We searched PubMed from January, 1989, until October, 2009, for reports in English with the keywords “lymphoma”, “T-cell”, “B-cell”, “natural killer cell”, “Hodgkin”, “immunophenotyping”, and “molecular analysis”. We also searched the reference lists of selected reports so that all relevant articles could be reviewed. Some articles before 1989 were included if they were pertinent.
ReviewCommon misdiagnoses in lymphomas and avoidance strategies
Introduction
Diagnosis of lymphoma is an evolving science. Initially based on morphology alone, classification of lymphomas has progressed to include lymphoid lineages, cell types, and clinical features. In WHO classifications, lymphomas are categorised on the basis of morphological, immunophenotypical, genetic, and clinical characteristics. An accurate diagnosis, apart from being pathologically important, provides useful guidance to clinicians for effective treatment.
Lymphoma diagnosis, however, is one of the most complicated tasks in histopathology. Importantly, reactive lymphoid disorders need to be distinguished from truly neoplastic lesions, because the exact classification greatly affects patient treatment. Lymphoma classification is not always concordant between histopathologists. For common B-cell lymphomas, the concordance rate between community and specialised lymphoma pathologists is about 95%.1 However, for more difficult subtypes of lymphomas, such as Burkitt's lymphoma and peripheral T-cell lymphoma, concordance based on morphology could be lower than 50%, although with immunophenotyping this rate might increase to 60–80%.2 Thus, 5% of patients with common B-cell lymphomas and up to 20–40% of patients with less common lymphoma types might be inaccurately diagnosed. Lymphoma diagnosis is based on morphological examination complemented by immunophenotyping and molecular genetic investigations. However, even pathologists with much experience can encounter difficulties in each of these steps.
Section snippets
Kikuchi lymphadenitis
Some reactive lymphoid proliferations exhibit a striking increase in large lymphoid cells, and when accompanied by distortion of tissue architecture, can strongly mimic lymphoma (panel 1). Kikuchi lymphadenitis is a self-limiting disorder, often affecting young women. It is of unknown cause and more prevalent in Asians than in white people.3 Patients usually present with enlarged lymph nodes in the neck, but are otherwise well. Typical laboratory findings are an increased ESR, lymphocytosis,
Malignant lymphoma often misdiagnosed as reactive disorders
Reasons that some lymphomas can mimic reactive lesions include: subtle cytological atypia and absence of cellular monotony, as in a small-cell variant of anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALCL) and extranodal marginal zone lymphoma; paucity of neoplastic cells or abundance of inflammatory cells, as in lymphohistiocytic and paucicellular variants of ALK-positive ALCL, lymphomatoid granulomatosis, certain variants of classical Hodgkin's lymphoma, and
Complexities of classification
Errors in classification of lymphomas are inevitable in view of the complexities of WHO classifications (webappendix). In some instances, misclassifications might be inconsequential in relation to treatment. However, if aggressive lymphomas are misclassified as low-grade lymphomas, patient outcomes are jeopardised because of undertreatment. In poorly fixed tissues, thickly-cut sections, or core needle-biopsy materials, neoplastic cells of high-grade lymphomas, such as lymphoblastic lymphoma,
Difficulties in lymphoma diagnosis
Immunophenotyping is important in lymphoma diagnosis, and is crucial for making treatment decisions. Although lineage assignment is often possible with flow cytometry, or immunohistochemistry with an extensive panel of antibodies; in the routine laboratory, usually a panel of fewer antibodies that identify T cells, B cells, and NK-cell lineages are applied. However, cross-lineage expression of antigens can occasionally arise, creating diagnostic challenges. This outcome has been attributed
Cases needing clonality analysis
During lymphocyte development, antigen receptor genes undergo rearrangement. This stepwise rearrangement of the IG or TCR gene joins V, D, and J gene segments, with nucleotides deleted or randomly inserted at the joining sites, leading to a large diversity of antigen receptors. Reactive lymphoid proliferations have polyclonally rearranged IG or TCR genes, whereas malignant lymphoid lesions show clonal rearrangement.
In clinical practice, standard histopathological assessment supplemented by
Conclusion
With careful assessment of the clinical history and methodical morphological examination complemented by appropriate immunophenotyping, most cases of lymphomas can be correctly diagnosed and classified. Molecular analysis will be helpful if doubts exist, especially when the size or quality of the biopsy limits a comprehensive morphological and immunophenotypical examination. However, some cases will remain challenging, necessitating teamwork from the clinician, pathologist, and molecular
Search strategy and selection criteria
References (74)
- et al.
Myeloperoxidase expression by histiocytes in Kikuchi's and Kikuchi-like lymphadenopathy
Am J Pathol
(2001) - et al.
Clinical, immunologic, and genetic features of an autoimmune lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis
Blood
(1997) - et al.
Pathological findings in human autoimmune lymphoproliferative syndrome
Am J Pathol
(1998) - et al.
Systemic IgG4-related lymphadenopathy: a clinical and pathologic comparison to multicentric Castleman's disease
Mod Pathol
(2009) - et al.
Frequent expression of the B-cell specific activator protein in Reed-Sternberg cells of classical Hodgkin's disease provides further evidence for its B-cell origin
Blood
(1999) - et al.
The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma
Blood
(2003) - et al.
Plasmablastic lymphomas of the oral cavity: a new entity associated with the human immunodeficiency virus infection
Blood
(1997) - et al.
