Certain histologic and molecular parameters, some of which have been alluded to previously, may provide clues to understanding the parameters governing the aggressive nature of some of these lesions. Further research is required to enhance our understanding of thin melanomas.
Disease Progression↗
Detection of microscopic melanoma metastases in sentinel lymph nodes.
BACKGROUND: Sentinel lymph node biopsy following radioisotope labeling is a recently developed, minimally invasive surgical staging procedure used in the management of primary cutaneous malignant melanoma. If histologic analysis reveals melanoma metastasis in the sentinel lymph node, completion lymphadenectomy is performed and adjuvant therapy considered. The routine pathologic assessment of the sentinel lymph node consists of bisecting the lymph node along its long axis and histologic examination of one hematoxylin and eosin-stained section of each cut surface. METHODS: In this study, the authors reexamined 235 sentinel lymph nodes reported as negative for melanoma metastasis following routine histologic examination, from 94 patients with American Joint Committee on Cancer (AJCC) Stage I and II cutaneous melanoma. RESULTS: Deeper sections into the lymph node and immunohistochemical stains with antibodies to S-100, HMB-45, NK1C3, and MART-1 led to the identification of microscopic metastases in 11 sentinel lymph nodes from 11 patients and capsular nevi in 9 sentinel lymph nodes from 8 patients. CONCLUSIONS: Deeper serial sections and immunohistochemical stains detected microscopic metastases in approximately 12% of cases that would be reported as negative for metastasis by routine pathologic analysis. These techniques also allowed for the identification of capsular melanocytic nevi in the sentinel lymph nodes of 9% of patients. [See editorial on pages 551-2, this issue.]
Adult↗