Extranodal NK/T-cell lymphoma, nasal type, with extranasal presentation – a case report and a review of the literature

Abstract

Background

Extranodal NK/T-cell lymphoma (ENKTCL), nasal type is a very rare and aggressive non-Hodgkin lymphoma. Most commonly it occurs in the upper aerodigestive tract. But, it can also manifest at locations such as the skin, soft tissue, gastrointestinal tract (GI), lungs, testis, etc. These locations are designated as extranasal ENKTCL. The patients with the latter have often more adverse clinical features and poorer survival rate compared with nasal sites. We present a case of an 83-year-old patient with a primary ENKTCL, nasal type, with extranasal presentation in the right upper eyelid.

Material and methods

Materials for the literature review was obtained by a comprehensive search on PubMed, which yielded 82 eligible cases with extranasal ENKTCL.

Results

Sixty-eight cases (83 %) were localized as primary ENKTCL in the lungs (17), central nervous system (CNS) (14), testis (11), GI-tract (7), skin (6), orbit and intraocular tissue (4), pancreas (2), adrenal gland (2), breast (1), etc. 14 cases (17 %) presented as extended or disseminated diseases involving exclusively organs outside the upper aerodigestive tract. There was no systematic pattern of organ involvement in the extended/disseminated ENKTCL. 63 % of the patient with localized extranasal ENKTCL and about 50% of patients with extended/disseminated disease were reported to have died of the disease. Treatment strategies varied with no preferred option. Among the used treatment options were chemotherapy, radiotherapy, surgery, stem cell transplantation alone or in different combinations.

Conclusion

ENKTCL is a highly aggressive disease which may present in extranasal areas. Although the tumors respond to both chemotherapy and radiotherapy, durable complete remissions are very rare.

Keywords:

• Primary extranodal NK/T-cell lymphoma
• nasal type
• extranasal presentation
• upper aerodigestive tract
• treatment
• prognosis

Introduction

Malignant lymphomas constitute around 4% of cancers in adults, and they are traditionally divided into Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). About 90% of lymphomas are NHLs, and they are divided into more than 70 separate disease entities based on histopathologic, immunophenotypic, genetic, and clinical features [1]. In adults, 85% of lymphomas are B-cell lymphomas and only 15% are T-cell lymphomas. Lymphomas may arise anywhere in the body, both within (nodal) and outside (extranodal) the lymphatic system. 20–25% of all NHLs are primary extranodal lymphomas.

Extranodal NK/T-cell lymphomas (ENKTCL) constitute around 10% of T-cell lymphomas, and consequently they are rare. The incidence is higher in Asia and Central and South America compared to the Western part of the world. In Denmark 24 cases have been registered between 2000 and 2011, which represents 0.2% of all NHLs [2]. Mean age at diagnosis is around 50 years and the male/female ratio is around 2:1 [3].

They are histologically characterized by angiodestruction and coagulative necrosis and are associated with Epstein Barr Virus (EBV) infection. The EBV demonstrates a type II latency pattern [4]. Most of the ENKTCL, around 60–90%, occur in the nasal cavity, nasopharynx, paranasal sinuses or palate, and the particular histopathologic type is therefore designated ENKTCL, nasal type. Less commonly, ENKTCL, nasal type, can manifest at extranasal locations such as the skin, soft tissue, gastrointestinal tract, and testis. ENKTCL is associated with a high rate of relapse, refractory disease and mortality.

There is an urgent need for effective targeted therapy. In a review by Sajay de Mei et al. [5], they have presented an overview of the key molecular and pathogenic pathways in ENKTCL and have suggested a summary of the most promising novel therapeutic options.

Sanjay de Mei et al. [5] have identified JAK/STAT, PDGF, aurora kinase, MYC and NF-xB as potential therapeutic targets. The review also described inhibition of (PD-1)/PD-L1 checkpoint signaling as a novel therapeutic option.

Table 1. Detailed information on 68 localized primary extranasal cases of ENKTCL.

