Burkitt's lymphoma differential diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editor-in-Chief: Soumya Sachdeva, Sowminya Arikapudi, M.B,B.S. [2], Kamal Akbar, M.D.[3]

Overview

Burkitt's lymphoma must be differentiated from other diseases such as Hodgkin's lymphoma, diffuse large B cell lymphoma, follicular lymphoma, Mucosa-Associated Lymphatic Tissue lymphoma (MALT), small cell lymphocytic lymphoma, and mantle cell lymphoma (MCL).

Differentiating Burkitt's lymphoma from other Diseases

Burkitt's lymphoma must be differentiated from other diseases such as:

• Diffuse large B cell lymphoma
• Hodgkin's lymphoma
• Follicular lymphoma
• Mucosa-Associated Lymphatic Tissue lymphoma (MALT)
• Small cell lymphocytic lymphoma
• Mantle cell lymphoma (MCL)

Differential Diagnosis of Sporadic Burkitt's Lymphoma

S.No.	Disease	Symptoms			Signs		Diagnosis			Comments
		Abdominal Pain	Hematuria	Headache	Abdominal mass	Abdominal tenderness	Ultrasonography	CT scan	Histology
1.	Wilms tumor	+	+	-	+	+	It is the best initial diagnostic study used in cases suspected with Wilms tumor. Ultrasonography can help identify the mass as a kidney mass. It can distinguish tumor mass from other causes of renal swelling like hydronephrosis. Doppler ultrasonography can help to detect invasion of renal vein and IVC by the tumor.	Findings on CT scan which can be suggestive of Wilms tumor include: Heterogeneous soft-tissue density masses These masses have frequent areas of calcification (~10%) and fat-density regions Lymph node metastasis CT scan of the renal mass can further reveal: Invasion of surrounding organs Thrombus in or occlusion of the renal vein and/or the inferior vena cava Abdominal lymph nodes and contralateral involvement	Wilms tumor has a triphasic appearance. It is comprised of 3 types of cells: Stromal Epithelial Blastemal All the 3 types are not required for the diagnosis of Wilms tumor. Primitive tubules and glomeruli are often seen comprised of neoplastic cells. Beckwith and Palmer reported in NWTS the different histopathologic types of Wilms tumor to categorize them based on prognosis. Spindled cell stroma surrounding abortive tubules and glomeruli is characteristic. The stroma may include: Striated muscle cartilage bone Fat tissue Fibrous tissue.
2.	Renal cell carcinoma	+	+	+/-	+	-	Ultrasound (US) may be helpful when CT scan results are equivocal. It is noteworthy to mention that not all renal cell carcinomas are detectable on ultrasound.	Both CT and MRI may be used to detect neoplastic masses that may define renal cell carcinoma or metastasis of the primary cancer. CT scan and use of intravenous (IV) contrast is generally used for work-up and follow-up of patients with renal cell carcinoma.	The histological pattern of renal cell carcinoma depends whether it is papillary, chromophobe or collecting duct renal cell carcinoma.
3.	Rhabdoid kidney disease	+	+	-	+	-	Ultrasound shows a complex cystic mass.	CT scan may be diagnostic of malignant rhabdoid tumor. Findings on CT scan suggestive of malignant rhabdoid tumor include a large, heterogenous, centrally located mass, which is lobulated with individual lobules separated by intervening areas of decreased attenuation, relating to either previous hemorrhage or necrosis. Enhancement is similarly heterogeneous. Calcification is relatively common, observed in 20-50% of cases and is typically linear and tends to outline tumor lobules.	Malignant rhabdoid tumor is characterized by the round blue tumor cells of high cellularity composed of atypical cells with eccentric nuclei, small nucleoli, and abundant amounts of eosinophilic cytoplasm with frequent mitotic figures.
4.	Polycystic kidney disease	+	+	+ (from hypertension)	+	-	Ultrasound may be helpful in the diagnosis of polycystic kidney disease. Findings on an ultrasound diagnostic of polycystic kidney disease include: At least three unilateral or bilateral cysts in patients 15 - 39 years old Atleast two cysts in each kidney in patients 40 - 59 years old Atleast four cysts in each kidney in patients 60 years of age or older	Renal CT scan may be helpful in the diagnosis of polycystic kidney disease. Findings on CT scan diagnostic of ADPKD include: Numerous renal cysts of varying size and shape with little intervening parenchyma with water attenuation and very thin wall. Reduction in sinus fat due to expansion of the cortex Occasional complex cysts with hyperdense appearance, with possible septations or calcifications Multiple homogeneous and hypoattenuating cystic lesions in the liver in patients with liver involvement	On microscopic histopathological analysis, interstitial fibrosis, tubular atrophy, thickening and lamellation of tubular basement membranes, microcysts and negative immunofluorescence for complement and immunoglobulin are characteristic findings of ADPKD.
5.	Pheochromocytoma	-	-	+ (as a part of the hypertension paroxysm)	-	-	CT is the preferred imaging modality for the diagnosis of pheochromocytoma.	The following findings may be observed on CT scan: Most common extra-adrenal locations are superior and inferior abdominal paraaortic areas, the urinary bladder, thorax, head, neck and pelvis. In sporadic pheochromocytoma, CT and MRI are good choices. The choice depends on availability and cost. In patients with the multiple endocrine neoplasia type 2 (MEN2) syndrome, CT may miss the tumors.	On microscopic pathology, Pheochromocytoma typically demonstrates a nesting (Zellballen) pattern on microscopy. This pattern is composed of well-defined clusters of tumor cells containing eosinophilic cytoplasm separated by fibrovascular stroma.
