dpc-arcive

Dermatopathology: Practical & Conceptual

October – December 2010 | Volume 16, No. 4

How do we classify this patient?

Sotcan, Rodica; Taran, Oxana

Introduction

Cytotoxic lymphomas are tumors derived from T- or natural killer (NK) lymphocytes. Neoplastic cells typically express at least one cytotoxic protein such as T-cell intracellular antigen (TIA)-1, granzyme B, or perforin. In the skin, primary cutaneous CD 8 + aggressive epidermotropic cytotoxic T-cell lymphoma and gamma/delta T-cell lymphoma have been recognized as distinctive entities. Both are rare conditions accounting for less than 1% of all cutaneous T-cell lymphomas (CTCL) and both are characterized by prominent skin involvement and an aggressive clinical course. [1-4]

The distinction of cutaneous gamma/delta T-cell lymphoma from primary cutaneous aggressive epidermotropic CD 8 + lymphoma is difficult, and can be subjective. Here we presented a patient with concurrent cutaneous and systemic involvement, who was diagnosed with a cytotoxic T-cell Lymphoma. Histopathologicaly, his skin lesions displayed all criteria for CD 8 + cytotoxic lymphoma, but immunohistochemical results were more consistent with a diagnosis of gamma/delta T-cell lymphoma. No reports on similar patients could be found in the literature.

Report of a patient

A 51-year-old man presented in the emergency room with fever, chills and a few cutaneous lesions on the abdomen. He had an 11-year history of panacinar emphysema due to deficiency of alpha-1 antitrypsin enzyme, and three months ago he had been diagnosed with demyelinizing polyneuropathy, thoracic myelitis, and right side facial nerve paralysis. The patient had no previous history of any cutaneous lymphoma, especially not of mycosis fungoides. His skin lesions were interpreted at first as bullous impetigo, but despite topical and oral antibiotic treatment, the number and the size of lesions gradually increased and spread over the trunk, face, and scalp, as well as genital and oral mucosa.

On physical examination, the patient appeared thin and weak; intermittent fevers up to 40° C were recorded. Well-circumscribed, infiltrated and elevated dull red patches and plaques, some with a central bulla or crust, were scattered over the entire body, especially on the abdomen (Figs. 1 and 2). Lesions ranged from 1 to 4 cm in diameter and were painless. No lymphadenopathy, hepatomegaly, or splenomegaly was accompanying.

Fig. 1A and B

Erythematous plaques, some with a central bulla and some crusted on the trunk.

Fig. 2

Involvement of the genitalia.

Pertinent laboratory results on admission included moderate anemia (Hb 8.4 g/dl, Ht 24.4%), LDH 506U/L, CRP 96 mg/dl, fibrinogen 800 mg/dl, Na 112.7 mmoll /L , and K 2.31 mmol/L. Human T-lymphotrophic virus types I and II testing both revealed negative results. The peripheral blood cell count was normal without any atypical lymphocytes. HIV testing was negative. Alpha-1 antitrypsin was low with 100.4 mg/dl. Blood cultures were repeatedly sterile.

Computed tomography revealed nodular lesions, alveolar-like, basal, bilaterally bullous emphysema, and small bilateral pleurisy in the lung, a proliferation in the corpus vertebrae T10, and a tumor of the right adrenal gland but no lymphadenopathies (Figs. 3A-C and Figs. 4A-D)

Fig. 3A-C

Panacinar emphysema with the note that in Fig, 1B there is a proliferation in the corpus vertebrae T10 with a lymphomatous aspect.

Figs. 4A-D

A. Right suprarenal gland showing a tumor (5,4/4 cm). B. Left lacrimal gland with an increased volume. C. Tegumental thickening of the anterior abdominal wall.

A skin biopsy specimen from an ulcerate lesion on the abdomen showed a diffuse proliferation of lymphocytes, with marked epidermotropism (Figs. 5A-M). Cytomorphology was variable, characterized by small, medium, and large pleomorphic cells. Intraepidermal spongiosis, vesiculation and numerous necrotic keratinocytes were seen. Invasion of the smooth muscle was reported. No involvement of the subcutaneous fat was apparent.

Figs. 5A-M

H&E. Proliferation of lymphocytes with epidermotropism , variable cytomorphology (Fig. 5C, magnification 100x), spongiosis (Fig. 5I, magnification 200x), vesiculation (Figs. E,F,J), necrotic keratinocytes (Figs. G,I), invasion of the smooth muscle (Fig. 5J, magnification 100x)

Immunohistochemically pleomorphic cells were positive with antibodies against CD3, perforin, myeloperoxydase, and CD45, but negative with CD20, CD79a, CD 30, and CD 56. CD8 was expressed inconsistently (Figs. 6A-E).

Figs. 6A-E

Immunohistochemical staining of biopsy specimen demonstrates that atypical lymphocytes are: A. CD 3 positive; B. inconsistent CD 8 positive; C. CD 30 negative; D. CD 56 negative; E. perforin positive.

Molecular biology showed a monoclonal rearrangement of the T-cell receptor (TCR) gene. No specifies genetic alterations have been identified.

The patient was transferred to the oncology department for further treatment. He received CHOP therapy (cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone) but he died in the hospital just two months after the initial diagnosis. No autopsy was done.