Reference	Primary extranasal cases (i.e., arising outside the upper aerodigestive tract): location and number of cases	Number of patients who received different treatment modalities (reference in parentheses)	Number of patients achieving different outcomes, observation times in parentheses	Demographics (age and sex distribution)
[15–28]	Lung: 17	5 CT [20,22,23,28] 4 Refused Tx [16,18,22] 2 No treatment [17,24] 1 Surgery + CT [22] 1 Surgery + refused other Tx [26] 1 CT + IT CT [27] 1 CT + CBT [15] 1 CT + ASCT [19] 1 Cyclophosphamide and methylprednisolone [25]	2 CR (observation time NR) 4 AWD (median 60 days, range 10–120 days) 10 DOD (median 25 days, range 1–210 days) 1 NR	Median age 43 years (range 19–83) 12 Male 5 Female
[29–39]	CNS: 14	4 CT [29,30,33,39] 4 RT + CT [30,36,37] 2 RT [31,37] 2 NR [32,34] 1 RT + CT + IT CT [35] 1 Surgery + RT + steroid [30]	1 CR (observation time 24 months) 4 AWD (median 24 months, range 4–139 months) 8 DOD (median 4,75 months, range 1–18 months) 1 NR	Median age 50 years( range 21–77) 9 Male 5 Female
[40–44]	Testis: 11	6 Surgery [41,44] 3 Surgery + RT + CT [40,41,43] 1 RT + CT [42] 1 Surgery + CT + RT + ASCT [44]	4 AWD (median 28,5 months, range 4–51 months) 5 DOD (median 5 months, range 2–12 months) 1 LFU (survival period 14 months) 1 NR	Median age 47 years( range 26–71) 11 Male
[45–49]	GI-tract: 7	4 Surgery + CT [48,49] 1 Surgery [45] 1 Surgery + CT [46] 1 CT [47]	6 DOD (median 5,5 weeks, range 1–24 weeks) 1 NR	Median age 64 years(range 40–75) 4 Male 3 Female
[50–54]	Skin: 6	4 CT [50,51,53,54] 1 RT [54] 1 RT + CT [52]	1 CR (observation time NR) 2 AWD (median 28 months, range 21–35 months) 3 DOD (median 120 days, range 3–150 days)	Median age 78 years (range 65–80)4 Male 2 cases, where age and sex were not specified.
[55–57]	Orbit and intraocular tissue: 4	2 RT [55] 2 RT + CT [56,57]	2 DOD (observation time NR) 1 DOD (11months) 1 CR (observation time NR)	Median age 65 years(range 57–66) 1 Male 3 Female
[58,59]	Pancreas: 2	1 No Tx [58] 1 Refused Tx [59]	1 DOD before diagnosis 1 DOD (6 months)	50 years, Male 62 years, Male
[60,61]	Adrenal: 2	1 CT [60] 1 No Tx [61]	1 DOD (3 months) 1 DOD before diagnosis	35years, Male 17 years, Male
[62]	Breast: 1	CT	1 DOD (1 month)	20 years, Female
[63]	Soft tissue; skeletal muscle: 1	CT + HSCT (Hematopoietic stem cell transplantation)	1 DOD (observation time NR)	38 years, Male
[64]	Esophagus: 1	CT	1 DOD (3 days)	40 years, Male
[65]	Thyroid: 1	Surgery + CT + RT	1 CR (observation time 28 months)	18 years, Male
[66]	Kidney, intravascular: 1	NR	1 DOD (3 weeks)	79 years, Male

ASCT: autologous stem cell transplantation; AWD: alive with disease; CBT: cord blood transplantation; CR: complete remission; CT: chemotherapy; DOD: dead of disease; HSCT: hematopoietic stem cell transplantation; IT: intrathecal; LFU: loss to follow-up; NR: not reported; PBSCT: peripheral blood stem cell transplantation; PR: partial remission; RT: radiotherapy; Tx: treatment.

Table 2. Detailed information on 14 disseminated cases of extranasal ENKTCL.

Reference	Disseminated cases location and number of cases	Treatment modalities	Number of patients achieving different outcomes, observation times in parentheses	Demographics (age and sex distribution)
[67]	Lymph nodes and skin lesions on the left side of the abdomen: 1	CT	1 PR (lesions became smaller) (2 months follow-up post-treatment)	43 years, Female
[68]	Right breast and left and right axillary lymph nodes: 1	RT + CT	1 AWD (8 months)	41 years, Female
[30]	Primary CNS ENKLTCL and meningioma: 1	CT	1 DOD (2 months)	50 years, Male
[69]	GI tract, multiorgan failure and hemophagocytotic syndrome: 1	No Tx	1 DOD (during admission)	11 years, Male
[70]	Heart, lung, kidney, spleen, liver, brain: 1	No Tx	1 DOD before diagnosis	54 years, Male
[71]	Adrenal gland and pericardial effusion: 1	CT	1 DOD (3 weeks)	46 years, Male
[72]	Stomach and skin: 1	CT	1 DOD (1 week)	69 years, Male
[73]	Adrenal gland and subcutanous involvement: 1	CT + ASCT	1 CR (observation time NR)	40 years, Female
[74]	Heart,lungs, kidneys, and gallbladder: 1	Not mentioned	NR	38 years, Male
[75]	Vitreoretina and breast involvement: 1	CT + IT CT + Intravitreal CT	1 CR (observation time NR)	50 years, Female
[21]	Lung and liver: 1	Glucocorticoid Tx	1 DOD (during admission)	39 years, Male
[76]	Testis and 2x sinonasal relapse: 1	RT + CT + ASCT + Allograft	1 CR (7 months), second CR (4 months), third CR (alive 2 years after and ongoing)	35 years, Male
[77]	Skin upper limb, relapse site skin: 1	CT	1 AWD (10 months)	34 years, Female
[78]	Skin nodule on arm, relapse site skin, CNS: 1	RT + CT	1 DOD (24 months)	70 years, Male

