|Ahead of print publication
Extranodal natural-killer/T-cell lymphoma, nasal type: An immunomorphological study from a regional cancer institute in India
Mohit Agrawal1, G Champaka1, Usha Amirtham1, Linu Abraham Jacob2, CS Premalata1
1 Department of Pathology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India
2 Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India
|Date of Submission||26-Feb-2020|
|Date of Decision||30-May-2020|
|Date of Acceptance||12-Aug-2020|
|Date of Web Publication||11-Mar-2021|
Department of Pathology, Kidwai Memorial Institute of Oncology, Dr. M.H Marigowda Road, Bengaluru - 560 029, Karnataka
Source of Support: None, Conflict of Interest: None
Introduction: Extranodal natural-killer/T-cell lymphoma, nasal type (ENKTL), is a rare, aggressive, predominantly extranodal non-Hodgkin lymphoma (NHL) of putative natural-killer (NK) cell and rarely T-cell origin, always associated with Epstein–Barr virus (EBV) infection and characterized by highly distinctive histopathological features with predilection for the upper aerodigestive tract. While the nasal cavity is the prototypical site, less frequently extranasal ENKTL can also occur. The objective of this case series is to study the immunomorphological features of ENKTL from a tertiary cancer centre as the data are sparse from India despite it being a distinct entity with characteristic clinicopathological features.
Methods: We identified 11 cases of ENKTL from the departmental archives between January 2015 and June 2018. The clinicopathological and immunohistochemistry (IHC) findings of these tumors were analyzed. EBV encoded RNA (EBER) in situ hybridization (EBER-ISH) for EBV was done in eight cases.
Results: The disease was more common in males (male: female ratio 1.8:1) with the mean age of 45 years (range 31–65 years). Sinonasal region was the most common site with 9 cases and skin and penis were involved in one case each. The patient with penile involvement on further investigations was found to have occult nasal involvement, Histomorphological features such as angiocentricity/angioinvasion was seen in seven cases (63.6%) and significant necrosis was present in all 11 cases (100%). All cases were uniformly positive for cytoplasmic CD3 and CD56 with high Ki67 proliferating index and EBER-ISH test for EBV was positive in all the eight cases.
Conclusion: ENKTL is an aggressive NHL and should be differentiated from other T- and B-cell lymphomas as the prognosis and therapy differ. Nasal biopsies showing predominant necrosis and atypical lymphoid cells with angiocentricity must raise the suspicion of ENKTL and should be confirmed by immunomorphological and molecular studies.
Keywords: Epstein–Barr virus associated lymphoma, extranodal natural-killer/T cell lymphoma-nasal type, lethal midline granuloma
|How to cite this URL:|
Agrawal M, Champaka G, Amirtham U, Jacob LA, Premalata C S. Extranodal natural-killer/T-cell lymphoma, nasal type: An immunomorphological study from a regional cancer institute in India. J Can Res Ther [Epub ahead of print] [cited 2022 Jul 3]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=311076
| > Introduction|| |
Extranodal natural-killer/T cell lymphoma, Nasal type (ENKTL), is a predominantly extranodal lymphoma of natural-killer (NK)-cell or T-cell lineage, characterized by vascular invasion, prominent necrosis, cytotoxic phenotype, and association with Epstein–Barr virus (EBV) as defined by the WHO. It typically involves the nose and nasopharynx, less frequently ENKTL can involve extranasal sites such as skin, gastrointestinal tract, salivary gland, and very rarely testis., It shows substantial variation in incidence across the geographical regions and racial populations and is more prevalent in South Asia, Central and South America as compared to North America and European Countries. This lymphoma shows predilection to middle-age males with a median age of 44–54 years.
The diagnosis of ENKTL is often delayed, as clinically it simulates bacterial or fungal sinusitis leading to repeated, but unsuccessful antimicrobial therapy. In addition, histological diagnosis is difficult because of extensive tissue necrosis which requires multiple biopsies., Delayed diagnosis and treatment increase the risk of locoregional extension, compromising survival.
