Diagnostic Considerations

A significant number of medical disorders can produce local or generalized lymph node enlargement. Thus, the diagnosis of non-Hodgkin lymphoma (NHL) relies on pathological confirmation following appropriate tissue biopsy.

The following are some of the conditions that can result in clinical manifestations similar to those observed in lymphoma patients:

Solid tumor malignancies: metastatic disease to lymph nodes secondary to carcinoma, melanoma, or sarcoma
Other hematologic malignancies or lymphoproliferative disorders: granulocytic sarcoma, multicentric Castleman disease
Benign lymph node infiltration or reactive follicular hyperplasia secondary to infection (eg, tuberculosis; other bacterial, fungal, and, rarely, viral infections), and collagen-vascular diseases
Hodgkin lymphoma, which requires a different treatment strategy than NHL

If the diagnosis of NHL is doubtful, acquire a second or third opinion from an expert hematopathologist before instituting therapy. Flow cytometry and cytogenetics should also be performed and can be especially helpful in difficult situations.

Differential Diagnoses

Workup

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Media Gallery

Posteroanterior (PA) chest radiograph in a man with thoracic non-Hodgkin lymphoma (NHL) shows mediastinal widening due to grossly enlarged right paratracheal and left paratracheal nodes.
Posteroanterior (PA) chest radiograph in a 16-year-old male adolescent with thoracic non-Hodgkin lymphoma (NHL) shows subtle enlargement of the lower paratracheal lymph nodes.
Nonenhanced CT scan through the mediastinum shows multiple enlarged lymph nodes in the prevascular space, in the right and left paratracheal region. Nodes in the left paratracheal region cause the trachea to be indented and narrowed on the left side. Note the small, bilateral pleural effusion
Nonenhanced CT scan through the mediastinum at the level of the carina shows enlarged tracheobronchial and subcarinal nodes. Note the small bilateral pleural effusion.
Contrast-enhanced axial CT scan in a child shows hypoattenuating, enlarged, subcarinal lymph nodes with splaying of the tracheal bifurcation.
Posteroanterior (PA) chest radiograph shows a large mass in the right parahilar region extending into the right upper and middle zones, with silhouetting of the right pulmonary artery. Smaller mass is seen in the periphery of the right lower zone. The masses did not respond to a trial of antibiotics. Core-needle biopsy of the larger lesion revealed NHL deposits in the lung.
Lateral image shows a large mass in the anterior aspect of the right upper lobe of the lung.
Posterior bone scan shows no abnormally increased uptake in the thoracic vertebrae. Image shows an unusual pattern of non-Hodgkin lymphoma (NHL) of the upper thoracic vertebra.
This 28-year-old man was being evaluated for fever of unknown origin. Gallium-67 study shows extensive uptake in the mediastinal lymph nodes due to non-Hodgkin lymphoma (NHL).
T1-weighted coronal MRI of the thorax in a 55-year-old woman with lower dorsal pain. Note the signal-intensity changes in the body of D12; these are associated with a right-sided, large, paravertebral soft-tissue mass involving the psoas muscle. Biopsy confirmed non-Hodgkin lymphoma (NHL).
T1-weighted coronal MRI of the thorax in a 55-year-old woman with lower dorsal pain (same patient as in the previous image). Note the signal-intensity changes in the body of D12; these are associated with a right-sided, large, paravertebral soft-tissue mass involving the psoas muscle. Biopsy confirmed non-Hodgkin lymphoma (NHL).
Positron emission tomography (PET) CT in an 80-year-old woman with diffuse, large B-cell NHL of the skin and subcutaneous tissues that recently transformed from previous low-grade non-Hodgkin lymphoma (NHL). PET shows high level of uptake in the anterior subcutaneous nodule in the chest (white arrows). CT scan of similar nodules (arrowheads) on the anterior left chest does not show PET uptake; these may represent regions of lower-grade NHL. PET image of posterior lesions shows only mild uptake (gray arrow).
Non-Hodgkin lymphoma of the terminal ileum. Note the doughnut sign, ie, intraluminal contrast material surrounded by a grossly thickened bowel wall. This appearance is highly suggestive of small noncleaved cell lymphoma (Burkitt type).
Computed tomography of the throat in highly-malignant non-hodgkin lymphoma present as lymph node swelling in a child (transverse section with contrast). DE: Computertomographie des Halses bei einem hoch-malignen Non-Hodgkin
Malignant lymphoma high grade_B_cell
Ultrasound throat lymphadenopathy non-hodgkin-lymphoma

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Table 1. Non-Hodgkin lymphoma staging.

