Digital Gangrene as a Paraneoplastic Manifestation of Peripheral T-cell Lymphoma Not Otherwise Specified Type.

BACKGROUND: Peripheral T cell lymphoma (PTCL), not otherwise specified (NOS) is a heterogenous group of predominantly nodal T cell lymphomas that generally presents with lymphadenopathy with or without extra nodal involvement. Acral vascular syndrome clinically presents as digital ischemia with Raynaud's phenomenon and acral cyanosis. Although, this condition is commonly associated with connective tissue disorder, smoking and vasculitis, its association with lymphoid malignancy is very rare. Here, we present a case report of a patient with digital gangrene of all toes and fingers as a presenting symptom of PTCL-NOS. CASE DESCRIPTION: A 62 year old male presented with digital ischemia associated with pain, low grade fever, loss of appetite and significant weight loss of 6 kilograms over a period of 3 months. On examination, he was found to have bilateral inguinal and axillary lymph nodes with gangrenous changes over toes and fingers but peripheral pulses were palpable. On evaluation he had anemia, elevated ESR and CRP. CT angiogram revealed thinned out digital arteries with multifocal areas of narrowing. Patient was screened for other causes of digital gangrene and was tested negative for ANCA, ANA, cryoglobulins and viral markers. Lymph node biopsy with IHC was suggestive of peripheral T-cell lymphoma-NOS and was started on CHOP regimen. Lymph nodes size decreased and gangrenous changes resolved. CONCLUSION: Though digital ischemia is a rare paraneoplastic presentation of lymphoma, it should be considered if there is a rapid progression of gangrene. Early initiation of chemotherapy may result in the reduction of further progression of digital gangrene and thus prevent permanent disability. In our patient, progression of gangrene was prevented even though it was an aggressive variant of T cell lymphoma.

Extranodal natural killer/T-cell lymphoma coexisting with peripheral T-cell lymphoma, not otherwise specified.

We report the case of a 52-year-old male who presented to our hospital with cervical lymphadenopathy. Lymph node biopsy revealed small atypical lymphoid cells positive for CD3 and CD5 and negative for CD56 and Epstein-Barr virus (EBV)-encoded small RNA (EBER) by in situ hybridization. CD4-positive cells and CD8-positive cells were mixed in almost equal numbers. He was diagnosed with peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). The patient received one cycle of chemotherapy, resulting in severe sepsis. While undergoing treatment in the intensive care unit with an antimicrobial agent and prednisone, ascitic fluid appeared. Abdominal aspiration revealed neutrophil-predominant ascites and microbiological studies revealed Candida albicans. However, ascites did not improve when treated with micafungin for Candida peritonitis. Abdominal aspiration was re-performed, and atypical lymphoid cells that were positive for CD3 and CD56 were detected. EBV-DNA levels in whole blood were significantly elevated. Atypical lymphoid cells were positive for EBER by in situ hybridization and Southern blot analysis showed EBV terminal repeat monoclonal patterns. Bone marrow examination revealed the same atypical lymphoid cells. Therefore, the patient was diagnosed with extranodal natural killer/T-cell lymphoma (ENKTL) with bone marrow involvement 3 months after the diagnosis of PTCL-NOS. Complications associated with PTCL-NOS and ENKTL are rare. PTCL-NOS, chemotherapy, sepsis, and prednisone might have led to immunodeficiency and reactivation of EBV, which might be one of the pathophysiologies for developing ENKTL. Our case indicates that measuring EBV-DNA in the blood is a simple and prompt examination to detect complications of EBV-associated lymphoma.

Unraveling the mystery of fever of unknown origin: a remarkable journey towards the diagnosis of peripheral T-cell lymphoma-T follicular helper type: A rare case report.

INTRODUCTION: Fever of unknown origin (FUO) remains one of the most challenging clinical conditions. It demands an exhaustive diagnostic approach, considering its varied etiologies spanning infectious, autoimmune, inflammatory, and malignant causes. PATIENT CONCERNS: This report shows the journey of diagnosing a 28-year-old male who presented with persistent fever and lower-extremity weakness over 9 months. Despite seeking care at multiple hospitals, a definitive diagnosis remained elusive. DIAGNOSIS: The patient underwent a series of evaluations in various specialties, including gastroenterology, infectious diseases, rheumatology, hematology, and cardiology. Multiple tests and treatments were administered, including antiviral therapy for hepatitis B and antibiotics for suspected infections. INTERVENTIONS: After an initial misdiagnosis and unsuccessful treatments, a positron emission tomography-computed tomography scan and lymph node biopsy ultimately led to the diagnosis of peripheral T-cell lymphoma-T follicular helper type (PTCL-TFH) lymphoma. The patient was referred to the hematology clinic and initiated on CHOEP (cyclophosphamide, vincristine, etoposide, and prednisone) chemotherapy. OUTCOMES: The patient showed a positive response to CHOEP therapy, as indicated by a posttreatment positron emission tomography-computed tomography scan. He reported a significant improvement in his quality of life. Additional rounds of the same regimen were planned to further manage the lymphoma. CONCLUSION: This case emphasizes the importance of a comprehensive and persistent diagnostic approach in managing FUO. Initially, the focus on infectious causes led to extensive treatments, but the disease's progression and complications shifted attention to other specialties. The eventual diagnosis of PTCL-TFH lymphoma highlights the significance of advanced imaging techniques and multidisciplinary collaboration in uncovering elusive diagnoses. Thorough surveillance, timely reassessments, and repeated testing can uncover definitive changes critical for diagnosis. PTCL-TFH lymphoma, although rare, should be considered in the differential diagnosis of FUO, especially when initial evaluations are inconclusive.

