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Skin manifestation of mantle cell lymphoma

European Journal of Dermatology. Volume 16, Number 4, 435-8, July-August 2006, Clinical report

Summary

Author(s) : Sei-ichiro Motegi, Etsuko Okada, Yayoi Nagai, Atsushi Tamura, Osamu Ishikawa , Department of Dermatology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.

Summary : Mantle cell lymphoma (MCL) is a distinct type of non-Hodgkin’s lymphoma that commonly affects extranodal sites. The most commonly affected sites are bone marrow, gastrointestinal tract and Waldeyer’s ring, however, skin is rarely involved. We reported a 62-year-old Japanese patient with MCL, exhibiting multiple small dome-shaped red nodules and skin ulcers. Histopathological examination demonstrated numerous atypical lymphoid cells in the dermis and subcutis. Immunohistochemically, tumor cells were positive for CD20 (L26), CD5, CD43 and cyclin D1, but negative for CD45RO (UCHL-1), CD3, CD10 and CD23. Our patient showed a significant improvement of skin lesions and lymphadenopathy with a combination chemotherapy. Awareness of skin manifestations of MCL is essential for dermatologists to establish an early diagnosis and perform appropriate treatment.

Keywords : mantle cell lymphoma (MCL), B-cell lymphoma, skin manifestation, cyclin D1

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ARTICLE

Auteur(s) : Sei-ichiro Motegi, Etsuko Okada, Yayoi Nagai, Atsushi Tamura, Osamu Ishikawa

Department of Dermatology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan

accepté le 9 Mars 2006

Mantle cell lymphoma (MCL) is an uncommon but aggressive form of non-Hodgkin’s lymphoma that typically involves lymph nodes. The extranodal involvement is frequent, especially in bone marrow, spleen, gastrointestinal tract and Waldeyer’s ring [1, 2], however, skin is rarely affected. MCL was listed in the new World Health Organization (WHO)- European Organization for Research and Treatment for Cancer (EORTC) classification of cutaneous lymphomas as an extracutaneous lymphoma involving the skin secondarily [3-5]. We herein report a case of MCL with cutaneous involvement and review skin manifestations of previously reported cases of MCL.

Case report

A 62-year-old Japanese man was referred to our hospital with a one-year history of multiple reddish nodules on the back and upper extremities. Painful ulcers had developed on his oral mucosa for the last 3 months. The family and past history were not contributory.

Physical examination revealed several dome-shaped small red nodules scattered on the back and upper extremities ( (figure 1A) ). In addition, pale-reddish ulcerated erythemas were seen on the chest and penis shaft ( (figure 1B) ). Aphthoid lesions were noted on the buccal and hard palate mucosa. Non-tender lymph nodes measuring 2-3cm in diameter were palpated on the left neck.

Abnormal laboratory results included slight anemia with a hemoglobin of 11.4 g/dL (normal 13.2-17.3), elevated serum total protein (9.3 g/dL: normal 6.3-7.9) and high levels of gamma-globulin (3.4 g/dL: normal 1.0-1.9). Elevated serum soluble IL-2 receptor was noted (1241 U/mL: normal 135-483). Serum lactate dehydrogenase level was normal. Anti human T-cell leukemia virus-1 antibody was negative. Computed tomographic scans of the whole body disclosed multiple lymphadenopathy in the cervical, supraclavicular, para-aortic, axillary and inguinal regions and enlargement of the bilateral tonsillae. ⁶⁷Ga scintigraphy showed unremarkable uptake of the whole body. Fluorodeoxyglucose-positron emission tomography (FDG-PET) scan showed areas of abnormal uptake in bilateral cervical, axillary and inguinal lymph nodes, as well as tonsillae and spleen. The gastrointestinal fiberscopic examination revealed erosive lesions in gastric mucosa.

Histopathological examination of a nodule on the back showed a massive proliferation of small- to medium-sized atypical lymphoid cells throughout the dermis and subcutis ( (figure 2A) ). There was a grenz zone with sparing the epidermis. The neoplastic cells had irregular nuclear contours, coarse chromatin, inconspicuous nucleoli and scant cytoplasm ( (figure 2B) ). On immunohistochemical analyses, tumor cells were positive for CD20 (L26) ( (figure 2C) ), CD5, CD43 and cyclin D1 ( (figure 2D) ), but negative for CD45RO (UCHL-1), CD3, CD10 and CD23. The additional biopsied specimens from the oral and stomach lesions showed the same histopathological and immunohistochemical findings.

Based on the clinico-pathological and immunohistochemical findings, the diagnosis of mantle cell lymphoma was established. He received the fractionated Hyper-CVAD/MTX-AraC chemotherapy regimen (cyclophosphamide/ vincristine/ doxorubicin/ dexamethasone alternated with methotrexate/ cytarabine) combined with rituximab. With two cycles of the chemotherapy, he achieved partial response with complete remission of skin lesions and improvement of lymphadenopathy. Increasing lactate dehydrogenase level was not shown. During a 4-month follow-up period, he has been in complete remission of skin lesions.