6.	Burkitt lymphoma	+/- (in non-endemic or sporadic form of the disease)	-	-	-	-	Abdominal ultrasonography may show splenomegaly and ascites.	Chest, abdomen, and pelvis CT scan may be helpful in the diagnosis of Burkitt's lymphoma but it is not done routinely.	On microscopic histopathological analysis, characteristic findings of Burkitt's lymphoma include: Medium-sized (~1.5-2x the size of a RBC) with uniform size ("monotonous") -- key feature (i.e. tumor nuclei size similar to that of histiocytes or endothelial cells) Round nucleus Small nucleoli Relatively abundant cytoplasm (basophilic) Brisk mitotic rate and apoptotic activity Cellular outline usually appears squared off "Starry-sky pattern": The stars in the pattern are tingible-body macrophages (macrophages containing apoptotic tumor cells. The tumour cells are the sky
7.	Intussusception	+	-	-	+/-	+	Ultrasound is the gold standard imaging modality used to diagnose intussusception Target or doughnut sign Edematous intussuscipien forms an external ring around the centrally located intussusceptum Target sign is usually seen in right lower quadrant Layers of intussusception forms pseudo-kidney appearance on the transverse view	CT scan may be helpful in the diagnosis of intussusception. CT scan maybe used when other image modalities like x-ray and ultrasound have not given positive results but suspicion of intussusception is high.	Intussusception occurs if there is an imbalance between the longitudinal and radial smooth muscle forces of intestine that maintain its normal structure. This imbalance leads to a segment of intestine to invaginate into another segment and cause entero-enteral intussusception. Etiology of intussusception is either idiopathic or pathologic (lead point).
8.	Hydronephrosis	+	+/-	-	-	+ (CVA tenderness in case of pyelonephritis)	Ultrasound allows for visualization of the ureters and kidneys and can be used to assess the presence of hydronephrosis and/or hydroureter.	In the case of renal colic (one sided loin pain usually accompanied by a trace of blood in the urine) the initial investigation is usually an intravenous urogram. This has the advantage of showing whether there is any obstruction of flow of urine causing hydronephrosis as well as demonstrating the function of the other kidney. Many stones are not visible on plain x ray or IVU but 99% of stones are visible on CT and therefore CT is becoming a common choice of initial investigation.	The kidney undergoes extensive dilation with atrophy and thinning of the renal cortex.
9.	Dysplastic kidney	N/A	N/A	N/A	N/A	N/A	MCDK is usually diagnosed by ultrasound examination before birth. Mass of non-communicating cysts of variable size. Unlike severe hydronephrosis, in which the largest cystic structure (the renal pelvis) lies in a central location and is surrounded by dilated calices, in multicystic dysplastic kidney the cyst distribution shows no recognizable pattern. Dysplastic, echogenic parenchyma may be visible between the cysts, but no normal renal parenchyma is seen.	MCKD can be discovered accidentally on CT scan. CT scan shows myltiple cysts with absence of renal parenchyma.	MCKD is the result of abnormal differentiation of the renal parenchyma.
10.	Pediatric Neuroblastoma	+	-	-	+/-	+/-	On ultrasound, neuroblastoma is characterized by a heterogeneous echogenicity due to the vascular, necrotic, and calcified content of the mass.	CT scan is the investigation of choice for the diagnosis of neuroblastoma. On CT scan, neuroblastoma is characterized by: Heterogeneous mass Calcification Necrosis Compression of the surrounding vessels Invasion of the psoas muscle or kidneys Swollen lymph nodes	On microscopic histopathological analysis the presence of round blue cells separated by thin fibrous septa are characteristic findings of neuroblastoma. Other findings of neuroblastoma on light microscopy may include: Homer-Wright rosettes (rosettes with a small meshwork of fibers at the center) Neuropil-like stroma (paucicellular stroma with a cotton candy-like appearance) On electron microscopy neuroblastoma is characterized by: Dendritic processes with longitudinally oriented microtubules Membrane bound electron-dense granules that contain catecholamines Presence of desmosomes Absence of glycogen
11.	Pediatric Rhabdomyosarcoma	+	+/-	+/-	-	+/-		On CT scan, rhabdomyosarocma is characterized by: Soft tissue density Some enhancement with contrast Adjacent bony destruction (over 20% of cases)	Rhadbomyosarcoma has an appearance similar to the other round blue cell tumors such as Ewing sarcoma and small cell osteoblastoma.
12.	Mesoblastic nephroma	+	+	-	+	-	Ultrasound may be helpful in the diagnosis of mesoblastic nephroma. Mesoblastic nephroma may presents as a well-defined mass with low-level homogeneous echoes. The presence of concentric echogenic and hypoechoic rings can be a helpful diagnostic feature of mesoblastic nephroma.	CT scan may be helpful in the diagnosis of mesoblastic nephroma. Findings on CT scan suggestive of mesoblastic nephroma include: Solid hypoattenuating renal lesion Variable contrast enhancement No calcification	Classic mesoblastic nephroma Spindle cells in fascicles Infiltrative border Cellular mesoblastic nephroma Plump cells with vesicular nuclei Well-defined border Mitotically active Mixed mesoblastic nephroma Both classic pattern and cellular pattern areas are present	Most common renal tumor that occurs in 1st month of life

