Non-Hodgkin lymphoma differential diagnosis

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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 like:

Diseases Clinical manifestations Para-clinical findings Pathogonomic finding
Symptoms
Lab Findings Biopsy
Lymphadenopathy Fever Weight loss Night Sweats Rash Other symptoms Immunochemistry Blood work
Non-Hodgkins lymphoma
  • Painless
 + + + +
  • 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
INFECTIONS Bacteria Syphilis[1][2][3][4]
  • Painless
  • Localized
 + - - + Primary syphilis:
  • Chancer

Secondary syphilis:

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

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[5][6][7][8][9]
  • Painful
 + - - +
  • Abdominal pain
  • hepatosplenomegaly
  • Arthritis
  • Brucella is most commonly isolated from blood cultures
 Night sweats, often with characteristic smell, likened to wet hay
Viral Infectious mononucleosis[10]
  • Painful
 + - - +
  • A positive reaction to a mono spot test
  • Direct detection of EBV in blood or lymphoid tissues
 Presence of atypical lymphocytes (a type of mononuclear cell) on the peripheral blood smear.
CMV[11][12]
  • Painful
 + - - + Owl Eye inclusion bodies.
HIV[13][14][15][16]
  • Painful or painless
 - + - -
  • 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
 Plasma HIV RNA viral load
Cat scratch disease[17][18][19][20]
  • Painful
 + - - +
  • 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
 Painful buboes
Mycobacteria Tuberculosis[21][22][23][24][25]
  • Painful
 + + + + Gohn's focus
Parasite Toxoplasmosis[26][27][28][29]
  • Painless
 + - + -
  • IgG, IgM, IgA antibodies against toxoplasmosis seen by ELISA
  • PCR
 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)[30][31][32][33]

  • Painless
 + +/- - + On microscopic histopathological analysis, 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[34][35][36][37]
  • Painless
 - - - +
  • Anti-Ro/SSA
  • Anti-La/SSB
  • Presence of rheumatoid factor (RF)
  • Presence of anti–alpha-fodrin antibody (diagnostic marker of juvenile Sjögren's syndrome)
Sarcoidosis[38][39][40]
  • Painless
 - - - -
  • Can involve all organ systems to varying extent and degree.
  • serum ACE level
 Biopsy of lung shows non-caseatinggranuloma Non-caseatinggranuloma
Diseases Lymphadenopathy Fever Weight loss Night sweats Rash Other symptoms Immunochemistry Blood work Biopsy

Histopathology

Pathogonomical

findings

NEOPLASIA Hodgkin's disease[41][42][43][44]
  • Painless
 + + + +
  • Presents with "B" symptoms
    • Lactate dehydrogenase (LDH) may be increased.
    • ESR elevated
    • Serum creatinine elevated in nephrotic syndrome.
    • Alkaline phosphatase (ALP) increased
    • Hypercalcemia, hypernatremia, and hypoglycemia.

Fine-needle aspiration

  • Mononucleate and binucleate Reed-Sternberg cells in a background of inflammatory cells
 Reed-Sternberg cells on microscopic pathology.
Chronic lymphocytic leukemia[45][46][47][48]
  • Painless
 + + + -
  • Monoclonality of kappa and lambda producing B cells
  • Presence of smudge cells

CBC

Small cell carcinoma of the lung[49][50][51][52][53]
  • Painless
 - - - -

Nearly all SCLC are immunoreactive for

Neuroendocrine and neural differentiation result in the expression of molecules like

  • 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.
Melanoma[54][55][56]
  • Painless
 - - - -
  • Positive for CD133+
  • Positive for CD34+
  • 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[57][58][59][60][61][62][63]
  • Painless
 + + - + -

CBC

- On chest CT scan, Halo sign is seen due to the angioinvasive nature of the disease
Angioimmunoblastic lymphadenopathy[64][65][66][67]
  • Painless
 + + + +
  • Immunophenotyping
  • Fluorescence in situ hybridization (FISH)
Lymph node or extranodal tissue biopsy is diagnostic of angioimmunoblastic T-cell lymphoma.
  • 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)[68]
  • Painless
 + + - - - -
  • Hypersecretion of the cytokine IL-6.

