Cutaneous B cell lymphoma in chronic Borrelia burgdorferi infection. Report of 2 cases and a review of the literature

Low-grade malignant B-cell lymphomas of the skin can be distinguished from lymphadenosis benigna cutis (B?fverstedt) by immunohistological methods developed in the last few years. Its coexistence with Borrelia burgdorferi infection can be shown by clinical and serological findings. In the chronic stage of this infection, lymphocytic cell infiltrations consistent with histological and immunohistological findings of malignant B-cell lymphoma can be found. Predominantly at the extremities, multiple plaque-shaped or nodular lesions are seen, showing a follicular pattern in their periphery. The tumors do not respond to antibiotic therapy. They regress totally after X-ray treatment, but local recurrences are rather common. They show a long persistent course with only slow progression and seem to be of low-grade malignancy independent from the cytological findings. In most cases the tumors remain limited to the skin and to one anatomical site; nevertheless, the development of systemic involvement has been reported. We present two cases of malignant B-cell lymphoma of the skin in patients with chronic B. burgdorferi infection. Both cases showed the typical clinical and histological features of this entity. Similar reports from the literature indicate close relationships with the chronic stage of Borrelia infection, with the simultaneous presence of acrodermatitis chronica atrophicans as an indicator. We conclude that an elevated titer indicating Borrelia infection is an important finding for the diagnosis and prognosis of this particular type of cutaneous B-cell lymphoma.     

Alkaline phosphatase positive lymphoma

Alkaline phosphatase (AP) activity on cryostat sections of the skin of 38 cases of non-Hodgkin's lymphomas of the B cell type and of 10 cases of lymphadenosis benigna cutis have been studied. Membrane-bound AP activity has been found in 8 out of 28 cases of low-grade malignant lymphomas of the B cell type and in 2 out of 10 cases of lymphadenosis benigna cutis. This is a known phenomenon in the latter. In the literature of non-Hodgkin's lymphoma AP activity is related to the intermediate type of lymphocytic lymphoma. Further studies are needed to demonstrate that the AP activity correlates with a specific cell type in the B lymphoid cell differentiation.     

Borrelia burgdorferi, clinical aspects, cultivation and identification of the pathogen in erythema migrans in Berlin

Among other manifestations, the following diseases caused by Borrelia burgdorferi in Europe are transmitted by ticks of the species ixodes ricinus: erythema migrans (EM), lymphadenosis benigna cutis (LBC), lymphocytic meningo-radiculitis (Bannwarth's syndrome), and acrodermatitis chronica atrophicans (ACA). We report on a female patient, who developed EM 10 days after a-tick bite in Berlin. Borrelia burgdorferi could be cultivated from a skin biopsy specimen taken from the periphery of the EM. The isolates were identified as Borrelia burgdorferi by indirect immunofluorescence using the monoclonal antibodies H 9724 and H 5332.     

Clinical aspects of Borrelia burgdorferi infections

Skin lesions due to Borrelia burgdorferi-like erythema migrans, lymphadenosis cutis benigna, and acrodermatitis chronica atrophicans - are hall-marks of a systemic infection, which tends to a chronically relapsing course. Even if the skin lesions are missing, or disappear spontaneously, the infection may persist and affect other organs. This presumption is supported by the outcome of a long-term follow-up study on seropositive forest workers. In association with meningopolyneuritis (Garin-Bujadoux-Bannwarth disease) and acrodermatitis chronica atrophicans - myositis and fasciitis have been recently reported as further possible manifestations of Borrelia burgdorferi infection. Borrelial infection during pregnancy should promptly be treated with antibiotics in high dosages, in order to prevent maternal-fetal transmission of borrelial organisms resulting in stillbirth or congenital defects of the newborn.     

Infiltrating lymphadenosis benigna cutis as borreliosis of the skin

Forms of lymphadenosis benigna cutis (Lbc) which run an unusual course may present considerable problems and are sometimes difficult to distinguish from malignant lymphomas of the skin on the basis of the clinical and histological picture. The case of a female patient is reported, who presented with plaque-like infiltrative lesions on both lower arms. The lesions were interpreted as being malignant lymphomas of the skin. After a progressive course of 6 years' duration, the diagnosis of an unusual plaque-like infiltrative form of Lbc caused by Borrelia was serologically confirmed by the demonstration of anti-Borrelia burgdorferi antibodies. Immunohistochemical examinations yielded the picture of a follicular pseudolymphoma with the formation of germ centres. After several weeks of penicillin therapy the skin lesions cleared completely.     

