Cutaneous manifestations of non-hodgkin's lymphoma

Introduction

Numerous cutaneous manifestations can be associated with malignancies. About 50% of patients with lymphomas have cutaneous manifestations at some time during the course of disease.[1] Epstein and MacEachen[1] divided cutaneous manifestations of lymphomas into specific malignant infiltrates and non-specific manifestations. Specific malignant infiltrates are the ones which show characteristic malignant cells on histopathological examination. Non-specific lesions associated with lymphomas can be classified into infections, non-infective conditions and changes due to chemotherapy.[1]

Materials and Methods

Thirty - two confirmed cases of non-Hodgkin′s lymphoma which included inpatients and outpatients attending Department of Oncology, KMC Hospital, Attavar, Mangalore were studied for a period extending from November 1998 to December 2000. These patients were carefully examined for cutaneous manifestations. Investigations like nodel biopsy, biopsy of cutaneous lesions, ultrasound abdomen and X-rays were done. Pathologically these NHL patients were classified into low grade, intermediate grade, high grade and miscellaneous conditions (CTCL) according to working formulation.[3] These patients, excluding CTCL, were staged by Ann Arbor classification′ from stage I (limited disease) to stage IV (disseminated disease) depending on the extent of involvement. CTCL patients were staged by a staging system related to TNM classifications where T denoted cutaneous, N nodal and M visceral involvement. Another 32 patients admitted for non--dermatological and non-malignant diseases at KMC Hospital, Attavar were taken as controls.

All patients were subjected to a detailed cutaneous and systemic examination. Specific investigatjons for skin lesions such as skin biopsy were done when indicated. Patients were reassessed once a month and findings were noted.

Observations and Results

In the study group age of the patients ranged from 7 to 76 years. Twelve out of thirty two (37.5%) belonged to the age group 41 to 60 years. Study group had a male predominance with

a male: female ratio of 2.2:1. In the control group age of the patients ranged from 5 to 85 years with 11/32(34.37%) patients belonging to age group 61 to 80 years. The male: female ratio was 3:1

In the study group low grade lymphomc was present in 7/32 (21.88%) intermediate grade in 10/32 (31.25%) high grade lymphoma in 10/ 32 (31.25%) and mycosis fungoides and Sezary syndrome (CTCL) in 5/32 (15.62%).

In NHL patients, excluding CTCL, stage II disease was seen in 11/27 (40.74%) patients, stage III in 10/27 (37.04%) and stage IV disease in 6/27 (22.22%). None of the patients had stage I disease. In CTCLs stage IIA and stage IIB were seen in 1 /5 (20%) patients each, 2/5 (40%) had stage IVA disease, remaining 1 /5 (20%) had stage IVB disease.

In 20/32 patients (62.5%) first examination was done before starting specific treatment for lymphoma. In this group, cutaneous manifestations were present in 15/20 (75%) patients which included non-infective conditions (55%), infective conditions (30%) and specific infiltrates (25%). In another 12 patients (37.5%) first examination was done after starting specific treatment for lymphoma. In this group cutaneous manifestations were present in 11/12 (91.67%) patients which included changes due to chemotherapy (75%), non-infective conditions (58.33%) and infections (25%).

Specific infiltrate was seen in 6/32 (1875%) patients [Table - 1]. Specific infiltrates were present in all 5 CTCL cases. Extensive plaques with erosions, limited plaques and psoriasiform plaques were seen in one patient each, one patient had nodular lesion and erythroderma was present in one patient. Histopathologic examination of these lesions showed pautrier′s microabscess and upper dermal infiltrate of atypical lymphocytes. Specific lesion was also present in one patient with low grade lymphoma. These lesions appeared as generalized skin coloured papules.

Histopathological examination revealed nodular collections of atypical lymphocytes in the dermis.

Infections in the study group included superficial fungal in 7/32 and viral infection in 2/ 32 [Table - 1]. Infective conditions in the study group when compared with control was not found to be statistically significant. Infective conditions were seen only in stage III and stage IV [Table - 2]. Underlying HIV infection was present in 2/32 patients. Both these patients had stage IV lymphoma and disease showed rapid deterioration. Both these patients expired during the study period.

