A Rare Case of Primary Cutaneous CD4+ Small/Medium Size T-Cell Lymphoproliferative Disorder Responding to Rituximab Open Access

Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder (PCS-TCLPD) is a rare lymphoproliferative disorder characterized by a solitary erythematous plaque or nodule on the face, neck, or upper trunk that has a favorable outcome [1]. Very rarely multiple plaques or masses may be seen, which should prompt a précised evaluation to exclude other non-favorable conditions such as primary cutaneous peripheral T-cell lymphoma, non-otherwise specified [2].

Histologically, there is a dense dermal infiltrate mainly comprising small to medium-sized CD4-positive T cells, and less than 30% large pleomorphic T cells [3]. This infiltration may extend to the subcutis and epidermotropism may be seen focally [4]. Also, a reactive admixture of CD8+ T cells, CD20+ B cells, plasma cells, and histiocytes may be seen [3]. The TCR gene rearrangement study shows monoclonal T-cell expansion; no clonal Ig gene was detected in the previously reported cases [5, 6].

Conventional modalities for treating this type of lymphoproliferative disorder include excision, intralesional corticosteroid, or local radiotherapy, but not all cases are suitable for or respond to these modalities. Here we report a rare case of recalcitrant primary cutaneous small-/medium-sized CD4+ lymphoproliferative disorder in a 55-year-old male patient who responded well to rituximab injection but had recurrence after 1 year of the injections.

A 55-year-old male patient presented with multiple pruritic masses on lips and cheeks for a 10-year duration before visiting our department. On the exam, there were bilateral pre-auricular, erythematous nodules with firm consistency measuring 4 × 3 cm, right auricular nodule, in addition to a central upper lip erythematous nodule measuring 2 × 3 cm (Fig. 1a, b, c). These lesions were small and grew gradually throughout 10 years and caused cosmetic disfigurement of the upper lip and the face. He was constantly complaining of pruritus that was not confined to the lesions only but was generalized in nature. In addition, he had a peripheral sensory deficit, most probably due to prolonged treatment of the pruritus with Thalidomide. He also received Hydroxychloroquine, as he had a previous diagnosis of psuedolymphoma. There was no local lymph node enlargement.

No abnormal data were observed in CBC, liver function, renal function, lactate dehydrogenase, urine analysis, peripheral blood smear, and virology screen. Specific workup for chronic pruritus was not significant for any underlying condition and flow cytometry of peripheral blood and bone marrow was normal.

A deep elliptical biopsy of the left pre-auricular lesion revealed dense dermal infiltrates composed of small to medium-sized T-cell infiltration with admixed B cells and plasma cells (Fig. 2a–d). Immunohistochemistry markers were conducted on the skin specimen and were positive for small to medium-sized lymphocytes with CD3 and CD4. Scattered lymphocytes were immunoreacted with CD8, CD5, PD-1, and Ki-67, revealing a low proliferative rate (less than 20%) (Fig. 3a–f). Positron emission tomography was performed and there was no abnormal cellular activity. The overall clinical, pathological, and immunotyping picture was compatible with PCS-TCLPD.

Initial treatment with repeated intralesional corticosteroid was unsuccessful in resolving the skin lesions, and the lesions were progressively increasing in size. Multiple trials with doxycycline, Hydroxychloroquine, mycophenolate mofetil, occlusive corticosteroid, and methotrexate were unsuccessful in controlling the lesions. Lastly, a rituximab course was initiated, with weekly infusions for four consecutive weeks at a dose of 500 mg/m². The lesions subsided after 2 months from injecting rituximab (Fig. 4a–c). Unfortunately, he had a recurrence of the lesions after 1 year of injecting rituximab. A course of 2 g of rituximab is given every 6 months to control the lesions for the last 3 years with continuous lab checks to exclude other forms of lymphoma.