Borrelia burgdorferi-associated lymphocytoma cutis: clinicopathologic, immunophenotypic, and molecular study of 106 cases

Lymphocytoma cutis (LC) is considered as the stereotypical example of the cutaneous B-cell pseudolymphomas. It can be induced by various antigenic stimuli including arthropod bites, vaccination, and drugs among others. In endemic regions, Borrelia burgdorferi is the principal causative agent for LC. We studied retrospectively 108 biopsies from 106 patients (male : female, 48 : 58; mean age, 44.6; median, 51.5; range, 3-81) with B. burgdorferi-associated LC retrieved from the files of the Department of Dermatology of the University of Graz (Austria). Only cases with a B. burgdorferi etiology (typical locations, positivity of serologic and/or polymerase chain reaction (PCR) tests, clinical history) were included in the study. Lesions were located on the nipple (63 cases), earlobe (18 cases), genital region (9 cases), and trunk or extremities (16 cases). PCR analysis of B. burgdorferi DNA was positive in 54 of 80 cases tested (67.5%). In 47 cases, we could retrieve data on serologic examination for B. burgdorferi antibodies performed at the time of diagnosis of LC. Positivity was found in 45 patients (IgG+/IgM+, 5 cases; IgG+/IgM-, 37 cases; IgG-/IgM+, 3 cases; IgG-/IgM-, 2 cases). Histology revealed dense lymphoid infiltrates with prominent germinal centers (GCs) in all cases. Atypical morphologic and/or immunophenotypic features of the GCs were commonly observed. In 5 cases, due to confluence of large follicles, the histopathologic pattern simulated that of a large B-cell lymphoma. PCR analysis of the IgH gene rearrangement performed in 33 cases showed a polyclonal pattern in 31 cases and a monoclonal band in 2. In summary, B. burgdorferi-associated LC can present with misleading histopathologic, immunophenotypic, and molecular features, and integration of all data is necessary for a correct diagnosis.     

'Specific' cutaneous infiltrate of B-cell chronic lymphocytic leukemia at the site of a florid herpes simplex infection

Background: Specific cutaneous infiltrates in patients with leukemia generally carry a grim prognosis. However, non-neoplastic skin diseases may be associated with recruitment of normal and neoplastic leukocytes circulating in the peripheral blood. In those instances, neoplastic cells may be detected in skin lesions without an adverse effect on prognosis. Methods: In a patient with B-cell chronic lymphocytic leukemia, a specific infiltrate developed at the site of a florid herpes simplex infection. Clinically, the lesion presented itself as an ulcerated tumor. Results: Histopathologically, the lesion was characterized by a dense, diffuse infiltrate of small hyperchromatic lymphocytes throughout the entire dermis. Lymphocytes showed an aberrant CD20(+)/CD43(+)/CD5(+) phenotype of neoplastic B cells, and monoclonal rearrangement of immunoglobulin gamma genes could be demonstrated by polymerase chain reaction. Although criteria for leukemia cutis were fulfilled, the patient did well. Conclusions: The cutaneous infiltrate of neoplastic cells seemed to be part of a physiologic response to the antigenic stimulus, rather than indicating an exacerbation of leukemia. Ziemer M, Bornkessel A, Hahnfeld S, Weyers W. 'Specific' cutaneous infiltrate of B-cell chronic lymphocytic leukemia at the site of a florid herpes simplex infection.     

Antibodies to the Borrelia burgdorferi flagellum in patients with scleroderma, granuloma annulare and porphyria cutanea tarda

It is generally accepted that cutaneous Lyme borreliosis comprises erythema chronicum migrans, lymphadenosis benigna cutis, and acrodermatitis chronica atrophicans. In recent years the tick-borne spirochete Borrelia burgdorferi has been associated with a number of other cutaneous disorders. We therefore investigated sera from 175 patients with localized scleroderma (morphea) (n = 64), systemic sclerosis (n = 74), granuloma annulare (n = 16) and porphyria cutanea tarda (n = 21) with the new, highly sensitive and specific Borrelia burgdorferi flagellum ELISA assay. As controls (n = 297) served normal healthy volunteers and patients with other skin diseases. It was found that the distribution of individual antibody values and the median antibody levels were identical in controls and in patients with scleroderma, granuloma annulare and porphyria cutanea tarda. These data do not support the hypothesis of an etiological association between Borrelia burgdorferi infection and scleroderma, granuloma annulare or porphyria cutanea tarda.     

