Papers by Jivko Kamarashev
Primary cutaneous lymphomas constitute a spectrum of diseases characterized by a clonal accumulat... more Primary cutaneous lymphomas constitute a spectrum of diseases characterized by a clonal accumulation of lymphocytes in the skin. Cutaneous T-cell lymphomas of the cytotoxic phenotype, including CD8+ and CD56+ lymphomas, are rare entities that have only been recently recognized and characterized. These lymphomas often show an aggressive clinical course. We investigated the expression of human leukocyte antigen G (HLA-G) and interleukin 10 (IL-10) in conjunction with expression of HLA-G killer-cell inhibitory receptor ligand immunoglobulin-like transcript 2 (ILT2) in 3 CD56+CD4+ and 4 CD8+ cutaneous T-cell lymphomas. HLA-G expression was detected in 2 of 3 lymphomas of the CD56+CD4+ type and in all lymphomas of CD8+ type. It is of note that CD56+CD4+ lymphomas displayed stronger HLA-G reactivity. The expression of IL-10 matched the expression of HLA-G. Together with the expression of IL-10, HLA-G might be one of the factors accounting for the evasion of immunosurveillance, thus contributing to aggressive phenotype of these lymphoma entities.
Microarray analysis is a promising new approach for creating specific expression profiles of mult... more Microarray analysis is a promising new approach for creating specific expression profiles of multiple genes simultaneously. We quantitatively analyzed differential gene expression patterns in mycosis fungoides- derived clonal T cells and autologous, identically cultured CD41 lympho- cytes using microarrays containing 588 cDNA segments from genes rele- vant to cell signaling, carcinogenesis, and apoptosis. Among other dissimilarities, neoplastic T cells showed
European journal of dermatology : EJD, Jan 17, 2015
Melanoma is a common type of skin cancer with poor survival in advanced stages. Screening efforts... more Melanoma is a common type of skin cancer with poor survival in advanced stages. Screening efforts aim to detect and tackle tumors at an early stage. However, regional population-based data at the time of initial diagnosis are sparse. To analyse clinical and pathologic tumor characteristics in a Swiss population. Melanoma samples diagnosed at a large Swiss academic department were evaluated for demographic, clinical and histopathologic data. We analysed a total of 254 melanoma samples. In situ tumors were more common in females than in males (70.6% vs. 29.4%; p = 0.0032). The acro-lentiginous subtype was more common in in situ compared to invasive tumors (14.7% vs. 5.5%; p = 0.0011). Invasive tumors showed a preference for male gender in patients beyond 60 years of age (p = 0.0080). The most frequent anatomic sites were the trunk in males and the legs in females. Regression was more common in males than in females (35.2% vs. 11.7%; p = 0.0001). Breslow's thickness correlated sign...
Human pathology, 2005
CD4+CD56+ hematodermic neoplasms (HNs) with initial presentation in the skin are characterized by... more CD4+CD56+ hematodermic neoplasms (HNs) with initial presentation in the skin are characterized by highly aggressive behavior and poor prognosis. Recent studies indicate that malignant cells, which are devoid of common T-, B-, NK-, and myeloid lineage markers, may be of plasmacytoid dendritic cell (pDC) origin. We undertook a study to assess the expression of several pDC-associated molecules on a series of 5 CD4+CD56+ HN cases. CD123 was expressed in all 5 cases, with some heterogeneity in individual cases. All but one case revealed fine membranous BDCA-2 staining of the dermal infiltrate. pDC-like phenotype of the malignant infiltrating cells was confirmed by costaining of BDCA-2+ cells with CD123 and CD4. MxA protein, representing the surrogate marker for lesional type I interferon activity, was expressed in 4 of 5 evaluated cases. Our findings further substantiate the putative pDC origin of CD4+CD56+ HNs.
European journal of dermatology : EJD
Familial cerebral cavernous malformations (FCCM) are vascular malformations inherited as an autos... more Familial cerebral cavernous malformations (FCCM) are vascular malformations inherited as an autosomal-dominant condition. Mutations in three genes have been described so far. Extra-neurological involvement includes retinal and cutaneous vascular malformations. Hyperkeratotic cutaneous vascular malformations are considered specific for FCCM and are always associated to KRIT1/CCM1 mutations.