The present study aims to analyze the clinical and immunomorphological features of this rare and aggressive lymphoma.
| > Methods|| |
Eleven cases of ENKTL were identified over a period of 3 1/2 years from departmental archives between January 2015 and June 2018. The clinical findings of these patients were retrieved from Medical Records Department. Hematoxylin and Eosin (H and E)-stained slides of all cases from the routinely processed formalin-fixed paraffin embedded (FFPE) tissue were reviewed. Immunohistochemistry (IHC) was performed using the HRP polymer method, with 3,3'-diaminobenzidine tetra hydrochloride (DAB) as chromogen. FFPE tissue were sectioned at 4 μ thickness and taken on silane coated slides, dewaxed and heat-induced antigen retrieval was done using the multi-epitope retrieval system, blocked with 2% skimmed milk blocking solution and then incubated with a primary antibody. The bound primary antibody was detected by the addition of secondary antibody conjugated with HRP polymer and DAB chromogen. The slides were counterstained with hematoxylin and covered in a mounting medium. The following antibodies were used depending on the differential diagnosis based on histomorphological features: LCA, cCD3, CD56, Ki67, CD15, CD30, PAX5, CD20, CD4, CD8, CD5, CD10, BCL2, BCL6, Cyclin D1, ALK1, MUM1, LMP1, TdT, MPO, CK, EMA, p63, Granzyme B and perforin. Positive external controls were used along with test samples.
EBV was demonstrated by rapid in situ hybridization (RISH) on FFPE tissue with Digoxin labelled probe for EBV encoded RNA (EBER) using BioCare RISH™ HRP Detection kit. The sections were fixed and deparaffinized as per standard procedure. Protein digestion/retrieval was done using BioCare's decloaking chamber followed by a wash in distilled water. Probe hybridization was carried out in preheated humid chamber at 55°C for 30–60 min followed by posthybridization washing for 5 min in Tris-buffered saline (TBS) at 55°C and counterstaining with Harris hematoxylin. The probe hybridizes to specific EBER targets, which are concentrated in the nuclei of latently infected tumor cells.
Bone marrow biopsy was done in all cases for staging of lymphoma. Basic hematological, biochemical and serological test results were obtained from the case files.
| > Results|| |
Demographic and clinical features
Of the 594 non-Hodgkin lymphoma (NHL) diagnosed at our institute between January 2015 and June 2018, B-cell lymphoma constituted 86% and 14% were T-cell lymphomas which included 11 cases of ENKTL comprising 1.85% (11/594) of all NHL and 13.2% (11/83) of Mature T and NK cell lymphoma at our Institute. Among 11 cases of ENKTL, there were 7 males and 4 females (male: female ratio of 1.8:1) with a mean age of this cohort being 45 years (range 31–65 years). Nine (81.8%) patients came from rural India and belonged to low socioeconomic status (SES). The duration between the onset of symptoms and consultation to hospital ranged from 1 to 6 months (average 3.5 months). The presenting sign and symptoms were localized to the site of involvement; most common being sino-nasal region with common complaints of nasal obstruction, swelling and ulceration, epistaxis, periorbital edema and palatal pain [Figure 1]a,[Figure 1]b,[Figure 1]c. Tumor in extranasal sites was observed in two patients; one presented with dysphagia and multiple erythematous plaque like skin lesions on face, trunk, and extremities [Figure 1]d, and the other patients presented with ulcerated destructive penile growth [Figure 1]e. In two nonnasal ENKTL, one patient with penile involvement had occult nasal primary, while other patient with skin involvement did not show clinical or radiological (fluorodeoxyglucose positron emission tomography) evidence of occult primary.
|Figure 1: Clinical presentation of Extranodal natural-killer/T-cell lymphoma, nasal type: (a) Nasal swelling and obstruction. (b) Proliferative growth over nose with extension into orbit and facial edema. (c) Ulcerative lesion destroying nasal septum and cartilages of nose. (d) Cutaneous hyperpigmented patch over face and legs. (e) Penile mass showing ulceration and necrosis. (f) Ulceration of hard palate with oronasal fistula|
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All cases of sinonasal lesions on examination showed ulcerative, necrotic, friable and hemorrhagic masses occupying one or both nasal cavities. In one patient, the tumor had ulcerated through the hard palate resulting in oronasal fistula formation [Figure 1]f. Eight of 11 patients had Ann Arbor Stage I/II disease, whereas three patients had Stage IV disease. None of the patients had bone marrow involvement. Serological tests for HIV and HBsAg were nonreactive in all cases.