A morphologic study of lymphadenosis benigna cutis

Two skin biopsies of lymphadenosis benigna cutis have been analyzed by morphological and immunological methods using monoclonal and polyclonal antibodies on cryostat and paraffin sections. Follicular structures containing active germinal centers are composed of identical cell types as germinal centers of normal lymphatic tissue, e.g. centrocytes, centroblasts, immature plasma cells, dendritic reticulum cells and some T lymphocytes. Outside and inbetween the secondary follicles the infiltrate is composed of small T lymphocytes (OKT-3+, focal positive acid phosphatase reaction). Among T lymphocytes the OKT-4+ to OKT-8+ ratio was 2:1. Within these areas, consisting almost exclusively of T lymphocytes, cells with electron microscopical features of indeterminate cells and interdigitating reticulum cells were recognized. Those cells are OKT-6+. It can be concluded that in lymphadenosis benigna cutis the infiltrate of the dermis is composed of B and T cell areas which show the same microarchitecture and morphology as in normal lymphatic tissue.     

Subclinical chronic lymphocytic leukaemia associated with a 13q deletion presenting initially in the skin: apropos of a case

INTRODUCTION: B-cell chronic lymphocytic leukaemia (B-CLL) represents a low-grade B-cell lymphoproliferative disease that is the most common leukaemia in adults. The neoplastic cell is an autoreactive CD5 CD23 B lymphocyte. B-CLL may involve the skin, typically in the context of known disease. We present a case of subclinical B-CLL presenting initially in the skin. CASE REPORT: A 73-year-old male developed a lesion on his right cheek in April 2003 compatible with basal cell carcinoma. The re-excision specimen contained a well-differentiated atypical lymphocytic infiltrate consistent with B-CLL along with residual carcinoma. Subsequent laboratory studies revealed peripheral blood lymphocytosis with smudge cells. A diagnosis was made of Rai stage 0 CLL. Chromosomal studies on peripheral blood showed a deletion at 13q14.3. Excision of a second primary skin carcinoma revealed a squamous cell carcinoma in association with B-CLL that was identical to his previously diagnosed skin involvement. CONCLUSION: This case identifies a cutaneous presentation of subclinical B-CLL. There are two prior reports describing B-CLL presenting initially in the skin. In one case, the infiltrates were incidental on a re-excision specimen. The second report suggests 16% of B-CLL patients have cutaneous manifestations as the first sign of disease.     

Immunocytoma of the skin simulating lymphadenosis benigna cutis

We report a case of primary cutaneous lymphoma, of the lymphoplasmacytoid type (immunocytoma), in which a small neoplastic component was obscured by a dominating reaction exhibiting characteristic features of lymphadenosis benigna cutis. This abnormal cell population was identified because of the unusual cytomorphology of the tumor cells, which showed deeply indented nuclei in combination with a distinctly plasmacytic cytoplasm. Monoclonality was revealed by the cytoplasmic positively of the tumor cells for lambda chains only. This case strongly suggests that in at least a number of cases of lymphadenosis benigna cutis, a low-grade malignant lymphoma may be present.     

Successful treatment of lymphadenosis benigna cutis with topical photodynamic therapy with delta-aminolevulinic acid

BACKGROUND: Photodynamic therapy (PDT) using topical delta-aminolevulinic acid (ALA) has been used for nonmelanoma skin cancers, including malignant cutaneous T-cell lymphomas. Moreover, PDT has been tried for benign inflammatory or infectious skin lesions. OBJECTIVE: To evaluate the effects of ALA-PDT on skin lesions of lymphadenosis benigna cutis (LABC). PATIENTS AND METHODS: Two 16-year-old females with solitary and infiltrated nodules were treated 5 times with topical ALA-PDT. RESULTS: Both patients responded well and showed dramatic clinical and histopathological improvement without visible scars. CONCLUSION: The results confirm that topical ALA-PDT is an effective and safe modality for the treatment of LABC, and that such treatment may be cosmetically beneficial.     

Immunocytoma of the skin simulating lymphadenosis benigna cutis

Summary We report a case of primary cutaneous lymphoma, of the lymphoplasmacytoid type (immunocytoma), in which a small neoplastic component was obscured by a dominating reaction exhibiting characteristics features of lymphadenosis benigna cutis. This abnormal cell population was identified because of the unusual cytomorphology of the tumor cells, which showed deeply indented nuclei in combination with a distinctly plasmacytic cytoplasm. Monoclonality was revealed by the cytoplasmic positively of the tumor cells for lambda chains only. This case strongly suggests that in at least a number of cases of lymphadenosis benigna cutis, a low-grade malignant lymphoma may be present.     

Malignant transformation of lymphadenosis benigna cutis: a possibly transformed case and B-cell lymphoma

This study presents a patient who had had a 10 year history of lymphadenosis benigna cutis (LABC) before malignant lymphoma of the skin subsequently developed. During the LABC stage, the lesion showed several foci of cavernous hemangioma-like nodules which disappeared spontaneously but reccurred repeatedly. These cutaneous nodules were finally diagnosed as malignant lymphoma of the skin with a histology of diffuse, mixed small and large cell type according to the classification of the Working Formulation. Among the subpopulations of tumor cells, B-cells were highly predominant. It is suggested that LABC may have the potential to transform into malignant lymphoma (probably B-cell lymphoma).     

