Primary cutaneous acral CD8⁺ lymphoproliferative disorder: Clinicopathologic and immunophenotypic features

Dear Editor,

Primary cutaneous acral CD8⁺ lymphoproliferative disorder is a recently described rare clinical entity, previously classified under acral CD8⁺ cutaneous T-cell lymphomas. It presents with solitary or multiple skin lesions in acral regions (e.g., ears, fingers, nose) and follows an indolent course. To date, few cases have been published and diagnostic criteria remain a matter of debate due to overlapping features with more aggressive lymphomas.¹

We present the case of a 44-year-old woman with a six-week history of a painless, non-ulcerated nodule on her right nasal ala. The lesion had been unsuccessfully treated with oral antibiotics and corticosteroids. Physical examination revealed a 2 cm sized erythematous, firm nodule [Figure 1]. Histopathological analysis showed a dense pandermal lymphoid infiltrate separated from the overlying epidermis by a clearly defined grenz zone. Empty spaces consistent with prior attempted fine-needle aspiration (FNAC) were observed [Figure 2a]. Aggregates of histiocytes surrounding these spaces were present, but no infectious pathogens (Leishmania, fungi or acid-fast bacilli) were identified. The lymphocytes were predominantly medium-sized [Figure 2b]. No epidermotropism, necrosis or angiodestruction were observed. Immunohistochemistry demonstrated CD3, CD5, CD8 and CD4 positivity with clear predominance of CD8⁺ cells [Figures 2c-e]. The lesional cells were negative for CD30, CD56, CD20, PAX5, CD10, CD23 and granzyme B [Figures 2f and g]. Epstein–Barr virus–encoded RNA (EBER) in situ hybridisation was also negative. CD68 immunostaining highlighted histiocytes, while occasional lymphocytes demonstrated a characteristic dot-like cytoplasmic staining pattern [Figure 2h]. Molecular analysis confirmed TCR-γ and TCR-β clonality. The Ki-67 proliferative index was 15% [Figure 2i]. These findings were consistent with a diagnosis of primary cutaneous acral CD8⁺ lymphoproliferative disorder. The absence of epidermotropism, the indolent clinical course and a low proliferative index make mycosis fungoides and primary cutaneous CD8⁺ aggressive epidermotropic cytotoxic T-cell lymphoma unlikely.

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Figure 1: Erythematous nodule on right nasal ala at initial presentation.

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Figure 2a: Photomicrograph shows the overall tumour architecture with a dense pandermal lymphoid infiltrate below a clearly defined grenz zone (Haematoxylin and eosin, 25x).

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Figure 2b: Dense dermal lymphoid infiltrate composed predominantly of medium-sized lymphocytes with empty spaces consistent with prior fine-needle aspiration, and surrounding histiocytic aggregates (Haematoxylin and eosin, 400x).

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Figure 2c: Immunohistochemistry demonstrating CD3-positive lymphoid cells (50x).

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Figure 2d: Immunohistochemistry showing CD4-positive lymphocytes within the infiltrate (100x).

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Figure 2e: Immunohistochemistry demonstrating a predominance of CD8-positive cells (250x).

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Figure 2f: Immunohistochemistry demonstrating negative CD20 staining in the lymphoid infiltrate (400x).

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Figure 2g: Granzyme B immunostaining negative in the lesional cells (100x).

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Figure 2h: CD68 immunostaining highlighting histiocytes (black arrow); occasional lymphocytes show a characteristic dot-like cytoplasmic staining pattern (green arrow) (200x).

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Figure 2i: Ki-67 immunostaining demonstrating a proliferation index of approximately 15% in tumour cells (100x).

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Laboratory evaluation was within normal limits, including normal serum β2-microglobulin levels. Peripheral blood smear and peripheral blood flow cytometric immunophenotyping showed no evidence of haematologic involvement.

Over the two subsequent months, the lesion showed spontaneous regression, leaving only subtle soft tissue thickening [Figure 3]. No systemic manifestations were observed. The benign clinical course and histopathological profile supported the classification of this entity as indolent, distinct from aggressive CD8⁺ cytotoxic lymphomas.

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Figure 3: Near-complete spontaneous regression of the nasal nodule two months later.

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Primary cutaneous acral CD8⁺ lymphoproliferative disorder typically presents as nodules or tumours on acral sites; however, it has rarely been described in other locations.¹ Reports in the literature describe indolent nodular lesions most commonly involving the ear or other acral sites. Petrella et al.² documented a series of adult patients presenting with solitary indolent nodules of the ear. Hathuc et al.³ further characterised the clinicopathologic features of this entity, highlighting its typical acral presentation and indolent behaviour. Rare cases with extracutaneous progression have also been described, including a long-standing case by Alberti-Violetti et al.⁴ with extension beyond the primary lesion involving additional cutaneous sites and bone. More recent studies have expanded the clinical spectrum, as illustrated in the retrospective cohort study by Stephan et al.¹ which included both acral and nonacral presentations such as thighs and eyelids. Additional case reports have documented recurrent lesions or atypical localisations, such as those reported by Nova-Villanueva et al.⁵ and Pasco Peña et al.,⁶ further supporting the generally favourable behaviour of this entity while emphasising the need for ongoing clinical surveillance. Although its aetio-pathogenesis remains unclear, an association with contact hypersensitivity reactions to gold has been suggested.⁷

In view of its characteristically indolent clinical course, rigorous diagnostic differentiation from other lymphoproliferative processes remains essential, as misclassification may lead to overtreatment. Within the spectrum of cutaneous CD8⁺ T-cell proliferations, the main differential diagnoses include primary cutaneous CD8⁺ aggressive epidermotropic cytotoxic T-cell lymphoma, CD8⁺ variants of mycosis fungoides, lymphomatoid papulosis, primary cutaneous gamma-delta T-cell lymphoma, pseudolymphomas and primary cutaneous anaplastic large cell lymphoma.³ Aggressive CD8⁺ cytotoxic lymphomas typically exhibit rapid progression, ulceration, marked epidermotropism, cytologic atypia and higher proliferative activity, features that clearly contrast with the indolent and localised acral presentation of primary cutaneous acral CD8⁺ lymphoproliferative disorder.³ Immunophenotypically, aggressive CD8⁺ cytotoxic cutaneous T-cell lymphomas typically show strong expression of cytotoxic markers and a high proliferative index. In contrast, our case lacked granzyme B expression and demonstrated a low Ki-67 index (15%), supporting an indolent CD8⁺ lymphoproliferative process. Preservation of CD3 and CD5 expression, together with absence of CD30, further argues against other aggressive CD8⁺ lymphoproliferative disorders.³ Another differential diagnosis of primary cutaneous follicle centre lymphoma was also excluded based on the immunophenotypic profile. Accurate diagnosis relies on clinical correlation, histopathological features, immunophenotyping and molecular studies.

Although debate persists regarding its precise classification, this case reinforces that primary cutaneous acral CD8⁺ lymphoproliferative disorder could represent a distinct clinicopathological entity. Future reports of additional cases may help refine diagnostic criteria and clarify its position within the spectrum of cutaneous lymphoproliferative disorders.