[The therapy of malignant melanoma].
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Antineoplastic Agents↗
Biomedical subjects
H Kerl
Publications and source records attributed to H Kerl.
[The modern diagnosis of malignant melanoma].
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Diagnosis, Differential↗
Effect of dequalinium on K1735-M2 melanoma cell growth, directional migration and invasion in vitro.
Cationic lipophilic compounds have an antiproliferative effect on certain tumour systems in vitro and in vivo. We have investigated whether the cationic lipophilic compound dequalinium affects not only proliferation but also motility and invasion of the highly metastatic and highly invasive melanoma cell line K1735-M2. Proliferation was assessed in monolayer cultures and in multicellular spheroids, motility was estimated in the assay of directional migration, and invasiveness was tested through confrontation cultures of tumour multicellular spheroids with embryonic chick heart tissue evaluated by computerized image analysis. 2 mumol/l dequalinium impaired melanoma cell proliferation, reduced directional migration and significantly blocked invasion in vitro. On the ultrastructural level, dequalinium caused obvious changes in mitochondria of both melanoma and embryonic chick heart cells. The mechanisms of the antiproliferative, antimigrating and antiinvasive effects remain to be determined. Inhibition of protein kinase C, calmodulin antagonism, DNA intercalation and/or direct effects on mitochondrial functions may be considered.
Animals↗
Relationship of tumor cell motility and morphologic patterns. Part 1. Melanocytic skin tumors.
In the diagnosis of melanocytic skin tumors, the assessment of the overall architectural pattern (silhouette) is often essential. We have previously shown by a computer simulation model that tumor patterns are likely to depend on the relative degrees of proliferation and motility of the tumor cells. In this study, we examined the morphological pattern of 12 cases each of nevocellular nevi, primary melanoma, and metastatic melanoma by image analysis. The patterns of the individual melanocytic skin tumors were compared statistically with patterns generated by computer simulation, which facilitates estimates of biological properties of the tumor cells. Additionally, mitotic counts were made to measure tumor cell proliferation. A comparison of the three diagnostic groups revealed that the cells of nevocellular nevi show a low degree of motility, which, however, still exceeds the very low degree of proliferation. Thus, an "invasive" pattern with numerous small nests and single cells at the base of the lesion is common. In primary malignant melanoma, tumor cell motility and tumor cell proliferation are significantly increased in various proportions, thus leading to varying morphological patterns. In metastatic melanoma, a strikingly elevated degree of proliferation exceeds the only slightly elevated degree of motility and leads to sharply demarcated, "expansive" lesions. To check the validity of the technical procedure, estimates of proliferation based on pattern analysis alone were compared with the results obtained by mitotic counts. There was a significant correlation, indicating that the assumptions of the computer model and the image analysis procedure are in fact applicable to real-life melanocytic skin tumors.(ABSTRACT TRUNCATED AT 250 WORDS)
Cell Division↗
Relationship of tumor cell motility and morphologic patterns. Part 2. Analysis of tumor cell sublines with different motility in vitro.
We have previously demonstrated by computer simulation that the relationship of proliferation and motility is likely to influence the morphological pattern of a tumor. Our study of a set of melanocytic skin tumors provided evidence that the assumptions of the model were correct with respect to proliferation. In order to test the validity of the assumptions concerning motility, we injected a tumor cell line with low motility in vitro and a subline of the same tumor cell line with high motility in vitro into the thigh of syngeneic rats. When we evaluated the morphological patterns of the resulting tumors by image analysis and compared them with computer simulations, we found that the differences of the morphological patterns were the same as predicted by the computer model. This finding further supports the concept that estimates of tumor cell proliferation and motility can be derived from the analysis of static histological patterns.
Animals↗
Clinicopathologic and immunologic features associated with transformation of mycosis fungoides to large-cell lymphoma.