References

  1. ↑ Carlson JA, Dabiri G, Cribier B, Sell S (2011). "The immunopathobiology of syphilis: the manifestations and course of syphilis are determined by the level of delayed-type hypersensitivity". Am J Dermatopathol. 33 (5): 433–60. doi:10.1097/DAD.0b013e3181e8b587. PMC 3690623. PMID 21694502.
  2. ↑ Fitzgerald TJ (1992). "The Th1/Th2-like switch in syphilitic infection: is it detrimental?". Infect Immun. 60 (9): 3475–9. PMC 257347. PMID 1386838.
  3. ↑ Singh AE, Romanowski B (1999). "Syphilis: review with emphasis on clinical, epidemiologic, and some biologic features". Clin Microbiol Rev. 12 (2): 187–209. PMC 88914. PMID 10194456.
  4. ↑ Engelkens HJ, ten Kate FJ, Vuzevski VD, van der Sluis JJ, Stolz E (1991). "Primary and secondary syphilis: a histopathological study". Int J STD AIDS. 2 (4): 280–4. PMID 1911961.
  5. ↑ Pappas G, Akritidis N, Bosilkovski M, Tsianos E (2005). "Brucellosis". N Engl J Med. 352 (22): 2325–36. doi:10.1056/NEJMra050570. PMID 15930423.
  6. ↑ Zhan Y, Liu Z, Cheers C (1996). "Tumor necrosis factor alpha and interleukin-12 contribute to resistance to the intracellular bacterium Brucella abortus by different mechanisms". Infect Immun. 64 (7): 2782–6. PMC 174139. PMID 8698508.
  7. ↑ Gazapo E, Gonzalez Lahoz J, Subiza JL, Baquero M, Gil J, de la Concha EG (1989). "Changes in IgM and IgG antibody concentrations in brucellosis over time: importance for diagnosis and follow-up". J Infect Dis. 159 (2): 219–25. PMID 2915152.
  8. ↑ Arenas GN, Staskevich AS, Aballay A, Mayorga LS (2000). "Intracellular trafficking of Brucella abortus in J774 macrophages". Infect Immun. 68 (7): 4255–63. PMC 101738. PMID 10858243.
  9. ↑ Lapaque N, Moriyon I, Moreno E, Gorvel JP (2005). "Brucella lipopolysaccharide acts as a virulence factor". Curr Opin Microbiol. 8 (1): 60–6. doi:10.1016/j.mib.2004.12.003. PMID 15694858.
  10. ↑ Chapman AL, Watkin R, Ellis CJ (2002). "Abdominal pain in acute infectious mononucleosis". BMJ. 324 (7338): 660–1. doi:10.1136/bmj.324.7338.660. PMID 11895827.
  11. ↑ Griffiths P, Lumley S (2014). "Cytomegalovirus". Curr Opin Infect Dis. 27 (6): 554–9. doi:10.1097/QCO.0000000000000107. PMID 25304390.
  12. ↑ Pytka D, Czarkowska-Pączek B (2016). "[CMV infection in elderly]". Przegl Lek. 73 (4): 241–4. PMID 27526428.
  13. ↑ Pantaleo G, Graziosi C, Fauci AS (1993). "New concepts in the immunopathogenesis of human immunodeficiency virus infection". N Engl J Med. 328 (5): 327–35. doi:10.1056/NEJM199302043280508. PMID 8093551.
  14. ↑ Coovadia, H. (2004). "Antiretroviral agents—how best to protect infants from HIV and save their mothers from AIDS". N. Engl. J. Med. 351 (3): 289–292. PMID 15247337.
  15. ↑ Lifson AR (1988). "Do alternate modes for transmission of human immunodeficiency virus exist? A review". JAMA. 259 (9): 1353–6. PMID 2963151.
  16. ↑ WHO (2007). "WHO and UNAIDS announce recommendations from expert consultation on male circumcision for HIV prevention". WHO.int. Retrieved 2007-07-13.
  17. ↑ Chomel BB; Kasten RW; Floyd-Hawkins K; et al. (1996). "Experimental transmission of Bartonella henselae by the cat flea". J. Clin. Microbiol. 34 (8): 1952–6. PMC 229161. PMID 8818889. Unknown parameter |month= ignored (help); Unknown parameter |author-separator= ignored (help)
