An accurate diagnosis of dermal CD8 ⁺ lymphoproliferative disorders requires clinicopathological and immunophenotypic correlation

Short abstract

Linked Article: Kempf et al. Br J Dermatol 2022; 186:887–897.

Cutaneous lymphomas are diagnostically challenging from a clinical and pathological perspective. Most cases are CD4⁺, and the CD8⁺ lymphoproliferative disorders (LPDs) in the skin are largely accounted for by mycosis fungoides (typically paediatric and hypopigmented lesions), lymphomatoid papulosis (types D and E) and cutaneous anaplastic large cell lymphoma. ¹ , ² In 2007, Petrella et al. ³ reported the occurrence of a group of LPDs in acral locations (nose, ears and toes/fingers) with a CD8⁺ phenotype and a benign clinical behaviour. The term ‘indolent CD8⁺ lymphoid proliferation of the ear’ was proposed, and was later confusingly changed to ‘cutaneous acral CD8⁺ T‐cell lymphoma’ (CD8⁺ ATCL), in the updated World Health Organization–European Organisation for Research and Treatment of Cancer (EORTC) classification of haematopoietic neoplasms (2018). ² This entity was originally mistakenly perceived by many to be the CD8⁺ variant of the so‐called small‐to‐medium CD4⁺ T‐cell lymphoma, an entity now believed to be a form of pseudolymphoma.

CD8⁺ dermal LPDs (excluding mycosis fungoides and CD30⁺ lymphoid proliferations) are exceedingly rare and diagnostically challenging. The prognosis ranges from an almost entirely indolent process (CD8⁺ ATCL) to neoplasms with the potential for high rates of local recurrence and aggressive clinical behaviour [CD8⁺ peripheral T‐cell lymphoma (PTCL) not otherwise specified, CD8 PTCL]. ⁴ , ⁵ More recently, an unusual subtype of CD8⁺ LPD has been described in patients with congenital or acquired immunodeficiencies, which show striking expression of CD8, in association with a dermal infiltrate and a granulomatous pattern. The behaviour of such lesions appears to be somewhat dependent on the status of immunosuppression. ⁶

Because there is morphological overlap between these three conditions, an accurate clinicopathological correlation that includes immunophenotypic studies is key to differentiate between them. To this end, Kempf et al. ⁴ present the largest series of these three conditions ever reported to date (n = 47), with special focus on CD8⁺ ATCL. This comprehensive study collected cases from numerous European centres, and the clinical, pathological and immunophenotypic features, and the treatments used, were subsequently reviewed at an EORTC Cutaneous Lymphoma Group workshop. Notably, cases of CD8⁺ ATCL were solitary acral small nodules of small‐to‐medium‐sized CD8⁺ lymphocytes, lacking significant cytologic atypia. Immunophenotypically, a dot‐like pattern of immunoreactivity with CD68, ⁷ expression of TIA‐1, and absence of granzyme B were characteristic. Like primary cutaneous small‐to‐medium CD4⁺ LPD, the Ki67 activity was always below 30%. In contrast, cases of CD8⁺ PTCL had a higher rate of multifocality (~27%), a higher degree of cellular pleomorphism and higher expression of multiple cytotoxic markers (granzyme B, perforin). They also lacked the CD68 dot‐like pattern and had much higher Ki67 proliferation (55% of cases with >50%). Local recurrences were seen in 45% of cases and one patient died from the disease. The patients with immunodeficiency‐associated LPD were much younger and had multiple lesions clinically.

From a clinical perspective, a diagnosis of PTCL of the skin has strong clinical connotations, and usually patients receive systemic treatment with chemo‐ and/or radiotherapy. ⁸ Separating reproducible diagnostic categories is key to individualizing therapeutic regimens and discovering their molecular profile. This study shows that appropriate distinction of CD8⁺ dermal LPDs into specific diagnostic categories is possible and reproducible (Figure 1).

Figure 1.

Left panels: an example of CD8⁺ acral T‐cell lymphoproliferative disorder (ATCL) on the hand. A discrete small papule is present. The infiltrate is composed of small‐to‐intermediate‐sized cells (original magnification × 400) strongly positive for CD8 (original magnification × 200). Middle panels: an example of CD8⁺ peripheral T‐cell lymphoma (PTCL). A large tumour is present in the leg. The malignant infiltrate is composed of medium‐to‐large cells with marked cellular pleomorphism (original magnification × 400) and strong expression of CD8 (original magnification × 40). Right panels: an example of a CD8⁺ lymphoproliferative disorder in the setting of combined variable immunodeficiency (CVID). There are numerous patches and plaques with a red‐brown appearance. The infiltrate has a vague granulomatous pattern (original magnification × 400) and expression of CD8 (original magnification × 100).