Primary Cutaneous Small to Medium-Size CD4+ Pleomorphic T-Cell Lymphoma: 48 Patients from Two Independent Centers and Revaluation of Clinico-Histological Criteria for Differential Diagnosis from Other CTCL
Authors: Alberti-Violetti Silvia , Talpur Rakhshandra , Torres-Cabala Carlos Antonio , Corti Laura , Berti Emilio , Duvic Madeleine 
Published: October 2019

Abstract
Introduction and Background: Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma (PC-CD4+ SM-PTL) was recently re-classified as a rare provisional subtype in the 2008 World Health Organization (WHO) classification. It is characterized by solitary nodules or plaques located mostly on the head and neck. Multiple lesions are associated with a worse prognosis; however, the paucity of patients has prevented the definition of prognostic factors. Histologically, a dense cutaneous infiltrate of clonal small/medium hyperchromatic lymphocytes admixed with numerous reactive cells is observed, sometimes leading to the diagnosis of pseudolymphoma or other lymphoma: Mycosis Fungoides (MF) or peripheral T cell lymphoma – not otherwise specified (PTCL-NOS). Differential diagnosis with other aggressive cutaneous lymphomas is very important due to the favorable prognosis of PC-CD4+SM-PTL and complete response to conservative therapies. The purpose of this retrospective study was to evaluate and compare clinical and histological features of PC-CD4+ SM-PTL in 48 cases collected from two independent centers, MD Anderson Cancer Center (Houston, TX) and Dermatological Clinic of the University of Milan (Milan, Italy).
Results: Forty-eight patients were identified (26 MDACC and 22 Milan cases). Women out-numbered men (women 67% and 55% respectively, and men 33% and 45% respectively). The mean age at onset was 53 and 50 years. The mean follow-up time was 19 months (1-84 months) for the American group and 31 months (3-180 months) for the Italian group. All patients in both groups were alive at the time of last follow up, without evidence of extra-cutaneous disease.
Seventy-four percent of American patients and 73% of Italian patients developed single lesions, most common were nodules in the head and neck area. Multifocal lesions were found in other body sites besides head and neck in 6/7 American patients and in all Italian patients. Multifocal disease was characterized by plaques rather than nodules.
Histological features showed a dense infiltrate composed of small to medium-sized hyperchromatic “grouped” atypical lymphoid cells occupying superficial and deep dermis. The infiltrate also showed admixed reactive B-cells, plasma cells, macrophages, and few dendritic cells. Vascular hyperplasia was noted. Adnexotropism was frequently found. Focal epidermotropism was also present. The neoplastic cells were CD3+, CD4+, CD5+, PD1+, CD8-, CD30-. A peculiar perivascular and small cluster arrangement of PD-1+ cells was noted. T-bet nuclear expression was recorded in 3 Italian cases. Mib1/Ki-67 proliferation index was between 5 and 30% in all Italian patients.
The treatments used for patients with complete responses included surgical excision, local radiotherapy, and high potency topical steroids, occasionally combined with topical nitrogen mustard. Patients who had complete responses without relapse also had single lesions on the head and neck (67% and 68 % respectively), except for one US patient with multifocal disease. A small group of patients (18.5% and 4%, respectively) relapsed one time. Seven percent of American patients and 18% of Italian patients developed multifocal plaques on the trunk and extremities and had dramatic responses to therapy with a “waxing and waning” course. Only one Italian patient developed rapidly progressive tumors confined mainly to the legs and was resistant to cyclophosphamide and oral steroids.
Conclusion: This case series demonstrates that PC-CD4+ SM-PTL is characterized by heterogeneous clinical presentations. There are no definite criteria to predict an aggressive course reported rarely in the literature. Histological findings useful, but not sufficient for diagnosis, and not sufficiently underscored by classical description of this tumor, are the arrangement of PD-1+ atypical cells in small clusters or rosettes surrounding reactive cells and the perivascular distribution of the neoplastic cells. Absent or minimal epidermotropism, a mixed B cell infiltrate and the clinical presentation of a solitary dermal nodule, may help to distinguish PC-CD4+ SM-PTL from the other CD4+ PD1+ CTCLs, mycosis fungoides and PTCL-NOS.

Disclosures
No relevant conflicts of interest to declare.