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A Solitary Facial Nodule of a 48-year-old Man
Abstract
CASE REPORT A 48-year-old man presented with a reddish skin tumor over face for three months. He denied any systemic disease and history of insect bite. The skin examination revealed a reddish dome-shaped elastic fi rm nodule, 1.2 cm in diameter, over left zygomatic area (Fig. 1). Other physical exam did not show any abnormal findings such as lymphadenopathy or hepatosple-nomegaly. The nodule was partially excised for pathological examination. The histopathology revealed superficial and deep patches of atypical lymphoid cell infiltrates around the append-ages with a characteristic lymphoepithelial pattern and Grenz zone. The infi ltrate is composed of small lymphocytes, centrocyte-like cells, and plasma cells admixed with a small proportion of large blastoid cells (Fig. 2). Immunohistochemical stains showed that the infi ltrate was strongly positive for CD20 and Bcl-2 (Fig. 3). A complete blood count, liver and renal function, lactate dehydrogenase, and serum immunoglobulin analysis were normal, and hepatitis B/C serology and HIV tests were negative. A positron emission tomography (PET) scan did not show any evi-dence of systemic involvement. After total excision of the lesion, he was regularly followed up without local recurrence at our clinic for more than half a year.
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Primary cutaneous marginal zone B-cell lymphoma (PCMZL) is included as one of the major types of primary cutaneous B-cell lymphoma in the revised World Health Organization-European Organization for Research and Treatment of Cancer classification. Clinically, PCMZL is an indolent disease and has an excellent prognosis. PCMZL is composed of a polymorphous infiltrate that includes centrocyte-like, monocytoid, and lymphoplasmacytoid lymphocytes and plasma cells. Numerous reactive T cells and lymphoid follicles are commonly associated with the neoplasm. The neoplastic cells express B-cell markers and usually bcl-2 and are negative for CD5, CD10, and bcl-6. Borrelia burgdorferi is a suspected etiologic agent identified in a subset of cases. Although all of these neoplasms presumably are monoclonal, monoclonal IgH rearrangement can only be detected in approximately 75% of cases. Most molecular studies to assess for clonality have used polymerase chain reaction-based methods, and thus this false-negative rate may be attributable to somatic mutation of the IgH variable region genes. Approximately 10% to 20% of PCMZLs have recurrent chromosomal translocations, including the t(14;18)(q32;q21)/IgH-malt1, t(11;18)(q21;q21), and t(3;14)(p14;q32). The t(14;18)(q32;q21) and t(11;18)(q21;q21) have been shown to activate the NF-kappaB pathway.
Cutaneous marginal zone B-cell lymphoma is a recently proposed entity and constitutes a cutaneous counterpart of extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT). Borrelia burgdorferi infection has been suggested as a possible causative agent in European cutaneous cases of marginal zone B-cell lymphoma, whereas API2-MALT1 fusion and BCL10 mutation are highly associated with MALT lymphoma. Aberrant nuclear BCL10 expression may be closely correlated with API2-MALT1 fusion in gastric and pulmonary MALT lymphomas. We examined 24 Asian cases of cutaneous marginal zone B-cell lymphoma for B. burgdorferi involvement, API2-MALT1 fusion, BCL10 cellular expression, and BCL10 mutation. Neither Borrelia DNA nor API2-MALT1 fusion transcript was detected. Nuclear BCL10 expression was evident in tumor cells of 11 of 24 cases, although BCL10 mutation was found in one case only. Clinicopathologically, nuclear BCL10 was more frequently expressed in macroscopically nodular lesions than in plaques or papules (p = 0.0031). These data suggest that 1) B. burgdorferi infection may not play an important role in developing cutaneous marginal zone B-cell lymphoma in Asian cases, 2) neither API2-MALT1 fusion nor BCL10 mutation is closely associated with the pathogenesis, 3) aberrant nuclear BCL10 may frequently be expressed in the absence of these genetic abnormalities, and 4) nuclear BCL10 expression may be clinically important because it was observed in locally aggressive tumors. Primary cutaneous B-cell lymphoma (CBCL) is a rare entity. However, increasing numbers of B-cell lymphomas of primary cutaneous origin are now being recognized. 26 According to recent studies of primary cutaneous lymphoma, 20–25% of the cases are of B-cell lineage. 10,33 Among CBCLs, marginal zone B-cell lymphoma (MZBL) may be the most common subtype. 10 Histologic characteristics of cutaneous MZBL include a proliferation of marginal cells outside reactive lymphoid follicles and the cytologic appearance of centrocyte-like (CCL) cells or monocytoid B cells with plasmacytic differentiation. 