Non-Hodgkin lymphoma differential diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [4]; Associate Editor(s)-in-Chief: Preeti Singh, M.B.B.S.[5]

Overview

Non-Hodgkin lymphoma must be differentiated from Hodgkin's disease, viral infections, metastatic carcinoma, and autoimmune diseases.

Differential Diagnosis

Non-Hodgkin lymphoma must be differentiated from common disorders with localized or generalized lymphadenopathy such as:

• Neoplasm

• Hodgkin's disease
• Chronic lymphocytic leukemia
• Small cell carcinoma of the lung
• Melanoma
• Lymphomatoid granulomatosis
• Angioimmunoblastic lymphadenopathy
• Giant lymph node hyperplasia (Castleman disease)

• Infections

• Syphilis
• Brucellosis
• Infectious mononucleosis
• CMV
• HIV
• Cat scratch disease
• Tuberculosis
• Toxoplasmosis

• Autoimmune diseases

• Systemic lupus erythematosus
• Sjögren's syndrome
• Sarcoidosis

Diseases		Clinical manifestations						Para-clinical findings			Pathogonomic finding
		Symptoms
								Lab Findings		Biopsy
		Lymphadenopathy	Fever	Weight loss	Night Sweats	Rash	Other symptoms	Immunochemistry	Blood work
NEOPLASMS
Non-Hodgkins lymphoma		Painless	+	+	+	+	Presents with "B" symptoms Constant fatigue Shortness of breath and cough Abdominal pain or swelling Constipation Nausea andvomiting.	Coombs test may be positive Hypogammaglobulinemia HIV serology Elevated lactate dehydrogenase Abnormal liver function test Hypercalcemia	Anemia Thrombocytopenia Leukopenia Lymphocytosis	Monomorphic medium to large sized lymphocytes seen	N/A
Hodgkin's disease		Painless	+	+	+	+	Presents with "B" symptoms Constant fatigue Shortness of breath and Cough Abdominal pain or swelling Constipation Nausea andvomiting.	Lactate dehydrogenase (LDH) may be increased. ESR elevated Serum creatinine elevated in nephrotic syndrome. Alkaline phosphatase (ALP) increased Hypercalcemia, hypernatremia, and hypoglycemia.	N/A	Fine-needle aspiration Mononucleate and binucleate Reed-Sternberg cells in a background of inflammatory cells	Reed-Sternberg cells on microscopic pathology.
Chronic lymphocytic leukemia		Painless	+	+	+	-	Recurrent bleeding Muscle wasting Generalized weakness Anorexia Abdominal pain Recurrent infections	Monoclonality of kappa and lambda producing B cells Presence of smudge cells Express CD19, CD20, CD23, and CD5 on the cell surface	CBC Absolute lymphocytosis (>5000 cells/μl) Decreased hemoglobin concentration Decreased platelets count	On microscopic histopathological analysis: Small lymphoid cells Thin cytoplasmic border Dense nucleus Lack of nucleolus Clumped chromatin aggregates The presence of smudge cells The presence of gumprecht nuclear shadows	N/A
Small cell carcinoma of the lung		Painless	-	-	-	-	Syndrome of inappropriate antidiuresis (SIADH) Hypercalcemia Cough (most common symptom) Wheezing Dyspnea Hemoptysis Chest pain	Nearly all SCLC are immunoreactive for keratin thyroid transcription factor 1 epithelial membrane antigen Neuroendocrine and neural differentiation result in the expression of molecules like dopa-decarboxylase calcitonin neuron-specific enolase, chromogranin A CD56 gastrin-releasing peptide insulin-like growth factor 1	N/A	The tumor cells are small and round, but they can sometimes be ovoid or spindle shaped. They have a scantycytoplasm with a high mitotic count and a hyperchromatic nuclei.	N/A
Melanoma		Painless	-	-	-	-	Rapid growth of an existing nevus Bleeding nevus Cutaneous nodules Hyper/hypopigmented skin lesion Melanonychia (brown/blue nail discoloration) Non-healing skin ulcer Painful skin lesion Pruritus Bone pain	Positive for CD133+ Positive for CD34+	N/A	An excisional biopsy (either elliptical, punch, or saucerization) of the thickest portion of the lesion with 1-3 mm margins.	Epidermal atrophy and flattening and prominent dermal invasion
