|Year : 2021 | Volume
| Issue : 6 | Page : 1307-1313
Primary gastrointestinal anaplastic large cell lymphoma: A critical reappraisal with a systematic review of the world literature
Pritinanda Mishra1, Susama Patra1, Anand Srinivasan2, Somanath Padhi1, Mukund Namdev Sable1, Subash Chandra Samal3, Sonali Mohapatra4
1 Deprtment of Pathology, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India
2 Deprtment of Pharmacology, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India
3 Deprtment of Gastroenterology, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India
4 Deprtment of Medical Oncology/Hematology, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India
|Date of Submission||16-Nov-2019|
|Date of Acceptance||14-Oct-2021|
|Date of Web Publication||14-Dec-2021|
Department of Medical Oncology, All India Institute of Medical Sciences, Bhubaneswar, Odisha
Source of Support: None, Conflict of Interest: None
Anaplastic large cell lymphoma (ALCL) is a distinct T-cell non-Hodgkin lymphoma involving both nodal and extra-nodal sites with a specific anaplastic lymphoma kinase 1 (ALK-1) gene rearrangement. The commonly involved extranodal sites include skin, bone, soft tissue, lungs, and liver. ALCL primarily involving gastrointestinal (GI) tract is rare. In this manuscript, we describe a case of primary esophageal ALK1 positive-ALCL (null phenotype) in a young female, who presented with fleshy mucosal lesion in the lower third of the esophagus and present a systematic review of 35 cases of GI-ALCL reported in the English literature over the past 28 years (1990–2018) with regard to the clinicopathological characteristics, therapy, and outcome.
Keywords: Anaplastic large cell lymphoma, anaplastic lymphoma kinase 1, CD30, gastrointestinal tract
|How to cite this article:|
Mishra P, Patra S, Srinivasan A, Padhi S, Sable MN, Samal SC, Mohapatra S. Primary gastrointestinal anaplastic large cell lymphoma: A critical reappraisal with a systematic review of the world literature. J Can Res Ther 2021;17:1307-13
|How to cite this URL:|
Mishra P, Patra S, Srinivasan A, Padhi S, Sable MN, Samal SC, Mohapatra S. Primary gastrointestinal anaplastic large cell lymphoma: A critical reappraisal with a systematic review of the world literature. J Can Res Ther [serial online] 2021 [cited 2022 Jan 20];17:1307-13. Available from: https://www.cancerjournal.net/text.asp?2021/17/6/1307/332381
| > Introduction|| |
Anaplastic large cell lymphoma (ALCL) is a distinct category of T/null cell lymphoma described in the recent World Health Organization classification for hematolymphoid tissue, 2008. This entity is characterized by the cohesive group of large pleomorphic cells, with an embryoid looking irregular nuclei, known as hallmark cells which creates diagnostic dilemma with other nonlymphoid malignancies. Although the gastrointestinal (GI) tract is the most common site of extranodal non-Hodgkin lymphoma, primary GI lymphoma is uncommon accounting for 1%–4% of the malignancies of the GI tract. In GI lymphomas, B-cell lymphomas dominate over the T-cell phenotypes, as diffuse large B-cell lymphoma (DLBCL) is the most common histological subtype, followed by MALT lymphoma (mucosa-associated lymphoid tissue, MALT). Esophageal involvement is very rare and constitutes 1% of all GI lymphoma and mostly is an extension of pathology from gastric or mediastinal lymph nodes. According to the criteria by Dawson et al., our case is a primary esophageal ALCL because the absence of involvement in distal lymph node, liver, spleen, and other GI sites. Only 36 cases (including our case) of primary ALCL of GI tract have been described till date. In this manuscript, we describe a case of primary esophageal ALCL in a young girl and present a detail review summarizing the clinicopathological features, treatment, and clinical outcome of patients in the previously published series.
