Lymphoma Clinical Presentation and Diagnosis in

Lymphoma Presentation

Patients with Hodgkin lymphoma typically present with nontender, palpable lymphadenopathy of the cervical, anterior mediastinal, supraclavicular, or axillary lymph nodes. Less commonly, there may be lymphadenopathy of the inguinal area.^8,9 Patients may be asymptomatic with lymphadenopathy detected incidentally on physical examination or radiograph for a different reason.⁴

Other symptoms at the time of lymphoma clinical presentation can include fatigue, generalized pruritus, night sweats, fever >38℃, weight loss >10% of body weight over six months, cough, dyspnea, or chest pain. Symptoms at presentation may sometimes be related to paraneoplastic syndromes and extranodal involvement. Night sweats, weight loss, and fever are collectively referred to as B symptoms.^4,8,9

Non-Hodgkin’s lymphoma (NHL) can similarly present with lymphadenopathy, B symptoms, cough, or dyspnea. However, in NHL, B symptoms are more common in patients with aggressive or highly aggressive disease. Also similar to Hodgkin lymphoma, indolent NHLs may present with asymptomatic lymphadenopathy, which can develop over an extended period of time along with cytopenias. By contrast, aggressive tumors may present acutely or subacutely due to rapidly increasing size.⁵

Because about one-third of NHL cases involve extranodal sites, unusual presentations can occur based on the specific disease site. Thus, a thorough history of all organ systems should be obtained from patients to evaluate for localizing symptoms.^5,7

Physical Examination

Lymphadenopathy, hepatomegaly, and splenomegaly may be identified on physical examination in patients with any type of lymphoma. Identification of epitrochlear nodes; a testicular, breast, or abdominal mass; involvement of the Waldeyer tonsillar ring; abdominal ascites: pleural or pericardial effusions; or cutaneous involvement are important findings on physical examination in patients with suspected lymphoma.^4,5,7

Diagnosis

Biopsy

Excisional lymph node biopsy is necessary for diagnosis of Hodgkin lymphoma. Because tumor cells make up a minority of the total cells in Hodgkin lymphoma, an excisional biopsy is needed to capture the presence of pathognomonic Reed-Sternberg cells in the landscape of reactive lymphocytes, eosinophils, and histiocytes.⁹

Fine needle biopsy and narrow-diameter core needle biopsy are considered inadequate for diagnosis of Hodgkin lymphoma. However, core biopsies may be utilized in situations where affected lymph nodes are only located in deep areas that are difficult to access for excisional biopsy.^2,9

Excisional or incisional surgical biopsy can be performed for diagnosis of NHL. Image-guided core needle biopsies may be used if no peripheral adenopathy is present, but fine needle biopsy is not considered adequate for diagnosis.^2,5

Tissue biopsy should also be performed as part of the workup of NHL and evaluated for histology, immunophenotype, and genetics.⁵ Bone marrow biopsy may also be required as part of the staging evaluation of NHL.

Laboratory Evaluation

It is important to note that initial laboratory evaluation can be normal in patients with lymphoma. However, this remains an important part of the diagnostic workup for suspected lymphoma both to evaluate for disease complications and to obtain baseline levels prior to treatment initiation, if needed:

Complete blood count with differential
Comprehensive metabolic panel
Erythrocyte sedimentation rate (ESR)
Lactate dehydrogenase level (LDH)
Liver function tests
HIV, hepatitis B, and hepatitis C serology
Serum protein electrophoresis
Serum β-2 microglobulin level^4,5,8

Diagnostic Imaging

Selection of diagnostic imaging modality for patients with NHL depends on histology and clinical presentation of disease. For those with indolent lymphomas, chest, abdominal, and pelvic computed tomography (CT) scans are important for staging and assessment of lymph node involvement.⁷

Positron emission tomography (PET) using ¹⁸F-fluorodeoxyglucose (FDG PET) is often the test of choice for diagnostic imaging in more aggressive forms of NHL. FDG PET is highly sensitive for detecting nodal and extranodal involvement and FDG avidity correlates with histologic aggressiveness.⁷

Magnetic resonance imaging (MRI) may be a useful diagnostic tool for the detection of bone, bone marrow, and central nervous system disease.⁷

For patients with Hodgkin lymphoma, a PET/CT scan should be used for staging. This is more accurate than bone marrow biopsy for the evaluation of bone marrow involvement, as bone marrow involvement may be patchy and, therefore, not detected on biopsy.^4,8,13

Staging

Hodgkin Lymphoma Staging

Staging for Hodgkin lymphoma depends mainly on the anatomic location of affected nodes and uses the Ann Arbor staging system.^8,13 Presence of lymph nodes of one or both sides of the diaphragm, number of sites involved, whether sites are bulky, the presence of contiguous or disseminated extranodal disease, and the presence or absence of B symptoms are all factors that contribute to staging.⁹

Each stage in the Ann Arbor system is further subdivided into A and B categories. The A category encompasses patients without systemic symptoms and the B category includes those with B symptoms.

