Subcutaneous panniculitis-like T cell lymphoma arising in association with chronic lymphocytic leukaemia
- Lakshmi Shree Kulumani Mahadevan and
- Metin Ozdemirli
- Department of Anatomic and Clinical Pathology, Georgetown University Medical Center, Washington, DC, USA
- Correspondence to Dr Metin Ozdemirli; MO7@gunet.georgetown.edu
Abstract
Subcutaneous panniculitis-like T cell lymphoma (SPTCL) is a rare cutaneous T cell malignancy of cytotoxic T cell origin. It is frequently associated with autoimmune diseases. It is known to preferentially involve subcutaneous adipose tissue and histologically resembles lupus panniculitis. The aetiology and risk factors of SPTCL are unclear and there are limited studies available since this entity was initially described in 2001. There are even fewer case reports describing the association between SPTCL and chronic lymphocytic leukemia (CLL). In this article, we present a case of SPTCL arising during treatment for CLL. We conducted an extensive review of literature to delve into the possible risk factors for SPTCL development in association with CLL, including pre-existing haematological malignancies, autoimmune conditions, immunomodulation and immunosuppressive chemotherapy.
Background
Subcutaneous panniculitis-like T cell lymphoma (SPTCL) is a rare primary cutaneous T cell lymphoma of cytotoxic T lymphocyte origin, constituting <1% of non-Hodgkin lymphomas.1
SPTCL is more common in young or middle-aged women. About 20% of the cases are associated with pre-existing autoimmune conditions like systemic lupus erythematosus (SLE).1 Clinically, SPTCL presents as insidious slow growing subcutaneous nodules, most commonly in the extremities. SPTCL has no ulcerations or plaques on the overlying skin unlike mycosis fungoidosis. The indurated appearance of these nodules may be mistaken for an abscess and often treated with incision and drainage. Apart from the subcutaneous nodule, SPTCL may present with systemic symptoms such as fever, polyarthritis, pericarditis similar to SLE or other autoimmune diseases. Lymphoproliferative disorders that occur as a result of chronic immunosuppression are usually associated with EBV infection,2 but these tumours are always negative for Epstein-Barr virua (EBV), negating the role of chronic immunosuppression. However, there have been rare cases of EBV positive SPTCL in Asian men with rheumatoid arthritis treated with methotrexate.3
Histologically, these tumours may resemble the subcutaneous form of SLE, like lupus profundus or lupus panniculitis. Biopsies often show small to medium atypical lymphoid cells with clumped chromatin, enlarged nuclei and scant cytoplasm rimming the fat spaces. Associated fat necrosis with karyorrhexis and histiocytes engulfing the granular debris and even occasional granuloma formation may be seen. Lupus profundus, lupus panniculitis and injection site fat necrosis and reactive lymphoid proliferation are some of the non-neoplastic conditions that mimic SPTCL.
Immunohistochemistry shows neoplastic cells to be cytotoxic T cells positive for CD3 and CD8, and express cytotoxic proteins like granzyme B, perforin and TIA-1. Rarely these tumours co-express CD4 with CD8, but dual negative cells suggest gamma delta phenotype. In the majority of the cases, these express αβ T-cell receptor (TCR) and in minority gamma delta T cell receptor.
SPTCL with αβ TCR expression usually have excellent prognosis. Most lesions spontaneously regress on discontinuation of immunosuppressive chemotherapy. The presence of haemophagocytic syndrome is considered a poor prognostic factor. The γδ subtype has more aggressive clinical course and poorly respond to multiagent chemotherapy. Because of these characteristics, the γδ cytotoxic cutaneous T cell lymphomas are considered as separate entities. No specific cytogenetic mutations have been identified.4
In this article, we describe a case of SPTCL arising in association with chronic lymphocytic leukemia (CLL) and discuss possible aetiologic factors.