Stage		Area of Involvement	Extranodal (E) Status
I	Single node or adjacent group of nodes		Single extranodal lesions without nodal involvement
II	Multiple lymph node groups on same side of diaphragm		Stage I or II by nodal extent with limited contiguous extranodal involvement
II bulky*	Multiple lymph node groups on same side of diaphragm with “bulky disease”		N/A
III	Multiple lymph node groups on both sides of diaphragm; nodes above the diaphragm with spleen involvement		N/A
IV	Multiple noncontiguous extranodal sites		N/A

Table 2. Comparison of Lugano and Paris staging systems

Lugano Staging System		Paris Staging System
Stage	Area of Involvement	TNM	Tumor extension
I_E1	Confined to GI tract—mucosa, submucosa	T1m N0 M0 T1sm N0 M0	Mucosa Submucosa
I_E2	Confined to GI tract—muscularis propria, serosa	T2 N0 M0 T3 N0 M0	Muscularis propria Serosa
II_E1	Extending into abdomen—local nodal involvement	T1-3 N1 M0	Perigastric lymph nodes
II_E2	Extending into abdomen—distant nodal involvement	T1-3 N2 M0	More distant regional nodes
II_E	Penetration of serosa to involve adjacent organs or tissues	T4 N0 M0	Invasion of adjacent structures
IV	T1-4 N3 M0 T1-4 N0-3 M1	Lymph nodes on both sides of the diaphragm/distant metastases (eg, bone marrow or additional extranodal sites)

Table 3. International Society for Cutaneous Lymphoma/European Organization for Research and Treatment of Cancer tumor-node-metastasis classification for cutaneous B-cell lymphoma

Tumor	Involvement	Node	Involvement	Metastatic Spread	Involvement
T1	Solitary skin involvement T1a: ≤5 cm diameter T1b: >5 cm diameter	N0	No lymph node involvement	M0	No evidence of extracutaneous non-lymph node disease
T2	Multiple lesions limited to one body region or two contiguous body regions T2a: all-disease in a < 15-cm diameter T2b: all-disease in a >15- and < 30-cm diameter T2c: all-disease in a >30-cm diameter	N1	Involvement of one peripheral lymph node region	M1	Evidence of extracutaneous non-lymph node disease
T3	Generalized skin involvement T3a: multiple lesions involving two noncontiguous body regions T3b: multiple lesions involving three body regions	N2	Involvement of two or more peripheral lymph node regions or involvement of any lymph node region that does not drain an area of current or prior skin involvement
		N3	Central lymph nodes involvement

Table 4. International Society for Cutaneous Lymphoma/European Organization for Research and Treatment of Cancer tumor-node-metastasis-blood revised classification for mycosis fungoides and Sezary syndrome

Skin	Involvement	Node	Involvement	Viscera	Involvement
T1	Patchy or plaquelike skin disease involving ≤10% of the skin surface area	N0	No abnormal lymph nodes	M0	No visceral organ involvement
T2	Patchy or plaquelike skin disease involving ≥10% of the skin surface area	N1	Histopathology Dutch Gr 1 or NCI LN 0-2	M1	Visceral organ involvement
T3	Tumors are present ≥1 cm in diameter	N2	Histopathology Dutch Gr 2 or NCI LN 3	MX	Abnormal visceral site; no histologic confirmation
T4	Erythroderma ≥80% of body area	N3	Histopathology Dutch Gr 3-4 or NCI LN 4	Blood	Involvement
		Nx	Abnormal lymph nodes; no histologic confirmation	B0	≤5% of peripheral blood lymphocytes are Sezary cells
				B1	>5% of peripheral blood lymphocytes are Sezary cells but do met B2 criteria
				B2	≥1000/mcL Sezary cells or CD4/CD8 ≥10 or ≥40% CD4+/CD7- or ≥30% CD4+/CD26- cells

