Red nodule on the face of a middle-aged woman

Question

What is the diagnosis?

Answer

Diagnosis: Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder

Discussion

Histopathological examination revealed epidermal hyperkeratosis [Figure 2a] and focal liquefactive degeneration of the basal layer. Dermal infiltrate comprised of small to medium-sized lymphocytes, with some migration towards the follicular epithelium [Figure 2b]. The nuclei of lymphocytes were slightly hyperchromatic, and some were even irregularly shaped [Figure 2c]. Immunohistochemical staining was positive for CD4 [Figure 3a], CD3 [Figure 3b], CD5, PD-1 [Figure 3c], and cytokeratin (CK), with weak positivity for CD8 [Figure 3d]. CD30, CD68, and MUM-1 were focally positive, while CD10, CD20, CD21, CD79α, and CXCL-13 were negative. The Ki67 proliferation index was 20% positive. Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder (CD4+ PCSM-TCLD) is a rare benign lymphoproliferative disease with an estimated annual incidence of < 2 per 10 million. In 2008, the World Health Organisation (WHO) named this disease primary cutaneous CD4+ small/medium T-cell lymphoma based on characteristics such as cell morphology and the immunophenotype of the disease.¹ In 2016, due to its indolent course and favourable prognosis the WHO changed the name to primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder (CD4+ PCSM-TCLD) ². CD4+ PCSM-TCLD occurs in the face, neck, and upper limbs and often presents as a single nodule or plaque without subjective symptoms.

Histopathology and immunohistochemistry examination are gold standards for the diagnosis of CD4+ PCSM-TCLD. The characteristic histologic manifestation is dense, nodular, or diffuse lymphocytic infiltration of the dermis; however, no apparent epidermotropism or folliculotropism is observed. Immunohistochemistry often reveals CD4+, CD3+, CD8-, and CD30- markers. Atypical CD4+ T cells can also express follicular helper T cell markers such as PD1, BCL6, and CXCL13. In CD4+ PCSM-TCLD, the Ki-67 proliferation index of most patients is at a relatively low level (≤5–30%).³ Notably, the immunohistochemistry results in this case included weakly positive detection of CK. CK is a marker of epithelial cells and can be used to distinguish epithelial from non-epithelial tumours. However, a few cases of CK expression in non-epithelial tumours may be positive. This indicates that the origin of a tumour cannot be definitively determined based on CK expression alone. A comprehensive judgment based on clinical manifestations, histopathology, immunohistochemistry results, and other factors is necessary.

The following differential diagnosis may be considered- (1) T-cell pseudolymphoma—The lesions of CD4+ PCSM-TCLD have difficulty in spontaneous remission. Abnormal loss of T-cell antigens is common, and monoclonal T Cell Receptor (TCR) rearrangement can contribute to differentiation; (2) primary cutaneous follicular helper T-cell lymphoma—there are generally multiple skin lesions. Some patients have abnormal blood cell and Lactate Dehydrogenase (LDH) levels. They can express CD10 and require systemic treatment; and (3) mycosis fungoides, which has three stages of manifestations. Epidermotropism can be observed in histopathology.³

The treatment regimens for CD4+ PCSM-TCLD include surgical resection, radiotherapy, and local injection of steroids. Low-dose radiotherapy (4 Gy in two fractions) is preferred for isolated lesions.⁴ Additionally, some drugs can be used to treat CD4+ PCSM-TCLD, such as methotrexate, doxycycline, and BRAF inhibitors. Furthermore, it has been reported that the following situations often indicate a poor prognosis: (1) Rapid tumour progression and relatively large tumour size (diameter ≥ 5 cm); (2) A high tumour proliferation index (Ki-67); (3) A small number of infiltrating B cells and CD8+ T lymphocytes, as well as low CD4 expression; and (4) Central nervous system involvement.⁵ In this case, the patient underwent resection of skeletal muscle soft tissue tumour and random flap plasty. No signs of recurrence were observed after one year of follow-up.