3,4,6,7,36 There is general agreement that patients with cutaneous MZBL pursue a favorable clinical course. 26 This type of extranodal lymphoma would be classified among the extranodal MZBL of mucosa-associated lymphoid tissue (MALT) according to the World Health Organization Classification for Tumors of Haematopoietic and Lymphoid Tissues. 3,6,17,36 The pathologic sequence leading to MALT lymphoma in general suggests an immunologic involvement after infection by Helicobacter pylori or in association with autoimmune diseases such as Hashimoto's thyroiditis or Sjogren's syndrome. 17 Dermatologic evidence suggesting a link with Borrelia burgdorferi has been reported in the European literature, 5,11–13,18,25,27 and penicillin therapy may cure B. burgdorferi-associated CBCLs. 18,25,27 However, involvement of B. burgdorferi infection in cutaneous CBCL seems to be rare in the United States. 35 Both t(11;18)(q21;q21) and t(1;14)(p22;q32) have been identified as recurring cytogenetic abnormalities specific to MALT lymphomas. The former translocation, which is more common than the latter, results in API2-MALT1 fusion 1,8 and has been found in up to 50% of cases. 2,15,22,24API2 is a member of the IAP (inhibitor of apoptosis) gene family, and API2 oligomerization with MALT1 may maintain or increase API2 function and thereby help MALT lymphomas to survive. 22BCL10, cloned from the latter translocation, exhibits a variety of truncating mutations in t(1;14)-bearing MALT lymphomas, which may lead to anti-apoptotic function of BCL10 and activation of NF-κB, a transcription factor for several survival-related genes, via interaction with MALT1 protein. 19,20,30,34,37,38 Similarly, the API2-MALT1 fusion protein also strongly activates NF-κB through a common signaling pathway. 20 In normal marginal zone cells, BCL10 is localized in the cytoplasm, whereas in tumor cells of a t(1;14)-positive MALT lymphoma, aberrant BCL10 expression is found in the nuclei. 37 Nuclear BCL10 expression has also been observed in cases without t(1;14) and may be closely associated with API2-MALT1 fusion in gastric and pulmonary MALT lymphomas. 19,21,23 However, API2-MALT1 fusion, BCL10 mutation, and nuclear BCL10 expression have rarely been studied in cutaneous MZBL. Because of its rarity and recent recognition, cutaneous MZBL has not been studied intensively. To the best of our knowledge, no Asian cases have been investigated. The aim of this study is to detect the underlying biologic or genetic abnormalities in cutaneous MZBL and to correlate such abnormalities to clinicopathologic factors. B. burgdorferi involvement, API2-MALT1 fusion, aberrant nuclear BCL10 expression, and BCL10 mutation were examined in 24 Asian cases of cutaneous MZBL, and their clinicopathologic significance was analyzed.
Classification of primary cutaneous lymphomas (PCLs) is the subject of ongoing controversy. Based on a series of 556 patients, the applicability of the European Organization for Research and Treatment of Cancer (EORTC) classification for PCLs was assessed and compared to the proposed World Health Organization (WHO) classification of hematologic malignancies. The large majority of patients could be properly classified according to the scheme proposed by the EORTC. Comparison of estimated 5-year survival for specific diagnostic categories of PCLs demonstrated nearly complete concordance of the present results with those of the EORTC study for most of the indolent cutaneous T-cell lymphomas and cutaneous B-cell lymphomas, whereas differences were found for mycosis fungoides-associated follicular mucinosis and Sezary syndrome. A few patients with newly described entities (CD8(+) epidermotropic cytotoxic T-cell lymphoma, primary cutaneous natural killer/T-cell lymphoma) could not be classified according to the EORTC scheme. Comparison of the EORTC with the WHO classification showed that the EORTC scheme allows a more precise categorization of the patients, especially for cutaneous B-cell lymphoma. In conclusion, the study confirmed that the EORTC classification allows a better management of patients with PCL. Small amendments to that classification should be carried out to account for recently described entities and to unify some of the diagnostic categories.
Primary cutaneous marginal zone B-cell lymphoma (MZCL) has recently been described. Differentiation from follicular centre cell lymphomas and lymphocytomas is often difficult due to insufficient experience and a lack of large series of patients.
To characterize primary cutaneous MZCL better, we report clinical, histopathological, immunophenotypic and molecular genetics features in a series of 22 patients.
