Rapidly progressive hyperpigmented keratotic plaques with epidermotropism

Question

What is your diagnosis?

Answer

Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma

Discussion

Skin biopsies showed irregularly acanthotic epidermis with dense diffuse pan-dermal infiltrate of lymphocytes and histiocytes. There were scattered large and atypical lymphocytes in the epidermis, present singly and in clusters forming microabscesses [Figures 2a and b]. We observed mild-to-moderate epidermal spongiosis and focal spongiotic vesicles, along with few necrotic keratinocytes [Figures 2c and d]. The lymphocytes were strongly immunopositive for CD3 and CD8 [Figure 3a], focally positive for CD4 [Figure 3b] and negative for CD20 and CD30. Peripheral blood examination and bone marrow biopsy were unremarkable. 18-fluorodeoxyglucose whole body positron emission tomography scan demonstrated metabolically active uptake limited to cutaneous and soft-tissue lesions. The patient was treated with methotrexate (15–30 mg/week) for three months, followed by all-trans-retinoic acid (80 mg/day) for a month without much improvement. Subsequently, pegylated doxorubicin (50 mg/month) was administered with partial flattening of the plaques. Six months following treatment, the disease worsened with multiple new plaques and new-onset bullous lesions and crusted erosions, with immunohistological features of aggressive epidermotropic CD8+ T-cell lymphoma. He was subsequently administered one cycle of gemcitabine (1.2 g/m²) and oral prednisolone 40 mg/day, however, COVID-19 lockdown prevented further follow-up visits. We lost the patient after three months due to worsening of skin lesions and general condition.

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Figure 2a:

Skin biopsy from abdomen showing lymphocytes in the epidermis, both singly and in a few clusters, with minimal spongiosis (epidermotropism) (hematoxylin and eosin, ×100)

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Figure 2b:

Higher magnification shows the lymphocytes to be large, pleomorphic and atypical; a necrotic keratinocyte is also visible (hematoxylin and eosin, ×400)

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Figure 2c:

Skin biopsy from sole shows clusters of atypical lymphocytes (Pautrier microabscesses) in the epidermis (hematoxylin and eosin, ×200)

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Figure 2d:

Another focus from the same biopsy shows epidermal spongiosis with spongiotic blisters as well as lymphocyte epidermotropism (hematoxylin and eosin, ×100)

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Figure 3a:

Immunohistochemistry showing strong CD8 expression in lymphocytes (×40)

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Figure 3b:

Immunohistochemistry showing focally positive CD4 lymphocytes (×40)

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Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma represents less than 1% of all cutaneous T-cell lymphomas and is included as a provisional entity in the latest WHO/EORTC classification.¹ It was referred to as “Berti’s lymphoma,” “generalized pagetoid reticulosis,” or “Ketron-Goodman disease” before the category of primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma was established.^2-4 It is characterized by rapidly progressing disseminated patches, papules, plaques, nodules and tumors with central necrosis and ulceration.⁴ There is a propensity for visceral metastasis to lung, testis, central nervous system and oral mucosa, but lymph nodes are often spared. However, skin-limited disease has been reported rarely, similar to our case.⁵ Histological features include dense dermal lymphocytic infiltrates, with marked pagetoid epidermotropism composed of pleomorphic small- to medium-sized T-cells. The neoplastic T-cells have a CD8+/CD4- cytotoxic T-cell profile with granzyme B, perforin and TIA-1 marker expression.⁶ Conventional therapies for cutaneous T-cell lymphomas are generally ineffective, while interferon-alpha and multiagent chemotherapy have been tried with unsatisfactory results.^7,8 It has an aggressive clinical course and poor prognosis with a median survival of 12–32 months.^4,7 Allogenic hematopoietic stem cell transplantation has induced partial or complete remission in few patients.⁴ A recent report has highlighted long-term remission with brentuximab vedotin monotherapy.⁹ In the absence of a standard accepted treatment for this lymphoma and skin-limited disease in our patient, we tried methotrexate initially, but later escalated to monoagent chemotherapies such as doxorubicin and gemcitabine due to inadequate response.

Apart from primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma, differential diagnoses of CD8+ lymphoproliferative disorders include CD8+ mycosis fungoides, pagetoid reticulosis, lymphomatosis papulosis type D, primary cutaneous acral CD8+ lymphoma and subcutaneous panniculitic T-cell lymphoma. Of these, CD8+ mycosis fungoides particularly can be a close differential diagnosis due to its clinical and histologic similarity (epidermotropism). Although both can present with plaques and ulcerated tumors, the verrucous or hyperkeratotic and annular morphology of plaques, accentuated palmoplantar involvement and rapid disease progression favour the diagnosis of primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma. On histopathology, features such as spongiosis with spongiotic blisters, necrotic keratinocytes, deep dermal infiltrate, angio- and adnexotropism in addition to epidermotropism should raise the possibility of primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma [Table 1]. It is not unusual for these patients to be initially misdiagnosed as mycosis fungoides.⁴ Correct diagnosis of this aggressive lymphoma requires a strong clinicopathological correlation.