| > Presentation of the Case|| |
A 20-year-old female presented with progressive dysphagia and vomiting for 3 months with intermittent high grade fever and weight loss for the same duration. There was no prior history of instrumentation of the esophagus. There was no significant history for medical illness in the past with negative family history. Serological markers for viruses were negative. Both hematological and biochemical investigations were within the normal limit. Computed tomography (CT) at the presentation showed a gross diffuse mass with circumferential wall thickening of thoracic esophagus extending into gastroesophageal junction and luminal narrowing. The mass was compressing the left atrium with right hilar, pretracheal, and paratracheal lymph nodes. A whole-body positron emission tomography (PET)-CT scan showed increased fluorodeoxyglucose (FDG) uptake in the circumferential thickening involving the mid and lower third esophagus (length: 10 cm, max thickness: 2.7 cm, suv max: 28.07) extending inferiorly up to but not involving the gastro oesophageal junction. The fat plane with the left atrium, bilateral main stem bronchi and descending thoracic aorta appeared effaced. In addition, a discrete FDG avid deposit measuring 3.5 cm × 2.7 cm was noted abutting the lateral aspect of the left kidney and adjacent 11th rib with diffuse increased FDG uptake was noted in the marrow of the visualised bones (max SUV: 4.68 in sacrum). Endoscopic examination revealed a fleshy necrotic mucosal lesion in the distal third of the esophageal lumen, measuring approximately 10 cm in length with maximum thickness 2.7 cm and endoscopic biopsies were obtained. Histopathological examination showed large areas of mucosal ulceration and underlying granulation tissue-containing dense mixed inflammatory infiltrates. Several proliferated vascular channels with endothelial swelling, transmigration of polymorphs, and fibrinoid necrosis of vessel wall were seen. Adjoining epithelium showed intraepithelial neutrophilic and eosinophilic infiltration. However, no malignant cells were seen. A repeat biopsy was undertaken from the viable areas. It showed sheets of medium-to-large sized atypical lymphoid cells with round to oval nuclei, irregular nuclear membrane, conspicuous nucleoli with moderate amount of pale eosinophilic to vacuolated cytoplasm [Figure 1]a. Occasional giant cells with peripheral arrangement of nuclei are seen. Extensive areas of karyorrhectic debris were seen. The neoplastic cells were immunopositive for CD45-RO, CD30, epithelial membrane antigen (EMA) and anaplastic lymphoma kinase (ALK), which showed both nuclear and cytoplasmic positivity [Figure 1]a, [Figure 1]b, [Figure 1]c, [Figure 1]d. Nuclear expression of MUM1 and BCL6 was also noted. Cells were negative for CD3, CD2, CD20, CD79a, CD43, PAX5, Tdt, CD56, CD138, CD10, BCL2, and MPO. The final diagnosis rendered was ALK positive ALCL, null cell phenotype. The patient initially received prephase COP (cyclophosphamide, vincristine, and dexamethasone) and triple intrathecal therapy. Cerebrospinal fluid analysis did not reveal any malignant cells. Then, she received six cycles of chemotherapy consisting of (high dose methotrexate, dexamethasone, ifosfamide, cytarabine, and etoposide) and (high dose methotrexate, dexamethasone, cyclophosphamide, and doxorubicin) alternately, according to ALCL 99 protocol. She was kept on Ryle's tube feeding for the initial 2 months for dysphagia. Following therapy, she was able to swallow but required five times controlled radial expansion of the esophageal stricture in regular intervals during the treatment. Magnetic resonance imaging after the completion of chemo revealed circumferential wall thickening (5.9 mm) involving lower esophagus, which was confirmed on PET-CT as residual disease. Bone marrow aspirate and biopsy did not reveal lymphoma infiltration. She was put on vinblastine maintenance therapy on the weekly basis for 15 months. Her latest PET-CT did not show any active disease. At 30 months from the diagnosis, she is well under regular follow-up and is free of disease.
|Figure 1: (a) Pleomorphic lymphoid cells arranged in sheets (H and E, ×400). (b) Neoplastic cells are immunopositive for LCA (IHC ×400). (c and d) The atypical lymphoid cells are diffusely immunopositive for CD30 (IHC 400X) and anaplastic lymphoma kinase 1 (IHC ×400)|
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Collection of data of gastrointestinal-anaplastic large cell lymphoma
A systematic search of GI-ALCL, over the last 28 years (January 1990–September 2018) was done.
PubMed, PubMed Central, Medline, and Directory of Open Access Journal databases. The following keywords were used for the literature search: ALCL GI tract, ALCL esophagus, ALCL pancreas, ALCL small intestine, and ALCL colon.
Inclusion and exclusion criteria
All cases where the primary involved site was GI tract without involvement of distal lymph node, liver, and spleen were included in the study. We followed the guidelines proposed by Dawson et al. to define a primary extranodal lymphoma of GI tract. Although Ten Berge et al. reported 14 patients of primary GI-ALCL and Mneimneh et al. reported two cases, the data available were incomplete, and hence, both the studies were excluded for our data analysis.
