Katalin Ferenczi

Decreased T-Cell Receptor Excision Circles in Cutaneous T-Cell Lymphoma

Purpose: The T cell repertoire in patients with advanced cutaneous T cell lymphoma (CTCL) is significantly contracted despite the presence of relatively normal absolute numbers of T cells. We propose that many normal T cells were being lost in patients with CTCL, with the remaining normal T cells expanding clonally to fill the T cell compartment. T-cell receptor excision circles (TREC) form as a result of the initial gene rearrangement in naïve T cells. Although they are stable, they do not replicate and are subsequently diluted with the expansion of a population of T cells. Their concentration is therefore a measure of unexpanded naïve T cells relative to T cells that have undergone expansion. Experimental Design: We analyzed TRECs from unfractionated peripheral blood T cells from 108 CTCL patients by quantitative PCR. In patients with obvious peripheral blood involvement, we also analyzed TRECs from clonal and nonclonal T cells. Results: We found a decrease in the number of TRECs in peripheral blood of patients with CTCL at all stages of disease, and this decrease was proportional to the loss of complexity of the T cell repertoire as measured by complementarity-determining region 3 spectratyping. In patients with leukemic CTCL and a numerically expanded clone, we also found a significantly lower-than-expected number of TRECs in the nonclonal normal T cells. Conclusions: We hypothesize that the nonmalignant T cells have proliferated to fill the empty T cell repertoire space left by the loss of other T cells, leading to diminished TRECs and loss of T-cell receptor diversity.

A case of CD30+ nasal natural killer/T-cell lymphoma

Extranodal nasal natural killer (NK)/T-cell lymphoma is a very rare lymphoma characterized by strong association with Epstein-Barr virus infection, very aggressive clinical behavior, and poor prognosis. The typical phenotype of neoplastic natural killer cells in this entity is as follows: CD2+, CD56+, surface CD3-, cytoplasmic CD3epsilon+, and cytotoxic granule-associated protein positive. CD30 expression, a phenotype characteristic of anaplastic large-cell lymphomas, is not a typical feature of nasal NK/T-cell lymphomas. We describe the case of a 42-year-old woman with chronic nasal congestion and septal deviation who presented with progressive generalized tender erythematous plaques. A skin biopsy revealed an atypical angiocentric mononuclear cell infiltrate. Strong CD30 and CD3e immunoreactivities were noted in large atypical mononuclear cells within the infiltrate initially suggestive of a CD30+ T-cell lymphoma. However, flow cytometry of the skin lesion indicated that the cells were CD2+, CD4-, CD8-, and lacked surface CD3 more typical of a neoplasm of natural killer cells. Further studies revealed that the cells were CD56+, T-cell-restricted intracellular antigen-1+, and contained Epstein-Barr virus sequences consistent with a nasal-type NK/T-cell lymphoma. High titers of Epstein-Barr virus in the blood, evidence of sinonasal disease, and absence of a T-cell receptor gene rearrangement were additional features consistent with the diagnosis. The patient had a very aggressive clinical course and, despite combination chemotherapy, died 8 months after the onset of skin lesions. This case represents an example of nasal-type NK/T-cell lymphoma with expression of CD30. When presenting in the skin, the phenotypic and morphologic features of this lymphoma may lead to an erroneous diagnosis of a CD30+ large-T-cell lymphoma.

Herpes zoster granulomatous dermatitis: histopathologic findings in a case series

Several types of cutaneous reactions have been reported to arise at the site of herpes zoster (HZ) infection weeks to years after the acute disease. Among these, granulomatous reactions are the most frequently reported. In this study, we describe the spectrum of histopathologic findings of HZ granulomatous reactions observed in 26 patients with cutaneous lesions confined to the area of previous HZ eruption and compare them with biopsy specimens taken from 25 patients with acute HZ. All patients with persistent reactions from whom history was available presented within 12u2009weeks of the onset of the acute eruption. The most frequent findings were interstitial granulomatous dermatitis with lymphocytes, histiocytes and multinucleated giant cells displaying elastophagocytosis and a perineural, perivascular and perieccrine mononuclear inflammatory infiltrate rich in lymphocytes and plasma cells. Less common features included intra‐arrector and peri‐arrector pili granulomas, follicular dilatation and hyperkeratosis, and vasculitis. Specimens from patients with acute HZ were found to have small numbers of perineural plasma cells and most had subtle granulomatous inflammation, in patterns similar to the group with late granulomatous reactions. Our findings suggest that granulomatous reactions to varicella zoster virus represent a persistent evolving inflammatory reaction after acute infection.

Could follicular helper T-cells play a role in primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphomas?