Angioimmunoblastic T-cell lymphoma and Kaposi sarcoma: A fortuitous collision?

AIMS: Follicular helper T-cell (TFH) lymphoma of the angioimmunoblastic-type (AITL), one of the most prevalent T-cell lymphomas, typically encompasses proliferation of high endothelial venules and Epstein-Barr virus-positive immunoblasts, but neither infection with HHV8 nor association with Kaposi's sarcoma (KS) have been described. The aims of this study are to characterise the association between AITL and HHV8 infection or KS. METHODS AND RESULTS: Three male patients aged 49-76 years, HIV-negative, with concurrent nodal involvement by AITL and KS, were identified from our files and carefully studied. Two patients originated from countries where endemic KS occurs, including one with cutaneous KS. The lymphomas featured abundant vessels, expanded follicular dendritic cells and neoplastic TFH cells [PD1+ (three of three), ICOS+ (three of three), CXCL13+ (three of three), CD10+ (two of three), BCL6 (two of three)] but lacked EBV+ immunoblasts. The foci of KS consisted of subcapsular proliferations of ERG+, CD31+ and/or CD34+ , HHV8+ spindle cells. High-throughput sequencing showed AITL-associated mutations in TET2 (three of three), RHOA (G17V) (three of three) and IDH2 (R172) (two of three), which were absent in the microdissected KS component in two cases. Relapses in two patients consisted of AITL, without evidence of KS. No evidence of HHV8 infection was found in a control group of 23 AITL cases. CONCLUSION: Concurrent nodal involvement by AITL and KS is rare and identification of both neoplastic components may pose diagnostic challenges. The question of whether the association between AITL and KS may be fortuitous or could reflect the underlying immune dysfunction in AITL remains open.

Allogeneic Blood or Marrow Transplantation with Post-Transplantation Cyclophosphamide for Peripheral T Cell Lymphoma: The Importance of Graft Source.

The use of post-transplantation cyclophosphamide (PTCy) for graft-versus host-disease (GVHD) prophylaxis has revolutionized allogeneic blood or marrow transplantation (alloBMT), but there is limited published experience in peripheral T cell lymphoma (PTCL). We sought to assess outcomes in patients with PTCL who underwent alloBMT with PTCy. We reviewed the charts of all adult patients age ≥18 years who underwent alloBMT with nonmyeloablative conditioning and PTCy-based GVHD prophylaxis at the Sidney Kimmel Comprehensive Cancer Center between January 2004 and December 2020. Sixty-five patients were identified. The median age was 59 years (range, 24 to 75 years). Lymphoma histology included PTCL not otherwise specified (n = 24), anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (n = 14), angioimmunoblastic T cell lymphoma (n = 7), enteropathy-associated T cell lymphoma (n = 6), hepatosplenic T cell lymphoma (n = 4), and others (n = 10). Eleven patients were in first complete remission (17%); the remaining patients were in first partial remission or underwent salvage therapy to at least PR prior to transplantation. Forty-eight patients underwent alloBMT from a haploidentical related donor (74%), 10 from a fully matched donor (15%), and 7 from a mismatched unrelated donor (11%). All patients received fludarabine, cyclophosphamide, and total body irradiation (TBI). The graft source was bone marrow (BM) in 46 patients (71%) and peripheral blood (PB) in 19 patients (29%); all patients in the BM cohort received 200 cGy TBI, and most patients in the PB cohort (15 of 19) received 400 cGy TBI. GVHD prophylaxis comprised PTCy, mycophenolate mofetil, and a calcineurin inhibitor or sirolimus. With a median follow-up of 2.8 years (range, 290 days to 14.2 years), the 2-year progression-free survival (PFS) for the entire cohort was 49% (95% confidence interval [CI], 38% to 64%), and the 2-year overall survival (OS) was 55% (95% CI, 44% to 69%). Outcomes were significantly improved in those receiving PB compared to those receiving BM, including a 2-year PFS of 79% (95% CI 63% to 100%) versus 39% (95% CI, 27% to 56%), 2-year OS of 84% (95% CI, 69% to 100%) versus 46% (95% CI, 33% to 63%), and 1-year cumulative incidence of relapse of 5% (95% CI, 0 to 16%) versus 33% (95% CI, 19% to 46%), with no difference in GVHD and nonrelapse mortality. AlloBMT with PTCy is safe and well-tolerated in patients with PTCL. Our data suggest that increasing the TBI dose to 400 cGy and using PB allografts may offer improved disease control and better survival outcomes, though additional studies are needed to confirm these findings.