ASCT: autologous stem cell transplantation; AWD: alive with disease; CBT: cord blood transplantation; CR: complete remission; CT: chemotherapy; DOD: dead of disease; HSCT: hematopoietic stem cell transplantation; IT: intrathecal; LFU: loss to follow-up; NR: not reported; PBSCT: peripheral blood stem cell transplantation; PR: partial remission; RT: radiotherapy; Tx: treatment.

The presentation of the disease at extranasal locations is nonspecific and may mimic many other benign or malignant lesions. Patients with extranasal presentation often have more adverse clinical features (e.g., higher stage, elevated LDH, more bulky disease, and poor performance status), and the survival rate is inferior compared with the nasal sites. However, there are no significant differences in the immunophenotypic or genotypic profiles between the nasal and the extranasal cases.

Here, we present a case report of a patient presenting with a very rare primary ENKTCL, nasal type, with extranasal presentation in the right upper eyelid, and a review of the literature on extranasal ENKTCL, nasal type.

We have followed the guidelines for clinical case reporting (CARE) [6] whenever possible or relevant. The CARE checklist is provided as Supplementary material.

Case report

An 83-year-old male patient with a present history of chronic atrial fibrillation, diabetes mellitus type 2, prostate disease (not specified) and urinary retention necessitating a permanent catheter, asymptomatic cerebral aneurism in the internal carotid artery observed on MR scan of the brain, asymptomatic intracranial meningioma observed on magnetic resonance (MR) scan of the brain, psoriasis, and olecranon bursitis was presented. He had a past history of right knee replacement for osteoarthrosis, anal fissure with bleeding, pyelonephritis, sepsis, gastroenteritis or colitis, diabetic ulcers of the foot, dehydration, and acute cystitis. He did not have any family history of cancer or other conditions.

The patient was referred for treatment of a basal cell carcinoma in the scalp. At consultation, an accidental finding of a tumor on the right upper eyelid was made. The patient did not remember when this tumor was first diagnosed.

The patient was referred to an ophthalmologist who took total three biopsies within a period of seven months. The first biopsy showed seborrheic keratosis. The condition worsened and a new biopsy showed granulomatous inflammation. The tumor continued to grow, and the third biopsy gave the final diagnosis of extranodal NK/T-cell lymphoma of nasal type.

The histologic examination of the biopsy tissue taken from the eyelid (Figure 1) showed a dense, diffuse infiltrate composed of small to medium-sized lymphocytes with a characteristic angiocentric growth pattern. There was extensive necrosis. The lymphoma cells showed a partial T-cell phenotype with positive staining for CD3 and CD2, negative for CD4, CD5, CD7, and CD8. There was a positive reaction for perforin, a cytotoxic molecule, CD56, and EBV (EBER). Cytomorphology, growth pattern and phenotype leading to the diagnosis of an extranodal NK/T-cell lymphoma, nasal type.

Figure 1. H&E stain (×100) showing a dense, diffuse, angiocentric lymphocytic infiltrate composed of small to medium-sized cells. There is extensive necrosis.

Staging was performed with physical examination, blood tests, Fluorodeoxyglucose (FDG) positron emission tomography (PET)/computerized tomography (CT) scan, and bone marrow examination. None of these examinations showed any sign of disease elsewhere. Hence, this patient had Stage IE NK/T-cell lymphoma of nasal type in the subcutaneous tissue of the right upper eyelid.

Because of the patient’s age and comorbidities systemic, treatment was not possible and the patient was treated with local radiotherapy according to the involved site radiation therapy (ISRT) principles [7] (see Figure 2 for details).

