Primary Cutaneous Methotrexate-Associated T-Cell Lymphoproliferative Disorder in the Setting of Autoimmune Disease: A Case Series and Review of the Literature

Abstract

Methotrexate (MTX), an antimetabolite targeting certain autoimmune conditions and various hematologic malignancies, has been associated with iatrogenic lymphoproliferative disease (LPD) primarily of B-cell lineage. Less commonly are T-cell neoplasms where primary skin involvement is considered rare. Three cases were encountered in the medical practice of one of the authors. The patients ranged in age from 38 years to 99 years (2 women and 1 man) with 2 having rheumatoid arthritis and 1 having ankylosing spondylitis. All 3 patients received MTX. The cases included subcutaneous peripheral T-cell lymphoma not otherwise specified (NOS) (1 patient), mycosis fungoides (1 patient), and a primary aggressive epidermotropic cytotoxic T-cell lymphoma (1 patient) that proved to be fatal. One patient had spontaneous regression following MTX withdrawal; she later developed a recurrence while off MTX. Two patients died, 1 of unrelated causes and 1 of lymphoma. Seven previously reported cases included subcutaneous panniculitis-like T-cell lymphoma (2 cases), primary cutaneous CD4+ LPD (2 cases), peripheral T-cell lymphoma (NOS) (1 case), anaplastic large cell lymphoma (1 case), and peripheral T-cell lymphoma localized to fat (1 case). Regression without recurrence occurred in 6 of the 7 patients with MTX withdrawal. The patients were on the MTX for an average of 4 years and had a median age of 61 years with a slight dominance of men over women. Three of the 7 cases showed Epstein-Barr encoding region (EBER) positivity while the 3 cases reported in this series were negative. MTX-associated T-cell LPD involves older patients on long-term MTX where EBER positivity is more frequent than extracutaneous MTX-associated T-cell LPD. A spectrum of classic forms of CTCL is seen with subcutaneous involvement representing a significant percentage of cases. Regression with MTX withdrawal occurs although not in every case.

FIGURE 1.

The patient (case 2) is a 38-year-old woman who developed erythema and tenderness of the thigh and pretibial surfaces. She is otherwise asymptomatic. She has a medical history of ankylosing spondylitis.

FIGURE 2.

A, The collage of images is from case 2. In this low-power image there is significant localization of lymphocytic infiltration within the fat [Hematoxylin and Eosin (H&E), 20×]. B, There is permeation of the interstitial spaces of the fat by atypical lymphocytes. The lymphocytes are intimately opposed to the inner cytoplasmic membrane of the adipocytes (H&E, 400×). C, A number of activated appearing macrophages course through the interstitial spaces of the fat. The cells have abundant cytoplasm and exhibit erythrocyte phagocytosis (note arrow) (H&E, 1000×). D, The lymphocytes are a heterogeneous mixture of small, intermediate, and larger-sized lymphocytes exhibiting nuclear hyperchromasia and nuclear contour irregularity (H&E, 100×).

FIGURE 3.

A, In regard to the phenotypic profile in case 2, the subcutaneous lymphocytes are extensively positive for CD3 (red chromagen, 100×). B, Relative to CD3, there is a decrement in staining for CD7. The reduction is in the 50% realm (red chromagen, 100×). C, Despite a morphology resembling subcutaneous panniculitis-like T-cell lymphoma, the neoplastic lymphocytes are CD4⁺ (red chromagen, 100×). D, There is a minor CD8⁺ T-cell population that is interpreted as being of reactive-based etiology (red chromagen, 200×). E, A few atypical lymphocytes stain positively for CD30. Overall, the extent of CD30 positivity is not diagnostic of CD30⁺ T-cell LPD (red chromagen, 200×).

FIGURE 4.

The patient is a 99-year-old man who developed an abrupt onset of multiple nodules on the chest 6 months after starting MTX (case 3).

FIGURE 5.

A, The collage of images is representative of the pathology for case 3. The biopsy shows a dense effacing highly atypical lymphocytic infiltrate that spanned the entire sampled thickness of the dermis [Hematoxylin and Eosin (H&E), 40×]. B, The lymphocytes exhibit marked nuclear hyperchromasia and nuclear contour irregularity. There is prominent infiltration of the epidermis where the neoplastic cells assume a relatively passive pattern of colonization of the epidermis without eliciting any significant epidermal response (H&E, 400×). C, The neoplastic cells are CD8 positive (DAB, 200×). D, There is staining of the malignant lymphocytes for TIA (DAB, 200×).