  18. ↑ Higgins JA, Radulovic S, Jaworski DC, Azad AF (1996). "Acquisition of the cat scratch disease agent Bartonella henselae by cat fleas (Siphonaptera:Pulicidae)". J. Med. Entomol. 33 (3): 490–5. PMID 8667399. Unknown parameter |month= ignored (help)
  19. ↑ Telford SR III, Wormser GP (2010). "Bartonella spp. transmission by ticks not established". Emerg Infect Dis. 16 (3): 379–84. doi:10.3201/eid1603.090443. PMID 20202410. Unknown parameter |month= ignored (help)
  20. ↑ Foil L; Andress E; Freeland RL; et al. (1998). "Experimental infection of domestic cats with Bartonella henselae by inoculation of Ctenocephalides felis (Siphonaptera: Pulicidae) feces". J. Med. Entomol. 35 (5): 625–8. PMID 9775583. Unknown parameter |month= ignored (help); Unknown parameter |author-separator= ignored (help)
  21. ↑ Herrmann J, Lagrange P (2005). "Dendritic cells and Mycobacterium tuberculosis: which is the Trojan horse?". Pathol Biol (Paris). 53 (1): 35–40. PMID 15620608.
  22. ↑ Silva Miranda M, Breiman A, Allain S, Deknuydt F, Altare F (2012). "The tuberculous granuloma: an unsuccessful host defence mechanism providing a safety shelter for the bacteria?". Clin Dev Immunol. 2012: 139127. doi:10.1155/2012/139127. PMC 3395138. PMID 22811737.
  23. ↑ Silva Miranda M, Breiman A, Allain S, Deknuydt F, Altare F (2012). "The tuberculous granuloma: an unsuccessful host defence mechanism providing a safety shelter for the bacteria?". Clin Dev Immunol. 2012: 139127. doi:10.1155/2012/139127. PMC 3395138. PMID 22811737.
  24. ↑ Lawn SD, Zumla AI (2011). "Tuberculosis". Lancet. 378 (9785): 57–72. doi:10.1016/S0140-6736(10)62173-3. PMID 21420161.
  25. ↑ Zumla A, Raviglione M, Hafner R, von Reyn CF (2013). "Tuberculosis". N Engl J Med. 368 (8): 745–55. doi:10.1056/NEJMra1200894. PMID 23425167.
  26. ↑ Wolf A, Cowen D, Paige BH (1940). "TOXOPLASMIC ENCEPHALOMYELITIS : IV. EXPERIMENTAL TRANSMISSION OF THE INFECTION TO ANIMALS FROM A HUMAN INFANT". J Exp Med. 71 (2): 187–214. PMC 2135077. PMID 19870956.
  27. ↑ FRENKEL JK (1949). "Pathogenesis, diagnosis and treatment of human toxoplasmosis". J Am Med Assoc. 140 (4): 369–77. PMID 18128617.
  28. ↑ Frenkel JK (1974). "Pathology and pathogenesis of congenital toxoplasmosis". Bull N Y Acad Med. 50 (2): 182–91. PMC 1749352. PMID 4592096.
  29. ↑ Conley FK, Jenkins KA, Remington JS (1981). "Toxoplasma gondii infection of the central nervous system. Use of the peroxidase-antiperoxidase method to demonstrate toxoplasma in formalin fixed, paraffin embedded tissue sections". Hum Pathol. 12 (8): 690–8. PMID 7026410.
  30. ↑ Elkon K (1995). "Autoantibodies in systemic lupus erythematosus". Curr Opin Rheumatol. 7 (5): 384–8. PMID 8519610.
  31. ↑ Yaniv G, Twig G, Shor DB, Furer A, Sherer Y, Mozes O, Komisar O, Slonimsky E, Klang E, Lotan E, Welt M, Marai I, Shina A, Amital H, Shoenfeld Y (2015). "A volcanic explosion of autoantibodies in systemic lupus erythematosus: a diversity of 180 different antibodies found in SLE patients". Autoimmun Rev. 14 (1): 75–9. doi:10.1016/j.autrev.2014.10.003. PMID 25449682.
  32. ↑ Dye JR, Ullal AJ, Pisetsky DS (2013). "The role of microparticles in the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus". Scand. J. Immunol. 78 (2): 140–8. doi:10.1111/sji.12068. PMID 23672591.