Figure 2. Treatment plan. Target contour shown as a red line. The target included the whole upper eyelid, the adjacent extraocular soft tissues of the anterior part of the orbit, and the soft tissues of the face surrounding the eye. Radiation doses shown in color wash. One coplanar and one non-coplanar partial arc were used. The total prescribed dose was 50 Gy in 25 fractions with 5 fractions/week. 6 mm bolus was added over the entire eye.

ENKTCL is locally destructive and may extensively infiltrate the surrounding tissues beyond macroscopically evident disease. The target volume therefore extended to include the soft tissues in the anterior part of the orbit surrounding the eyeball and the soft tissues of the face surrounding the eye. The target was therefore too deep to cover with electrons, and photon therapy was needed.

The lymphoma responded promptly to the treatment (Figure 3). However, due to the high radiation, dose close to the eye the patient had considerable acute side effects of the treatment with intense irritation and pain in the eye. Two months after the end of radiation therapy the patient was admitted to the Department of Ophthalmology with keratitis and a corneal ulcer measuring 3 × 3 mm.

Figure 3. Affected eyelid before (left), at the end of (middle), and 6 months after radiotherapy (right).

The eye complications were to be expected because of the higher radiation dose than usual for lymphomas and the fairly large radiation volume. There was no sign of recurrence of the lymphoma.

Material and methods

Patient consent

Informed consent was obtained from the patient for publication of this case report and any accompanying images.

Literature search

A comprehensive search between 16 December 2019 and the 5 January 2020 was done to identify eligible publications to be included in our article. The searches were done by combining the Medical Subject Headings (MeSH) terms with the free text search in PubMed. The initial search yielded 1549 publications (see Supplementary figure 1).

Evaluation and selection of the eligible publications

Inclusions criteria

The publications were evaluated according to the title and abstract. And publications which might contain descriptions of cases were selected. Furthermore, publications were selected if they contained a description of cases concerning primary ENKTCL, nasal type, with extranasal location or localized outside the upper aerodigestive tract.

Exclusions criteria

If the reported cases did not contain information about the precise location of the disease, whether it was localized or disseminated/extended, and information about the treatment or outcome, they were excluded. Furthermore, publications containing cases with recurrences after primary nasal presentation were also excluded.

Additional search

An additional search was done by evaluating and reviewing the reference lists of the selected publications from the first evaluation and selection process. And, these additional publications were furthermore evaluated according to the above-mentioned inclusion and exclusion criteria. The selection process yielded 64 eligible articles containing a total of 82 cases (see supplementary figure 2), and these were included in our review.

Results

A total of 82 reported cases of primary extranasal ENKTCL, nasal type, were identified. All cases were characterized as not involving the upper aerodigestive tract. See Tables 1 and 2 for the detailed information on the 82 cases, including the location of disease, treatment offered to the patient and the outcome.

68/82 cases (83%) presented with localized disease. Their median age was 45 years (range 17 to 83), 49 were males, and 17 were females. 14/82 cases (17%) presented with extended/disseminated disease. Their median age was 41 years (range 11 to 70), 9 were males, and 5 were females.

The most frequent locations in patients with localized disease were lung (25%), CNS (21%), testis (16%), GI-tract (10%), skin (9%), orbit and intraocular tissue (6%), pancreas (3%), and adrenal gland (3%). See information on the rest of the locations in Table 1.

In the cases with extended/disseminated ENKTCL, there was involvement of different and often multiple organs. There did not seem to be any systematic pattern in the anatomic distribution of these cases, for details see Table 2. The prognosis of patients with both localized and disseminated extranasal ENKTCL was very poor.

Among the cases with primary localized disease, 43/68 (63%) of the patients died with a median time to death of 1 month (range 0 days to 11 months). We found a particularly poor prognosis in patients with GI-tract involvement, where 6/7 cases (86%) died and the information on the last patient (1/7 case) was not reported. The median time to death for those patients was 5.5 weeks (range 1–24 weeks). The prognosis of patients with extended/disseminated disease in our review was also very poor. 7/14 (50%) of the patient died with a median time to death of 1 week (range 0 days to 24 months).

Different treatment strategies were applied in the studies of localized disease reviewed here. Chemotherapy, radiotherapy, surgery, and stem cell transplantation were used, either alone or in different combinations.

The category of patients with the lowest percentage who died was those with testicular involvement, 5/13 cases (45%), where the median time to death was 5 months (range 2 to 12 months). Most of these patients were treated with surgery, either alone in 6/11 cases (57%) or in combination with chemotherapy, radiotherapy and/or autologous stem cell transplantation in 4/11 cases (36%). They also had the highest percentage of patients alive with disease with a median of 28.5 months (range 4–51 months).

