
==== Front
Neoplasia
Neoplasia
Neoplasia (New York, N.Y.)
1522-8002
1476-5586
Neoplasia Press

S1476-5586(24)00090-3
10.1016/j.neo.2024.101048
101048
Original Research
Clinical and genetic profile of Chinese patients with indolent natural killer-cell lymphoproliferative disorder of the gastrointestinal tract
Chen Hongyun 2196293418@qq.com
ab1
Jia Congwei david_jia0814@163.com
c1
Zhou Daobin zhoudb@pumch.cn
a
Zhao Danqing zhaodanqing@pumch.cn
a
Zhang Yan zhangyan10659@pumch.cn
a
Cai Hao caihao@pumch.cn
a
Wang Qiang pekingunion@aliyun.com
d
Zhang Yueyi zhangyueyi13@163.com
bd
Zhang Wei vv1223@vip.sina.com
a⁎
a Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan, Dong Cheng District, Beijing 100730, China
b Medical College, Chinese Academy of Medical Sciences, Beijing, China
c Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
d Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
⁎ Corresponding author. vv1223@vip.sina.com
1 Hongyun Chen and Congwei Jia contributed equally.

13 9 2024
11 2024
13 9 2024
57 10104818 7 2024
27 8 2024
28 8 2024
© 2024 Published by Elsevier Inc.
2024

https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Highlights

• NKLPD-GI is a rare, indolent atypical NK-cell proliferation that calls for timely recognition to prevent unnecessary interventions.

• “Watch and wait” therapy was preferable to intense chemotherapy.

• Recurrent JAK3 mutation may be the underlying mechanism responsible for the neoplastic nature of the disease and may serve as a potential target for patients with severe symptoms.

Indolent natural killer cell lymphoproliferative disorder of the gastrointestinal tract (iNKLPD-GI) is an uncommon, recently recognized lymphoid proliferation of mature NK cells primarily manifesting in the GI tract. Unlike NK/T lymphoma, iNKLPD-GI exhibits a rather indolent clinical course, underscoring the need for cautious management to prevent unnecessary interventions. However, clinical and molecular features of this entity have not been thoroughly understood. This study aimed to add more information to the current knowledge of this disease. Seven patients with iNKLPD-GI were included in our study. Clinical data included initial symptoms, endoscopic manifestations, pathological features, and therapies. Besides, next-generation sequencing was arranged to explore the underlying genetic mechanism of this disease. In our study, iNKLPD-GI in the urinary bladder was first identified. Edema of extremities (3, 42.8 %) was the most prevalent onset symptom which was reported for the first time. Pathological and immunohistological features were found to display the phenotype of NK cells. Unlike extranodal NK/T cell lymphoma, Epstein-Barr virus-encoded small RNA (EBER) were negative in all patients. Moreover, we found that two patients harbored JAK3 mutation. Apart from JAK3 K563_C565del previously reported in the literature, we discovered new JAK3 mutation sites. Other mutations including BRAF, KRAS, and SH2B3 were also identified. In conclusion, iNKLPD-GI was an indolent atypical NK-cell proliferation with diverse clinical characteristics. “Watch and wait” therapy was preferable to intense chemotherapy. Recurrent JAK3 mutation may be the underlying mechanism responsible for the neoplastic nature of the disease and may serve as a potential target for patients with severe symptoms.

Keywords

Natural killer cell lymphoproliferative disorder
Gastrointestinal tract
Indolent clinical course
Genetic profile
Abbreviations

iNKLPD-GI indolent natural killer cell lymphoproliferative disorder of the gastrointestinal tract

