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Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 4  |  Issue : 4  |  Page : 324-327

Age-adjusted survival analysis of lymphoma patients diagnosed from extranodal sites


Department of Medicine, King Saud University, Riyadh, Saudi Arabia

Date of Submission07-Mar-2021
Date of Decision13-Jul-2021
Date of Acceptance01-Aug-2021
Date of Web Publication06-Oct-2021

Correspondence Address:
Musa Alzahrani
Department of Medicine, King Saud University, PO Bo × 55068 (37), Riyadh 12372
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jnsm.jnsm_29_21

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  Abstract 


Background: Lymphoma is a cancer of the lymphoid system that typically presents in nodal tissues. Involvement of extranodal sites is less common and has been shown to be associated with worst outcomes. The site of the initial diagnosis could give an idea about the accessibility of diagnostic tissue, disease presentation, behavior, and maybe associated with prognostic significance. Methodology: We retrospectively reviewed all adult lymphoma cases diagnosed with lymphoma in our center from 2008 to 2018 and studied the association between extranodal site of biopsy and overall survival (OS). Logrank method was used to calculate P value, and cox proportional hazard was used for age-adjusted survival analysis. Results: A total of 433 patients were included. Median age was 48 years, 183 (42%) were female, and 143 patients (33%) were diagnosed from extranodal sites. The most common site of extranodal involvement was gastrointestinal tract with 69 cases (16%), followed by lung 16 (4%) then central nervous system 11 (2.5%). The most common pathologic diagnosis was diffuse large B-cell lymphoma 182 (42%), followed by classical Hodgkin lymphoma 139 (32%) and then follicular lymphoma 31 (7%). Patients who were diagnosed from a biopsy obtained from extranodal site had a worst OS as compared to patients diagnosed from nodal sites with a significant P value in univariate analysis 0.049 and P = 0.05 after adjusting for age. Conclusion: Patients diagnosed with lymphoma from an extranodal site have a worst OS even after adjusting for age as compared to those diagnosed from nodal sites.

Keywords: Extranodal, Hodgkin, lymphoma, non-Hodgkin


How to cite this article:
Alzahrani M. Age-adjusted survival analysis of lymphoma patients diagnosed from extranodal sites. J Nat Sci Med 2021;4:324-7

How to cite this URL:
Alzahrani M. Age-adjusted survival analysis of lymphoma patients diagnosed from extranodal sites. J Nat Sci Med [serial online] 2021 [cited 2021 Nov 29];4:324-7. Available from: https://www.jnsmonline.org/text.asp?2021/4/4/324/327598




  Introduction Top


Lymphoma is a cancer of the lymphoid cells that are divided into Hodgkin and non-Hodgkin lymphoma (NHL) and classified according to the World Health Organization.[1] Lymphoma typically arises from lymph node tissues, so called nodal disease. However, extranodal involvement can also occur. Extranodal lymphoma is usually defined as the involvement of sites other than lymph nodes, spleen, thymus, and the Waldeyer's pharyngeal lymphatic ring.[2] Staging in lymphoma usually involves radiologic assessment by computed tomography scans for neck, chest, abdomen, and pelvis with or without fluorodeoxyglucose (FDG) positron emission tomography (PET) scans.[3] In addition, bone marrow biopsy is needed in the staging evaluation of Hodgkin lymphoma (HL) patients if 18F FDG-PET scan is not available and in NHL cases as well.[4] With the comprehensive radiologic assessment, especially with increased sensitivity of PET scans, extranodal involvement can be seen in more cases that expected.[5],[6] The finding of extranodal disease may have prognostic and management implications. Several prognostic scores have shown that extranodal involvement can be associated with worst overall survival (OS) and higher risk for relapse and central nervous system (CNS) involvement.[7],[8],[9],[10] However, finding of extranodal involvement usually is detected during staging investigations after having had a diagnosis that is already made from a nodal site. Cases in which the original diagnostic biopsy was obtained from extranodal sites deserve special attention. These cases can present in many atypical ways mimicking other diseases and usually do not have accessible nodal sites for biopsy. Previous studies have focused on the prognostic value of extanodal sites detected during staging but not on the significance of the site of the original diagnostic sample.