Collection of data
A systematic search found a total of 21 articles describing nearly 49 cases of GI-ALCL (excluding our case) were found in the world literature from 1990 till date. The references of all articles were cross-checked for relevant articles. The following data were collected for only in 36 cases (including our case) and placed in Microsoft Office Excel 2016 for statistical analysis: Age, gender, site, symptoms, endoscopic findings, histopathology and immunohistochemistry, complete blood count including bone marrow evaluation, stage, and final outcome (alive or dead).
The Kaplan − Meier method was used to determine the survival patterns for the variables identified as having a significant effect on survival. Differences between survival curves were evaluated using log rank tests. P <0.05 was considered to be statistically significant.
| > Results and Discussion|| |
The clinicopathological characteristics of all the 36 cases are summarized in [Table 1].,,,,,,,,,,,,,,,,,,, There were 25 males (69.4%) and 11 females (30.5%) with a male-to-female ratio of 2:1. The median age at the presentation was 48 years (range: 10–89 years); and 4 cases (11.1%) were under the age of 25 years. The symptoms ranged from days to months before diagnosis. Epigastric pain, dysphagia, and intestinal obstruction were the common symptoms. Endoscopic findings were obtained from 22 cases and showed variable findings such as ulcerative lesions (n = 9) followed by polypoidal, fungating, and infiltrating lesions. Most of the cases (44.4%) clinically were diagnosed with carcinomas. Bone marrow involvement was not seen in 90% cases (19/21).
|Table 1: Clinicopathological characteristics of all the 36 cases of primary gastrointestinal-anaplastic large cell lymphoma published in the world literature|
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Sites of involvement
The most common site of GI ALCL in our review was small intestine (37%) followed by esophagus (22.8%), stomach (20%), pancreas (14.2%), and large intestine (5.7%). Because epithelial malignancies are rare in the small intestine, lymphomas constitute a high proportion of all malignancies at this GIT site. Cooperberg and Fiedler reported CD30 positive ALCL, occurring at a very unusual site the ileocolonic anastomotic site in a patient treated surgically for colonic adenocarcinoma. Ileocecal junction is commonly involved by intestinal lymphomas and involvement of the appendix and anorectum is not uncommon, but the esophagus is rarely involved. Most esophageal lymphomas are due to secondary involvement from other sites and <50 cases of primary esophageal lymphomas have been reported in the literature. Primary esophageal lymphomas are overwhelmingly B-cell neoplasms, with mucosa-associated lymphoid tissue lymphomas and DLBCL being most common, but T-cell lymphomas and primary esophageal Hodgkin lymphomas have also been reported., Till date, only eight cases (including the present case) of primary esophageal ALCLs have been described in the English literature.,,,,,,
ALCL is a great mimicker and can mimic a carcinoma, melanoma, or a round cell tumor. It is characterized by the groups of cohesive cells with abundant cytoplasm, with a lobated nuclei and a prominent nucleoli. Nuclei resembling embryoid forms are also noted. The large cells can have multinucleation, with wreath like nuclei known as hallmark cells and Reed Sternberg giant-like cells can also be found, the so called classical/common pattern, Type I. The Type II, lymphohistiocytic pattern is a variant where the tumor cells are obscured by large number of histiocytes and lymphoid cells. This variant is difficult to diagnose at times, as it is misdiagnosed as a reactive lesion. The Type III, small cell pattern where the neoplastic cells are small to medium sized, with irregular centrally placed nuclei with pale cytoplasm, referred to as fried egg cells. The cells sometimes may be spindloid, simulating a sarcoma, is the sarcomatoid pattern Type IV. Sometimes, the histomorphological features fail to resemble the above-mentioned categories and are segregated into ALCL-not otherwise specified, ALCL-NOS, Type V. Keeping this in mind, our review showed Type I as the most common type (33/36, 91.6%) followed by Type II (3/36, 8.3%). No cases of Type III, IV, and V were noted.
ALCL is a T-cell lymphoma. The large cells can be negative for LCA and T-cell markers indicating a null phenotype. In our study, the T-cell phenotype constituted 28 cases (77.7%), whereas the null phenotype was seen in eight cases (22.2%). In the index case, the neoplastic lymphoid cells were negative for B-cell markers CD20, CD79a as well as T-cell markers such as CD3, CD2, CD5, CD4, CD7 and showed positivity for CD30, ALK, and EMA, indicating a null phenotype.