Non-infective conditions were more common in patients with advanced disease [Table - 2]. Non-infective conditions seen were acquired ichthyosis (10/32) generalized pruritus in CTCL patients (5/32), insect bite reaction (1/32) and maculopapular drug eruption (1/32) [Table - 1]. When compared to controls acquired ichthyosis and generalised pruritus were found to be statistically significant. Insect bite reaction was seen in stage IV lymphoma.

Of the 32 patients, 26(81.25%) were treated with combination chemotherapy schedules like CHOP, COP COMP BFM protocol, Melphalan and prednisolone and patients were treated with methotrexate alone and one patient was treated with chlorambucil alone. 1 (3.12%) patient was treated with radiotherapy and 2 (6.25%) received no treatment. Diffuse alopecia was seen in all the patients treated with combination chemotherapy. )ther cutaneous changes seen in combination chemotherapy schedules were bluish pigmentation >f proximal part of nail (4/29), localized pigmentation of plams and soles (1 /29), diffuse )igmentation at injection site (1 /29), pigmentation it scar sites (1/29) and stomatitis (4/29) [Table - 2].

Discussion

Specific lesions were present in 6/32 18.75%) patients. According to a study done by Epstein and MacEachern[1] incidence of specific lesion in NHL was reported to be 13.9% But in his study CTCL patients were not included under JHL. In our study incidence of specific lesions in 4HL excluding CTCLs was 1/27 (3.7%).

Non specific manifestations were found o be more common than specific lesions. Infective conditions seen were superficial fungal and viral infections. These infections were localized. Superficial fungal infection responded well to topical antifungal agents. These conditions when compared to control were not found to be statistically significant. In this study 2 patients had stage IV lymphoma with HIV infection. Rapid deterioration of lymphoma was seen in these patients. Non-infective conditions seen were acquired ichthyosis, generalized pruritus, insect bite reactions and maculopapular drug eruption. Acquired ichthyosis was confined to upper and lower limbs with sparing of the trunk. Chemotherapy was not found to improve this condition.

Generalised pruritus was present only in CTCI cases . Although the reported incidence of generalised pruritus in NHL was 15%[8] none of the NHL patients excluding CTCL had generalised pruritus. Etiology of generalised pruritus is not known. This condition when compared to controls was found to be statistically significant. This condition showed improvement with specific treatment for lymphoma. Insect bite reaction and drug eruption were noted in advanced disease.

The specific infiltrates in CTCL patients showed excellent response with combination chemotherapy. Lesions resolved with one cycle of chemotherapy. In 2 CTCL patients who were treated with methotrexate alone lesions resolved 2-3 months after starting treatment.

All the patients treated with combination chemotherapy developed diffuse alopecia. But it was not seen in patients treated with single agent chemotherapy. The drugs reported to be commonly associated with alopecia include cyclopho-sphamide, vinblastine, vincristine.[9] In this study all the patients treated with above drugs developed diffuse alopecia. Alopecia in these patients started after first cycle of chemotherapy. Thinning of the eyebrows, axillary and pubic hair was also noted. Even though chemotherapy was continued these patients showed regrowth of hair after 3-4 months. These hairs were found to be thinner and less pigmented. Although methotrexate is reported to be commonly associated with alopecia,[9] in this study 2 patients with CTCL treated with methotrexate alone did not develop alopecia.

Bluish pigmentation of proximal part of nail was seen in 4/12 (33.33%) patients on CHOP regimen. Drugs causing pigmentation of nail are cyclophosphamide[10] and doxorubicin.[11] Although cyclophosphamide is known to cause nail pigmentation, such pigmentation was not seen in patients on COP, COMP regimen. Cyclopho-sphamide is reported to cause diffuse pigmentation. Diffuse pigmentation at injection site and multiple spotty pigmented macules on palms and soles were noted in patients on cyclophosphamide which subsided with cessation of chemotherapy. Four out of twenty-nine patients treated with combination chemotherapy developed stomatitis.