Eosinophilic Fasciitis with Hypereosinophilia as the Initial Clinical Manifestation of Peripheral T-Cell Lymphoma, Not Otherwise Specified.

A 58-year-old man presented with painful edema of the extremities, and a diagnosis of eosinophilic fasciitis (EF) was confirmed. He also met the criteria for hypereosinophilic syndrome (HES), but there were no findings suggestive of malignancies or hematologic neoplasms despite a close examination. He was started on steroid therapy but subsequently developed severe liver dysfunction, hemophagocytic lymphohistiocytosis, hepatosplenomegaly, and renal involvement. The diagnosis of peripheral T-cell lymphoma, not otherwise specified was finally established by a bone marrow reexamination and liver biopsy. In cases of eosinophilia, EF, and/or HES, it is important to suspect an intrinsic abnormality, including potential T-cell lymphoma.

Safety considerations with the current treatments for peripheral T-cell lymphoma.

INTRODUCTION: Peripheral T-Cell Lymphomas (PTCL) constitute a heterogeneous group of aggressive T - and natural killer (NK)-cell disorders and are associated with a poor prognosis. Frontline treatments often consist of anthracycline-based combination chemotherapy with the exception of NK-T cell lymphomas, where such combinations are ineffective due to the presence of P-glycoprotein which leads to multidrug resistance. Infectious and immune mediated side effects might be more pronounced in or unique to T-cell lymphomas due to the selection of agents which target multiple T-cell subtypes and also an immunocompromised state induced by the lymphomas themselves. AREAS COVERED: This review provides a comprehensive overview of safety considerations of treatment regimens used for peripheral T-cell lymphomas. We cover regimens used in both frontline and relapsed settings including combination chemotherapy, single agent chemotherapies and immunotherapies. EXPERT OPINION: Treatment of T-cell lymphomas often requires sequencing of several therapies due to lower efficacy of available treatment regimens in curing the disease compared to that seen in B-cell non-Hodgkin lymphomas. In addition, certain complications are more common in T-cell lymphomas due to their unique immunobiology. An understanding of these salient aspects is important for all providers who treat patients with this challenging disease group.

Primary peripheral T-cell lymphoma of the cervix with mononeuritis multiplex: an unusual case presentation

Peripheral neuropathy (PN) is characterized by the injury to the peripheral nervous system of varied etiology. Lymphoma is one of the etiologies of PN, presenting various neurological manifestations. Neuropathy associated with peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) is unusual and fewer cases are documented in the literature. In addition, PTCL, NOS is extremely rare as primary in the female genital tract, especially uterine cervix, and exhibits aggressive clinical course with poor therapy response. We hereby describe a 47-year-old female who presented with fever and chills for 15 days. Clinical examination revealed left-sided lower motor neuron type of facial nerve palsy with Bell's phenomenon. Nerve conduction study of all four limbs illustrated asymmetrical axonal neuropathy (motor > sensory), suggesting mononeuritis multiplex. She developed vaginal bleeding during her hospital stay. Pelvic examination and imaging revealed a 4x3cm polypoidal mass on the posterior lip of the cervix, which was excised and diagnosed as extranodal primary PTCL, NOS based on morphology, immunohistochemistry, and in-situ hybridization findings. Besides, the cerebrospinal fluid (CSF) was infiltrated by the lymphoma cells, detected on cell block preparation. The patient succumbed to her illness within one week despite best efforts and the commencement of chemotherapy. No consent was obtainable for nerve biopsy and autopsy. Thus, we report an extremely rare case of primary extranodal PTCL, NOS of the uterine cervix with unusual presentation of mononeuritis multiplex. Further, we discussed the differentials of PTCL, NOS at this extranodal site.

Hemophagocytic Lymphohistiocytosis Secondary to Peripheral T Cell Lymphoma with Rapid Onset and Fatal Progression in a Young Patient: A Case Report and Review of the Literature.