ENKTCL extranodal NK/T-cell lymphoma

MEITL monomorphic epitheliotropic intestinal T cell lymphoma

PTCL NOS, peripheral T cell lymphoma, not otherwise specified

FFPE formalin-fixed paraffin-embedded

EBV Epstein-Barr virus

EBER Epstein-Barr virus-encoded small RNA

EATL enteropathy-associated T-cell lymphoma
==== Body
pmcIntroduction

Indolent natural killer cell lymphoproliferative disorder of the gastrointestinal tract (iNKLPD-GI) constitutes a rare atypical NK-cell proliferation, initially elucidated by Vega et al. [1]. Due to rarity, no more than 70 cases are reported worldwide [[1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15]]. Lesions are usually localized in the GI tract. Instances of extragastrointestinal occurrences, such as in lymph nodes, nasopharynx, and the female genitourinary tract, have been sporadically documented [[2], [3], [4]]. Patients may exhibit either asymptomatic presentation or vague, nonspecific gastrointestinal symptoms. Diagnosis relies on biopsies of lesions, coupled with their unique, indolent clinical trajectory. Patients may be diagnosed initially as extranodal NK/T-cell lymphoma (ENKTCL), monomorphic epitheliotropic intestinal T cell lymphoma (MEITL), and peripheral T cell lymphoma, not otherwise specified (PTCL, NOS), especially when they exhibit atypical features. In contrast to NK/T lymphoma, it is considered self-limited. No disease-specific disability or mortality has been reported. Thus, it is of great significance to recognize this entity promptly to avoid excessive treatment.

Helicopter pylori infection was regarded as a potential pathogenesis, but this was unconfirmed. In previous literature, most patients were positive for H. Polyri infection and the majority of these patients received eradication therapy. Regression was observed after the treatment. However, patients who did not undergo eradication therapy also exhibited regression of iNKLPD-GI. Thus, there was no definite relation between the eradication therapy of H. Pylori and the recovery of the lesions [6,10,11,14,16].

The genetic profile of this disease was also not elucidated. One study showed that patients harbored JAK3 mutation in three of seven cases, while seven cases stained with p-STAT5 were positive, indicating this pathway may be the underlying mechanism responsible for the neoplastic nature of the disease [17]. In a recent study, next-generation sequencing and immunohistochemistry were performed in four cases with NKPLD-GI. Only one patient was found to harbor JAK3 mutation, but phospho-STAT5 was detected positive in all three stained cases. Further studies are still warranted to explore the molecular mechanisms of this disease. Notably, we reported the first iNKLPD-GI in China(5) and subsequently encountered six additional cases in clinical practice. Herein, we summarized its clinicopathological, immunohistological, and molecular features to augment the understanding of this etiology.

Materials and methods

Population and data collection

Seven cases, including two consulting cases with diagnoses of iNKLPD-GI between May 2017 and January 2024 at our center were included. The diagnosis was confirmed by two experienced pathologists based on World Health Organization classification criteria for hematopoietic and lymphoid tissue tumors [18]. Clinical data of iNKLPD-GI patients including age, gender, symptoms, site of the disease, endoscopic manifestations, and pathological findings were retrieved from medical records. Patient follow-up was conducted via telephone and calculated from the beginning of diagnosis of iNKLPD-GI to the end of follow-up. The study was approved by the Ethics Committee of Peking Union Medical College Hospital.

Immunohistochemistry and in situ hybridization

Immunohistochemistry was performed on 10 % formalin-fixed paraffin-embedded (FFPE) tissue. The following antibodies were used, including CD2, CD3, CD4, CD7, CD8, CD56 (Leica, Germany); AE1/AE3, Granzyme B, Ki-67, CD20, CD5, TIA-1(Dako, Denmark).

Epstein-Barr virus (EBV) was detected by in-situ hybridization (ISH) with Epstein-Barr virus-encoded small RNA (EBER) probes (Leica, Germany). EBER-positive control tissue was used in every sample.

Nucleic acid extraction and next-generation sequencing

Sufficient DNA from seven cases was extracted from formalin-fixed paraffin-embedded (FFPE) tissues using a paraffin-embedded tissue DNA extraction kit (Tiangen, China) and then underwent a target next-generation sequencing panel on MGISEQ-2000 (Beijing Genomics Insititute, China) targeting all exons and selected non-coding and regulatory regions of 275 genes (Supplementary Table 1).

Results

Clinical features

The clinical features are summarized in Table 1. In our study, the patients had a median age of 56 years (range 40–65) with a nearly equal gender distribution (3 males, 4 females). Seven patients presented with diverse clinical symptoms, including reflux, abdominal pain, bloody stool, and lower extremity edema. The involved sites included the stomach (n = 5), duodenum(n = 4), ileum(n = 2), colon(n = 3), gallbladder(n = 2), and urinary bladder(n = 1). Endoscopic examinations of these patients showed erosions, erythematous changes, and superficial ulcers (Fig. 1). In our study, two patients presented with lymphatic dilation (Fig. 1b) which was seldom documented in previous cases and may explain the hypoalbuminemia leading to edema of the lower extremities. Helicopter pylori was tested by histology in all six patients. Only one patient (case 1) was positive.Table 1 Clinical features, endoscopic findings, and follow-up.