Herein, we aim to study the association between the age-adjusted OS and diagnosis made from extranodal site as compared to nodal site.


  Methodology Top


Study participants

The Saudi Cancer Registry database at King Saud University Medical City was searched to identify all adult lymphoma cases (18 years or older) diagnosed consecutively from 2008 to 2018. Data were collected included patients' age, gender, site of the diagnostic biopsy, date of diagnosis, date of last follow-up, Ann Arbor stage,[11] pathologic diagnosis, and survival at last follow-up. Lymphoma subtypes were classified according to the 2008 WHO classification of tumors of hematopoietic and lymphoid tissue.[12]

The study protocol was approved by the Institutional Review Board Committee in King Saud University College of Medicine Board Research on research project No. E21-5743 on March 25, 2021. Titled: “King Khalid University Hospital Lymphoma Cohort Study” and the patient confidentiality was ensured.

Statistical analysis

The survival outcomes for the univariate analysis were estimated using the Kaplan–Meier method, and P values were determined using the logrank test. Adjusted multivariate analysis of OS was conducted using multivariable Cox proportional hazard regression model. All analyses were performed using two-tailed tests, with the Type 1 error rate fixed at 0.05. Simple frequency statistics were used to summarize the rest of the variables. Data were analyzed using R studio statistical program.[13] OS was defined as the time from the date of the original diagnosis till death from any cause.


  Results Top


A total of 433 patients were included in the current study, the median age of patients was 48 years (range: 18–87), out of them, 183 (42%) were female, and 143 patients (33%) were diagnosed from extranodal sites. The most common site of extranodal involvement was gastrointestinal (GI) tract with 69 cases (16%), followed by lung 16 (4%) and then CNS 11 (2.5%). The most common pathologic diagnosis was diffuse large B-cell lymphoma in 182 (42%), followed by classical HL in 139 (32%) and then follicular lymphoma in 31 (7%).

Of the evaluable patients, 201/270 (74%) had advanced stage, while limited stage was seen in 69/270 (26%) patients (163 cases were not evaluable for stage). With a median follow-up of 15 months (range: 0–141), 351 patients (81%) were alive at the time of last follow-up. [Table 1] summarizes the baseline patients' characteristics.

With regard to survival analysis, patients who were diagnosed from a biopsy obtained from extranodal site had a worst OS as compared to patients diagnosed from nodal sites in univariate analysis done using logrank test with a P = 0.049. Kaplan–Meier curve for OS for the whole group and for patients with extranodal versus nodal sites, in [Figure 1] and [Figure 2], respectively.
Figure 1: Kaplan–Meier survival curve showing overall survival for the whole cohort

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Figure 2: Kaplan–Meier survival curve showing overall survival difference between patients diagnosed from extranodal site (lower line) and nodal site (upper line)

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Table 1: Baseline patients' characteristics

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After adjusting for age more than 60 years, extranodal site of diagnosis was still associated with worse OS but with a borderline statistical significance, P = 0.05 as compared to nodal site.


  Discussion Top


In this large single-institution retrospective study of lymphoma patients, we compared the adjusted survival analysis for patients diagnosed from extranodal sites to those diagnosed from nodal site. As far as, we know this is the largest study addressing this particular question. Furthermore, there is no data published regarding this question from the Gulf countries.

