Nodules on Leg in a Middle-Aged Female: Unravelling a Malignant Aetiology

Dear Editor,

Nodular swellings on the leg are a common presentation in dermatology clinics, but their underlying causes can range from benign to malignant. In certain patient groups, the appearance can mimic more common conditions and potentially misdirect the diagnosis. Among the malignant causes, primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is uncommon and typically reported in older adults. We present this case because of its unusual age of onset, an atypical immunophenotype and its rarity.

A 48-year-old woman attended the dermatology outpatient department with two firm, painless, non-pruritic, reddish swellings on the posteromedial aspect of the right leg that had been enlarging over 6 months. The lesions began as pea-sized nodules and gradually increased in size. There was no preceding trauma, ulceration or systemic symptoms such as fever, night sweats or weight loss.

On examination, two erythematous, scaly, indurated nodules measuring 2 × 2.5 cm and 3 × 3.5 cm were seen [Figure 1a]. They were non-tender but fixed to deeper tissue. Right inguinal lymph nodes, 0.5 × 1 cm to 1 × 1 cm in size, were palpable, firm, discrete and mobile. General and systemic examination was unremarkable, and blood tests including viral markers were within normal limits. Positron emission tomography-computed tomography (PET-CT) revealed a metabolically active, irregular lesion involving skin and subcutaneous tissue on the medial aspect of the right leg, with ipsilateral pelvic and inguinofemoral lymph nodes, as well as pre-aortic and lower paratracheal lymphadenopathy [Figure 1b].

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Figure 1:

(a) Two erythematous indurated nodules with superficial scaling on posteromedial aspect of right leg. (b) Positron emission tomography -computed tomography images in the coronal section demonstrate fluorodeoxyglucose avid cutaneous lesions on the posteromedial aspect of the right leg, corresponding to two distinct cutaneous nodules with intense uptake (Standardised Uptake Value maximum [SUVmax]: 4.1).

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Deep incisional biopsy from one nodule showed a dense dermal infiltrate of atypical lymphoid cells extending into subcutaneous tissue, separated from the epidermis by a clear grenz zone. The cells included large centroblasts and immunoblasts, with occasional mitotic figures. Immunohistochemistry (IHC) was positive for leukocyte common antigen, cluster of differentiation (CD) 20, CD5, B-cell lymphoma 2 (BCL2) and Ki-67 proliferation index (~50%) and negative for pancytokeratin, human melanoma black-45, CD3, CD30, BCL6, multiple myeloma oncogene 1 (MUM1) and cyclin D1 [Figure 2a-d]. Bone marrow examination was normal. These findings supported the diagnosis of PCDLBCL-LT.

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Figure 2:

(a) Low-power view showing dense diffuse dermal infiltrate of atypical lymphoid cells (black asterisks) with a clear grenz zone beneath the epidermis (arrow). (Haematoxylin and eosin stain [H&E] 20×). (b) Section showing diffuse sheets and focal clustering of atypical lymphoid cells (red oval) (H&E, 1000×). (c) High-power view showing strong CD20 membranous staining in large atypical lymphoid cells (Diaminobenzidine, 200×). (d) Immunohistochemistry for Ki-67 showing nuclear positivity in approximately 50% of tumour cells (red arrow), indicating a high proliferation index (Diaminobenzidine, 400×)

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She was referred to haematology and commenced on rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) chemotherapy for stage IIIAE disease as per Ann Arbor staging criteria. After six cycles, the lesions had resolved clinically, and PET-CT showed complete metabolic remission [Figure 3].

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Figure 3:

Healed nodules with remnant scar after six cycles of chemotherapy.

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In women of this age group, panniculitis is an important differential diagnosis and requires deep biopsy. Dermatofibrosarcoma protuberans may also present as indurated nodules, but histology shows storiform spindle-cell proliferation rather than diffuse large B-cell infiltrates.

PDDLBCL is related to its nodal counterpart but remains confined to the skin at presentation. It typically shows rapid growth of solitary or multiple nodules and carries an unfavourable prognosis, with 5-year survival rates reported between 41% and 58%.^[1] Most cases arise de novo, although transformation from other cutaneous BCL2s can occur. The t(14;18) chromosomal translocation, seen in nodal DLBCL, is suggestive of secondary skin involvement.^[2]

The classical IHC profile of PCDLBCL-LT includes positivity for MUM1, BCL2, Forkhead box protein P1, immunoglobulin M and weak BCL6, with negativity for CD10, CD30 and CD5. Variations occur, and occasional cases show CD10 or CD5 expression. The Ki-67 index is generally high (>50%).^[3] Our patient showed CD5 positivity and lacked MUM1 and BCL6, underscoring that not all cases follow the textbook profile. BCL2 expression remains useful in distinguishing this entity from primary cutaneous follicle centre lymphoma. This case illustrates that clinicopathological correlation is essential, and rigid reliance on an IHC “checklist” can be misleading.

Staging requires exclusion of systemic spread through imaging and bone marrow assessment, and classification depends on nodal involvement above and below the diaphragm, extranodal extension and the presence or absence of B-symptoms.^[4] The present case was stage III E A, denoting bilateral nodal disease, local extranodal spread and absence of constitutional symptoms.

The R-CHOP regimen is widely accepted for both nodal DLBCL and PCDLBCL-LT, often with adjunct radiotherapy in localised disease.^[5] Most primary cutaneous BCL2s have an indolent course, but PCDLBCL-LT remains an aggressive variant in which early diagnosis and treatment are vital.

This case highlights the importance of recognising atypical presentations of PCDLBCL-LT, particularly in younger patients, to avoid diagnostic delays. A tailored approach integrating histopathology, immunophenotyping and imaging ensures accurate staging and effective management.