Case presentation
A man in his late 70s presented with a medical history of congestive heart failure, coronary artery disease, chronic obstructive pulmonary disease, non-small cell lung carcinoma, prostate cancer, immune thrombocytopenic purpura (ITP) and chronic lymphocytic leukaemia (Rai stage IV with del 11q, ZAP70 positive at the time of diagnosis). His CLL was untreated for 8 years after diagnosis due to multiple comorbidities and poor functional status. He was then started on acalabrutinib, a second generation Bruton’s tyrosine kinase (BTK) inhibitor. He also had recurrent respiratory tract infections; he was started on monthly intravenous immunoglobulin infusions. He is a former smoker, positive for germline BRCA2 mutation and has a family history of breast carcinoma but no history of familial cancer syndromes.
One year after initiating treatment for CLL with acalabrutinib, he developed raised subcutaneous nodules on his right thigh that were erythematous but non-tender and non-pruritic. He had no recent injections or instrumentation that triggered this process. He also had worsening B symptoms after starting acalabrutinib, which have not resolved despite dose reduction. The subcutaneous nodules showed hypermetabolic uptake on positron emission tomography- computed tomography (PET-CT) and he underwent excisional biopsy for histopathological evaluation.
Investigations
Pathological findings
Grossly, the specimen received at surgical pathology consisted of an elliptical shaped deep soft tissue lesion measuring 3×1.2 cm, excised to a depth of 1.6 cm. The overlying skin was unremarkable. The tissue sections revealed atypical lymphoid infiltrate in the adipose tissue with extensive necrosis and atypical cells rimming the adipocytes. The differential diagnosis included SPTCL and lupus panniculitis. There were no sheets of large cells to consider Richter’s transformation of known CLL.
Immunohistochemistry, flow cytometry and molecular studies
Immunohistochemistry showed that the atypical lymphocytes were αβ cytotoxic T cells positive for CD3, CD8, granzyme B and βF-1. The atypical cells were negative for B cell markers (CD20, CD79a and PAX5) and mum-1, CD30, EBV LMP and CD56 (figure 1). In-situ hybridisation for EBV-encoded RNA was negative. Ki-67 proliferative index was 60% in tumour cells. These results ruled out CLL and SLL). However, PCR analysis for immunoglobulin heavy chain gene rearrangement and immunoglobulin kappa light chain gene rearrangement revealed monoclonal gene rearrangement, indicating the presence of minimal residual CLL at the molecular level. PCR was also performed for TCR gamma and beta chain gene rearrangements, which revealed clonality for both. These findings confirmed the diagnosis of SPTCL.
H&E section and immunohistochemistry with hematoxylin counterstain of the subcutaneous nodule biopsy. (A) Histopathology of the subcutaneous nodule showing atypical lymphocytes surrounding the adipose tissue (H&E stain, 40×). (B) CD3 highlights all the T cells. (C) CD4 staining the tumour histiocytes. (D) CD8 staining the cytotoxic T cells (E and F) Granzyme B and BF-1 staining the cytotoxic tumour T cells.
Treatment
His CLL was untreated for 8 years after diagnosis due to poor functional status, and then treated with acalabrutinib. After he was diagnosed with SPTCL with mild residual CLL, he was treated with six cycles of CEOP regimen (cyclophosphamide–etoposide–vincristine–prednisone). He also received pegfilgrastim during his chemotherapy. After diagnosis of SPTCL, acalabrutinib was discontinued.
Outcome and follow-up
After completion of chemotherapy, he came to ED and presented with fever, fatigue and drenching night sweats. COVID-19 and all other infectious aetiologies were ruled out. Flow-cytometric analysis was performed on his peripheral blood and showed approximately 3% CD19, and CD5+ monoclonal B lymphocytes consistent with minimal residual CD38− CLL/SLL. This indicates that the CLL has remained stable and has not progressed after the diagnosis of SPTCL.
He had resolution of the nodules with significant improvement of the systemic symptoms, and he is currently being followed up for his CLL. One year later, he developed nodules on his left arm, which were diagnosed as granuloma annulare, and not lymphoma recurrence.