Obtaining a biopsy from a lymph node is usually the preferred diagnostic site for lymphoma. However, in many cases of lymphoma, patients do not present with the classical overt lymphadenopathy, they may have inaccessible lymph nodes, or they may present directly with symptoms or signs related to the involvement of other extranodal organs. Previous studies have focused on whether extranodal sites were discovered during the routine staging investigations after obtaining an initial diagnostic sample, however, studies are limited on those who present and diagnosed from the offset with extranodal disease. Lymphoma is known to be a great mimicker of many different diseases and an initial pathologic specimen from extranodal sites need to always consider lymphoma as part of the differential diagnosis in any tissue specimen. Patients could present in many unusual or bizarre ways and manifest with symptoms or signs related to the affected system. For example, patients with GI involvement could present with symptoms that can range from as mild as nausea or vomiting to as severe as bowel obstruction or perforation. It is plausible to think that patients presenting with extranodal site may have worst outcomes as compared to those present with nodal sites even after adjusting for age.

The prognostic importance of extranodal sites when found by staging investigations has been shown by many investigators to be associated with worst outcomes and has been incorporated in many lymphoma prognostic scores.[14],[15],[16] In the famous international prognostic index (IPI) for NHL, number of extranodal sites >1 was found to be associated with worst OS and complete remission rate in multivariate analysis.[7]

The IPI remained prognostically important even in the current rituximab era and after age adjustment.[9],[17],[18] Similarly, the National Comprehensive Cancer Network-IPI which incorporated more detailed clinical than that used in the original IPI also assigned one prognostic point in its score for extranodal disease involving the bone marrow, CNS, liver, GI tract, or lung.[10],[19] The CNS-IPI which was derived from a large population of patients enrolled in the German clinical trials and then subsequently validated in another large cohort of patients treated in British Columbia, Canada, also found extranodal involvement to be an important prognostic factor that increases the risk of CNS progression and relapse.[8],[20] In HL, involvement of extranodal sites is very uncommon and usually happens in the setting of direct contiguous extension of the nodal disease.[21] The extranodal presentation of HL is more likely to happen in HIV or immunosuppressed patients.[1],[22] Moreover, further studies are needed to identify the prognostic importance of such finding in HL.

Our study has also shown that the most common extranodal involvement is GI system.[23],[24] This is in concordance with previously published data internationally.[25],[26],[27] The reason for the peculiar common involvement of GI tract by lymphoma requires further studies but may have to do with enrichment of lymphoid cells in these sites and their involvement as a critical protective barrier against stimulant antigens or pathogens. Lymphoid cells of different types are found along the whole GI tract and could be found in mucosa, loose connective tissues, lamina propria, Peyer's patches, and appendix. Lymphoma arising from mucosal-associated lymphoid tissue is frequently diagnosed in the GI tract particularly in the gastric mucosa and in association with Helicobacter pylori infection.[28],[29],[30],[31]

Our study showed that when a lymphoma is diagnosed from an extranodal site, the OS is worse as compared to cases diagnosed from nodal tissues even after adjusting for age.

Our study has several strengths. First, the sample size is a relatively large one considering that this is a single-center experience. Second, here, we also report the baseline epidemiologic data for the different types of lymphoma and their proportions. These are valuable information valuable for national and local scientific committees. Third, we have revealed a clear prognostic value of extranodal biopsy site for lymphoma patients.

Despite these strengths, the study also has several limitations. First, one important limitation is inherent to the retrospective study design. Second, the study did not adjust for other potentially important prognostic markers such as lactate dehydrogenase, number of extranodal sites, stage, or performance status. However, these variables were not available in the Saudi Cancer registry. Third, most cases were diagnosed before PET era, and thus, some cases with extranodal involvement are likely missed. Finally, the diagnosis of lymphoma cases in the current study was not based on the most recent WHO that was published in 2017. This is because the cases included were from 2008 to 2018. The pathologists in our hospital only later adopted the new WHO classification. We do believe, however, that the changes made in the new WHO classification are unlikely to change the results of this current study.


  Conclusion Top


Making a diagnosis of lymphoma through biopsies obtained from extranodal sites is associated with worst OS even after adjusting for age.

