Case report

A 77-year-old male with a history of Parkinson’s disease un dergoing levodopa treatment, who began studies in August 2019 by symptoms of asthenia, adinamia and progressive weight loss of approximately 8 months of evolution, associ ated with oropharyngeal candidiasis diagnosed by upper gastrointestinal videoendoscopy. At the time of admission, the laboratory showed severe lymphopenia, with less than 6% of leukocyte counts (8200 cell/mm³), with an absolute count of 450 cell/m³ with no further alterations in the blood count (hematocrit 39.3%, platelets 363 000 cell/mm³). During hos pitalization additional tests were performed: viral serological tests were all negative including HIV, HBV, HCV HTLV and CMV, no vitamin deficiencies were presented, celiac disease antibodies were negative and gammaglobulines levels be tween normal range (1.45 g/dl). B and T cells subpopulation were studied, finding a CD4 lymphocyte count of 14% and an absolute count of 85 cells/mm³ (reference value 800-1200). A bone marrow biopsy and a PET-CT scan were performed, considering a possible underlying oncohaematological disease. Bone marrow biopsy did not identify abnormal cells related to clonal process and PET-CT just revealed small non-specific cervical and mediastinal nodes with low uptake. The patient continued with ambulatory controls.

Two months later, he was admitted to the emergency room due to a 12-hour evolution, sharp abdominal pain, with perito neal reaction signs and stiffness of the abdominal wall. He had no fever, nausea, vomiting or any other related symptoms. A CT scan showed signs of pneumoperitoneum, parietal thick ening of the small intestines associated with an alteration of the adjacent fat planes, with no clear view of the appendix. A surgical intervention was carried out with an exploratory laparotomy, after which a purulent peritonitis was diagnosed. The patient presented a pointed injury to the terminal ileum, therefore a 10 cm intestine resection was made, together with a subsequent enteroanastomosis. After a long-lasting postoperative period, with multiple infectious complications, the patient was released to home care.

The pathology report of the surgical material showed a large ulcerated injury containing pathological lymphocytic infiltration mainly by intermediate to large sized cells with moderate pleomorphism, arranged in clusters, associated to lymph nodes with distortion of their histoarchitecture at the expense of an expansion of CD8 T cells. Immunohisto chemistry showed positivity with CD3, CD8, Granzyme, CD30 and CD56; resulting negative with CD20, CD4 (with positive control in macrophages), and ALK. The technique of in situ hybridization for the detection of EBV was carried out with an EBER 1 DNP probe (Ventana, Roche), being intensely positive (Fig. 1). A molecular study of T lymphoid clonality with PCR technique was carried out showing monoclonal rearrangement of the TCR gamma receptor in the VJA segments of the gene that encodes this receptor (TCR Gamma Rearrangements Mo lecular Analysis Kit, Master Diagnóstica, Spain). These results led to a diagnosis of EBER + extranodal T/NK lymphoma with nasal phenotype⁷.

Fig. 1 Lymph node in terminal ileum biopsy 

During this last hospitalization a new CD4 cells dosing was conducted, being the value of 54 cell/mm³, which were even lower than the previous ones. EBV serology was also tested, being positive for IgG, however, its viral load was not detectable.

Due to the poor general clinical condition of the patient after the long-term hospitalization, in addition to the chronic comor bidities and a performance status >2, he was not considered suitable for high intensity systemic chemotherapy. Finally, it was agreed to continue palliative care at home, dying 4 months later as a result of disease progression.

Discussion

The exact pathophysiology of ICL is currently unknown but it is understood that it should be due to the combination of multiple immunological disorders such as an inefficient production, an increase of the destruction and tissue sequestration of T lymphocytes⁸.The main hypothesis focuses on a defective cytokine production of tumor necro sis factor alpha or gamma-interferon that would lead to a decrease in the CD4 cell lymphogenesis and an increase in its apoptosis^8,9.

Its clinical presentation distinguishes itself by the emergence of opportunistic severe diseases such as the widespread cryptococcal disease, atypical myco bacterial infections, Pneumocystis pneumonia or oro pharyngeal candidiasis. There have also been cases of progressive multifocal leukoencephalopathy, autoimmune pathologies and oncohaematological processes such as Kaposi’s sarcoma or different types of lymphomas⁴.

There is still no specific treatment for this syndrome, although diverse alternatives have been developed to increase and promote the CD4 cell pool, as in the case of the administration of IL-2, IFN and IL-78. Stem cell trans plantation would be another option, but only for specific cases. The therapeutic standard for these patients is the treatment of opportunistic diseases and the administration of specific antimicrobials (as indicated in patients with HIV) for prophylaxis¹⁰.

During the last 20 years, few case reports have as sociated ICL with the appearance of lymphomas, without having a predominant lymphoma subtype. It is striking how in most of them, as in our case, the lymphoproliferative process was associated with EBV, which shows the im mune compromise in this group of patients¹¹. Regarding the pathophysiological mechanism, we could hypothesize that the inflammatory cytokines alteration could leads to a decrease of CD4+ T lymphocytes, which would gener ate a lower cytotoxic T response, necessary to avoid a reactivation of latent EBV in host cells, which would finally contribute to lymphomagenesis⁸.

Currently, the World Health Organization in its 2016 review of lymphoid neoplasms classified extranodal T/NK lymphomas of the nasal type within the group of mature T and NK neoplasms⁷. The diagnosis is made by patho logical anatomy of the lesion where a marked vascular involvement and abundant inflammatory component is seen with the presence of lymphocytes of variable sizes, mixed with eosinophils, plasmocytes or histiocytes. Im munohistochemistry is positive for CD2, cytoplasmic CD3 and CD56, in addition to cytotoxic molecules such as perforin and granzyme¹².Treatment consists of polyche motherapy with or without the combination of radiotherapy; regimens such as the SMILE scheme using a combination of methotrexate, etoposide, asparaginase and ifosfamide are commonly used¹³.

We present this case report because there are few documented evidence of ICL associated with EBER+ ex tranodal T/NK lymphoma^14,15. As it does not have a specific treatment or a clear pathogenesis of the process, clinical suspicion is of vital importance for an early diagnosis that helps to prevent opportunistic infections and oncohema tological processes in advanced stages.