Advanced Stage CTCL, PTCL with Cutaneous Involvement

Abstract

Dr. Porcu obtained his medical degree in 1987 and Board certification in Medical Oncology in 1991 from the University of Torino, Italy. He then held a post-doctoral laboratory position at Temple University from 1990 to 1992 and was a research associate at Thomas Jefferson University from 1992 to 1993, both in Philadelphia, U.S. He completed a residency in Internal Medicine in 1996 and a Fellowship in Hematology/Oncology in 1999 at Indiana University, Indianapolis, IN. He is currently an Associate Professor of Internal Medicine at The Ohio State University (OSU) and a member of the Viral Oncology Group of the OSU Comprehensive Cancer Center (OSUCCC), where he conducts clinical and translational research in lymphoma. He is a faculty member inductee of the Alpha Omega Alpha. Dr. Porcu’s work has been published in Blood, Journal of Clinical Oncology, Clinical Cancer Research, Cancer Research, PNAS, Oncogene, and Molecular and Cellular Biology. Dr. Porcu was on the editorial board of the journal Leukemia from 2002 to 2005 and is a member of the Scientific Advisory Board of the Cutaneous Lymphoma Foundation (CLF). Since 2000 he has been a member of the NCCN committee for NHL practice guidelines. Currently his research focuses on the biology and experimental therapy of T-cell lymphomas and cutaneous lymphoproliferative disorders. Dr. Porcu also works extensively in the field of lymphoma education and mentoring. He teaches numerous graduate and post-doctoral classes in the College of Medicine on the biology, diagnosis, and treatment of lymphoma and was recently selected as the Cancer Signature Program liaison of the OSUCCC for the OSU Research Education Council Committee. Dr. Porcu is very active in patient education forums, on behalf of patient advocacy organizations, such as the Cutaneous Lymphoma Foundation, CancerCare, and the Leukemia and Lymphoma Society. INTRODUCTION T-cell lymphomas (TCL) are a relatively rare form of nonHodgkin lymphoma (NHL), representing approximately 10-15% of all NHL cases. TCL have a predilection for the skin and are therefore of great clinical interest to dermatologists and hematologists alike. Cutaneous T-cell lymphomas (CTCL) define a heterogeneous group of malignancies encompassing many different clinical and pathological presentations. Mycosis fungoides (MF) is the most common type of CTCL. While MF follows an indolent clinical course, other more aggressive forms of CTCL present a challenge to the clinician from both a diagnostic and treatment standpoint. It is not uncommon that MF and other types of CTCL may coexist in the same patient. Recent advances in drug development have increased the effectiveness of CTCL treatment. INITIAL PRESENTATION A 65-year-old Caucasian female presented to an outside oncologist with a progressively enlarging marble-sized lesion on her left posterior thigh without other cutaneous findings. A biopsy containing more than 90% tumor cells revealed a CD3+ CD4+ CD30small to medium size T-cell lymphoma. Upon further immunophenotypic characterization it was found that CD10, CD20dim, and terminal deoxynucleotidyl transferase (TdT) were also expressed on tumor cells. The tumor showed monoclonal rearrangement of both the T cell receptor beta and immunoglobulin heavy chain (IgH) loci. Expert pathological review confirmed these findings. The expression of both CD10 and TdT, as well as the dual rearrangement, suggested a diagnosis or T-lymphoblastic lymphoma (T-LBL). However, the patient had no systemic symptoms, no findings of extracutaneous involvement and normal laboratory values. She was offered systemic chemotherapy for a presumptive diagnosis of limited stage T-LBL or peripheral T-cell lymphoma (PTCL) but she declined and elected to Advanced Stage CTCL, PTCL with Cutaneous Involvement 2 of 5 receive radiation therapy to her thigh, which resulted in full resolution of her lesion. After two years without progression, multiple new lesions appeared in the same location. The small, nodular lesions were again asymptomatic. Again a punch biopsy showed that the tumor cells were CD3+, CD4+, CD30with aberrant CD20 and CD10 expression. This time, however, they failed to express TdT. TCR beta and IgH gene rearrangements were not analyzed. The diagnostic conclusion was peripheral T-cell lymphoma (PTCL) with aberrant CD20 expression. CT scans, PET scan and bone marrow biopsy showed no involvement outside of the skin. The patient once again declined systemic chemotherapy and received instead four weekly doses of rituximab, based on the perceived need for systemic therapy on the part of the oncologist and the expression of CD20 in the tumor cells. No response was observed and the patient was retreated with radiation therapy, leading to a second complete response. A few months later she developed a recurrence in the same location. At that point she was referred to the Ohio State University (OSU). At presentation to OSU the patient