Stage I and II disease are considered early stage while stage III and stage IV are considered late-stage disease.⁸ Prognostic factors differ between early and late-stage disease and can assist with optimizing treatment for the individual patient. Because cure rates are so high for Hodgkin lymphoma, avoidance of overtreatment to prevent long term treatment-related sequelae is as much a consideration as preventing undertreatment and increasing risk of morbidity and mortality from the disease itself.^8,9

Non-Hodgkin Lymphoma Staging

Prognosis of NHL is more complex than for Hodgkin lymphoma because disease spreads in an unpredictable manner, rather than the typically contiguous spread of Hodgkin lymphoma. The Ann Arbor staging system used for Hodgkin lymphoma was adapted for NHL and is known as the Lugano criteria.

However, as opposed to Hodgkin lymphoma, staging is not the sole determinant of prognosis, but instead is one of multiple factors.⁵ In fact, histopathology and clinical presentation, including non-Hodgkin’s lymphoma physical exam findings, are considered more important prognostic factors than staging.⁷

The IPI encompasses factors that are independently prognostic in NHL. These include age, serum lactate dehydrogenase, performance status, stage, and presence of absence of extranodal involvement, which are assessed and scored. Based on their score, patients fall into one of four categories: low, low-intermediate, high-intermediate, and high risk.⁷

References

Gonzalez B, Wang L, Campo E. Pathology of lymphomas. In: Kaushansky K, Prchal JT, Burns LJ, Lichtman MA, Levi M, Linch DC. eds. Williams Hematology, 10e. McGraw Hill; 2021.
Linch DC. General considerations of lymphomas: incidence rates, etiology, diagnosis, staging, and primary extranodal disease. In: Kaushansky K, Prchal JT, Burns LJ, Lichtman MA, Levi M, Linch DC. eds. Williams Hematology, 10e. McGraw Hill; 2021.
Hochberg J, Goldman SC, Cairo MS. Lymphoma. In: Kliegman RM, St. Geme JW III, Blum NJ, Shah SS, Tasker RC, Wilson KM, eds. Nelson Textbook of Pediatrics. 21st ed. Elsevier; 2020.
Clinical overview: Hodgkin lymphoma. Elsevier Point of Care. Updated May 28, 2021. Accessed December 2, 2021. https://www.clinicalkey.com/#!/content/clinical_overview/67-s2.0-a7a4af70-89a1-4587-98ce-d84a3f7e3aaf
Clinical overview: Non-Hodgkin lymphoma. Elsevier. January 1, 2022. Accessed December 2, 2021. https://www.clinicalkey.com/#!/content/derived_clinical_overview/76-s2.0-B9780323755702006433
Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375-2390. doi:10.1182/blood-2016-01-643569
Jacobson CA, Longo DL. Non-Hodgkin’s Lymphoma. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. eds. Harrison’s Principles of Internal Medicine, 20e. McGraw Hill; 2018.
Jacobson CA, Longo DL. Hodgkin’s lymphoma. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. eds. Harrison’s Principles of Internal Medicine, 20e. McGraw Hill; 2018.
Ansell SM. Hodgkin lymphoma: a 2020 update on diagnosis, risk-stratification, and management. Am J Hematol. 2020;95(8):978-989. doi:10.1002/ajh.25856
NHL subtypes. Leukemia & Lymphoma Society. Accessed December 2, 2021. https://www.lls.org/lymphoma/non-hodgkin-lymphoma/nhl-subtypes
Cancer stat facts: Non-Hodgkin lymphoma. National Cancer Institute Surveillance, Epidemiology, and End Results Program. Accessed December 4, 2021. https://seer.cancer.gov/statfacts/html/nhl.html
Cancer stat facts: Hodgkin lymphoma. National Cancer Institute Surveillance, Epidemiology, and End Results Program. Accessed December 4, 2021. https://seer.cancer.gov/statfacts/html/hodg.html
Hoppe RT, Advani RH, Ai WZ, et al. Hodgkin lymphoma, version 2.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2020;18(6):755-781. doi:10.6004/jnccn.2020.0026
Spinner MA, Mou E, Advani RH. Hodgkin lymphoma. In: Kaushansky K, Prchal JT, Burns LJ, Lichtman MA, Levi M, Linch DC. eds. Williams Hematology, 10e. McGraw Hill; 2021. Accessed December 05, 2021. https://accessmedicine.mhmedical.com/content.aspx?bookid=2962&sectionid=252534235
Davids MS, Fisher DC. Overview of care for adult survivors of non-Hodgkin lymphoma. Wolters Kluwer UpToDate, Inc. Updated July 16, 2021. Accessed December 5, 2021. https://www.uptodate.com/contents/overview-of-care-for-adult-survivors-of-non-hodgkin-lymphoma
Treating non-Hodgkin lymphoma. American Cancer Society. Accessed December 5, 2021. https://www.cancer.org/content/dam/CRC/PDF/Public/8720.00.pdf
Chemotherapy for Hodgkin lymphoma. American Cancer Society. Updated October 29, 2020. Accessed December 5, 2021. https://www.cancer.org/cancer/hodgkin-lymphoma/treating/chemotherapy.html
Immunotherapy for Hodgkin lymphoma. American Cancer Society. Updated October 29, 2020. Accessed December 5, 2021. https://www.cancer.org/cancer/hodgkin-lymphoma/treating/monoclonal-antibodies.html
Lexi-Drugs. Updated November 22, 2021. Accessed December 5, 2021. https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6979556?cesid=34bbicfyk0C&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3DTafasitamab%26t%3Dname%26va%3DTafasitamab#
Loncastuximab tesirine. Lexi-Drugs. Updated November 22, 2021. Accessed December 5, 2021. https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7097198?cesid=6jdLQSxmMSw&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3DLoncastuximab%252520tesirine-lpyl%26t%3Dname%26va%3DLoncastuximab%252520tesirine-lpyl
Lexi-Drugs. Updated November 22, 2021. Accessed December 5, 2021. https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6295?cesid=6GlCJanO6pg&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3DAlemtuzumab%26t%3Dname%26va%3DAlemtuzumab#
Brentuximab vedotin. Lexi-Drugs. Updated November 22, 2021. Accessed December 5, 2021. https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/3509801?cesid=3EEHurCUixR&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3DBrentuximab%252520vedotin%26t%3Dname%26va%3DBrentuximab%252520vedotin#
Polatuzumab vedotin. Lexi-Drugs. Updated November 22, 2021. Accessed December 5, 2021. https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6827191?cesid=7LiZ7YBk2Wj&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3DPolatuzumab%252520vedotin%26t%3Dname%26va%3DPolatuzumab%252520vedotin#
Lexi-Drugs. Updated December 3, 2021. Accessed December 5, 2021. https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/5320082?cesid=17GWnduMyla&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3DPembrolizumab%26t%3Dname%26va%3DPembrolizumab#
Lexi-Drugs. Updated November 23, 2021. Accessed December 5, 2021. https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/5467454?cesid=51mgXgk3cV4&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3DNivolumab%26t%3Dname%26va%3DNivolumab#
Lexi-Drugs. Updated November 22, 2021. Accessed December 5, 2021. https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/361321?cesid=6wntbU3y858&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3DLenalidomide%26t%3Dname%26va%3DLenalidomide#
Freedman AS, Friedberg JW. Histologic transformation of follicular lymphoma. Wolters Kluwer UpToDate, Inc. Updated May 25, 2021. Accessed December 5, 2021. https://www.uptodate.com/contents/histologic-transformation-of-follicular-lymphoma
Fricker LD. Proteasome inhibitor drugs. Annu Rev Pharmacol Toxicol. 2020;60:457-476. doi:10.1146/annurev-pharmtox-010919-023603
Updated November 22, 2021. Accessed December 5, 2021. https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6469?cesid=8UcTEiGLDDJ&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3DBortezomib%26t%3Dname%26va%3DBortezomib#
Sun Y, Sun Y, Yue S, Wang Y, Lu F. Histone deacetylase inhibitors in cancer therapy. Curr Top Med Chem. 2018;18(28):2420-2428. doi:10.2174/1568026619666181210152115
Lexi-Drugs. Updated November 22, 2021. Accessed December 5, 2021. https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/5240903?cesid=8fvaWZm37dQ&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3DBelinostat%26t%3Dname%26va%3DBelinostat
Kim HO. Development of BTK inhibitors for the treatment of B-cell malignancies. Arch Pharm Res. 2019;42(2):171-181. doi:10.1007/s12272-019-01124-1
Duncan L, Shay C, Teng Y. PI3K Isoform-selective inhibitors in cancer. Adv Exp Med Biol. 2020;1255:165-173. doi:10.1007/978-981-15-4494-1_14
Duan R, Du W, Guo W. EZH2: a novel target for cancer treatment. J Hematol Oncol. 2020;13(1):104. Published 2020 Jul 28. doi:10.1186/s13045-020-00937-8
Lexi-Drugs. Updated November 15, 2021. Accessed December 5, 2021. https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6913621?cesid=6PmZ23DvCWc&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3DTazemetostat%26t%3Dname%26va%3DTazemetostat#
Azizian NG, Li Y. XPO1-dependent nuclear export as a target for cancer therapy. J Hematol Oncol. 2020;13(1):61. Published 2020 Jun 1. doi:10.1186/s13045-020-00903-4
Lexi-Drugs. Updated November 22, 2021. Accessed December 5, 2021. https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6837563?cesid=27RrW8u7VdO&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3DSelinexor%26t%3Dname%26va%3DSelinexor#