Primary cutaneous marginal zone B-cell lymphomas: are they different from other extranodal marginal zone B-cell lymphomas? The WHO-EORTC classification identifies three subgroups of primary cutaneous B-cell lymphomas (PCBCL): primary cutaneous follicle center lymphoma (PCFCL), primary cutaneous marginal zone B-cell lymphoma (PCMZL) and primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCLLT).1 With the exception of the PCLBCL-leg type, most primary cutaneous B-cell lymphomas have an excellent prognosis with a 5-year survival rate higher than 95%.1 PCMZL has been regarded as the cutaneous counterpart of extranodal marginal zone lymphomas (MZL), in particular, the mucosa-associated lymphoid tissue (MALT) lymphoma. All marginal zone Bcell lymphomas, regardless of the anatomic location (nodal or extranodal: cutaneous, extracutaneous) are believed to originate from the marginal zone of the B-cell follicles. The marginal zone is the outermost portion of the follicle and is most developed in tissues with the highest rate of antigen exposure, such as spleen, lymph node, and mucosal lymphoid tissues. Marginal zone B-cell lymphoma can arise at any of these anatomic sites. Tumor cells express bcl-2 and B-cell antigens: CD19, CD20, CD22, CD79a with immunonegativity for CD5, CD10, CD23, cyclin D1 and bcl-6. The neoplastic cells in all extranodal MZLs have a common origin, present with similar histologic changes and immunophenotypic profiles, and often display similar cytogenetic anomalies/translocations. However, the difference between MALT lymphomas and cutaneous MZLs may be related to emerging information regarding the effects of the inflammatory environment. The focused article of this review is a recent report by van Maldegem et al.2 in which the authors show that when compared with other extranodal MZLs, PCMZLs appear to lack CXCR3 and demonstrated class-switched immunoglobulin, expressing IgA, IgG, and IgE, and occasional dual isotypes. This is distinguished from extranodal MZLs which predominantly express IgM and express CXCR3. A summary of the distinctive features of PCMZL and MALT lymphomas is illustrated in Table 1. One of the differences between PCMZL and MALT lymphomas relates to the etiology. MZLs, irrespective of the primary site, originate from B cells in the marginal zone that typically function as a first line of defense against microbial pathogens.3 The development of gastric MALT lymphoma is highly dependent on Helicobacter pylori infection and can often be cured with antibiotic treatment.4 Although certain microbial pathogens such as Epstein–Barr virus (EBV), human herpesvirus 8 (HHV-8), and human T-lymphotropic virus 1 (HTLV-1) are lymphotropic oncogenic viruses that can cause direct lymphocyte transformation, other infectious agents such as H. pylori can indirectly promote lymphocyte transformation and contribute to lymphomagenesis via chronic antigenic stimulation.5,6 MALT lymphomas of the salivary gland are typically seen in association with Sjogren syndrome, likely as a result of exposure to autoantigens and chronic inflammation. Although a strong association exists between lymphomagenesis and chronic antigenic stimulation/infection, chronic inflammation in the pathogenesis of MALT lymphomas, infection does not appear to be commonly involved in the development of PCMZLs. Borrelia burgdorferi infection has been associated with only a small proportion of primary cutaneous marginal zone lymphomas in Europe but not in the United States and Asian countries.7– 9 Regression of the lymphoma in such cases has been reported after antibiotic therapy.10,11 No link with infectious agents has been established in the majority of PCMZLs. Maldegem et al. suggest that two types of PCMZL exist: PCMZL which are CXCR3–/Th2+ and represent the vast majority of cutaneous MZL and the rare subtype of infection-related PCMZL, which is CXCR3+/Th1+ and more closely resembles extracutaneous MALT lymphomas.2 Extranodal marginal

Interferon beta-1a–induced morphea

Interferon beta-1a (IFN-β1a) is a cytokine therapy used in the treatment of relapsing-remitting multiple sclerosis. The most common adverse injection site reactions include local erythema, pain, and induration.1 Other less frequently encountered reactions include vascular thrombosis, ulceration, panniculitis, and lipoatrophy.1 More recently, IFN-β rarely has been noted to be associated with sclerosing skin disorders including limited and diffuse systemic sclerosis; however, the development of morphea has not been reported.2 Here we describe a patient with multiple sclerosis who had woody induration clinically and histologically consistent with morphea at the sites of subcutaneous IFN-β1a injections.

Disseminated Lyme Disease Presenting With Nonsexual Acute Genital Ulcers

IMPORTANCEnNonsexual acute genital ulceration (NAGU) is a rare vulvar skin condition typically affecting girls and young women, characterized by acute onset of singular or multiple painful vaginal ulcers. The etiology of this ulcerative dermatosis has not been identified, although it has been associated with systemic infections. To our knowledge, this is the first report of an association with Lyme disease.nnnOBSERVATIONSnA case of a woman with early disseminated Lyme disease presenting with NAGU is reported. A thorough workup ruled out other causes of genital ulceration, and the ulcers completely resolved after treatment with topical steroids and oral doxycycline.nnnCONCLUSIONS AND RELEVANCEnAlthough the etiology of NAGU is unknown, the vulvar ulcers may result from an exuberant immune response to infection. Most patients with NAGU exhibit nonspecific symptoms such as myalgias and fever, suggesting an infectious agent, but the majority have no identifiable pathogen. In addition to previously reported associations with systemic infection, which are reviewed herein, Lyme disease should be considered in women presenting with acute-onset genital ulcers.