Case Reports, 2015
A 52-year-old Colombian woman, a patient with psoriasis, undergoing phototherapy with (ultraviole... more A 52-year-old Colombian woman, a patient with psoriasis, undergoing phototherapy with (ultraviolet B narrowband) UVBnb, presented with a symptomless solitary diffuse erythaematous plaque on her nose for 3 months. Initially, she was treated with pimecrolimus 1% cream for 8 weeks, which was then combined with metronidazole cream for 4 weeks, with the initial diagnosis of UV-triggered rosacea, without improvement. A punch biopsy was performed and the histology showed a pseudolymphomatous reaction. The diagnosis of nasal pseudolymphoma of borreliosis was confirmed with PCR. The lesion completely resolved following oral doxycycline therapy.
Journal of Investigative Dermatology, 2001
On testing cutaneous T cell lymphoma cell lines and skin lesions, we found that the transcription... more On testing cutaneous T cell lymphoma cell lines and skin lesions, we found that the transcription factors STAT2, STAT3, STAT5, and STAT6 (STAT, signal transducer and activator of transcription) were present in the nuclei of these cells and that the binding to their specific DNA binding sites was stimulated by interleukin-7 and interleukin-15. DNA binding studies also revealed the presence
Monoclonal antibody (MAb) A103 specifically detects Melan A/MART-1 protein expression. Melan A/MA... more Monoclonal antibody (MAb) A103 specifically detects Melan A/MART-1 protein expression. Melan A/MART-1-derived peptides are recognized by CD8+ T-cells and are used in immunotherapy. We examined formalin-fixed paraffin-embedded tissue from 57 melanomas (34 primary, 23 metastatic) and 39 control cases (junctional, dermal, compound, Spitz, Reed and balloon-cell naevi) using the alkaline phosphatase and anti-alkaline phosphatase immunochemical method after antigen retrieval. Immunoreactivity was rated as low, medium or high, and staining pattern as homogeneous or heterogeneous. Staining with MAb A103 showed a sensitivity of 88% for melanoma, with a very high specificity for melanocytic cells. Immunopositivity decreased along with clinical stage, with stage I showing 100%, stage II 88%, stage III 90% and stage IV 75% immunoreactivity. Staining changed from an exclusively homogeneous pattern in the early clinical stages to a more heterogeneous pattern in the later stages. Melanocytic control tissues consisting of naevi of different subtypes all showed weak to moderate homogeneous immunoreactivity, with polarity towards the epidermis. Analysis of short-term melanoma cell cultures using reverse transcription-polymerase chain reaction (RT-PCR) enzyme-linked immunosorbent assay (ELISA) demonstrated mRNA expression in only one third of the originally immunopositive tumours, suggesting rapid mRNA expression loss in culture. MAb A103 allows the detection of melanoma-associated Melan A/MART-1 protein expression in routine archival tissue and thus enables the profiling of melanomas suited for immunotherapy approaches involving Melan A/MART-1 derived epitopes.
International Journal of Dermatology, 2007
Mycosis fungoides (MF) is a low-grade malignant primary cutaneous T-cell lymphoma which, in its e... more Mycosis fungoides (MF) is a low-grade malignant primary cutaneous T-cell lymphoma which, in its evolution, passes through five distinct stages (patch, plaque, and tumor stages, lymph node infiltration, and, finally, multiple organ infiltration). Furthermore, a blast transformation into a high-grade malignant lymphoma can occur. In order to better understand the dynamics of the disease and the prognostic implications in patients who progress, we studied the duration of each stage and the time at which blast transformation occurred. We reviewed the records of 48 MF patients who had been followed in the lymphoma clinic of the Department of Dermatology, University Hospital Zurich, Zurich, Switzerland for a median of 10 years. Forty-two cases were eligible for evaluation. Our study showed that MF in patients who progress is a disease which, after an initial patch stage with an average duration of 7.2 years, a plaque stage lasting for an average of 2.3 years, and a tumor stage with an average duration of 1.8 years, leads to a stage of lymph node infiltration with an average duration of 0.6 years, internal organ infiltration lasting for an average of 0.5 years and, finally, a fatal outcome. Consequently, the overall average disease duration in progressing patients is 12.4 years. Blast transformation occurs in 85% of all cases in the tumor stage. The course of progressing MF is chronic and advancing. The progression is initially slow and later accelerates. Important prognostic factors are the stage of disease and the presence of blast transformation. The prognosis is better in the early stage and when blast transformation is absent.
