Large Cell Transformation of Mycosis Fungoides Unresponsive to Skin Directed Therapies: A Case Report

INTRODUCTION

Primary cutaneous lymphomas are the second most common extranodal non-Hodgkin Lymphomas. They may be of either T-cell, B-cell or NK cell origin. Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma (CTCL). Large cell transformation (LCT) of MF represents a rare but clinically significant event in the disease course, characterised by the transition of the typical small lymphocytes of MF into larger, more aggressive cells resembling Hodgkin’s or non-Hodgkin’s lymphoma.^[1]

CASE REPORT

We report a case of LCT of MF nonresponsive to skin directed therapies. A 38-year-old female presented with hyperpigmented, scaly lesions associated with itching all over the body since one year. Lesions were initially small red, and flat on right thigh which gradually increased in size, encircling the thigh, became pigmented and raised over a period of one year with associated itching. Subsequently lesions developed over breast, back and arms. There was a history of fever, weight loss and reduced appetite. She was also a known case of hepatitis B.

Cutaneous examination revealed large, hyperpigmented, indurated, scaly plaque almost involving the entire right thigh, extending from inguinal region to knee on the anterolateral aspect [Figure 1a] multiple (12–15), erythematous to pigmented, ill-defined patches of varying sizes (3 × 3 to 5 × 7 cm) with fine scaling over the breasts, back, arms and shoulders with relative sparing of midline [Figure 1b and c].

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Figure 1:

(a) Large, hyperpigmented, indurated, scaly plaque almost involving the entire right thigh, extending from inguinal region to knee on the anterolateral aspect. (b and c) Multiple (12–15), erythematous to pigmented, ill-defined patches of varying sizes (3 × 3 to 5 × 7 cm) with fine scaling over back, arms and shoulders with relative sparing of midline.

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Lymph node examination revealed Inguinal lymphadenopathy – four in number on the right side and three on the left side, non-tender, discrete, mobile, of varying sizes from 2 × 2 to 3 × 3 cm. Bilateral axillary lymphadenopathy – three on the right and two on the left side, non-tender, discrete, mobile, of varying sizes from 2 × 1 to 3 × 2 cm. Few cervical and jugulodigastric nodes were palpable on right side.

Hair, nails, mucosae, palms and soles were normal.

General and systemic examination was unremarkable.

Differential diagnosis considered were psoriasis, large plaque parapsoriasis and MF.

Routine investigations such as complete blood count, liver and renal function test, erythrocyte sedimentation rate, chest X-ray and ultrasonography abdomen were within normal limits. Contrast-enhanced computed tomography chest and abdomen revealed axillary lymphadenopathy and multiple right inguinal nodes (largest measuring 2.6 × 3.7 × 2.3 cm).

Skin biopsy showed lymphocyte exocytosis with moderate, diffuse infiltrate of small lymphocytes in superficial and mid dermis admixed with large cells and plasma cells [Figure 2a].

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Figure 2:

(a) Haematoxylin and eosin-stained section (10× magnification) showing lymphocyte exocytosis with a moderate (black arrow), diffuse infiltrate of small lymphocytes admixed with large atypical cells and plasma cells in the superficial and mid dermis (orange arrow). (b) Immunohistochemistry demonstrating CD3 positivity in approximately 80% of the infiltrating lymphocytes 40×. (c) Immunohistochemistry showing strong CD4 positivity in approximately 70% of the neoplastic T-cell population 40×. (d) CD30 positivity observed in approximately 30–40% of the large transformed cells on immunohistochemistry, consistent with large cell transformation HPE 40×.

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Lymph node section showed preserved lymphoid follicles with prominent germinal centres, there is expansion of paracortical areas with lymphocytes, histiocytes and plasma cells, some of the histiocyte nuclei show nuclear grooves, focal pigmented cells suggestive of dermopathic lymphadenopathy. Immunohistochemistry of MF panel consisting of CD3, 4, 5, 7, 8 and 30 was performed over skin biopsy which showed CD3+, CD 4+ and CD 30+ [Figure 2b-d].

A diagnosis of cutaneous T-cell lymphoma CD 30+ LCT MF stage IIA (T2 N1 M0 B0) was made and patient was started on steroids with narrowband ultraviolet B therapy. Steroids were given to manage inflammation and for symptomatic relief. Patient showed no response and was shifted to CHOP regimen consisting of cyclophosphamide, doxorubicin, vincristine and prednisone after the oncologist consultation. After three cycles, there was reduction in scaling and itching [Figure 3]. Three months after the last cycle, she succumbed due to sepsis.

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Figure 3:

Significant reduction in scaling and improvement in plaque thickness over the right thigh after three cycles of CHOP chemotherapy.

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DISCUSSION

MF typically presents with patch, plaque, tumour and erythrodermic stage. MF tends to be an indolent disease, where serial biopsies are required for the diagnosis.^[2] LCT within skin or lymph node biopsies is defined as large cells ≥4 times the size of a small lymphocyte, which are CD30+ or CD30– in ≥25% of the dermal infiltration. Incidence of LCT vary between 8% and 55%, more common in advanced disease.^[3,4]

Campo et al. proposed that genetic alterations and dysregulation of signalling pathways may contribute to this phenomenon. Talpur et al. further suggested that alterations in cytokine expression and immune dysregulation may drive the transformation process.^[5,6]

Patients with LCT-MF present with rapidly enlarging skin tumours, nodal involvement and systemic symptoms such as fever, weight loss and night sweats indicating an aggressive disease course. Treatment options include multi-agent chemotherapy, targeted therapies such as brentuximab vedotin, radiation therapy and hematopoietic stem cell transplantation. The prognosis for patients with LCT-MF is generally poor compared to those with early-stage MF. The median survival after transformation is significantly reduced between 1 and 3 years. Talpur et al.^[6] and Diamandidou et al.^[7] found that early transformation and advanced stages were associated with poor prognosis. Talpur et al.^[6] reported poor prognosis in combination with advanced age, LCT at the time of initial diagnosis of MF.^[6,7]

Similarly, the recent study by Cappelli et al. reported improved initial responses in LCT patients treated with low-dose total skin electron beam therapy (TSEBT), but their duration of response and progression-free survival were significantly shorter–mirroring the aggressive nature seen in this case. CD30 positivity, as noted in the current patient, has also been associated with transformation and poor outcomes in multiple studies.^[8]

A comparison of the present case with the existing literature is summarised in Table 1.^[2-4,6-8]

CONCLUSION

We conclude that LCT-MF represents a complex clinical entity requiring initiation of systemic therapies at the earliest. A multidisciplinary approach involving dermatologists, oncologists and pathologists is essential for accurate diagnosis and appropriate management which could impact the prognosis of the patient.