Discussion

Cutaneous cytotoxic lymphomas are rare but distinctive clinically because of the morphology of their skin lesions and their aggressive clinical behavior.

Aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma and cutaneous gamma/delta T-cell lymphoma are included as provisional entities in the WHO-EORTC classification [4] and as a distinct entity in the WHO classification of 2008. [5] The clinical features of aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma and cutaneous gamma/delta positive T cell lymphoma are indistinguishable and very similar to those of generalised pagetoid reticulosis and of advanced mycosis fungoides (“a tumeur d’emblee”). [5] In contrast of mycosis fungoides, patients with cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma and cutaneous gamma/delta positive T-cell lymphoma present at the onset of the disease with rapidly growing, disseminated patches, plaques, and tumors wich often ulcerate. Involvement of the mucosa is common. Metastatic spread to unusual sites, such as the lung, testis, and central nervous system but not to the lymph nodes is often seen in cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma. Hemophagocytic syndrome is a frequent complication in cutaneous gamma/delta T-cell lymphoma. [6,7] For diagnosis of primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma and cutaneous gamma/delta T-cell lymphoma it is crucial to exclude a history of mycosis fungoides. [6]

Histopathologically, cutaneous cytotoxic lymphomas are characterized by infiltrates consisting of pleomorphic T-cells or blasts showing a diffuse infiltration of an acanthotic epidermis with variable degrees of spongiosis, intraepidermal blistering, and necrosis. [8]

Distinction of primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma from primary cutaneous gamma/delta T-cell lymphoma is difficult and often arbitrary. Cases with a gamma/delta phenotype usually show a more prominent involvement of the subcutaneous fat than those of primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma. Another feature differentiating is the presence of interface alterations in many cases of primary cutaneous gamma/delta T-cell lymphoma.

The patient presented here illustrates very well the difficulty in distinguishing primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma from primary cutaneous gamma/delta T-cell lymphoma and the overlapping histhopathological features of the two variants of aggressive cutaneous cytotoxic lymphoma. Because CD8 was expressed by neoplastic cells only inconsistently, interface changes were prominent, and the subcutis was not involved by the infiltrate, we considered primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma that lost CD8 expression and primary cutaneous gamma/delta T-cell lymphoma without subcutaneous fat involvement. It remains to be determined whether or not these two diseases represent phenotypic variations of the same entity of aggressive cutaneous cytotoxic T-cell lymphoma.

Summary

Cytotoxic lymphomas are tumors derived from T- or natural killer (NK) lymphocytes. Neoplastic cells typically express at least one cytotoxic protein such as T-cell intracellular antigen (TIA)-1, granzyme B, or perforin. In the skin, primary cutaneous CD 8 + aggressive epidermotropic cytotoxic T-cell lymphoma and gamma/delta T-cell lymphoma have been recognized as distinctive entities. The distinction of cutaneous gamma/delta T-cell lymphoma from primary cutaneous aggressive epidermotropic CD 8 + lymphoma is difficult and can be subjective. Here we presented a patient with concurrent cutaneous and systemic involvement, who was diagnosed with a cytotoxic T-cell lymphoma. Histopathologicaly, his skin lesions displayed all criteria for CD 8 + cytotoxic lymphoma, but immunohistochemical results were more consistent with a diagnosis of gamma/delta T-cell lymphoma. No reports on similar patients could be found in the literature.

Rodica Sotcan, M.D., is a dermatologist at Medical Center Sanador in Bucharest, Romania, and Oxana Taran, M.D., is a resident in dermatology at Central Military Hospital in Bucharest, Romania. This article was reviewed by Contact corresponding author via email: sotcanr@yahoo.com .

References

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2. Massone C, Chott A, Metze D et al. Subcutaneous, blastic natural killer (NK), NK/T-cell, and other cytotoxic lymphomas of the skin: a morphologic, immunophenotypic, and molecular study of 50 patients. Am J Surg Pathol. 2004;28(6):719-35.

3. El Shabrawi-Caelen L, Cerroni L, Kerl H. The clinicopathologic spectrum of cytotoxic lymphomas of the skin. Seminars in Cutaneous Medicine and Surgery. 2000;19 (2):118-123.

4. Burg G, Kempf W, et al. WHO/EORTC classification of cutaneous lymphomas 2005: histological and molecular aspects. J Cutan Pathol. 2005;32(10):647-74.

5. Cerroni L, Gatter K, Kerl H. Skin Lymphoma: The illustrated guide. Oxford:Wiley-Blackwell, 2010:97-113.

6. Weaver J, Mahindra AK, Pohlman B, Jin T, Hsi ED. Non-mycosis fungoides cutaneous T-cell lymphoma: reclassification according to the WHO-EORTC classification. J Cutan Pathol. 2010;37(5):516-24.

7. Koch R, Jaffe ES, Mensing C, Zeis M, Schmitz N, Sander CA.Cutaneous gamma/delta T-cell lymphoma. J Dtsch Dermatol Ges. 2009;7(12):1065-7

8. Kempf W, Sander CA. Classification of cutaneous lymphomas—an update. Histopathology. 2010;56(1):57-70.