Seminars in Cutaneous Medicine and Surgery, 2000
Cutaneous lymphomas are a heterogeneous group of lymphoproliferative disorders derived from T cel... more Cutaneous lymphomas are a heterogeneous group of lymphoproliferative disorders derived from T cells, B cells and, in rare cases, natural killer cells. The precise mechanisms of the lymphomagenesis are still obscure. However, there are various factor's involved. These factors include environmental, especially infectious factors, translocations, mutations and genetic instability. The special microenvironment in the skin is responsible for the peculiar behavior of these neoplasms by providing various key factors, such as adhesion molecules and cytokines. Newly identified molecular disturbances in cutaneous lymphomas might be fargeted by specific molecular or immunologic interventions in the future.
International Journal of Dermatology, 2000
Pemphigus is a disease showing an uneven geographical distribution. In Bulgaria pemphigus has alw... more Pemphigus is a disease showing an uneven geographical distribution. In Bulgaria pemphigus has always represented a substantial part of diagnosed bullous diseases, but previous epidemiological data are incomplete. Our purpose was to evaluate retrospectively the incidence and prevalence of pemphigus in the district of Sofia (the capital of Bulgaria; population 1 200 000) for a sixteen-year period. The files of all the newly registered patients with pemphigus in the City Hospital of Dermatology in Sofia during the period Jan 1 1980 to Dec 31 1995, were collected and analysed with regard to personal statistics, ethnic origin, profession, history of the disease including age and season of onset, symptoms, clinical diagnosis, severity, laboratory findings, associated illnesses, therapy, and cure rate. Special attention was paid to smoking, alcohol abuse, and the presence of triggering factors such as emotional stress, drug intake, underlying diseases, neoplasias, or others. During the 16-year period studied, 74 newly diagnosed cases of pemphigus occurred in the district of Sofia, giving a prevalence of 0.38 per 100 000 inhabitants and a mean incidence of 0.47/100 000/year for the overall population and 0.51/100 000/year for the population aged above 20 years. The most common clinical variant is pemphigus vulgaris, frequently occurring in the fifth-sixth decades. The vast majority of the patients are workers or professionals. The results of the present retrospective study reveal a relatively high prevalence and incidence of pemphigus in Bulgaria, compared to that encountered in other countries. Our data is similar to that reported from Greece. Whether the Balkan Peninsula represents a focus of population groups with high susceptibility to pemphigus is a problem which could be highlighted by further epidemiological studies in this geographic area.
International Journal of Dermatology, 1993
Journal of the American Academy of Dermatology, 2010
The Journal of Pathology, 2003
for the presence of Bcl-2 gene family members and found that the two apoptosis-inhibiting members... more for the presence of Bcl-2 gene family members and found that the two apoptosis-inhibiting members Bcl-xL and Mcl-1 and the two apoptosis-supporting members Bad and Bax were expressed. However, Bad was at least partially inactivated by phosphorylation. In skin lesions, the translocation of Bad from the nucleus to the cytoplasm may reflect the Bad inactivation by phosphorylation identified in vivo. Bax is also ineffective, as the non-steroidal anti-inflammatory drug sulindac, whose cytotoxic effect is mediated by Bax, could not induce apoptosis in CTCL cell lines. The expression of Bcl-2, Bcl-xL, and Mcl-1 may therefore be sufficient to guarantee the survival of malignant CTCL cells. The Bcl-x, Mcl-1, Bad, and Bax proteins were also expressed in all CTCL skin lesions tested. In two patients from whom two biopsies from two different time points of the disease were available, a significant increase in Mcl-1 expression was found in the later-stage skin lesion. Overexpression of Mcl-1 and synthesis of non-functional Bax may be responsible for the resistance of CTCL cells to the anti-cancer drugs chlorambucil and sulindac.