Morphologically, coagulative necrosis admixed with apoptotic bodies were found in all cases (100%) [Figure 2]a. An angiocentric and angiodestructive pattern of tumor growth was observed in 7 (63.6%) of 11 cases [Figure 2]b. In majority of cases (9/11), neoplastic cells were of medium size with hyperchromatic nuclei, whereas two cases showed predominantly large size cells with vesicular nucleus and 1–2 prominent nucleoli [Figure 2]c and [Figure 2]d. The biopsy from skin lesion showed lymphoma cells predominantly in dermis around adnexal structures and blood vessels without epidermotropism. The background was often accompanied by the admixture of inflammatory cells, including neutrophils, plasma cells, and frequent eosinophils. The morphological differential diagnosis included diffuse large B-cell lymphoma, peripheral T-cell lymphoma-not otherwise specified, lymphoblastic lymphomas, and granulocytic sarcomas. IHC and EBER ISH were helpful in arriving at the correct diagnosis.
|Figure 2: Histomorphological features of extranodal natural-killer/T-cell lymphoma, nasal type: Coagulative necrosis and admixed apoptotic bodies (a) (H and E stain, ×100). Angiocentric and angiodestructive growth pattern (b) (H and E stain, ×400). Neoplastic cells of medium size with hyperchromatic nuclei (H and E stain, ×400) (c) and large cells with vesicular nuclei with 1–2 prominent nucleoli (H and E stain, ×400) (d)|
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The neoplastic cells showed membranous positivity to LCA, CD56 and cytoplasmic immunoreactivity to CD3 in all cases (100%) [Figure 3]a,[Figure 3]b,[Figure 3]c. IHC for cytotoxic molecules, Granzyme B and Perforin performed in one case showed granular cytoplasmic positivity [Figure 3]d. The neoplastic cells were nonreactive to other T-cell markers like CD5, CD4, CD8 in majority of cases. The Ki67 proliferation index ranged from 30 to 90% and most cases (8 out of 11) had a proliferation index more than 60% [Figure 3e]. IHC results of all 11 cases are summarized in [Table 1].
|Figure 3: Immunohistochemical features of extranodal natural-killer/T-cell lymphoma, nasal type: Neoplastic lymphoid cells expressing LCA (a), CD56 with membranous immunoreactivity (b), cytoplasmic CD3 expression (c). Immunoreactivity for cytotoxic molecule-granzyme-B (d). Neoplastic cells showing high proliferation with Ki67 (e) (immunoperoxidase stain, HRP polymer method). Neoplastic cells showing nuclear positivity for Epstein–Barr virus encoded RNA in situ hybridization (rapid in situ hybridization by digoxin-antidigoxin method) (f)|
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|Table 1: Immunohistochemical features of extranodal natural killer/T-cell lymphoma, nasal type cases|
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Epstein–Barr virus encoding RNA in situ hybridization
EBER-ISH was done in eight cases, including the case involving the skin and penis, all showed nuclear positivity ranging from 30% to 90% of neoplastic cells [Figure 3]f. This test could not be done in other three cases due to nonavailability of paraffin block or inadequate tissue in paraffin block. In these cases, the diagnosis was based on the distinctive clinical presentation of destructive nasal masses and characteristic immunomorphologic findings with expression of cytoplasmic CD3, CD56, and absence of staining for other T- and B-cell markers.