Table 1Patient no.	Age, y/sex	Clinical symptoms	Localization of disease	Macroscopic manifestation	Initial diagnosis	Management	Follow-up	Status	
1	51/F	Regurgitation	Stomach	Elevated lesion with a superficial ulcer	ENKTL	Observation	65	Residual disease	
2	56/F	Epigastric pain	Stomach, duodenum, colon, and gallbladder	Multiple erosions and superficial ulcers	iNKLPD-GI	Cholecystectomy
Lenalidomide	33	Residual disease	
3	40/M	Abdominal discomfort and bloody stools	Stomach, duodenum, ileum, colon, gallbladder, and urinary bladder	Erythematous changes, erosions, and superficial ulcers	iNKLPD-GI	Cholecystectomy
Glucocorticoids
and tacrolimus	31	Residual disease	
4	64/M	Edema of both lower extremities	Efferent loop 10–15 cm from the anastomosis	Mucosal swelling and lymphatic dilation	iNKLPD-GI	Glucocorticoids
and cyclosporine	9	Residual disease	
5	56/F	Chronic diarrhea and edema of both lower extremities	Duodenum and ileum	Ulcers and lymphatic dilation	iNKLPD-GI	Observation	2	Residual disease	
6	65/M	Chronic diarrhea and edema of both lower extremities	Stomach, duodenum, and colon	Erythematous changes	iNKLPD-GI	Observation	1	Residual disease	
7	60/F	Asymptomatic	Stomach	Erosions	iNKLPD-GI	Observation	1	Residual disease	

Fig. 1 Endoscopic manifestations of iNKLPD-GI.

The gastric lesions appeared as superficial ulcers with surrounding edema and erythema (a). Lymphatic dilation in the duodenum was seen in two patients who presented with severe hypoalbuminemia (b). Erythematous changes and erosions were also observed in the gastrointestinal tract (c-d).

Fig 1

Follow-up and clinical management

All patients received a close follow-up by clinical evaluation and endoscopic examination. Follow-up time was 1–65 months (Table 1). Four patients in our study adopted “watch and wait” therapy. Though case 1 was misdiagnosed as ENKTL, she did not receive chemotherapy because her atypical pathological aroused skepticism of the initial diagnosis. INKPLD-GI was diagnosed after a repeated biopsy. Cases 2 and 3 received cholecystectomy due to acute cholecystitis. The lesion of the gallbladder was confirmed iNKLPD-GI by pathology. Case 2 was treated with lenalidomide, an immunomodulator. Cases 3 and 4 were administered glucocorticoids and immunosuppressors for their severe gastrointestinal symptoms. By the end of this study, all seven patients had residual disease but none developed lymphoma.

Histologic results

Biopsies of all cases presented similar morphological features (Fig. 2). The lamina propria was expanded by the infiltration of medium to large cells with irregular nuclei, abundant amounts of pale or eosinophilic cytoplasm, and fine chromatin. The glands were displaced and sometimes destroyed by the infiltration. No case displayed an angiocentric and angiodestructive growth pattern, which was an important feature of ENKL.Fig. 2 Histopathology of iNKLPD-GI.

INKLPD-GI involves stomach (a), small intestine (b), large intestine (c), gallbladder (d) and bladder (e), which shows expansion of the lamina propria by a relatively well circumscribed but confluent infiltrate of atypical cells. Glands are displaced or destroyed. The atypical cells show medium to large-sized with irregular nuclei and moderate amount of pale cytoplasm (f-g), often with paranuclear coarse eosinophilic cytoplasmic granules (h). Other inflammatory cells (plasma cells, neutrophils, eosinophils) can be seen (i). (a-e, low to medium magnification; f-i, high magnification, f-I inside pictures show cytomorphology better.)