  33. ↑ Kirou KA, Lee C, George S, Louca K, Papagiannis IG, Peterson MG, Ly N, Woodward RN, Fry KE, Lau AY, Prentice JG, Wohlgemuth JG, Crow MK (2004). "Coordinate overexpression of interferon-alpha-induced genes in systemic lupus erythematosus". Arthritis Rheum. 50 (12): 3958–67. doi:10.1002/art.20798. PMID 15593221.
  34. ↑ Ramos-Casals M, Brito-Zerón P, Solans R, Camps MT, Casanovas A, Sopeña B, Díaz-López B, Rascón FJ, Qanneta R, Fraile G, Pérez-Alvarez R, Callejas JL, Ripoll M, Pinilla B, Akasbi M, Fonseca E, Canora J, Nadal ME, de la Red G, Fernández-Regal I, Jiménez-Heredia I, Bosch JA, Ayala MD, Morera-Morales L, Maure B, Mera A, Ramentol M, Retamozo S, Kostov B (February 2014). "Systemic involvement in primary Sjogren's syndrome evaluated by the EULAR-SS disease activity index: analysis of 921 Spanish patients (GEAS-SS Registry)". Rheumatology (Oxford). 53 (2): 321–31. doi:10.1093/rheumatology/ket349. PMID 24162151.
  35. ↑ Yazdany J, Schmajuk G, Robbins M, Daikh D, Beall A, Yelin E, Barton J, Carlson A, Margaretten M, Zell J, Gensler LS, Kelly V, Saag K, King C (March 2013). "Choosing wisely: the American College of Rheumatology's Top 5 list of things physicians and patients should question". Arthritis Care Res (Hoboken). 65 (3): 329–39. doi:10.1002/acr.21930. PMC 4106486. PMID 23436818.
  36. ↑ Beckman KA, Luchs J, Milner MS (2016). "Making the diagnosis of Sjögren's syndrome in patients with dry eye". Clin Ophthalmol. 10: 43–53. doi:10.2147/OPTH.S80043. PMC 4699514. PMID 26766898.
  37. ↑ Both T, Dalm VA, van Hagen PM, van Daele PL (2017). "Reviewing primary Sjögren's syndrome: beyond the dryness - From pathophysiology to diagnosis and treatment". Int J Med Sci. 14 (3): 191–200. doi:10.7150/ijms.17718. PMC 5370281. PMID 28367079.
  38. ↑ Iannuzzi MC, Rybicki BA, Teirstein AS: Sarcoidosis. N Engl J Med 357:2153–2165, 2007.
  39. ↑ Zissel G: Cellular activation in the immune response of sarcoidosis. Semin Respir Crit Care Med 35:307–315, 2014.
  40. ↑ Rosen Y: Pathology of sarcoidosis. Semin Respir Crit Care Med 28(1):36–52, 2007.
  41. ↑ Scientific Style and Format: The CBE Manual for Authors, Editors, and Publishers. Cambridge University Press. 1994. pp. 97–. ISBN 978-0-521-47154-1.
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  43. ↑ Shishodia S, Aggarwal BB (2004). "Nuclear factor-kappaB activation mediates cellular transformation, proliferation, invasion angiogenesis and metastasis of cancer". Cancer Treat Res. 119: 139–73. PMID 15164877.
  44. ↑ Bargou RC, Leng C, Krappmann D, Emmerich F, Mapara MY, Bommert K; et al. (1996). "High-level nuclear NF-kappa B and Oct-2 is a common feature of cultured Hodgkin/Reed-Sternberg cells". Blood. 87 (10): 4340–7. PMID 8639794.
  45. ↑ Nabhan C, Rosen ST (2014). "Chronic lymphocytic leukemia: a clinical review". JAMA. 312 (21): 2265–76. doi:10.1001/jama.2014.14553. PMID 25461996.
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  47. ↑ Chronic Lymphocytic Leukemia. Libre Pathology (2015) http://librepathology.org/wiki/index.php/B_cell_small_lymphocytic_lymphoma/chronic_lymphocytic_leukemia Accessed on October, 12 2015
  48. ↑ Hallek M (2015). "Chronic lymphocytic leukemia: 2015 Update on diagnosis, risk stratification, and treatment". Am J Hematol. 90 (5): 446–60. doi:10.1002/ajh.23979. PMID 25908509.