Journal of Cutaneous Pathology, 1998
Monoclonal antibody T311 specifically detects tyrosinase protein expression. Tyrosinase-derived p... more Monoclonal antibody T311 specifically detects tyrosinase protein expression. Tyrosinase-derived peptides are recognized by CD8+ T-cells and applied in immunotherapy. We examined formalin-fixed paraffin-embedded tissue of 50 melanoma (primary n=31, metastatic n=19) and 41 control cases (junctional, dermal, compound, Spitz, Reed, balloon-cell nevi) by immunochemistry using the alkaline phosphatase-anti-alkaline phosphatase method after antigen retrieval. Staining with mAb T311 showed a sensitivity of 94% for melanoma with a very high specificity for melanocytic cells. Immunopositivity (94% of melanomas overall) correlated inversely with clinical stage: clinical stage I and stage II showed 100%, stage III and stage IV 86% immunoreactivity each. Staining changed from an exclusively homogeneous pattern in early stages to a more heterogeneous pattern in later stages. Melanocytic control tissue like nevi of different subtypes all showed weak to moderate, homogeneous immunoreactivity with polarity towards the epidermis. RT-PCR ELISA analysis of short-term melanoma cell cultures displayed mRNA expression in only half of the originally immunopositive tumors only, suggesting rapid mRNA expression loss in culture. mAb T311 allows detection of melanoma-associated tyrosinase protein expression and thus profiling of melanomas using routine archival tissue suited for immunotherapy approaches involving tyrosinase derived epitopes.
Journal of Cutaneous Pathology, 2009
Symplastic glomus tumor -a rare but distinct benign histological variant with analogy to other 'a... more Symplastic glomus tumor -a rare but distinct benign histological variant with analogy to other 'ancient' benign skin neoplasms A 78-year-old woman presented with a nail deformity of the index finger of the left hand associated with paroxysmal pain upon cold exposure. Histologically, a well-circumscribed tumor of 3 mm diameter was found in the dermis. The neoplastic cells in some areas were of pronouncedly variable size and cytomorphology, mostly epithelioid in shape, with eosinophilic cytoplasm and indistinctly defined cell borders. Pronounced nuclear pleomorphism and atypia were striking features, but no mitotic figures were noted. Multinuclear cells were present as were numerous small-to-medium vessels throughout the tumor. The tumor stroma showed myxoid areas. Immunohistochemistry showed cytoplasmic and membranous expression of smooth muscle actin and vimentin. The histological features and immunoprofile were consistent with the diagnosis of symplastic glomus tumor, a rare histological variant, which has been defined as a glomus tumor exhibiting marked nuclear atypia, in the absence of any other criteria for malignancy. The biological behavior of the tumor is benign. It is essential to differentiate this entity from malignant glomus tumor, which has metastatic potential. Even prominent cellular atypia and nuclear pleomorphism in a glomus tumor as in our case is not a marker of malignancy in the absence of additional criteria.
Journal of Cutaneous Pathology, 2002
CD30-positive cutaneous lymphoproliferative disorders (LPD) represent a spectrum of diseases rang... more CD30-positive cutaneous lymphoproliferative disorders (LPD) represent a spectrum of diseases ranging from low-grade (lymphomatoid papulosis; LyP) to high-grade (pleomorphic and anaplastic large-cell lymphoma; PTL, ALCL) with overlapping morphologic and immunophenotypic features. The common phenotypic hallmark is the expression of CD30-antigen by the tumor cells which morphologically resemble Reed-Sternberg cells. Although LyP is a non-fatal recurring disorder, it is associated with systemic lymphomas including Hodgkin's lymphoma (HL), mycosis fungoides (MF) and ALCL in 5-20% of the cases. Currently there is no marker to predict the development of systemic lymphomas in patients with LyP. Fascin, an actin bundling protein, has recently been shown to be a unique marker found in almost 100% of classical HL. Because of the association of LyP with HL, fascin expression was analyzed by immunohistochemistry in LyP (n = 45), cutaneous CD30+ ALCL (n = 17) and pleomorphic T-cell lymphoma (n = 9) (PTL) and LyP associated with systemic lymphomas (7 HL, 2 ALCL, 1 MF), with the intent to determine if fascin expression can predict disease progression. Fascin was expressed by tumor cells in 11/45 (24%) cases of LyP, 11/17 (64%) cases of ALCL, 7/9 (77%) cases of PTL and 6/10 (60%) cases of LyP associated with systemic lymphomas. Fascin expression in LyP was significantly less frequent than in ALCL (p < 0.001) and also than in LyP associated with lymphomas (p < 0.05). There was no significant difference of fascin expression within the histological subtypes of LyP. We found no evidence of ALK expression nor of Epstein-Barr virus expression in any case either by in situ hybridization or immunohistochemistry in the LyP cases associated with HL. This is the first study to demonstrate that fascin is expressed in cutaneous CD30+ LPD and that it is a candidate marker of disease progression in LyP.