Mycosis fungoides (MF) can progress to a large-cell malignant lymphoma (LCL). This transformation is associated with a more aggressive biologic behavior and course. We reviewed cutaneous tumors of 36 MF patients and divided them into two groups, one showing histologic evidence of transformation into LCL, another characterized by infiltrates of small- to medium-sized cerebriform cells (nontransformed cases). Biopsies of patches or plaques from early MF stages were available from 34 patients. Twenty of the 36 cases (55.6%) showed transformation to a large-cell variant: nine tumor-stage (T) medium-sized and large-cell pleomorphic, five T immunoblastic, two T large-cell anaplastic, and four unclassified T LCL. Sixteen cases represented nontransformed tumor stage MF. In 23 cases, including both nontransformed (n = 6) and LCL (n = 17) groups, immunohistochemical investigations revealed aberrant patterns of antigen expression (partial loss of one or more T cell-associated antigens) and the presence of activation- and proliferation-associated antigens. Clusters of B-lymphocytes formed a distinctive component of the infiltrate in two nontransformed and nine LCL biopsies. Although survival rates after tumor onset did not significantly differ between the two groups (5-year survival rate 23% for nontransformed patients, 11.1% for LCL patients, p greater than 0.05), overall survival from first biopsy diagnostic of MF showed a statistically significant difference between patients with nontransformed tumor stage MF compared with LCL patients (10-year survival rate 46.6% and 11.2%, respectively, p less than 0.02). The recognition of transformation to LCL in MF should provide a better assessment of future therapeutic approaches.
Adult↗
Mycosis fungoides mimicking perioral dermatitis.
A 71-year-old woman under PUVA-treatment for mycosis fungoides developed erythematous patches around the nasolabial folds and papules on the chin with clinical features of perioral dermatitis. Histology showed a specific infiltrate of mycosis fungoides with predominance of medium to large-sized pleomorphic lymphocytes and immunoblasts. Immunohistochemical analysis revealed the T-phenotype of the neoplastic cells. Small clusters of B-lymphocytes could also be observed within the infiltrate. Perioral dermatitis-like lesions can be added to the spectrum of rare and unusual clinical manifestations of mycosis fungoides.
Aged↗
Analysis of the 14;18 translocation in cutaneous lymphomas using the polymerase chain reaction.
A series of 25 cutaneous B-cell lymphoid proliferations was analyzed for the presence of the (14; 18) translocation using the polymerase chain reaction. Junctional sequences of rearranged chromosomes 14 and 18 were amplified in vitro, and t (14; 18) specific sequences were detected in 1 of 14 primary cutaneous B-cell lymphomas, in 3 of 8 primary nodal B-cell lymphomas and in none of 3 B-cell pseudolymphomas. These results indicate that the t (14; 18) may occur in a small subset of primary cutaneous lymphoma. However, the difference in incidence of the t (14; 18) between primary nodal and primary cutaneous lymphomas suggests that different molecular mechanisms are involved in the pathogenesis of these lymphomas.
Base Sequence↗
Prognostic significance of proliferation and motility in primary malignant melanoma of the skin.
The metastatic cascade depends on the presence of tumor cells which are capable of proliferation as well as of invasion with active motility. In the present study, it was examined whether the demonstration of both features in the primary lesion of malignant melanoma of the skin carries prognostic significance. Proliferation was assessed by mitotic counts and Ki 67 staining, and motility was estimated by image analysis and comparison of the image analysis results with computer simulations; 27 cases of primary malignant melanoma with a maximum vertical tumor thickness exceeding 1 mm were prospectively sampled. Mitotic counts were carried out on H & E stained sections, image analysis of the tumor pattern on S-100 immunostained paraffin slides, and Ki 67 labeling of actively cycling cells was evaluated on frozen sections. Neither proliferation nor pattern analysis alone provided a significant prognostic result with respect to overall survival and to metastasis free survival. The estimates of motility, derived from a combination of pattern analysis and proliferation values, however, proved to be significant predictors of overall survival and metastasis-free survival (log rank test: p less than or equal to 0.05). The motility features were superior to Clark level and Breslow index in this set of cases. The results demonstrate that the assessment of tumor cell proliferation and motility in histological sections may reflect the metastatic potential of primary malignant melanomas of the skin.
Cell Division↗
Cutaneous myxoid fibroblastoma. A histological, immunohistochemical, and ultrastructural study.