Primary cutaneous lymphoma (PCL) represents 5–10% of total extra-nodal non-Hodgkin lymphoma with lymphocytic proliferation limited to the skin in its initial phase [7]. PCL that originates from T-cell proliferation accounts for 75% of the PCL. The most common known cutaneous T-cell lymphoma (CTCL) is mycosis fungoides, but not all CTCL fulfill the criteria for mycosis fungoides and some lymphocytic proliferation fell between cutaneous lymphoma, lymphoproliferative disorder, and reactive lymphocytic proliferation. Such lymphoproliferative disorder could be identified by its benign clinical course, pathological findings of reactive inflammatory cells, and immunophenotype study. Perhaps the most important way to distinguish between cutaneous lymphoma and lymphoproliferative disorder is the immunophenotype study which reveals different T-cell markers in different cutaneous T-cell proliferation. Treatment of such lymphoproliferative disorder includes intralesional corticosteroid injection, local radiotherapy, and surgical excision, but sometimes they are recalcitrant, and they need a more sophisticated modality of treatment. An example of a rare lymphoproliferative cutaneous lymphoma is PCS-TCLPD, which was considered to be a primary lymphoma until the recent reclassification by the WHO in 2017 in which the term lymphoma was replaced by lymphoproliferative disorder [8]. This type of lymphoproliferative disease expresses mainly small to medium-size CD4+ T-cell lymphocytic infiltration admixed with CD20+ B cells. The multiplicity of the lesions in this patient and expression of the CD20+ marker raised suspicion for other rare PCLs with poor prognosis, like primary cutaneous peripheral T-cell lymphoma, non-otherwise specified. However, the constellation of history and clinical findings like the slow growth of the masses without preceding patches or plaques within 10 years and the facial location of the lesions supported the diagnosis of PCS-TCLPD. Moreover, the pathological finding of diffuse dermal small-/medium-sized T-cell lymphocytes, the positive staining of the CD4 marker admixed with B cell CD20+ marker, and expression of PD-1, with normal lab findings and imaging studies, all supported the diagnosis of PCS-TCLPD. PD-1 is an important immunohistochemical marker in distinguishing CTCL from lymphoproliferative disorder, this marker is usually not expressed in the former and typically expressed in the latter [9]. PCS-TCLPD had been reported in association with immunosuppressive medications, but our patient was immunocompetent with no prior history of immunosuppressive medications [5]. When it is a single nodule or plaque, it might be confused clinically with primary cutaneous B cell lymphoma (follicle center or marginal zone) or reactive lymphoid hyperplasia, both of which have an indolent course and unwanted aggressive treatment should be avoided. The conventional modalities for treating such solitary lesions include surgical excision, intralesional corticosteroid, or local radiotherapy. Surgical excision was not a good choice in this case because of the multiplicity of the lesions, anatomical location, and possible unwanted cosmetic outcome. He declined to undergo local radiotherapy and repeated intralesional corticosteroid injection was not successful in clearing the lesions. Multiple trials with doxycycline, mycophenolate mofetil, hydroxychloroquine, occlusive corticosteroid, and methotrexate were unsuccessful in controlling the lesions. Lastly, rituximab was chosen based on previous reports of successful treatment of recalcitrant cases of lymphoproliferative disorder by this medication [10]. The effect of rituximab in this case might be attributed to the depletion of B cells which is commonly seen as additional cells in the infiltration of the small/medium CD4+ T lymphocytes, and a possible subsequent elimination of the cytokines that activate the proliferation of the T cells. There was a remarkable resolution of the facial masses after 2 months of injecting rituximab. Successful treatment of PCS-TCLPD has also been reported with potent occlusive corticosteroid, methotrexate, and spontaneous remission after biopsy of the lesions [11‒14]. Local recurrences are rare in PCS-TCLPD but we report recurrence of the lesions after 1 year from injecting rituximab.

The solitary lesion in PCS-TCLPD has an indolent course with no need for aggressive treatment. When multiple and not responding to conventional treatment, rituximab is an alternative option with remarkable clearance of the lesions, but with a possible recurrence of the lesions within a short period.

The authors are grateful to the Tehran University of Medical Science.

Ethical approval is not required for this study, in accordance with local guidelines. The patient gave written informed consent to the publication of the details of their medical case and any accompanying images. The authors completed the CARE checklist for this case report, which is attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000545747).

The authors have no conflicts of interest to disclose.

No funding was received.

Saman Al Zahawi: writing – original draft and writing – review and editing. Sara Masoomi: writing – review and editing. Alireza Ghanadan and Yasaman Sadeghi: visualization. Maryam Daneshpazhooh: supervision and visualization. Hamidreza Mahmoudi: supervision.

The data that support the findings of this study are not publicly available due to privacy reasons but are available from the corresponding author upon request.