Differential Diagnosis of Endemic Burkitt's Lymphoma

Endemic Burkitt's lymphoma typically presents as a cervico-facial mass and must be differentiated from other diseases that may present as a cervico-facial mass such as salivary glands tumors, sialolithiasis, human immunodeficiency virus, radiation, and systemic diseases such as, sarcoidosis, and sjögren's syndrome.

Diseases	Symptoms and sign							Laboratory Findings		Other Findings
	Onset	Unilateral/Bilateral	Pain	Swelling	Tenderness	Purulent discharge	Common site of involvement	ESR	Leukocytosis
Sialolithiasis	Acute	Unilateral	+	+	+	-	Submandibular gland	↑/NL	↑/NL	Radio-opaque in X-ray
Acute bacterial sialadenitis	Acute	Unilateral	+	+	+	+	Parotid	↑	↑	Other sign of infection may be present
Chronic bacterial sialadenitis	Chronic	Unilateral	+	+	-	+/-	Parotid	↑	↑	Other sign of infection may be present
Viral sialadenitis	Acute	Bilateral	+	+	+	-	Parotid	↑	↑	Coryza symptoms
Human immunodeficiency virus	Acute	Bilateral	+	+	-	-	Parotid	NL	NL	Other systemic findings of HIV/ check ELISA
Radiation sialadenitis	Acute	Unilateral	+	+	+	-	Depends on the treatment field	NL	NL	History of radiation in the salivary gland site
Salivary gland tumors	Subacute	Unilateral	-	+	-	-	Parotid	↑/NL	↑/NL	Advance age
Sarcoidosis	Gradual	Bilateral	-	+	-	-	Parotid	↑	↑	Systemic findings in other organs
Sjögren's syndrome	Gradual	Bilateral	+/-	+	-	-	Parotid or submandibular glands	↑/NL	↑/NL	Dry eye/dry mouth
Malnutrition	Gradual	Bilateral	+/-	+	-	-	Parotid	NL	NL	Systemic findings in other organs

Differentials Based on Cell Surface Markers

Based on the expression of cell surface markers, the table below differentiates Burkitt's lymphoma from other diseases that cause similar clinical presentations:

Differential Diagnosis	Surface Immunoglobulin	CD5	CD22/FMC7	CD23	CD79b	CD103
Chronic lymphocytic leukemia	Weakly positive	Positive	Negative	Positive	Negative	Positive/Negative
Prolymphocytic leukemia	Strongly positive	Negative	Positive	Negative	Positive	Negative
Hairy cell leukemia	Strongly positive	Negative	Positive	Negative	Positive/Negative	Positive
Mantle cell lymphoma	Positive	Positive	Strongly positive	Negative	Strongly positive	Negative
Follicular lymphoma	Strongly positive	Negative	Positive	Negative	Strongly positive	Negative

References

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