Clinical manifestations of erythema chronicum migrans Afzelius in 161 patients. A comparison with Lyme disease

Clinical symptoms were studied in 161 consecutive patients with erythema chronicum migrans Afzelius and in a follow-up study signs of late manifestations were investigated. General symptoms such as headache, fever, myalgia and/or arthralgia were found in about half of the patients with a disease duration of less than or equal to 3 weeks. Three patients had coexisting lymphadenosis benigna cutis. Two untreated patients developed meningitis/meningoradiculitis and one untreated patient arthritis. The importance of a sufficient antibiotic therapy to prevent late manifestations is stressed. Although there are many similarities between erythema chronicum migrans Afzelius and Lyme disease, the results of the present study also point to differences. Multiple skin lesions, pronounced general symptoms, laboratory abnormalities and major symptoms from the joints were less common in patients with erythema chronicum migrans Afzelius than reported in patients with Lyme disease, but a prolonged course of the skin eruption was more common.     

Acrodermatitis chronica atrophicans, erythema chronicum migrans and lymphadenosis benigna cutis--spirochetal diseases?

Seven cases of acrodermatitis chronica atrophicans (ACA), 11 cases erythema chronicum migrans (EMC) and 3 cases of lymphadenosis benigna cutis (LABC) have been analysed. In Warthin-Starry stained sections, spirochetal structures were present in all cases. The spirochetes were mesodermotropic and irregularly distributed.     

Successful treatment of leukaemia cutis with cladribine in a patient with B-cell chronic lymphocytic leukaemia

Cutaneous presentation of B-cell chronic lymphocytic leukaemia (B-CLL) is uncommon, and the influence of skin changes on B-CLL prognosis is unclear. We report a patient with B-CLL Rai II, with multiple nodular skin infiltrations on the trunk, upper arms and thighs as well as constitutional symptoms, who was successfully treated with cladribine. The peripheral blood (PB) lymphocytes were CD19, CD20, CD23 and CD5 positive, which confirmed the diagnosis of B-CLL. Skin biopsy of one of the lesions showed an intense infiltrate composed of small lymphocytes with no epidermotropism. These cells also showed the expression of CD19, CD20, CD23 and CD5 antigens similar to those presented on PB lymphocytes. Polymerase chain reaction performed on bone marrow lymphocytes and a lesional skin biopsy using consensus primers for immunoglobulin heavy-chain genes also showed the same monoclonal population of B lymphocytes both in the bone marrow and in the skin. The patient received four courses of cladribine 0.12 mg kg-1 daily as a 2-h infusion for five consecutive days. The courses were repeated at monthly intervals. The lymphocytosis gradually decreased and the PB count normalized after three courses. At the same time, a significant decrease in the cutaneous symptoms was observed. The patient became free of skin tumours after the fourth course of cladribine; only slight discoloration at the previous sites of cutaneous infiltration remained. There was no relapse of leukaemia cutis during a further 7 months of observation.     

Livedo racemosa: Ungewöhnliche Spätmanifestation einer Borreliose?

Classic variants of cutaneous borreliosis are erythema chronicum migrans (ECM), lymphadenosis benigna cutis (LBC) and acrodermatitis chronica atrophicans (ACA). Other dermatoses have been reported in the literature as possibly linked to borreliosis. A 59-year old female patient was seen in the late phases of cutaneous borreliosis with histologically confirmed ACA. In addition, prominent livedo racemosa was seen on the legs, also showing tissue changes similar to those of ACA. Borrelia burgdorferi infection was serologically confirmed by the presence of anti-IgM and anti-IgG antibodies. The clinical spectrum of late cutaneous borreliosis should be enlarged to include livedo racemosa.     

Lymphadenosis benigna cutis resulting from Borrelia infection (Borrelia lymphocytoma)

Swelling and erythema of the right pinna developed in a 7-year-old girl. Six months later a biopsy specimen showed a dense, diffuse lymphoplasmacytic infiltrate involving most of the dermis except for a thin Grenz zone. The appearance was consistent with lymphocytoma cutis. She had been bitten by a tick on the right ear in Switzerland 6 weeks before the onset of the lesion. Serologic tests by enzyme-linked immunosorbent assay for Borrelia burgdorferi, done 6 and 11 months after the bite, yielded optical density readings of 1.04 and 0.65, respectively; indirect immunofluorescence yielded titers of 1:256 and 1:128. A Borrelia-like organism was identified by a modified Steiner stain; immunohistochemistry was noncontributory. The spirochetal origin of lymphadenosis benigna cutis is briefly reviewed.