A fibroblastic skin tumor with a myxoid matrix is reported that cannot be easily classified as one of the well-known entities of fibrous/fibrohistiocytic and myxoid skin tumors. A 27-year-old white woman presented with a reddish, dome-shaped cutaneous nodule 8 mm in diameter on the left popliteal fossa that had developed spontaneously within the preceding 2 years. There was no sign of recurrence 30 months after excision. Light microscopic examination showed a well-circumscribed tumor confined to the upper dermis and consisting of stellate and spindle-shaped cells arranged loosely in a fascicular pattern resembling tissue cultures of fibroblasts. There were almost no collagen bundles between tumor cells, and Mowry's staining showed large amounts of glycosaminoglycans. Immunohistochemical studies of the tumor cells showed reactivity only to vimentin, whereas markers of histiocytes, dermal dendrocytes, and neurogenic and myogenic differentiation were negative. By electron microscopy, the majority of tumor cells contained elliptical nuclei, but some tumor cells had conspicuous multisegmented nuclei with several large and small nuclear segments connected by thin nuclear bridges (labyrinth nuclei). Single fibrils were found within the interstitium; collagen fibers were rare. Histological and ultrastructural examinations identified tumor cells as fibroblasts. High cellularity distinguishes this tumor from cutaneous myxoma. We conclude that this lesion represents a newly recognized tumor of fibroblastic origin. The name cutaneous myxoid fibroblastoma is proposed.
Adult↗
[Typing of infiltration cells in primary, localized, nodular, cutaneous amyloidosis].
Amyloid tumours in two patients with primary localized nodular cutaneous amyloidosis contained very dense infiltrates consisting mainly of plasma cells and lymphocytes. In one case IgM was detected on many cells of the infiltrate, while in the other IgA was found in morphologically apparently normal plasma cells. Immunohistochemical investigations did not reveal any immunoglobulin light chain restriction in either of the tumours. Numerous cells expressed B cell markers, such as CD20 or CD38. Rearrangement studies on material from the amyloid tumour of one of the patients confirmed the monoclonality of plasma cells. This observation indicates that the nodules of primary localized nodular cutaneous amyloidosis indeed represent an extramedullary plasmocytoma, which consists of amyloid-producing plasma cells. Of special interest was the unexpectedly high proportion of cells expressing T cell markers (CD3, CD5, CD4 greater than CD8) in the amyloid nodules of both patients. After excluding co-expression of B and T cell markers on identical cells by immunohistochemical studies on serial sections and also after molecular biological studies, we assume that this is a separate T cell population that may have a regulatory effect on the production of amyloid.
Aged↗
[The clinical spectrum of organ manifestations of tuberous sclerosis].
Since the first description of the classic triad of adenoma sebaceum, epilepsy and mental retardation by Vogt, various manifestations have been added to the clinical picture of Bourneville-Pringle disease or tuberous sclerosis. Diagnosis, therapy and potential complications of the more frequent manifestations are summarized. Since even oligosymptomatic patients may develop dangerous complications, the importance of thorough examination is emphasized.
Adenoma↗
Photodynamic therapy in patient with xeroderma pigmentosum.
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Administration, Topical↗
Proto-oncogene expression in dermal naevi and melanomas.
Overexpression of proto-oncogenes (c-onc) may be involved in the initiation and progression of human neoplasia. We investigated the mRNA expression of the proto-oncogenes c-myc, c-fos, c-neu (erb B-2) and Ha-ras in 12 cutaneous melanocytic lesions (four dermal naevi, seven melanomas; one cutaneous metastatis of melanoma) and in normal skin (five cases) by Northern blot analysis; mRNA expression levels were quantified by densitometry of the specific bands. The expression of c-myc mRNA was higher in naevi than in melanomas, whereas c-fos mRNA expression was significantly higher in melanomas than in naevi. No significant differences were detected in the c-neu and Ha-ras mRNA levels in naevi and melanomas. The expression of c-neu mRNA was higher in normal skin than in the melanocytic lesions examined. Our results suggest that enhanced c-myc and c-fos expression may play an important role in the growth of melanocytic naevi and melanomas. The overexpression of c-fos may be involved in the progression of a particular subset of melanoma. Activation of Ha-ras and the c-neu gene, as determined by mRNA overexpression, does not seem to play a significant role in the progression of cutaneous pigmented lesions. Expression of c-neu may have an important function in the proliferation and/or differentiation of normal cells of the epidermis.
Genes, fos↗
PUVA-induced lymphomatoid papulosis in a patient with mycosis fungoides.