BACKGROUND Constant stimulation of lymphocytes and histiocytes can result in hemophagocytic lymphohistiocytosis (HLH), which can be primary or secondary (sHLH). The main causes of sHLH are infections and hematological malignancies, especially non-Hodgkin lymphoma. Despite new insights into the pathogenesis of HLH, the diagnosis and treatment of this immune disorder remain a great challenge. CASE REPORT We present a case of a young adult without comorbidities whose clinical course was nonspecific for several months and resulted in late diagnosis of HLH secondary to peripheral T cell lymphoma (PTCL). The etiological factor of recurring fever, hepatosplenomegaly, and deteriorating condition was unidentified for a long time before fatal sHLH was finally diagnosed. The patient was treated according to the HLH-2004 protocol; however, he did not achieve any response. Unfortunately, due to nonspecific symptoms, lack of lymphadenopathy for a long time, and negative positron emission tomography results, the diagnosis of PTCL was established only after the patient's death. CONCLUSIONS It should be emphasized that early diagnosis is crucial for better prognosis of patients with sHLH. Bone marrow biopsy is worth considering in patients with prolonged fever of unknown origin, hyperferritinemia, splenomegaly, and unexplained cytopenia of 2 or more lineages. Despite the existence of diagnostic and therapeutic protocols available in the literature, the prompt diagnosis and treatment of HLH remains a great challenge. More precise and specific diagnostic tools for HLH are needed.

Peripheral T-Cell Lymphoma Possibly Due to Unrecognized Celiac Disease in an Elderly Patient: A Case Report.

Celiac disease (CD) is widely perceived as a childhood disorder. However, it has been demonstrated that 19-34% of new CD cases are diagnosed in patients over 60 years of age and lack the typical presentation. A 76-year-old female was admitted to the clinic due to a recurrent fever that had lasted over a year accompanied by progressive weakness, weight loss of about 10 kg, dehydration, and malnutrition. The patient had undergone resection of a fragment of the small intestine due to perforation and abscess 13 years previously (at which time no histopathological examinations were performed). During the current hospitalization, despite extensive laboratory, microbiological, and imaging tests, no specific diagnosis was made. Symptomatic treatment and empirical antibiotic therapy were conducted, but the patient died on the twenty-seventh day of hospitalization due to progressive respiratory failure. The autopsy revealed peripheral T-cell lymphoma in the mesentery of the small intestine, uterus, cecum, lung, and mediastinal lymph nodes. Based on the clinical picture, we believe that the lymphoma was induced by long-term, undiagnosed CD. Current knowledge allows us to see age-related differences in the manifestation of celiac disease and to be alert to the possible late-stage complications of the disease. The lack of awareness of how CD's symptoms vary with age may lead to misdiagnosis and serious consequences of delayed diagnosis, including death.

Peripheral T-cell lymphoma presenting as fever of unknown origin in a man with deranged liver function tests and pancytopenia.

Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) is a relatively rare condition in Australia. Here, we report a case of PTCL, NOS in a patient who presented with persistent fever and progressive pancytopenia on a background of mediastinal lymphadenopathy, initially presumed reactive and hepatosplenomegaly with deranged liver function tests. The diagnosis was challenging, with multiple negative blood cultures and inconclusive bone marrow studies, and it required extensive investigations that ultimately revealed the characteristic clinical, histopathological and immunophenotypic features of PTCL, NOS. The patient underwent multiple rounds of multiagent chemotherapy after the diagnosis. This case highlights the difficulty in diagnosing PTCL, NOS and the importance of including it as a differential diagnosis in younger patients who present with constitutional symptoms and hepatosplenomegaly.

Post-transplant primary cutaneous peripheral T-cell lymphoma not otherwise specified in a pediatric patient.

Solid organ and hematopoietic stem cell transplantation may be complicated by the development of post-transplant lymphoproliferative disorders (PTLDs). The World Health Organization categorizes PTLDs into four entities including non-destructive, monomorphic, polymorphic, and classical Hodgkin lymphoma types. The most common PTLDs are B-cell lymphomas, with T-cell lymphomas accounting for only a few cases. Cutaneous T-cell lymphomas are rarer still in post-transplant patients with primary cutaneous peripheral T-cell lymphoma being an extraordinarily rare subtype in this population. PTLDs may be aggressive and are often associated with high morbidity and mortality. Advances in medicine have led to increased awareness of PTLDs and improved diagnostic tools which assist in the diagnosis of these conditions. However, the clinical and histopathologic heterogeneity of PTLDs may make diagnosis a challenge. In the transplant patient population, the cutaneous manifestations of the lymphoproliferative disease may mimic other conditions, such as eczematous dermatitis and graft-vs-host disease. Herein, we report a case of post-transplant primary cutaneous peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) in a pediatric heart transplant patient and describe the clinical presentation and diagnostic histopathologic features.