Further studies need to examine the reason for this association and explore other prognostic covariants.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016;127:2375-90.  Back to cited text no. 1
    
2.
Kashyap R, Mittal B, Manohar K, Balasubramanian Harisankar CN, Bhattacharya A, Singh B, et al. Extranodal manifestations of lymphoma on [¹◻F] FDG-PET/CT: A pictorial essay. Cancer Imaging 2011;11:166-74.  Back to cited text no. 2
    
3.
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: The Lugano classification. J Clin Oncol 2014;32:3059-68.  Back to cited text no. 3
    
4.
El-Galaly TC, d'Amore F, Mylam KJ, de Nully Brown P, Bøgsted M, Bukh A, et al. Routine bone marrow biopsy has little or no therapeutic consequence for positron emission tomography/computed tomography-staged treatment-naive patients with Hodgkin lymphoma. J Clin Oncol 2012;30:4508-14.  Back to cited text no. 4
    
5.
Bangerter M, Moog F, Buchmann I, Kotzerke J, Griesshammer M, Hafner M, et al. Whole-body 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) for accurate staging of Hodgkin's disease. Ann Oncol 1998;9:1117-22.  Back to cited text no. 5
    
6.
Talbot JN, Haioun C, Rain JD, Meignan M, Wioland M, Misset JL, et al. [18F]-FDG positron imaging in clinical management of lymphoma patients. Crit Rev Oncol Hematol 2001;38:193-221.  Back to cited text no. 6
    
7.
Shipp MA, Harrington DP, Anderson JR, Armitage JO, Bonadonna G, Brittinger G, et al. A predictive model for aggressive non-Hodgkin's lymphoma. The international Non-Hodgkin's lymphoma prognostic factors project. N Engl J Med 1993;329:987-94.  Back to cited text no. 7
    
8.
Savage KJ, Zeynalova S, Kansara RR, Nickelsen M, Villa D, Sehn LH, et al. Validation of a prognostic model to assess the risk of CNS disease in patients with aggressive B-cell lymphoma. Blood 2014;124:394.  Back to cited text no. 8
    
9.
Ziepert M, Hasenclever D, Kuhnt E, Glass B, Schmitz N, Pfreundschuh M, et al. Standard International prognostic index remains a valid predictor of outcome for patients with aggressive CD20+B-cell lymphoma in the rituximab era. J Clin Oncol 2010;28:2373-80.  Back to cited text no. 9
    
10.
Schmitz N, Zeynalova S, Nickelsen M, Ziepert M, Pfreundschuh M, Glass B, et al. A New prognostic model to assess the risk of CNS disease in patients with aggressive B-cell lymphoma. Hematol Oncol 2013;31 Suppl 1:96-150.  Back to cited text no. 10
    
11.
Rosenberg SA. Validity of the Ann Arbor staging classification for the non-Hodgkin's lymphomas. Cancer Treat Rep 1977;61:1023-7.  Back to cited text no. 11
    
12.
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Stein H, Thiele J, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue. 4th ed. Lyon: IARC; 2008.  Back to cited text no. 12
    
13.
Available from: https://www.rstudio.com/products/rstudio/download/. [Last accessed on 2021 Aug 24].  Back to cited text no. 13
    
14.
Shipp M, Harrington D, Anderson J, Armitage J, Bonadonna G, Brittinger G, et al. A predictive model for aggressive non-Hodgkin's lymphoma: The International NHL Prognostic Factors Project. N Engl J Med 1993;329:987-94.  Back to cited text no. 14
    
15.
Conconi A, Zucca E, Roggero E, Bertoni F, Bernasconi A, Mingrone W, et al. Prognostic models for diffuse large B-cell lymphoma. Hematol Oncol 2000;18:61-73.  Back to cited text no. 15
    
16.
Giné E, Montoto S, Bosch F, Arenillas L, Mercadal S, Villamor N, et al. The follicular lymphoma international prognostic index (FLIPI) and the histological subtype are the most important factors to predict histological transformation in follicular lymphoma. Ann Oncol 2006;17:1539-45.  Back to cited text no. 16
    