Discussion
CLL is a low-grade lymphoproliferative neoplasm that is sometimes associated with secondary cutaneous malignancies, including T cell lymphomas. Chang et al looked at the SEER (surveillance, epidemiology and end results) 13 registries for patients with CLL and non-Hodgkin lymphoma (NHL) from 1992 to 2008 and showed that patients with CLL are at increased risk of developing cutaneous T cell lymphoma. They found 133 631 cases of CLL and NHL of which only one case was SPTCL.5 After this entity was initially described in 1991, there have been only three case reports on SPTCL arising in association with CLL.6–8
SPTCL is a rare form of cutaneous T cell lymphoma, initially described in 1991 in eight patients,9 and was recognised as a separate disease entity by WHO in 2001.
The association of SPTCL with various autoimmune diseases was first described by Willemze et al.10 They studied 63 cases of SPTCL with alpha beta phenotype in the European Organization for Research and Treatment of Cancer (EORTC) cutaneous lymphoma workshop, and 12/63 cases (19%) had an autoimmune disease association such as systemic lupus erythematosus, juvenile rheumatoid arthritis, rheumatoid arthritis, Sjogren’s syndrome, idiopathic thrombocytopenic purpura, multiple sclerosis, type 1 diabetes mellitus, Raynaud’s disease and Kikuchi’s disease. Interestingly, four cases were misdiagnosed as lupus panniculitis and later reclassified as SPTCL. Histologically, SPTCL has many features that overlap with lupus panniculitis. Peri-adipocytic rimming of lymphocytes with high Ki-67 positivity can be seen in both lupus panniculitis and SPTCL. However, lupus panniculitis has a mixed lymphoplasmacytic infiltrate, whereas SPTCL shows predominance of atypical cytotoxic T cells. Additionally, SPTCL lacks fat hyalinisation, calcium deposition, basement membrane thickening and lymphoid follicles, features commonly encountered in lupus panniculitis.11
Sluzevich et al described a case of a man in his late 70s with CLL developing SPTCL 2 weeks after treating CLL with rituximab and cyclophosphamide.8 The patient presented with smooth erythematous, nodular patches in the face and extremities. Biopsy showed cytotoxic T cell phenotype, negative for CD56 and B cell markers. After cessation of chemotherapy, the patient was maintained on palliation with fludarabine and mitomycin. The nodules completely resolved without treatment in 8 months. They postulate that B cell immunosuppression with rituximab and cyclophosphamide triggers formation of T cell lymphoma.
Wang et al reported a case of a man in his late 50s diagnosed with SPTCL with haemophagocytic syndrome, who also has more than 20-year history of CLL.7 He was treated with fludarabine, cyclophosphamide and rituximab for three cycles at reduced dosage considering his renal insufficiency. This case report again suggests the role of chronic B cell immunosuppression predisposing to T cell lymphoma.
In our present case, the patient was diagnosed with CLL and was not treated due to his comorbidities and poor functional status for 8 years. CLL was treated with acalabrutinib, which is a second generation inhibitor that targets B cell maturation. One year after starting this chemotherapy, the patient developed subcutaneous nodule that was diagnosed as SPTCL. After SPTCL diagnosis, acalabrutinib was discontinued and the patient was started on six cycles of CEOP regimen. He had complete response to this treatment after completing the six cycles. Other factors that could have caused immunomodulation in this case include the intravenous immunoglobulin treatment that was started for his respiratory infections and ITP, which was treated with prednisolone.
CLL and other low grade B cell malignancies are sometimes associated with cutaneous lymhomas.12–22 Majority of these tumours are of B cell origin and EBV associated. The immunosuppression caused by chemotherapeutic agents used to treat CLL cause reactivation of latent EBV infection that may result in formation of lymphomas. T cell lymphomas in association with CLL usually originate from CD4+ T cells. Cytotoxic T cell lymphomas are rare. To explain the pathogenesis of cutaneous T cell lymphoma in a patient with CLL, Sheibani et al 23 hypothesised that it could be (1) spontaneous development of T cell lymphoma that is neither related to CLL or chemotherapy, (2) chronic immunosuppression that causes lymphoproliferative disease arising from a cell line different from CLL or (3) immunological switch or modulation of the cell line derived from CLL. Wen et al 24 showed the existence of clonal population of T cells in CLL. They suggested that these T cell clones were a part of reactive process, but helped control the proliferation of premalignant B cells. In our present case, the patient still had residual CLL when SPTCL was diagnosed. It is possible that a subclone of T cell population that was regulating the B cells transformed to T cell lymphoma.