Discussion

Mantle cell lymphoma (MCL) is a malignant tumor derived from B cells in the mantle zone of lymphoid follicles characterized by specific pathologic, immunophenotypic and molecular genetic features, and usually takes an aggressive clinical course, defined in the World Health Organization (WHO) classification [3-5]. Histologically, it shows a diffuse or nodular monotonous proliferation of small lymphoid cells with scant cytoplasm and irregular nuclear contours in lymph nodes. Immunophenotypically, the tumor cells are positive for B-cell markers CD79a, CD19, CD20 and CD22 as well as CD5, and are usually negative for CD10 and CD23 [6, 7]. The majority of MCL carries a cytogenetic abnormality with t(11, 14) (q13; q32) translocation, which results in the juxtaposition of the CCND-1 gene on chromosome 11 with the immunoglobulin heavy chain gene on chromosome 14, and causes overexpression of cyclin D1 protein, which acts as a positive signal for the transition from the G1 to S phase [8-10]. Cyclin D1 overexpression is considered to be important as a diagnostic marker [11]. The result of our immunohistochemical analyses completes the different diagnosis from other small B-cell lymphomas (marginal zone lymphoma; negative for CD5, CD10, CD23 and cyclin D1, B-cell lymphocytic lymphoma; positive for CD5, CD23 and negative for CD10, cyclin D1, follicular lymphoma; positive for CD10 and negative for CD5, cyclin D1).

MCL frequently involves extranodal organs, particularly such as bone marrow, gastrointestinal tract and Waldeyer’s ring, and was fundamentally considered as the extracutaneous lymphoma, which rarely affects the skin. In two large series of 121 and 59 cases of MCL, only 3 and 2 patients had skin lesions, respectively [5, 12]. To the best of our knowledge, there have been only 17 patients reported who exhibited skin lesions described in detail in English literature [10, 13-18]. We summarized the clinical features of 17 patients in table 1( Table 1 ). The age ranged from 22 to 89 years old, with a mean age of 62.5. The ratio of male to female was 13: 4. The most common site of skin involvement was trunk in 11 of 17 patients, followed by face in 4 cases, arms in 3 cases and thighs, legs, scalp in each one case, respectively. Skin lesions manifested as nodular lesions in 6 patients (35%), macular or maculopapular lesions in 5 (29%), tumoral or infiltrated plaques in 4 (24%), and subcutaneous nodules in 2 (12%). Fourteen patients (82%; excluding No. 1, 12, 17) exhibited skin lesions at the time of the initial diagnosis of MCL. Most of the patients (82%) also had extracutaneous lesions such as lymph node, bone marrow or gastrointestinal tract, and were classified as stage IV. Aggressive combination chemotherapy was given to 16 patients. Four patients (No. 4, 6, 12, 15) achieved a complete remission of the skin lesions and no recurrence had been observed during a follow-up period (1-17 years).

A cutaneous eruption simulating insect bites has been incidentally described in association with MCL. It seems to be reactive rather than neoplastic because of no evidence of MCL involvement in the skin lesions [19-21]. The lesions of our case clinically resembled insect bite like eruptions associated with MCL. However, our case was not considered to exhibit exaggerated reactions to insect bites, because of the presence of tumor cells in the skin lesions.

Skin involvement is rare in MCL. Once developed, however, it usually suggests a disseminated stage. Although the prognosis of MCL is poor, aggressive chemotherapy may improve the survival rate. Since cutaneous lesions can be the first manifestation of MCL, awareness of MCL is important for dermatologists to establish an early diagnosis and perform an appropriate treatment.
Table 1 Reported cases of mantle cell lymphoma with skin lesions

No	Author	Age/Sex	Location	Clinical presentation	Extracutaneous Involvement	Stage	Prognosis
1	Ellison	66M	Temple	Macular skin lesions	LN, liver, spleen, lung, pleural cavity, CNS	IV	D (55d; after initial hospitalization)
2	Geerts	65F	Forehead	Nodules	LN, BM	IVA	D (1.5y; after diagnosis)
3	Geerts	77F	Back, breast, arm	Tumoral plaques	Bronchus wall	IVA
4	Bertero	51M	Breast	Subcutaneous nodule	LN, liver, spleen	IVA	A (17y; after onset)
5	Bertero	78F	Breast, back	Nodules	none	I E	D (3y; after diagnosis)
6	Bertero	43M	Back, face, arm	Infiltrated plaques	LN, liver, spleen	IVA	A
7	Bertero	22M	Breast	Nodules	none	I E	A
8	Marti	61F	Abdomen	Tumoral plaque	LN, BM, tonsils	IVA	D (15m; after diagnosis)
9	Moody	47M	Ear	Nodules	LN, BM	IVA	A (3y; after onset)
10	Dubus	56M	Breast, back	Erythematous papules	LN, BM, PB	IVA	D (1y; after treatment)
11	Dubus	89M	Breast, back, abdomen	Infiltrated purpuric papules	LN, BM, PB	IVA	D (5d; after diagnosis)
12	Dubus	72M	Face,breast, arm, axilla	Subcutaneous nodules	LN, BM	IVA	A (1y; after treatment)
13	Sen	85M	Leg	Macular rash	LN. BM, buccal mucosa	IVB	D (20m; after onset)
14	Sen	76M	Thigh	Nodule	none	I E	A (30m; after onset)
15	Sen	56M	Chest	Nodules	BM, GI	IVA	A (21m; after onset)
16	Sen	57M	Legs	Maculopapular rash	LN, BM, PB	IVB	D (9m; after onset)
17	Sen	61M	Flank back, thigh	Plaques	LN, BM, PB leptomeninges	IVB	D (15m; after onset)

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