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  52. ↑ K. Hibi, T. Takahashi, Y. Sekido, R. Ueda, T. Hida, Y. Ariyoshi, H. Takagi & T. Takahashi (1991). "Coexpression of the stem cell factor and the c-kit genes in small-cell lung cancer". Oncogene. 6 (12): 2291–2296. PMID 1722571. Unknown parameter |month= ignored (help)
  53. ↑ Yuri Pekarsky, Alexey Palamarchuk, Kay Huebner & Carlo M. Croce (2002). "FHIT as tumor suppressor: mechanisms and therapeutic opportunities". Cancer biology & therapy. 1 (3): 232–236. PMID 12432269. Unknown parameter |month= ignored (help)
  54. ↑ Miller AJ, Mihm MC (2006). "Melanoma". N Engl J Med. 355 (1): 51–65. doi:10.1056/NEJMra052166. PMID 16822996.
  55. ↑ Schanderdorf D, Kochs C, Livingstone E (2013). Handbook of Cutaneous Melanoma: A Guide to Diagnosis and Treatment. Springer.
  56. ↑ Mooi W, Krausz T (2007). Pathology of Melanocytic Disorders 2nd Ed. CRC Press.
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  59. ↑ Schmoldt A, Benthe HF, Haberland G (1975). "Digitoxin metabolism by rat liver microsomes". Biochem Pharmacol. 24 (17): 1639–41. PMC 5922622. PMID https://doi.org/10.1016/S0046-8177(72)80005-4 Check |pmid= value (help).
  60. ↑ Beaty MW, Toro J, Sorbara L, Stern JB, Pittaluga S, Raffeld M; et al. (2001). "Cutaneous lymphomatoid granulomatosis: correlation of clinical and biologic features". Am J Surg Pathol. 25 (9): 1111–20. PMID 11688570.
  61. ↑ Bartosik W, Raza A, Kalimuthu S, Fabre A (2012). "Pulmonary lymphomatoid granulomatosis mimicking lung cancer". Interact Cardiovasc Thorac Surg. 14 (5): 662–4. doi:10.1093/icvts/ivr083. PMC 3329320. PMID 22361129.
  62. ↑ Colby TV (2012). "Current histological diagnosis of lymphomatoid granulomatosis". Mod Pathol. 25 Suppl 1: S39–42. doi:10.1038/modpathol.2011.149. PMID 22214969.
  63. ↑ Hare SS, Souza CA, Bain G, Seely JM, Gomes MM; et al. (2012). "The radiological spectrum of pulmonary lymphoproliferative disease". Br J Radiol. 85 (1015): 848–64. doi:10.1259/bjr/16420165. PMC 3474050. PMID 22745203.
  64. ↑ Swerdlow, S.H.; Campo, E.; Harris, N.L.; Jaffe, E.S.; Pileri, S.A.; Stein, H.; Thiele, J.; Vardiman, J.W (2008). "11 Mature T- and NK-cell neoplasms: Angioimmunoblastic T-cell lymphoma". WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC WHO Classification of Tumours. 2 (4th ed.). IARC. ISBN 9283224310.
  65. ↑ [1] Quintanilla-Martinez L, Fend F, Moguel LR, Spilove L, Beaty MW, Kingma DW, Raffeld M, Jaffe ES. "Peripheral T-cell lymphoma with Reed-Sternberg-like cells of B-cell phenotype and genotype associated with Epstein-Barr virus infection." Am J Surg Pathol. 1999 Oct;23(10):1233-40. PMID: 10524524
  66. ↑ [2] Ree HJ, Kadin ME, Kikuchi M, Ko YH, Go JH, Suzumiya J, Kim DS. "Angioimmunoblastic lymphoma (AILD-type T-cell lymphoma) with hyperplastic germinal centers." Am J Surg Pathol. 1998 Jun;22(6):643-55. PMID: 9630171
  67. ↑ [3] Kaneko Y, Maseki N, Sakurai M, Takayama S, Nanba K, Kikuchi M, Frizzera G. "Characteristic karyotypic pattern in T-cell lymphoproliferative disorders with reactive "angioimmunoblastic lymphadenopathy with dysproteinemia-type" features." Blood. 1988 Aug;72(2):413-21. PMID: 3261178
  68. ↑ Aoki Y, Yarchoan R, Wyvill K, Okamoto S, Little RF, Tosato G. Detection of viral interleukin-6 in Kaposi sarcoma-associated herpesvirus-linked disorders. Blood 2001;97(7):2173-6.

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