Fig 2

Immunochemical and molecular findings

The results of immunohistochemistry and ISH are summarized in Table 2 and presented in Fig. 3. The abnormal lymphoid cells exhibited an NK-cell phenotype which expressed CD56 (100 %, seven of seven), granzyme B (83.3 %, five of six), and TIA (100 %, seven of seven). These cells were positive for CD2(83.3 %, five of six), cCD3(100 %, seven of seven), CD7(100 %, six of six), CD8(14.2 %, one of six), but negative for CD20/CD79αand CD4. The Ki-67 proliferation index ranged from 20 % to 75 %. EBER ISH was negative in all seven cases.Table 2 Immunophenotypical and TCR results.

Table 2Cases	Case 1	Case 2	Case 3	Case 4	Case 5	Case 6	Case 7	
CD20/CD79α	–	–	–	–	–	–	–	
CD4	–	–	–	–	–	–	–	
CD8	–	–	–	–	–	+	–	
CD2	NA	+	–	P+	P+	+	+	
cCD3	+	+	+	+	P+	+	+	
CD5	NA	–	–	–	–	–	–	
CD7	NA	+	+	+	P+	+	+	
CD56	+	+	+	+	+	+	+	
Granzyme B	P+	+	+	+	–	+	NA	
TIA-1	+	+	+	+	+	+	+	
Ki-67	75 %	stomach 60 %, gall bladder 70 %, colon 80 %	30 %	70 %	50 %	ileum 30 %, duodenum 50 %	gastric body 30 %, gastric antrum 50 %	
ISH-EBER	–	–	–	–	–	–	–	
TCR	–	–	–	–	–	–	–	
cCD3, CytoplasmicCD3; EBER, Epstein–Barr virus-encoded RNA; TCR, T cell receptorgene rearrangement; P, Partial; +, Positive; –, Negative; NA, Notavailable.

Fig. 3 Immunohistochemistry and in-situ hybridization of iNKLPD-GI.

Immunohistochemical stains show CD2+ (a) or CD2- (b), cytoplasmic CD3+ (c), CD5- (d), CD7+ (e), CD4- (f), mostly CD8- (g), rarely CD8+ (h), CD56 (i), CD20 (j), TIA-1 (k), and Granzyme B (i). CD4 stain shows positive of a few reactive histiocytes. Ki-67 proliferation index is from low to high (m-n). Epstein-Barr virus-encoded RNA in-situ hybridization (EBER ISH) is negative (o). (a–o, medium magnification)

Fig 3

PCR analysis for TCR was uniformly negative. To examine the genetic profile, FFPE tissues of these 7 patients were collected for next-generation sequencing using a panel targeting 275 genes. Sequencing results are shown in Table 3. Three types of JAK3 mutations were found. One patient harbored JAK3 K563_C565del while the other patient exhibited JAK3 M511I and V678L. Other mutations including BRAF, KRAS, and SH2B3 were also identified.Table 3 Genetic profiles of iNKLPD-GI.

Table 3Case	Somatic mutation	Protein change	VAF	
1	negative	–	–	
2	negative	–	–	
3	negative	–	–	
4	JAK3:NM_000215.4:exon11:c.G1533A	p.M511I	0.38	
JAK3:NM_000215.4:exon15:c.G2032T	p.V678L	0.37	
SH2B3:NM_005475.3:exon6:c.1033delG	p.L347Cfs*26	0.30	
5	BRAF:NM_004333.6:exon15:c.T1799A	p.V600E	0.1	
KRAS:NM_004985.5:exon3:c.C173T	p.T58I	0.1	
6	JAK3:NM_000215.4:exon12:c.1688_1696del	p.K563_C565del	0.26	
7	negative	–	–	

Discussion

In this study, we delineate an unusual series of seven patients presenting with diverse symptoms, encompassing reflux, abdominal pain, bloody stool, and lower extremity edema. Edema of extremities was seldom reported in previous literature, but three out of seven patients in our study suffered from severe edema of lower extremities which may be explained by hypoalbuminemia caused by gastrointestinal involvement. The median age at diagnosis is 56 years (range 40–65). Our series mirrors a nearly equal gender distribution, consistent with reports in the Japanese series [6,13]. Single as well as multiple involvements were observed in our series, affecting various sites of the gastrointestinal tract, including the stomach, small intestine, and colon. Notably, two patients exhibited gallbladder involvement, suggesting a potential predilection for the biliary region beyond the GI tract. A distinctive revelation in our investigation is the identification of iNKLPD-GI in the urinary bladder for the first time.

Biopsies of lesions in these four patients revealed uniform morphological and immunohistochemical features. Endoscopic examination unveiled erythematous lesions, erosions, and ulcers as the predominant manifestations. A notable endoscopic finding in Case 4 and Case 5 was lymphatic dilation, potentially explaining their hypoalbuminemia. Atypical cells exhibiting an NK-cell phenotype extensively infiltrated the lamina propria. Immunohistochemistry, performed across all seven patients, consistently revealed abnormal lymphocytes expressing CD2, CD3, CD7, CD56, TIA-1, and Granzyme B(+). These cells were negative for CD4, CD20/CD79α. CD8 was found positive in only one patient, which was seldom depicted in previous literature(4). In our study, the Ki-67 ranged from 30 % to 80 %. In situ EBER and PCR analysis for TCR were uniformly negative, excluding the diagnosis of ENKL and other enteropathy-associated T-cell lymphomas (EATL). Prior studies reported a Ki-67 proliferation index ranging from 10 to 90 % [6,7,19]. Notably, a high Ki-67 proliferation index was observed in five out of seven patients, challenging its utility as a malignancy indicator in this context. While Helicobacter pylori has been proposed as a potential causative factor in iNKLPD-GI, only one patient in our series tested positive for H. Polyri.

Concerning molecular genetics, the most significant discovery is the presence of recurrent JAK3 K563_C565del mutations occurring in 25–33 % of cases of iNKLPD-GI [4,17], suggesting the neoplastic nature of iNKLPD-GIs. Though JAK3 mutation was the most common genetic alteration in iNKLPD-GI, it was also frequently reported in other aggressive NK or T-cell lymphomas [[20], [21], [22], [23]]. These mutations lead to the activation of downstream targets such as STAT3 and STAT5. In addition, positive staining of phospho-STAT5 and STAT3 was observed in biopsy samples, underscoring the mechanism [4]. In our study, JAK3 K563_C565del was found in only one patient (14.3 %). Another two types of JAK3 mutations were first reported in iNKLPD-GI. Other mutations including BRAF V600E, and KRAS T58I were previously reported in other hematological malignancies such as myelodysplastic/myeloproliferative neoplasms, and B-cell lymphomas.

The clinical course of iNKLPD-GI is notably indolent, distinguishing it from the more aggressive ENKL. Consistent with prior iNKLPD-GI cases, spontaneous remission was observed with conservative management. Due to the rarity, there are no standardized therapeutic regimens. A "watch and wait" strategy is feasible, given the absence of documented progression to lymphoma. For symptomatic patients with residual disease, immunomodulatory agents such as glucocorticoids, thalidomide, and tacrolimus have proven effective in our study. For patients who are refractory to the aforementioned therapies, JAK3 inhibitors may be attempted, especially those who harbor this mutation.

In conclusion, we present seven new cases of indolent iNKLPD-GI with atypical features, warranting consideration in the differential diagnoses of diseases requiring aggressive management. Classic JAK3 mutation was observed in one patient in our study, suggesting the diagnosis of iNKLPD-GI still largely relies on clinical manifestations. Besides, for patients with severe symptoms, JAK3 inhibitors can be attempted.

Funding

This work was supported by National High Level Hospital Clinical Research Funding [2022-PUMCH-B-134 ], China and CAMS Innovation Fund for Medical Sciences (CIFMS) [2021-I2M-1-041 ].

CRediT authorship contribution statement

Hongyun Chen: Writing – original draft, Validation, Project administration, Methodology, Conceptualization. Congwei Jia: Writing – original draft, Methodology, Formal analysis. Daobin Zhou: Validation, Funding acquisition. Danqing Zhao: Validation, Formal analysis. Yan Zhang: Formal analysis. Hao Cai: Formal analysis. Qiang Wang: Formal analysis. Yueyi Zhang: Resources, Formal analysis. Wei Zhang: Validation, Supervision, Methodology, Funding acquisition, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix Supplementary materials

Image, application 1

Acknowledgments

The authors thank all patients for their understanding.

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.neo.2024.101048.
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