Lymphomatoid granulomatosis		Painless	+	+	-	+	Cough Dyspnea Chest tightness Malaise Fatigue Headaches Seizures Hemiparesis Ataxia Macules Papules Plaques Subcutaneous nodules Larger ulcerated nodules	N/A	CBC Leukopenia Lymphopenia Low CD4 count Leukocytosis is rare Elevated Hematocrit	N/A	On chest CT scan, Halo sign is seen due to the angioinvasive nature of the disease
Angioimmunoblastic lymphadenopathy		Painless	+	+	+	+	Edema Chest pain Abdominal pain Bone pain Fatigue Pale skin color Dark urine Chronic pain and swelling of the joints	Immunophenotyping Positivity for CD2, CD3, CD4, CD5, CD10, CD20, and focal positivity for CXCL13 Negative for ALK1 and CD30 Fluorescence in situ hybridization (FISH)	Complete blood count (CBC) Anemia Eosinophilia	Lymph node or extranodal tissue biopsy is diagnostic of angioimmunoblastic T-cell lymphoma. Characteristic findings on gross pathology, aborization and proliferation of high endothelial venules On microscopic histopathological analysis, CD4+ T-cells, CD8+ T-cells, and polyclonal plasma cells.	Epstein–Barr virus (EBV) has been found in both reactive B-cells and the neoplastic T-cells. Trisomy 3, trisomy 5, and +X are the most frequent chromosomal abnormalities found in cases.
Giant lymph node hyperplasia (Castleman disease)		Painless	+	+	-	-	Anemia Loss of appetite Cough Chest discomfort Fatigue Weakness	N/A	Complete blood count and differential count - low white blood cell counts, which may to be due to the overproduction of interleukin 6. Erythrocyte sedimentation rate - elevated in 80% cases.	N/A	Hypersecretion of the cytokine IL-6.
Diseases		Lymphadenopathy	Fever	Weight loss	Night sweats	Rash	Other symptoms	Immunochemistry	Blood work	Biopsy Histopathology	Pathogonomical findings
INFECTIONS
Bacteria	Syphilis	Painless and localized	+	-	-	+	Primary syphilis: Chancer Secondary syphilis: Rash Condylomata lata Patchy alopecia Tertiary syphilis Gumma Organ system involvement	Darkfield microscopy to detect T. pallidum. Nontreponemal tests (e.g., VDRLand RPR ) Treponemal tests (e.g. FTA-ABS, the TP-PA assay	N/A	On microscopic histopathological analysis, characteristic findings of syphilis: Mononuclear leukocytic infiltration, macrophages, and lymphocytes. Swelling and proliferation of small blood vessels.	Painless clean base chancre.
	Brucellosis	Painful	+	-	-	+	Abdominal pain hepatosplenomegaly Arthritis	Brucella is most commonly isolated from blood cultures Positive titer of anti-brucella antibodies on serological testing	N/A	N/A	Night sweats, often with characteristic smell, likened to wet hay
Viral	Infectious mononucleosis	Painful	+	-	-	+	Low-grade fever without chills Sore throat White patches on tonsils and back of the throat Muscle weakness Fatigue Petechial hemorrhage	A positive reaction to a mono spot test Direct detection of EBV in blood or lymphoid tissues	A normal to moderately elevated white blood cell count An increased total number of lymphocytes Greater than 10% atypical lymphocytes Presence of atypical lymphocytes (a type of mononuclear cell) on the peripheral blood smear.	N/A	Presence of atypical lymphocytes (a type of mononuclear cell) on the peripheral blood smear.
	CMV	Painful	+	-	-	+	Floaters Scotomata Peripheral visual field defects Odynophagia Nausea Lethargy Confusion Altered mental status	Positive PCR for CMV.	Hemolytic anemia Thrombocytopenia Disseminated intravascular coagulation Pancytopenia	CMV infection demonstrates the presence of intranuclear inclusion bodies. These inclusion bodies stain dark pink on an H&E stain, and are also called "Owl's Eye" inclusion bodies.	Owl Eye inclusion bodies.