Patients with CNS involvement had the second highest percentage of patients alive with the disease 4/14 cases (29%) with a median of 24 months (range 4–13 months).

The location of the lymphomas in the 14 CNS cases was in the cerebrum, the cerebral lobes (frontal, temporal, parietal), the pituitary, the cerebellar folia/vermis, the spinal cord dura, and as a leptomeningeal lymphoma.

Two of the patients were treated with radiotherapy in combination with methotrexate, one with radiotherapy alone and one patient with radiotherapy, steroid and surgical excision

Chemotherapy was used in almost all patient categories, most frequently in patients with skin involvement 4/6 cases (67%). One patient achieved CR (observation time not reported), one was alive with disease with a survival period on 35 months, and one died 5 months after the diagnosis. One patient received radiotherapy as the only treatment and that patient was alive with disease with a survival period of 21 months.

Patients with extended/disseminated disease were treated with chemotherapy in 10/14 cases (71%) either alone or in combination with radiotherapy, intrathecal chemotherapy, and/or stem cell transplantation, but the outcome was poor.

Discussion

A case of primary ENKTCL, nasal type, with extranasal presentation in the subcutaneous/cutaneous tissue in the right upper eyelid was presented. No other case with this clinical presentation was found in the literature.

In our review, 83% of the primary extranasal ENKTCL were localized and 17% were extended/disseminated in their presentation. This is in accordance with the publication by Yamaguchi et al. [8], who stated that more than 60% of patients presented with localized disease. This high occurrence of primary localized disease is in accordance with the stage distribution seen also in the more common nasal/upper aerodigestive tract ENKTCLs.

The most frequent locations in cases with primary localized presentation in our study were lung (25%), CNS (21%), testis (16%), GI-tract (10%), skin (9%). These locations were also found in other published reviews, but the most frequent location was not the lungs, but rather the skin, soft tissue, and GI-tract [9]. However, this may be due to a particular interest in clinics with specific case mixes.

In cases with extended/disseminated ENKTCL, there was involvement of different and often multiple organs. There did not seem to be any pattern in the distribution of these cases, but the number was small. ENKTCL is known to have a very aggressive clinical course and may therefore possibly involve many different organ systems through hematogenous spread, if the primary tumor is not detected in the early stage.

We found that the prognosis of patients with both localized and disseminated extranasal ENKTCL was very poor. The poor prognosis of patients with localized extranasal ENKTCL was recently evaluated in a publication by Yamaguchi et al. [8], where they stated that the prognosis is improved for ENKTCL, nasal type, of nasal origin but not in cases of extranasal origin. The most favorable extranasal site of ENKTCL in their material was the skin. Although we did not have a high number of patients with skin involvement 6/68 cases (9%), the percentage of patients that died was 3/6 cases (50%). Hence, we could not confirm their more positive results. They suggested a possible explanation for the favorable prognosis might be related to the fact that the skin is an organ easily examined and biopsied. They also stated that the skin tolerates radiotherapy well, and this is the main treatment. This was also investigated in a retrospective study by Ahn et al. [10]. They found that radiotherapy provided survival benefits in patients with only localized cutaneous involvements [8,10]. We found a particularly poor prognosis in the patients with GI-tract involvement. This very poor prognosis was also mentioned in [8], where they stated that intestinal ENKTCL is frequently complicated by perforation during therapy and that this complication is often fatal. Patients in our review who had primary ENKTCL involving the testis had the lowest percentage of patients dying of the disease. This might be related to the treatment the patients were offered, orchiectomy in combination with chemotherapy, but this needs to be evaluated with further studies.

The prognosis of patients with extended/disseminated disease in our review was also very poor. However, numbers of patients were small making these data very uncertain. There is a need for a more comprehensive study.

From our review, we could not see any specific pattern for an optimal treatment strategy. Yamaguchi et al. [11] stated in their review that there is a consensus that radiotherapy of 50 Gy is required to achieve local control of ENKTCL. This is in accordance with published guidelines [12,13].

With regard to chemotherapy, Yamaguchi et al. [8] only found 21% of patients in their review were fit for SMILE chemotherapy, which is a common modern first-line recommendation [14].

There is clearly a need for new, more effective and less toxic treatments and research is ongoing regarding new molecular targets, see introduction.

Conclusion

Extra upper aerodigestive tract ENKTCL is a highly aggressive disease which may present in many different organs, either localized or disseminated. The course of the disease seems to be at least as aggressive as in the upper aerodigestive tract, and although the tumors are responding to both chemotherapy and radiotherapy, durable remissions are rare.

Disclosure statement

No potential conflict of interest was reported by the author(s).