All patients were treated and followed up at the same institution. Diagnosis of MZCL was based on the World Health Organization classification criteria. All samples were routinely tested with a wide panel of monoclonal antibodies. DNA was extracted from every sample following standard methods. IgH rearrangement and t(14;18)(q32;q21) studies were performed in all samples.
Twenty-two patients (20 men, two women; mean age 50 years, range 24-77) were included. The mean follow-up was 43 months. Seventy per cent of patients presented with characteristic skin lesions on the trunk or extremities, consisting of deep red to violaceous infiltrated plaques, nodules or tumours frequently surrounded by diffuse or annular erythema. Four patients presented with lesions on the head and neck area. Two patients had disseminated skin lesions. The main histopathological features were non-epidermotropic, dense lymphocytic infiltrates mainly distributed in a nodular pattern. Adnexal involvement was usually present, with eventual formation of lymphoepithelial complexes. Cytologically, the infiltrate was polymorphous with marginal zone B cells and B-monocytoid cells. Blastoid CD30+ cells were often observed. Colonized reactive germinal centres and lymphoplasmocytoid differentiation were frequently present. Neoplastic cells were CD20+, CD79a+, CD5- and CD10-. Monotypic expression of light chains was observed in 18 cases (13 kappa; five lambda). Clonal IgH rearrangements were detected in 14 cases. The bcl-2 mutation t(14;18)(q32;q21) was demonstrated in two cases. Most patients were treated with local radiotherapy. Complete response rate with this approach was 100%. Six patients (27%) had skin recurrences from 6 months to 8 years after first treatment. Five patients (23%) had extracutaneous involvement. Two of them had a large cell transformation and one died of lymphoma. Three of four patients with head and neck presentation developed extracutaneous disease.
MZCL appears to be a well recognizable entity, clinically, histologically and immunophenotypically. Although prognosis is generally good, the disease has potential for skin as well as extracutaneous recurrences. Large cell transformation and head and neck presentation may be associated with a worse prognosis.
Cutaneous marginal zone B-cell lymphoma is a recently proposed entity and constitutes a cutaneous counterpart of extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT). Borrelia burgdorferi infection has been suggested as a possible causative agent in European cutaneous cases of marginal zone B-cell lymphoma, whereas API2-MALT1 fusion and BCL10 mutation are highly associated with MALT lymphoma. Aberrant nuclear BCL10 expression may be closely correlated with API2-MALT1 fusion in gastric and pulmonary MALT lymphomas. We examined 24 Asian cases of cutaneous marginal zone B-cell lymphoma for B. burgdorferi involvement, API2-MALT1 fusion, BCL10 cellular expression, and BCL10 mutation. Neither Borrelia DNA nor API2-MALT1 fusion transcript was detected. Nuclear BCL10 expression was evident in tumor cells of 11 of 24 cases, although BCL10 mutation was found in one case only. Clinicopathologically, nuclear BCL10 was more frequently expressed in macroscopically nodular lesions than in plaques or papules (p = 0.0031). These data suggest that 1) B. burgdorferi infection may not play an important role in developing cutaneous marginal zone B-cell lymphoma in Asian cases, 2) neither API2-MALT1 fusion nor BCL10 mutation is closely associated with the pathogenesis, 3) aberrant nuclear BCL10 may frequently be expressed in the absence of these genetic abnormalities, and 4) nuclear BCL10 expression may be clinically important because it was observed in locally aggressive tumors.
Primary cutaneous marginal zone B-cell lymphoma (PCMZL) is a low-grade B-cell lymphoma that originates in the skin, with no evidence of extracutaneous disease. Studies focusing on the optimal treatment of PCMZL have not been published thus far. We describe 50 patients with PCMZL to further characterize clinical characteristics and outcome and, in particular, to evaluate our current therapeutic approach.
The majority of the patients (36/50 [72%]) presented with multifocal skin lesions, and 14 patients (28%) presented with solitary or localized lesions. The initial treatment of patients with solitary lesions consisted of radiotherapy or excision, whereas patients with multifocal lesions received a variety of initial treatments, most commonly radiotherapy and chlorambucil therapy. Cutaneous relapses developed in 19 (48%) of 40 patients who had complete remission and were more common in patients with multifocal disease. After a median period of follow-up of 36 months, 2 patients developed extracutaneous disease, but none of the patients died of lymphoma.
Patients with PCMZL who have solitary lesions can be treated effectively with radiotherapy or excision. For patients with PCMZL who have multifocal lesions, chlorambucil therapy and radiotherapy are suitable therapeutic options. In case of cutaneous relapses, the beneficial effects of treatment should carefully be weighed against the potential adverse effects.