The occurrence of lymphomatoid papulosis in patients with cutaneous lymphoma, particularly mycosis fungoides, has been described in medical literature. A 68-year-old woman affected by mycosis fungoides in the plaque stage noticed that multiple papulonodular lesions of lymphomatoid papulosis developed suddenly after a few sessions of PUVA therapy. The PUVA induction of lymphomatoid papulosis was confirmed by the appearance of new lesions after a second cycle of PUVA exposure on a limited area of the body. Complete regression of all PUVA-induced lymphomatoid papulosis lesions was achieved within a few weeks with oral prednisone and topical steroids. During the entire treatment the patches and plaques of mycosis fungoides persisted unchanged.
Aged↗
Computer simulation analysis of morphological patterns in human melanocytic skin tumours.
Tumour cell proliferation and particularly tumour cell motility are considered to be essential pre-requisites for invasive tumour growth. Despite abundant in vitro data on tumour cell motility, the behaviour of tumour cells in complex human tumour tissues is yet unknown. In this study, estimates of proliferation and motility are statistically derived from morphological tumour patterns in human melanocytic skin tumours. Two-dimensional, discrete, random computer simulations of tumour growth were carried out in order to determine the influence of tumour cell proliferation and motility on morphological patterns. A set of binary morphological criteria turned out to facilitate a significant estimate of the relative probabilities of motility and proliferation (CART analysis). When the same morphological criteria were applied to H & E stained slides of 45 melanocytic skin tumours, benign common nevi showed a predominance of motility, whereas primary and metastatic malignant melanoma revealed a predominance of proliferation. The direct assessment of the number of proliferating cells by Ki-67 staining shows a steep increase from benign nevi to primary and metastatic melanoma. These data provide first evidence that in benign common nevi the overall motility exceeds the very low degree of proliferation, whereas in malignant melanocytic tumours proliferation considerably exceeds tumour cell motility.
Cell Division↗
Expression of cytoskeletal components in melanocytic skin lesions. An immunohistochemical study.
The cytoskeleton is considered to be important for maintaining cell shape and facilitating cell movement. In the present study, the expression of cytoskeletal components is examined in benign and malignant melanocytic skin tumors. Paraffin sections of 75 cases (25 each of nevocellular nevus, primary malignant melanoma, and cutaneous metastases of malignant melanoma) were stained with antibodies to tubulin, myosin, actin, and vimentin using a three-step immunoperoxidase method. The staining results were assessed independently for tumor cells and stroma cells in comparison to inbuilt reference structures. Vimentin is found in all melanocytic lesions in the tumor as well as in the stroma cells. In malignant lesions, the tumor cell staining intensity varies between neighboring regions; particularly in malignant melanoma the staining is pronounced in the tumor periphery (chi 2 test: p less than 0.05). Actin is only weakly positive in nevus cells and primary melanoma tumor cells, but strongly expressed in metastatic tumor cells (p less than 0.001). Nevus fibroblasts are only weakly positive, whereas the stroma fibroblasts in the malignant lesions are strongly positive (p less than 0.001). The same is true for myosin and tubulin expression in dermal fibroblasts (p less than 0.001), whereas the tumor cells are equally (weakly) positive in all melanocytic lesions. Our study shows that there are significant differences in the immunohistochemical expression of cytoskeletal components in various melanocytic tumors. There is an elevated expression of vimentin and actin in the tumor cells, particularly of metastatic lesions. However, the most pronounced differences are found in the dermal fibroblasts.(ABSTRACT TRUNCATED AT 250 WORDS)
Actins↗
Development of a highly specific and sensitive molecular probe for detection of cutaneous lymphoma.
Using DNA from formalin-fixed paraffin-embedded tissue of a patient with mycosis fungoides, a highly specific and sensitive molecular probe for the malignant lymphoid cells of this patient was developed. Polymerase chain reaction (PCR) was used to selectively amplify the region of the rearrangement of TCR-gamma genes. Randomly inserted nucleotides between rearranged segments (N-region) were used as a specific marker for the malignant lymphoid clone of this patient. Clonal cells in paraffin-embedded tissue of previous and later biopsies were detected. This technique provides a new and unique tool for retrospective detection of early evolving cutaneous lymphoma, as well as for detection of minimal residual and systemic disease.
Aged↗