It is unclear whether SPTCL arises as a manifestation of an inherited cancer syndrome. Given the patient’s history of multiple malignancies, we explored the molecular basis of SPTCL and whether it could be a manifestation of inherited cancer syndrome. While prostatic adenocarcinoma is known to be associated with BRCA2 mutation, to the best of our knowledge, based on thorough literature search and cancer genomic database search,25 SPTCL is not associated with germline BRCA2 mutation or any known inherited cancer syndromes.
With respect to chemotherapy-induced lymphoproliferative disease, Michot et al 26 described a case of SPTCL in a patient with rheumatoid arthritis that was treated with etanercept. Berthlot et al 27 described 2 cases of cutaneous CD8+ T cell lymphoma after immunomodulatory therapy with efalizumab and infliximab. Similarly, Nemoto et al 3 described a case of SPTCL arising in a patient who took methotrexate treatment for rheumatoid arthritis. Interestingly, the patient was an Asian male, and the tumour was positive for EBV. These evidences suggest a stronger association with immunosuppressive chemotherapy rather than CLL disease process itself.
CLL even in untreated state has relative expansion of CD8+ cells with reversal of normal CD4:CD8 cells. The CD4+ T cells increase the survival of CLL cells in the microenvironment through interleukin (IL) 4 and interferon-γ production that increases Bcl-2 antiapoptotic signalling,28 whereas the CD8+ T cells have antitumour activity.29 T cell clonal expansion parallels the numerical increase of clonal B cells.30 Targeting B cell receptor signalling by BTKs inhibition has become successful treatment modality in CLL. BTKs are a family of proteins that regulate B cell proliferation, maturation, differentiation and apoptosis, and are expressed in all haematopoietic cells except for T cells. First-generation BTK inhibitor ibrutinib was found to have off target effects on T cells through IL-2 inducible tyrosine kinase (ITK) inhibition. Ibrutinib has been shown to decrease the chronic activation of T cells in patients with CLL. In contrast, second-generation agents like acalabrutinib have less inhibition on ITK.31 No significant change in T cell numbers were seen in first 20 weeks of treatment. Eventually, after 15 cycles of acalabrutinib, the CD8+ cells decreased in number.32 According to Sharpe et al, ibrutinib causes higher inhibition of CD8+ T cells compared with CD4+ cells, whereas acalabrutinib did not inhibit CD4 or CD8 cells.33 In our case, it is possible that the loss of T cell inhibition after acalabrutinib therapy in a patient with CLL altered the balance between B cell and T cell proliferation possibly predisposing to SPTCL. Some of the earlier generation BTK inhibitors have off target effects on other cellular tyrosine kinases, including T cell kinases and potentially contributing to nodular panniculitis.34 It is conceivable that BTK inhibitor conjugated peptides when presented to host immune cells via histocompatibility complex leads to T cell immunomodulation that causes panniculitis and subsequently transform to T cell lymphomas.35
Learning points
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Subcutaneous panniculitis-like T cell lymphoma (SPTCL) is a rare form of cutaneous cytotoxic T cell lymphoma.
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It is frequently associated with autoimmune diseases and common in young or middle-aged women.
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These tumours histologically mimic lupus panniculitis.
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Our case report along with review of literature sheds new light on the possible role of chemotherapeutic agents for CLL in aetiology of this condition.
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Further studies are required to explore the molecular mechanisms underlying lymphomagenesis of SPTCL and to validate our hypothesis.
Ethics statements
Patient consent for publication
Footnotes
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Contributors Both authors, LSKM and MO, equally contributed to the conception and design, acquisition of data, drafting and revising the intellectual content, final approval of the version to be published and agree to be accountable for all questions regarding accuracy or integrity of the article.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.
References
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