	HIV	Painful/ painless	-	+	-	-	Fatigue Myalgia Arthritic pain Headache Memory loss, depression and other neurological disorders	ELISA Dot blot Latex agglutination assays Western blot assays P24 antigen assays CD4 T-cell count (CD4 count) Plasma HIV RNA viral load	Anaemia Thrombocytopenia Leukopenia	N/A	Plasma HIV RNA viral load
	Cat scratch disease	Painful	+	-	-	+	Back pain Headache Sore throat Abdominal pain Vision problems Malaise Alteration of mental status Convulsions	Indirect immunofluorescence or enzymatic immunoassay with titration of IgG or IgM antibodies to detect serum antibody to B henselae. Polymerase chain reaction (PCR) is the most sensitive test	Lymphocytosis is seen in the acute phase. Erythrocyte sedimentation rate - elevated.	N/A	Painful buboes
Mycobacteria	Tuberculosis	Painful	+	+	+	+	Hemoptysis Chest pain Anorexia Malaise Chills Fatigue Dyspnea	PCR of CSF for tuberculosis Mycobacterial culture of CSF Brain biopsy for acid-fast bacilli staining Culture and acid stain positive for acid-fast bacilli Hyponatremia Hypercalcemia Elevated alkaline phosphatase levels Mild elevation of liver enzymes	Mild normocytic anemia may be present in almost half of patients. Increased erythrocyte sedimentation rate (ESR) Mild leukocytosis	Macrophages, other immune cells such as blood monocytes (tissue macrophages) and lymphocytes also migrate to the Ghon focus aiding in the termination of the infection or initiation of a granulomatous containment.	Gohn's focus
Parasite	Toxoplasmosis	Painless	+	-	+	-	Sore throat Muscle aches and pains	IgG, IgM, IgA antibodies against toxoplasmosis seen by ELISA PCR	N/A	Microscopy of the lesions demonstrate periaqueductal and periventricular vasculitis with necrosis. Fetal tissue and placenta can demonstrate t.gondii cysts with the Wright-Giemsa stain and also with immunoperoxidase staining using t.gondii–specific antibodies.	Multiple ring enhancing lesion on CT Brain.
Diseases		Lymphadenopathy	Fever	Weight loss	Night sweats	Rash	Other symptoms	Immunochemistry	Blood work	Biopsy Histopathology	Pathogonomical findings
AUTOIMMUNE
Systemic lupus erythematosus (SLE)		Painless	+	+/-	-	+	Fatigue Myalgia Joint tenderness Muscle weakness Abdominal pain Bloating Distension	ANA positive Lupus anticoagulant (LA) IgG and IgM anticardiolipin (aCL) antibodies IgG and IgM anti-beta2-glycoprotein (GP) C3: Vary between varying between normal to slightly reduced C4: Reduced CH50: Reduced	Leukopenia Lymphopenia Mild anemia Thrombocytopenia ESR CRPelevated	Lupus erythematosus (LE) cells can be seen in SLE. LE cells are neutrophils that have engulfed an intact nucleus. LE cells are also known as LE bodies.	Malar rash and photosensitivity
Sjögren's syndrome		Painless	-	-	-	+	Xerosis Scaly skin Annular erythema	Anti-Ro/SSA Anti-La/SSB Presence of rheumatoid factor (RF) Presence of anti–alpha-fodrin antibody (diagnostic marker of juvenile Sjögren's syndrome)	Elevated erythrocyte sedimentation rate (ESR) Anemia Leukopenia Thrombocytopenia Eosinophilia	N/A	Keratoconjunctivitis sicca Presence of anti–alpha-fodrin antibody
Sarcoidosis		Painless	-	-	-	-	Can involve all organ systems to varying extent and degree.	Serum ACE level Serum chitotriosidase Soluble interleukin-2 receptor Hypercalcemia Kveim test	N/A	Biopsy of lung Non-caseating granuloma	Non-caseatinggranuloma

References

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