Serum free EBV DNA levels by the polymerase chain reaction was done in one case with cutaneous ENKTL, which showed high titer of IgG antibodies to virus capsid antigen (>200.00 U/ml; normal <8.0 U/ml) and viral nuclear antigen (39.70U/ml; normal <8.0 U/ml).
Treatment and follow-up
The primary modality of treatment was L-Asparaginase-based chemotherapy regimen with SMILE (Steroid, Methotrexate, Ifosfamide, L-Asparaginase, and Etoposide) followed by radiotherapy (>50 Gy in 25–30 fractions) followed by another three cycles of chemotherapy. The patient with cutaneous ENKTL who had nonobstructive cardiomyopathy received P-GEMOX (Pegaspargase, Gemcitabine, and Oxaliplatin) regimen, which is less cardiotoxic.
Follow-up was available in eight patients [Table 2]. The mean follow-up interval was 2 years 3 months (range 4–45 months). Five patients completed the treatment and are free of disease at mean follow up of 13.5 months (range 12–16 months). Two cases had relapse of disease; one with cutaneous ENKTL with high serum EBV DNA titers, relapsed 6 months post chemotherapy, subsequently received immunotherapy with Pembrolizumab following post chemotherapy relapse but had to stop therapy due to severe side effects and is alive with disease. Other patient with relapse died due to progressive disease. One patient died while undergoing chemotherapy, 4 months after the diagnosis. Two out of 5 disease-free patients underwent nasal reconstruction surgery with marked improvement in cosmesis and quality of life [Figure 4].
|Figure 4: Follow up images of two patients (a- case 3 and b- case 6) showing improved cosmesis after completion of treatment (refer to Figure 1 b and c respectively for comparison at presentation)|
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|Table 2: Treatment and follow up of patients of extranodal natural killer/T-cell lymphoma, nasal type in present study|
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| > Discussion|| |
In the past, malignant lymphomas originating from the nasal cavity, paranasal sinuses, and hard palate were known by various terms such as lethal midline granuloma, polymorphic reticulosis, and midline malignant reticulosis. In 1982, Ishii et al. first recognized expression of CD3 in this lymphoma. Later, Suzumiya et al. demonstrated the expression of CD3 and CD56, suggesting their NK-cell origin. ENKTL is classified under Mature T and NK-cell neoplasms and in view of its typical presentation in the nose and nasopharynx, the terminology “nasal type” was adopted by the WHO.,
ENKTL shows substantial variation in the incidence across the geographical regions and racial populations. It represents about 10% of NHLs in South Asia and Central/South America, whereas <1% of NHLs in North America, Canada, and Europe. According to International peripheral T-cell and NK/T-cell lymphoma study by Vose et al., ENKTL constituted 22.4%, 5.1%, 4.3% of Mature T and NK-cell lymphomas in Asia, North America, and Europe, respectively., Most of the studies in Asia are from China, Thailand, and Singapore.,,, Indian literature on ENKTL is sparse and most are limited to case reports and few studies wherein ENKTL constituted 0.5% to 0.7% of NHLs and 2.7% to 7% of mature NK/T cell lymphoma, respectively, in various studies.,,, In the present study, ENKTL formed 1.85% of NHLs and 13.2% Mature T and NK-cell lymphomas at our Institute, which is slightly more than what is reported by Bugalia et al., Naresh et al., and Shet et al.,, It is less than the prevalence in Asian countries (22.4%) indicating that this lymphoma might be underreported in India or there may be geographic variation in the incidence within the Indian subcontinent.
Our study showed male predominance (male: female ratio 1.8:1) with a median age of 45 years (range 31–65 years), which is in accordance with other studies in the literature.,,, The majority of patients with low SES and from rural India presented with advanced stage and aggressive features, which is similar to the findings in the study by Sánchez-Romero et al. suggesting that socioeconomic factors may contribute to delayed diagnosis.
ENKTL most commonly involves upper aerodigestive tract with the nasal cavity being prototypical site (81.8% cases in present study). Clinical presentation in this study was similar to those reported by other studies, with nasal obstruction due to mass or ulceration in nasal cavity being most common finding., Extensive ulceration and necrosis often needs repeat biopsies and Sánchez-Romero et al., in their study of 86 cases, had better results with oral mucosa biopsy whenever there was the involvement of palate. Ulceration of the hard palate with oro-nasal fistula formation was a unique presentation observed in this series. Penile involvement by this lymphoma is very rare, and to the best of our knowledge, it is the first case to be reported from India and 4th in the world literature.,
Histomorphological features of ENKTL were highly distinctive with necrosis (100%) and angiocentricity/angioinvasion (63.3%) being the most common features. In various major studies, presence of necrosis was reported in 62%–92% of cases and angiocentricity/angioinvasion in 36%–69% of cases. Though the above features are very characteristic, a diagnosis of ENKTL cannot be rendered based only on these findings, further studies with IHC and ISH for EBER are necessary.,,,,,,,,,,
In the present study, IHC for cCD3 and CD56 were positive in 100% cases. In literature, their expression has been reported to vary from 74% to 100% of cases. Cytotoxic molecules such as Granzyme B or Perforin are typically expressed in ENKTL. The Ki67 proliferative index was more than 60% in most cases and according to Jiang et al. proliferating activity of tumor cells is of prognostic significance.
Universal association of EBV with this lymphoma, suggest its etiological role in disease pathogenesis and geographical variation. EBV induced oncogenic proteins play a role in the progression of ENKTL by several mechanism. Most of studies demonstrated EBV association in 100% of cases.,, The WHO Classification of Tumors of Haematopoietic and Lymphoid Tissue-Revised Edition 2017 quotes “The diagnosis of ENKTL should be considered with skepticism if EBV is negative.” The present study also showed 100% EBV association by EBER-ISH in cases where the test was performed. A comprehensive comparison of immunomorphological features of various major studies of ENKTL in world literature is shown in [Table 3].
|Table 3: Immunomorphological features of extranodal natural killer/T-cell lymphoma, nasal type in various major studies|
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Serum EBV DNA quantification at diagnosis gives measurement of lymphoma load, response to treatment, minimal residual disease and prognosis., In this study, one case with cutaneous ENKTL showed high serum EBV DNA levels at diagnosis, was refractory to chemotherapy with early relapse of the disease.
Sequential chemotherapy and radiotherapy are the first-line treatment for Stage I/II NK/T-cell lymphoma. Prognosis of this lymphoma is poor in general and depends on stage, invasion of bone, serum EBV DNA levels and Ki67 proliferative index. Chemotherapy based on L-asparaginase containing regimen SMILE (Steroid, Methotrexate, Ifosfamide, L-Asparaginase, Etoposide) are effective for most cases of ENKTL. For relapsed/refractory cases, immunotherapy (PD-1 inhibitors) is advocated. The patient with cutaneous ENKTL also received immunotherapy with Pembrolizumab following relapse. In present study the disease free survival and overall survival was 62.5% and 75% respectively which is comparable to survival rates reported in most of the case series which varies from 40% to 60%.,,
| > Conclusion|| |
ENKTL constituted 1.85% (11/594) of all NHL and 13.2% (11/83) of Mature T and NK cell lymphoma in this study. Necrosis and angioinvasion were the consistent histomorphological features present in most of the cases. EBER–ISH for EBV done in 8 cases was positive in all. ENKTL are rare aggressive neoplasms, often pose a diagnostic challenge unless there is high index of suspicion. The differentiation of this lymphoma from other T-cell lymphomas, B-cell NHL is necessary as the prognosis and therapy differ. Early and accurate diagnosis of this aggressive lymphoma can assist the oncologist in making appropriate treatment decisions.
All cases in this study were collected from Department of Pathology, Kidwai Memorial Institute of Oncology, Bengaluru. Ethical principles related to patient's rights and privacy is fully respected by authors in accordance with norms laid down by Institutional Scientific review Board and Ethical committee.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]