Anaplastic lymphoma kinase
It is interesting to note that the ALK protein expression varies according to the site of involvement. In a study by Ten Berge et al., nodal ALCL showed ALK expression and none of the extranodal ALCLs in the GI, nasal or cutaneous showed ALK expression. He also observed that cases which showed ALK expression, retained the same in recurrent disease. However, other studies have shown that ALCL occurring in the bone and soft tissue, had the higher rates of ALK expression (>85%) while there is an equal proportion of ALK positivity and ALK negativity in central nervous system lymphomas. In an extensive review of world literature on primary bronchopulmonary ALCL (data unpublished) 1990–2018, (n = 39) the ALK positivity and negativity cases were noted in nearly equal proportion of cases. In a recent study by Lee et al. showed the rate of ALK expression among GI-ALCL was low constituting 24%. In this current review, the rate of ALK expression was found to be 39.2% (11/28).
There is a uniform expression of ALK by these large cells. Of the 36 cases reviewed, only 11 cases (n = 11/28; 39.2%) expressed ALK, 17 cases (n = 17/28: 60.7%) were negative, and in eight cases, ALK staining was not done. 72.7% of ALK-positive cases showed a nuclear, nucleolar, and cytoplasmic staining indicating t (2;5) translocation, as seen in our case too, whereas membrane and cytoplasmic staining was seen in 27.2% of cases which is usually associated with a t (1;2). The younger patients (n = 4. <25 years) showed ALK expression in the current study.
CD30, a transmembrane cytokine receptor which is expressed in ALCL, can also be expressed in the Reed–Sternberg giant cells of Hodgkin lymphoma, embyonal carcinoma, PTCL, and hence, a panel of markers are used for rendering a correct diagnosis. Strong, diffuse, membranous, and Golgi-associated staining pattern of CD30 is seen in ALCL which is a clue for differentiating other lymphomas which also expresses CD30. CD30 was expressed in all the 36 cases (n = 36/36, 100%) of GI-ALCL.
A study by Suzuki et al. showed that CD56 positivity in ALCL heralds a poor prognosis irrespective of ALK status; however, in our review, none of the cases were CD56 positive. Detailed IHC of all the cases is summarized in [Table 2].
Treatment and survival outcome
In 30 cases, therapeutic data were available and in 29 cases follow up data were available. 15 patients received combination of surgery and chemotherapy; one patient received combination of chemotherapy and radiotherapy; six patients received chemotherapy only; five patients underwent surgery; three patients received combination of chemotherapy and bone marrow transplant. Sixteen cases were alive with complete response and thirteen died. The median duration of the survival was 36 months [Figure 2]. There was no statistically significance survival difference between the comparison of upper and lower GI tract [log rank P = 0.08, [Figure 3]a]; male or female [log rank P = 0.7, [Figure 3]b]; T or null phenotype [log rank P = 0.4, [Figure 3]c]; bone marrow involvement [log rank P = 0.5, [Figure 3]d]; however, the ALK-positive patients had a significantly better survival compared to the ALK-negative patients [log rank P = 0.002, [Figure 3]e]. This could be attributed to the fact that all the patients were young patients (<40 years) as compared to the ALK-negative group. [Table 3] highlights the survival analysis by taking the various parameters.
|Figure 2: Kaplan − Meier survival analysis using log-rank test showing median survival of 36 months in primary gastrointestinal anaplastic large cell lymphoma|
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|Figure 3: (a) Kaplan − Meier survival analysis using log rank test in gastrointestinal-Anaplastic large cell lymphoma highlighting the impact of site, upper gastrointestinal tract versus lower gastrointestinal tract. (b) Kaplan − Meier survival analysis in primary gastrointestinal-Anaplastic large cell lymphoma using log rank test highlighting the gender. (c) Kaplan − Meier survival analysis using log rank test in gastrointestinal-Anaplastic large cell lymphoma highlighting the impact of bone marrow involvement (d) Kaplan − Meier survival analysis using log rank test in gastrointestinal-Anaplastic large cell lymphoma highlighting the impact of T versus null phenotype (e) Kaplan − Meier survival analysis using log rank test in gastrointestinal-Anaplastic large cell lymphoma highlighting the impact of anaplastic lymphoma kinase 1 status|
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| > Conclusion|| |
Our literature review indicates that GI-ALCL occurs commonly in the small intestine, with a low rate of ALK expression in older population and a dominance of T-cell phenotype. The prognosis of GI-ALCL is dichotomous, with an excellent outcome in ALK-positive cases and poor in ALK-negative cases.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initial s will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]