Table 5. Staging classifications for mycosis fungoides and Sezary syndrome

Clinical Stage	5-year Survival ^[87]	TNM (B) Stage
IA	96-100%	T₁N₀M₀B₀	T₁N₀M₀B₁
IB	73-86%	T₂N₀M₀B₀	T₂N₀M₀B₁
IIA	49-73%	T₁N₁M₀B₀	T₁N₁M₀B₁	T₁N₂M₀B₀	T₁N₂M₀B₁
IIA		T₂N₁M₀B₀	T₂N₁M₀B₁	T₂N₂M₀B₀	T₂N₂M₀B₁
IIB	40-65%	T₃N₀M₀B₀	T₃N₀M₀B₁	T₃N₁M₀B₀	T₃N₁M₀B₁
IIB		T₃N₂M₀B₀	T₃N₂M₀B₁
IIIA	50-57%	T₄N₀M₀B₀	T₄N₁M₀B₀	T₄N₂M₀B₀
IIIB	50-57%	T₄N₀M₀B₁	T₄N₁M₀B₁	T₄N₂M₀B₁
IVA	15-40%	T₁N₀M₀B₂	T₂N₀M₀B₂	T₃N₀M₀B₂	T₄N₀M₀B₂
		T₁N₁M₀B₂	T₂N₁M₀B₂	T₃N₁M₀B₂	T₄N₁M₀B₂
		T₁N₂M₀B₂	T₂N₂M₀B₂	T₃N₂M₀B₂	T₄N₂M₀B₂
		T₁N₃M₀B₀	T₂N₃M₀B₀	T₃N₃M₀B₀	T₄N₃M₀B₀
		T₁N₃M₀B₁	T₂N₃M₀B₁	T₃N₃M₀B₁	T₄N₃M₀B₁
		T₁N₃M₀B₂	T₂N₃M₀B₂	T₃N₃M₀B₂	T₄N₃M₀B₂
IVB	0-15%	T₁N₀M₁B₀	T₂N₀M₁B₀	T₃N₀M₁B₀	T₄N₀M₁B₀
		T₁N₁M₁B₁	T₂N₁M₁B₁	T₃N₁M₁B₁	T₄N₁M₁B₁
		T₁N₂M₁B₂	T₂N₂M₁B₂	T₃N₂M₁B₂	T₄N₂M₁B₂
		T₁N₃M₁B₃	T₂N₃M₁B₃	T₃N₃M₁B₃	T₄N₃M₁B₃

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Author

Sanjay Vinjamaram, MD, MPH Physician in Hematology/Oncology, Essentia/Innovis Health Cancer Center

Sanjay Vinjamaram, MD, MPH is a member of the following medical societies: American Association for the Advancement of Science, Sigma Xi, The Scientific Research Honor Society, American Society for Cell Biology

Disclosure: Nothing to disclose.

Coauthor(s)

Dolores A Estrada-Garcia, MD Consulting Staff in Hematology-Oncology, Cancer Care Specialists of Central Illinois

Dolores A Estrada-Garcia, MD is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology

Disclosure: Nothing to disclose.

Francisco J Hernandez-Ilizaliturri, MD Professor of Medicine, Department of Medical Oncology, Associate Professor of Immunology, Department of Immunology, Chief, Lymphoma and Myeloma Section, Director, The Lymphoma Translational Research Program, Roswell Park Cancer Institute, University of Buffalo State University of New York School of Medicine and Biomedical Sciences

Francisco J Hernandez-Ilizaliturri, MD is a member of the following medical societies: American Association for Cancer Research, American Society of Hematology

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Acknowledgements

Koyamangalath Krishnan, MD, FRCP, FACP Paul Dishner Endowed Chair of Excellence in Medicine, Professor of Medicine and Chief of Hematology-Oncology, James H Quillen College of Medicine at East Tennessee State University

Koyamangalath Krishnan, MD, FRCP, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, American Society of Hematology, and Royal College of Physicians

Disclosure: Nothing to disclose.

Lakshmi Rajdev, MD Site Director, Jacobi Medical Center; Assistant Professor, Department of Radiation Oncology, Albert Einstein College of Medicine

Disclosure: Nothing to disclose.

Joseph A Sparano, MD Professor of Medicine, Albert Einstein College of Medicine/Cancer Center; Program Director, Director of Breast Medical Oncology, Department of Internal Medicine, Division of Oncology, Montefiore Medical Center

Joseph A Sparano, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, and American Society of Hematology

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment