History and exam

Key diagnostic factors

uncommon

B symptoms (fever, night sweats, weight loss)

Clinical symptoms are often vague, but the presence of B symptoms (unexplained fever, drenching night sweats, and weight loss >10% of body weight within 6 months) is important.

fatigue/malaise

May be from anemia.

Other diagnostic factors

common

lymphadenopathy

May present with peripheral lymphadenopathy.

splenomegaly

Can be massive in splenic marginal zone lymphoma. May cause splenic infarction.

uncommon

hepatomegaly

Due to infiltration of the liver by lymphoma cells.

shortness of breath

May be from pulmonary involvement or pleural involvement (and resulting pleural effusions).

cough

May be from mediastinal involvement, lymph node involvement, or pneumonia.

abdominal discomfort

May be from gastrointestinal, liver, spleen, or lymph node involvement.

headache

May be from meningeal involvement or increased intracranial pressure from cerebral edema and parenchymal brain involvement.

change in mental status

May be from meningeal involvement, parenchymal brain involvement, and/or associated cerebral edema.

focal neurologic deficits

For example ataxia, cognitive changes, focal weakness. Possible central nervous system involvement.

chest pain

May be from cardiac ischemia secondary to severe anemia.

bone pain, back pain

May be from bone involvement (i.e., osseous or epidural spread of lymphoma).

jaundice

Due to liver infiltration and subsequent liver failure.

pallor

Due to anemia.

purpura

Due to thrombocytopenia, coagulation abnormalities secondary to liver involvement, or disseminated intravascular coagulation.

skin lesions

Cutaneous NHL presents primarily with skin lesions; other types of NHL may involve the skin. Lesions may be patches or raised plaques. Some may ulcerate. Itching is common.

neurologic abnormalities on exam

May result from involvement of the nervous system by direct invasion or metastases or, rarely, from paraneoplastic phenomena. Examination findings depend on the site and type of involvement.

breast pain

May occur in patients with breast implant involvement (breast implant-associated anaplastic large cell lymphoma).[68][69][70]​​​​

swelling or mass in the breast

May occur in patients with breast implant involvement (breast implant-associated anaplastic large cell lymphoma [BIA-ALCL]).[68][69][70]

Swelling around breast implants (seroma) occurring >1 year after implantation is the most common presentation in patients with BIA-ALCL.[68][69][70][71]

Risk factors

strong

age >50 years

Non-Hodgkin lymphoma incidence increases with age; median age at diagnosis in the US is 68 years.[4]

male sex

Men are more likely to be diagnosed with NHL than women (22.5 new cases per 100,000 vs. 15.5 new cases per 100,000, respectively).[4]

Epstein-Barr virus (EBV)

EBV is associated with Burkitt lymphoma, with HIV-related primary central nervous system lymphoma, and with nasal natural killer/T-cell lymphoma.[8][14][15]

human T-lymphocytotrophic virus-1 (HTLV-1)

HTLV-1 has been associated with T-cell lymphoma.[22]​​

human herpesvirus-8 (Kaposi sarcoma-associated herpesvirus)

One of the causative agents for primary effusion/body cavity lymphoma in HIV patients.[2]​​

Helicobacter pylori

There is a strong association between Helicobacter pylori and gastric mucosa-associated lymphoid tissue (MALT) lymphoma.​[21]

celiac disease

Enteropathy-associated T-cell lymphoma/intestinal T-cell lymphoma is an aggressive lymphoma that has been associated with celiac disease.[27]

HIV

Primary central nervous system lymphoma is common in patients with HIV/AIDS.[14][45] Etiology is likely associated with ineffective immunoregulation of EBV.

hepatitis C virus (HCV)

HCV has been linked to splenic marginal zone lymphoma and to diffuse large B-cell lymphoma.[16][17][46]

Sjogren syndrome

Marginal zone lymphoma (MZL) and gastric mucosa-associated lymphoid tissue (MALT) lymphoma have been linked to autoimmune disorders such as Sjogren syndrome.[24][28][29]​​

Wiskott-Aldrich syndrome

There is an association with hereditary immunodeficiency syndromes.[32]

ataxia-telangiectasia

There is an association with hereditary immunodeficiency syndromes.[33]

use of immunomodulatory drugs

Use of anti-tumor necrosis factor (anti-TNF) drugs (e.g., infliximab, adalimumab) is associated with an increased risk for NHL.[39]

weak

organ transplant

There is an association following organ transplantation.[30]

Borrelia burgdorferi

Borrelia burgdorferi has been linked with mucosa-associated lymphoid tissue (MALT) lymphoma (cutaneous type).[18]

Coxiella burnetii

Associated with B-cell NHL.[19]

Chlamydia psittaci

Chlamydia psittaci has been linked with mucosa-associated lymphoid tissue (MALT) lymphoma arising in the ocular adnexa.[20]

Campylobacter jejuni

Campylobacter jejuni has been linked with mucosa-associated lymphoid tissue lymphoma arising in the small intestine.[23]​ 

rheumatoid arthritis

There is an association with autoimmune disorders such as rheumatoid arthritis.[25][28]​​​

systemic lupus erythematosus (SLE)

There is an association with autoimmune disorders such as SLE.[26][28]​​​

common variable immunodeficiency

There is an association with acquired immunodeficiency states.[31]

Chediak-Higashi syndrome

There is an association with hereditary immunodeficiency syndromes.[34]

Klinefelter syndrome

There is an association with hereditary immunodeficiency syndromes.[35]

pesticides

Environmental factors such as exposure to pesticides have been linked to NHL in farmers.[36][38][47]

phenoxyherbicides

Environmental factors such as exposure to phenoxyherbicides have been linked to NHL in farmers.[37]

breast implants

Breast implants (reconstruction or augmentation) are associated with an increased risk of anaplastic large cell lymphoma (ALCL).[40][41][42][10][13]​​​​​ As of June 2023, the US Food and Drug Administration identified 1264 cases of breast implant-associated ALCL (BIA-ALCL) worldwide, with 63 related deaths.[11]​​ The American Society of Plastic Surgeons recognizes approximately 1602 cases of BIA-ALCL worldwide (August 2024).[12]

Most cases of BIA-ALCL have occurred with textured implants, but there have been reports of BIA-ALCL with smooth-surface implants.​​[11]​ Median time from implant to diagnosis of BIA-ALCL is 8 years.[11]

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