Granulomatous mycosis fungoides in a young man: A diagnostic challenge

Dear Editor,

A 33-year-old immunocompetent gentleman presented with dusky red, raised lesions on the medial aspect of both feet of 1.5 years duration. He also had similar lesions on the anterior surface of the left knee and bilateral forearms. The lesion on the left forearm subsided spontaneously in a few days; however, other lesions persisted. The examination revealed diffuse swelling of the lower legs with dusky erythematous, non-tender atrophic plaques with scaling, mild induration, measuring 6x6 cm, near the medial malleoli [Figure 1], left knee and right forearm. Non-tender inguinal lymphadenopathy (1.5x1.5 cm) was also present bilaterally.

Close

Figure 1:

Erythematous boggy atrophic with ulceration on medial aspect of lower legs bilaterally.

Export to PPT

Routine blood investigations were within normal limits. Serum and lesional fluid rK-39 as well as tissue polymerase chain reaction (PCR) for leishmaniasis were negative. Serum galactomannan and Mantoux Tuberculin Skin Testing (TST) were negative. Tissue culture for bacterial and mycobacteria showed no growth. Tissue staining for acid-fast bacilli was negative. Tissue staining for calcofluor white revealed septate hyphae. However, histopathology and multiple tissue cultures did not show any fungal organisms. Pan-fungal PCR was positive for Syncephalastrum racemosum.

A radiograph of bilateral legs did not reveal any bony changes. An ultrasound scan of bilateral lower legs revealed diffuse bilateral soft tissue oedema, subcutaneous plane thickening and superficial thrombophlebitis.

Whole body positron emission tomography-computed tomography (PET-CT) revealed soft tissue uptake of fluorodeoxyglucose (FDG) in areas of skin lesions and abdominal para-aortic, bilateral common iliac, external iliac and bilateral inguino-femoral FDG avid lymph nodes [Figures 2a and 2b].

Close

Figure 2a:

PET-CT showing FDG uptake in the skin and soft tissue around the plaque on the ankle.

Export to PPT

Close

Figure 2b:

PET-CT showing common FDG uptake in common iliac lymph nodes.

Export to PPT

Skin biopsy from a lesion revealed dermal granulomas arranged in perivascular distribution, with mild interstitial spill and dense lymphocytic infiltrate below the subcutis in the fascia. A repeat skin biopsy from multiple plaques revealed a dense dermal inflammatory infiltrate composed of lymphocytes, which were hyperchromatic and atypical in appearance, along with epithelioid cell tuberculoid granulomas and giant cells [Figures 3a-3d]. No epidermotropism or lymphocyte tagging along the basal layer of the epidermis was noted. Immunohistochemistry revealed lymphocytes to be of T-cell origin with CD3 and CD4 positivity, and loss of CD2, CD5, CD7, and CD8. Clonality studies revealed T-cell receptor (TCR) gamma (γ) clonality. Inguinal lymph node biopsy revealed reactive lymphoid hyperplasia.

Close

Figure 3a:

Pandermal dense granulomatous inflammatory infiltrate with foci of atypical lymphocytes (Haematoxylin and eosin, 40x).

Export to PPT

Close

Figure 3b:

Multi-nucleate giant cells within granulomas, admixed with atypical hyperchromatic lymphocytes (Haematoxylin and eosin, 200x).

Export to PPT

Close

Figure 3c:

CD4 positive staining of lymphocytes (Immunohistochemistry, 100x).

Export to PPT

Close

Figure 3d:

CD8 negative staining of lymphocytes (Immunohistochemistry, 200x).Granulomatous lower leg plaques

Export to PPT

The patient was initially started on voriconazole therapy, adjusted based on serum levels, for suspected deep fungal infection after septate hyphae were observed on calcofluor white stain. Due to poor response after one month and isolation of Syncephalastrum racemosum on PCR, liposomal amphotericin B (5 mg/kg/day for 12 days) was administered. This treatment showed only a minimal effect.

On re-evaluation, including clonality and immunohistochemistry studies, the fungus was identified as a contaminant, leading to a diagnosis of early granulomatous mycosis fungoides (GMF) (Stage IIA). Treatment with methotrexate (0.3 mg/kg/week) and prednisolone (0.5 mg/kg/day, tapered over four months) achieved rapid improvement, with oedema and ulceration resolving within 5–6 days and >80% lesion clearance within one month.

GMF is an uncommon variant of mycosis fungoides (MF), distinct from granulomatous slack skin. Granulomas occur in 1.6%-1.8% of all cutaneous lymphomas,^1,2 and 6.3% of MF.³ GMF is the more common form of granulomatous cutaneous T-cell lymphoma, while granulomatous slack skin is rare.⁴ The presence of granulomas can obscure the atypical lymphoid infiltrate and mask the diagnosis of a cutaneous T-cell lymphoma.⁵ Clonality may aid in establishing diagnosis;⁶ however, monoclonal cell infiltrate can be observed in non-lymphomatous conditions as well.⁷

GMF clinically resembles classical MF, presenting with persistent atrophic patches and plaques.^1,4 Lesions frequently involve the extremities in over 50% of cases.³ Diagnosis is often delayed due to its rarity and atypical features, with one-third of cases initially misdiagnosed as infectious, similar to the present case.⁴ GMF cases typically require more biopsies than classical MF.³

Epidermotropism is observed in 27–74% of cases, while small to medium atypical lymphocytes occur in 40–63%.^1,3,4 Multinucleated giant cells are reported in 53–81%,^1,4 subcutaneous involvement in 33% and eosinophilic infiltration in 60–63%.^3,4 Histologically, sarcoidal and perivascular granulomas with multinucleated giant cells and eosinophils are characteristic.^3,4 We also noted dense perivascular dermal granulomas, along with deeper lymphocytic infiltrate. Similar to the present case, immunohistochemistry shows CD3/CD4-positive lymphocytes with CD8 loss in 80% of cases.¹ T Cell Receptor (TCR) γ rearrangement demonstrates 75–94% sensitivity in GMF diagnosis.^3,4,6

GMF responds poorly to skin-directed therapy but shows similar outcomes to systemic treatments as classical MF.^3,4 Disease progression is more frequent in GMF (46% vs. 29%) with lower progression-free survival.³ Extracutaneous involvement occurs in 33%, primarily affecting lymph nodes, liver, and bone marrow.⁴ Despite these differences, overall survival rates and early-stage outcomes (up to stage IIA) are comparable between GMF and classical MF.³