Malignant T cells in cutaneous T‐cell lymphoma lesions contain decreased levels of the antiapoptotic protein Ku70

Backgroundu2002 Malignant T cells in primary cutaneous T‐cell lymphoma (CTCL) are genetically unstable and exhibit prolonged lifespans potentially explained by dysregulation of apoptosis, yet are responsive to apoptosis‐inducing therapies. The heterodimeric protein Ku70/80 is known to play a role in DNA repair (Ku70 and Ku80) and inhibition of apoptosis (Ku70 only).

Paired comparison of the sensitivity and specificity of multispectral digital skin lesion analysis and reflectance confocal microscopy in the detection of melanoma in vivo: A cross-sectional study

BACKGROUNDnSeveral technologies have been developed to aid dermatologists in the detection of melanoma in vivo including dermoscopy, multispectral digital skin lesion analysis (MDSLA), and reflectance confocal microscopy (RCM). To our knowledge, there have been no studies directly comparing MDSLA and RCM.nnnOBJECTIVEnWe conducted a repeated measures analysis comparing the sensitivity and specificity of MDSLA and RCM in the detection of melanoma (n = 55 lesions from 36 patients).nnnMETHODSnStudy patients (n = 36) with atypical-appearing pigmented lesions (n = 55) underwent imaging by both RCM and MDSLA. Lesions were biopsied and analyzed by histopathology.nnnRESULTSnRCM exhibited superior test metrics (P = .001, McNemar test) compared with MDSLA. Respectively, sensitivity measures were 85.7% and 71.4%, and specificity rates were 66.7% and 25.0%.nnnLIMITATIONSnThe sample size was relatively small and was collected from only one dermatologists patient base; there was some degree of dermatopathologist interobserver variability; and only one confocalist performed the RCM image evaluations.nnnCONCLUSIONnRCM is a useful adjunct during clinical assessment of in vivo lesions suspicious for melanoma or those requiring re-excision because of high level of dysplasia or having features consistent with an atypical melanocytic nevus with severe cytologic atypia.

Cutaneous lymphoma: Kids are not just little people

Cutaneous T-cell lymphomas (CTCLs) are non-Hodgkin lymphomas that predominantly affect older patients. Onset of cutaneous lymphoma in childhood is rare, but it can present as early as the first decade of life. In both adults and children, the diagnosis of cutaneous lymphoma can be challenging because inflammatory dermatoses can mimic CTCL both clinically and histologically. The clinicopathologic manifestations can be similar in adults and younger individuals; however, differences in the prevalence of certain CTCL variants among age groups exist. Whereas the classic Alibert-Bazin-type mycosis fungoides (MF) and Sézary syndrome represent the overwhelming majority of adult cutaneous T-cell lymphomas, in younger individuals, certain mycosis fungoides variants, such as hypopigmented MF, are over-represented and Sézary syndrome is extremely rare. CD30+ lymphoproliferative diseases, which include lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large cell lymphoma (ALCL), represent the second most common subtype of CTCL in both adults and children; however, in the pediatric population, most of these are represented by LyP, and primary cutaneous ALCL is very rare. The prognosis is stage dependent, and the most significant prognostic factor in MF is the extent of skin involvement and the presence or absence of extracutaneous disease. The overwhelming majority of pediatric patients present with early-stage disease, and progression to more advanced stages, such as tumor stage, erythrodermic MF, and large cell transformation, which can be seen in adults, is very rare. The choice of treatment, regardless of age, is dependent on the extent of skin involvement and the presence or absence of extracutaneous disease.

A quantitative comparison between SOX10 and MART-1 immunostaining to detect melanocytic hyperplasia in chronically sun-damaged skin

Histologic differentiation of melanoma in situ (MIS) from solar keratosis on chronically sun‐damaged skin is challenging. The first‐line immunostain is usually MART‐1/Melan‐A, which can exaggerate the epidermal melanocytes, causing a diagnostic pitfall for MIS. By comparing MART‐1 and SOX10 immunostaining, we scored the percentage of epidermal melanocytes per 2‐mm diameter fields in pigmented actinic keratosis (nu2009=u200916), lichenoid keratosis (nu2009=u20097), junctional melanocytic nevus (nu2009=u20096), keratosis with atypical melanocytic proliferation (nu2009=u200917) and MIS (nu2009=u200910). These cases represented an older population (68 years median age) and the head and neck (50%) was the most common anatomic site. MART‐1 score was significantly higher than SOX10 (P value <.05) in solar keratoses, but showed no difference in detecting melanocytic proliferations, demonstrating their equal detection rate of melanocytes. The sensitivity of both MART‐1 and SOX10 was 100%, while their specificities were 17% and 96%, respectively. These results show that SOX10 is more specific than MART‐1 in distinguishing epidermal melanocytes on sun‐damaged skin by avoiding overdiagnosis of melanoma.