complained of significant tenderness over multiple cutaneous nodular lesions, fatigue and night sweats, but her physical exam was otherwise unremarkable. Laboratory studies showed WBC of 3.4 with a normal differential, hemoglobin 14.1, platelets 235, and electrolytes, serum creatinine, transaminases and LDH in the normal range. A punch biopsy demonstrated a highly pleomorphic infiltrate effacing the dermal architecture and extending heavily in the subcutaneous fat. Tumor cells stained positively for CD3, CD10, and CD20 but this time they were CD8+ rather than CD4+. Granzyme B, TIA-1 and CD30 were negative. Flow cytometry showed no immunophenotypic evidence of an abnormal population of lymphocytes in the peripheral blood. TCR beta analysis of lesional skin showed a single monoclonal band and IgH showed a biclonal rearrangement. The patient received six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with complete resolution of the nodules. However a few weeks after completing therapy the nodules recurred and she was started on denileukin diftitox (DD, Ontak), 18 micrograms/kg IV on days 1-5. The clinical response was rapid and impressive. The lesions once nodular, erythematous and tender began to flatten with diminished surrounding redness. The patient received a total of 4 cycles of therapy, every 21 days, and tolerated the treatment well. She developed a hypersensitivity reaction and mild vascular leak syndrome (VLS) after her first cycle; her dose was reduced to 9 micrograms/kg for the remaining cycles. A subsequent follow-up three months after completion of therapy showed complete resolution of the lesions. The patient was without any signs of progressive disease for 2.5 years, then presented with multiple flat, scaly patches of rash involving less than 10% of the body surface area (BSA). The patient denied pruritus, night sweats, or weight loss. A biopsy showed an epidermotropic CD4+ CD7small cerebriform T-cell infiltrate, morphologically consistent with Mycosis Fungoides. CD8, CD10, and CD20 stains were negative. Molecular studies on the skin showed monoclonal and oligoclonal rearrangements of the TCR beta and IgH, respectively. She started topical corticosteroids. Within 2 months there was a significant progression of the rash to an estimated 30-40% BSA, with both plaque and patch stage lesions. No adenopathy was found on exam. Flow cytometry of peripheral blood revealed that T-cells represented 61% of the lymphocytes with a normal CD4:CD8 ratio but loss of CD26 expression on 43% of the T-cells. TCR beta analysis on the peripheral blood showed a monoclonal band. LDH was normal. The patient was started on PUVA. After three months of PUVA therapy the patient had experienced only a very modest response and new plaque stage lesions began to develop. Oral bexarotene (225 mg twice daily) was started. The combination of PUVA and bexarotene resulted in a partial response, but within 3 months tumor stage lesions began to develop on the hips, axillae and lower extremities. At this point denileukin diftitox (DD) was again started at the18 micrograms/kg daily dose for 5 days every 21 days, while continuing bexarotene. Treatment was well tolerated but response was transient, even after increasing the frequency of DD administration to every 14 days. The patient developed numerous large (4-5 cm) tumor lesions. Restaging CT scans showed no evidence of visceral disease. The patient declined a repeat bone marrow biopsy. Interferon alfa-2b, 10-15 MIU subcutaneously thrice weekly was started and electron beam radiation was used to treat large refractory tumors. A bone marrow transplant consultation has been obtained. Therapy is ongoing. CONSIDERATIONS FOR REFERRING DERMATOLOGIST/MEDICAL ONCOLOGIST At the patient first visit, the initial biopsy suggested T-LBL, but the clinical picture and subsequent studies refuted this Advanced Stage CTCL, PTCL with Cutaneous Involvement 3 of 5 diagnosis. Highly intensive combination chemotherapy was appropriately not given. The oncologist eventually determined the lesions to be limited stage PTCL and treated with involved field radiation. When the patient relapsed, two years later, it was concluded that systemic therapy was necessary but the patient declined aggressive lymphoma chemotherapy (CHOP). Therefore, the oncologist selected rituximab due to the aberrant expression of CD20 on tumor cells. It should be noted that the antibody used to detect CD20 expression by immunohistochemistry (clone L26) binds to the intracellular domain of the trans-membrane CD20 protein and that, although surface expression of CD20 generally correlates with L26 positivity, this assumption may not always be correct. The cutaneous lesions did not respond to rituximab and were again treated with radiotherapy leading to a second complete remission. When the patient was referred to the OSUCCC it was concluded that the patient’s clinical and pathological picture was most consistent with a skin-limited PTCL. The presence of sys