Journal of Cutaneous Pathology, 1998
Mycosis fungoides (MF) and Sézary syndrome (SS) are closely related cutaneous T-cell lymphomas, w... more Mycosis fungoides (MF) and Sézary syndrome (SS) are closely related cutaneous T-cell lymphomas, which differ in several clinical aspects. We compared histological and immunophenotypical features of these two entities, which could be implicated in the dermotropism and epidermotropism, characteristic for both of them. Thirteen biopsy specimens from patients with established plaque-stage MF and 13 from SS patients were examined retrospectively, and 21 histological criteria were assessed. Further, 9 cryosections from MF lesions and 9 from SS lesions were stained for LFA, ICAM1, CD40, CD40-ligand, CD28, CD80, CTLA-4, CD86, FAS, FAS-ligand, CLA and CD15s. The only histological criteria that showed persistent differences were acanthosis (in 12 of 13 SS and in 7 of 13 MF specimens) and Pautrier collections (detected in 6 SS and 11 MF biopsies). Patterns of staining with the antibodies mentioned above were found to be similar. Our results indicate that these interaction molecules seem to be involved in the pathogenesis of MF and SS, but their immunohistochemical distribution does not contribute to the differentiation between the two entities.
Journal of Cutaneous Pathology, 2001
Tumor-infiltrating lymphocytes (TILs) are considered to play an important role in the antitumoral... more Tumor-infiltrating lymphocytes (TILs) are considered to play an important role in the antitumoral immune response. The presence and percentage of CD8-positive tumor-infiltrating T cells have been shown to correlate with differentiation and prognosis in various neoplasms. The aim of this study was to determine the number of CD8-positive T cells in various primary cutaneous B-cell lymphoproliferative disorders and to evaluate its correlation with the histological type of tumor. Fifty-three lesions were examined by immunohistochemistry with antibodies targeting CD3, CD4, CD8 and TIA-1. Thirty-two lesions had been diagnosed as primary cutaneous B-cell lymphomas (CBCL) and 21 as B-cell pseudolymphomas (B-PSL). CBCLs included 15 follicular lymphomas (FL), 6 marginal zone lymphomas (MZL), and 11 diffuse large B-cell lymphomas (LCL). The number of CD8-positive cytotoxic T cells was determined by computer-assisted morphometrical microscopy. No significant difference could be detected in the density of CD8-positive T cells in B-PSL (101/105 microm(2)), FL (110/105 microm(2)), and MZL (122/105 microm(2)). In contrast, the number of CD8-positive cells (55/105 microm(2)) in LCL was significantly lower (p<0.01) compared to B-PSL, FL and MZL. In summary the number of CD8-positive T cells in B-cell lymphoproliferative disorders differs in regard to tumor type and differentiation with lowest numbers in diffuse large B-cell lymphomas. However, due to an overlap of the number of TILs, this parameter cannot be employed as a diagnostic parameter for individual cases.
International Journal of Cancer, 1999
In advanced stages of malignant melanoma (MM), metastases to the CNS are frequently observed. Few... more In advanced stages of malignant melanoma (MM), metastases to the CNS are frequently observed. Few results are available on trophic factors and immunological features involved in the process of invasion and adhesion of circulating metastatic cells into the CNS. A direct comparison of remote metastases found in different locations of the same patient might help to identify such properties. For this purpose, we screened a panel of MM cell cultures, which had been established from patients with surgically removed MM lesions of the CNS, for expression and regulation of immunorelevant molecules. The results were compared with standard controls and cultures established from non-CNS metastatic lesions of the same patients. No significant differences were observed for expression of HLA-I, HLA-II, ICAM-1 and the melanoma-associated antigens Mage-3, MelanA and tyrosinase. Constitutive expression of the neuronal cell adhesion molecule (NCAM) was found in all CNS-derived samples and in fewer than 50% of non-CNS derived cultures. IFN-gamma was found to have a weak up-regulating effect in all non-CNS-derived cultures, except normal melanocytes. However, in 6/7 CNS-derived cultures, pre-treatment with IFN-gamma reduced expression of NCAM to 28% to 77% of the level in untreated cultures. The presence and regulation of NCAM differs between MM cells derived from CNS metastases and non-CNS-derived melanocytic cells. Thus, NCAM might be a candidate immunoregulating molecule involved in the formation of CNS metastases of MM.
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Papers by Jivko Kamarashev