17.
Shipp MA. Prognostic factors in aggressive non-Hodgkin's lymphoma: Who has “high-risk” disease? Blood 1994;83:1165-73.  Back to cited text no. 17
    
18.
Scott DW, Mottok A, Ennishi D, Wright GW, Farinha P, Ben-Neriah S, et al. Prognostic significance of diffuse large B-cell lymphoma cell of origin determined by digital gene expression in formalin-fixed paraffin-embedded tissue biopsies. J Clin Oncol 2015;33:2848-56.  Back to cited text no. 18
    
19.
Schmitz N, Zeynalova S, Glass B, Kaiser U, Cavallin-Stahl E, Wolf M, et al. CNS disease in younger patients with aggressive B-cell lymphoma: An analysis of patients treated on the mabthera international trial and trials of the German high-grade non-Hodgkin lymphoma study group. Ann Oncol 2012;23:1267-73.  Back to cited text no. 19
    
20.
Kansara R, Villa D, Gerrie AS, Klasa R, Shenkier T, Scott DW, et al. Site of central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) by the CNS-IPI risk model. Br J Haematol 2017;179:508-10.  Back to cited text no. 20
    
21.
Hoh CK, Glaspy J, Rosen P, Dahlbom M, Lee SJ, Kunkel L, et al. Whole-body FDG-PET imaging for staging of Hodgkin's disease and lymphoma. J Nucl Med 1997;38:343-8.  Back to cited text no. 21
    
22.
Guermazi A, Brice P, de Kerviler EE, Fermé C, Hennequin C, Meignin V, et al. Extranodal Hodgkin disease: Spectrum of disease. Radiographics 2001;21:161-79.  Back to cited text no. 22
    
23.
Crump M, Gospodarowicz M, Shepherd FA. Lymphoma of the gastrointestinal tract. Semin Oncol 1999;26:324-37.  Back to cited text no. 23
    
24.
Perry AM, Diebold J, Nathwani BN, MacLennan KA, Müller-Hermelink HK, Bast M, et al. Non-Hodgkin lymphoma in the developing world: Review of 4539 cases from the international non-Hodgkin lymphoma classification Project. Haematologica 2016;101:1244-50.  Back to cited text no. 24
    
25.
Sutcliffe S, Gospodarowicz M. Primary extranodal lymphomas. In: The Lymphomas. Lyon:W.B. Saunders Company 1999. 1998.  Back to cited text no. 25
    
26.
Zucca E, Roggero E, Bertoni F, Cavalli F. Primary extranodal non-Hodgkin's lymphomas. Part 1: Gastrointestinal, cutaneous and genitourinary lymphomas. Ann Oncol 1997;8:727-37.  Back to cited text no. 26
    
27.
Das J, Ray S, Sen S, Chandy M. Extranodal involvement in lymphoma-A pictorial essay and retrospective analysis of 281 PET/CT studies. Asia Ocean J Nucl Med Biol 2014;2:42-56.  Back to cited text no. 27
    
28.
Isaacson PG. Extranodal lymphomas: The MALT concept. Verh Dtsch Ges Pathol 1992;76:14-23.  Back to cited text no. 28
    
29.
Isaacson PG, Spencer J. Gastric lymphoma and Helicobacter pylori. Important Adv Oncol 1996;1996:111-21. PMID: 8791131.  Back to cited text no. 29
    
30.
Thieblemont C, Berger F, Coiffier B. Mucosa-associated lymphoid tissue lymphomas. Curr Opin Oncol 1995;7:415-20.  Back to cited text no. 30
    
31.
Thieblemont C, Bastion Y, Berger F, Rieux C, Salles G, Dumontet C, et al. Mucosa-associated lymphoid tissue gastrointestinal and nongastrointestinal lymphoma behavior: Analysis of 108 patients. J Clin Oncol 1997;15:1624-30.  Back to cited text no. 31
    


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