Lymphomas with concurrent BCL2 and MYC translocations: the critical factors associated with survival
Blood
(2009) - et al.
Subcutaneous panniculitis-like T-cell lymphoma: definition, classification, and prognostic factors: an EORTC Cutaneous Lymphoma Group Study of 83 cases
Blood
(2008) - et al.
CD20: a regulator of cell-cycle progression of B lymphocytes
Immunol Today
(1994)
Down-regulation of CD20 expression in B-cell lymphoma cells after treatment with rituximab-containing combination chemotherapies: its prevalence and clinical significance
Blood
Peripheral T-cell lymphoma (excluding anaplastic large-cell lymphoma): results from the Non-Hodgkin's Lymphoma Classification Project
Ann Oncol
Clinicopathologic features and treatment outcome of mature T-cell and natural killer-cell lymphomas diagnosed according to the World Health Organization classification schemeL a single center experience of 10 years
Ann Oncol
Peripheral T-cell lymphoma with aberrant expression of CD79a and CD20: a diagnostic pitfall
Mod Pathol
Immunoreactivity of B-cell markers (CD79a, L26) in rare cases of extranodal cytotoxic peripheral T- (NK/T-) cell lymphomas
Mod Pathol
Comparison of referring and final pathology for patients with non-Hodgkin's lymphoma in the National Comprehensive Cancer Network
J Clin Oncol
A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project
Blood
Kikuchi's lymphadenitis. A morphologic analysis of 75 cases with special reference to unusual features
Am J Surg Pathol
Tumors of the lymphoreticular system. Part A. The lymph node
Infectious mononucleosis. The spectrum of morphologic changes simulating lymphoma in lymph nodes and tonsils
Am J Surg Pathol
Autoimmune lymphoproliferative syndrome: molecular basis of disease and clinical phenotype
Br J Haematol
Autoimmune lymphoproliferative syndrome with somatic Fas mutations
N Engl J Med
Histologic features of sinus histiocytosis with massive lymphadenopathy in patients with autoimmune lymphoproliferative syndrome
Am J Surg Pathol
Autoimmune pancreatitis: Prototype of IgG4-related sclerosing disease
Adv Anat Pathol
IgG4-related sclerosing mastitis: description of a new member of the IgG4-related sclerosing diseases
Am J Surg Pathol
IgG4-related sclerosing pachymeningitis: a previously unrecognized form of central nervous system involvement in IgG4-related sclerosing disease
Am J Surg Pathol
Chronic sclerosing dacryoadenitis: part of the spectrum of IgG4-related sclerosing disease?
Am J Surg Pathol
Lymphadenopathy of IgG4-related sclerosing disease
Am J Surg Pathol
Anaplastic large cell lymphoma: redefining its morphologic spectrum and importance of recognition of the ALK-positive subset
Adv Anat Pathol
Anaplastic large cell lymphoma (ALCL), ALK-positive
Hypocellular anaplastic large cell lymphoma mimicking inflammatory lesions of lymph nodes
Am J Surg Pathol
The perivascular cuff of large lymphoid cells: a clue to diagnosis of anaplastic large cell lymphoma
Int J Surg Pathol
Hodgkin's disease occurring in monocytoid B-cell clusters
Am J Clin Pathol
The foamy macrophages in Hodgkin's disease
Arch Pathol
Lymph-node infarction and malignant lymphoma: a multicentre survey of European, English and American cases
Histopathology
Antigen preservation in infarcted lymphoid tissue. A novel approach to the infarcted lymph node using monoclonal antibodies effective in routinely processed tissues
Am J Surg Pathol
Primary mediastinal (thymic) large B-cell lymphoma
Cited by (38)
Reactive Lymphadenopathy in the Pediatric Population with a Focus on Potential Mimics of Lymphoma
2023, Seminars in Diagnostic PathologyDermatological manifestations of hematologic neoplasms. Part I: secondary specific skin lesions
2023, Anais Brasileiros de DermatologiaCitation Excerpt :Very often, only clinical, histopathological, and immunohistochemical factors are not enough to establish the diagnosis of lymphoma. In these cases, molecular methods are also used to investigate clonality and identify the cell line involved.38 To differentiate between PCL and SCL, it is necessary to perform the patient’s staging through imaging tests, bone marrow biopsy, peripheral blood flow cytometry, or other methods, aiming to assess the presence of nodal or other organ involvement at the time of diagnosis, which characterizes the SCL.
The application of antigen receptor gene rearrangement of BIOMED-2 in the pathologic diagnosis of 348 cases with non-Hodgkin lymphoma in a single institution in Southwest of China
2019, Pathology Research and PracticeCitation Excerpt :The coexistence of B-cell and T-cell clones may due to the presence of a small amount of reactive T cells in small specimens or high-load B-cell lymphoma, so there are no enough cells produce a polyclonal background, and a small number of reactive cells produce surface-like clonal PCR products [19], or maybe there has cross-lineage gene rearrangement. Cross-lineage gene rearrangement is often considered to be a dominant PCR product rearranged at a single site [7]. It is also possible that the recombinase involved in Ig gene rearrangement at the early stage of differentiation of B lymphocytes is similar to that in TCR and has the same recombinant mechanism [39].
Diagnosis of aggressive B-cell lymphoma in children: A practical approach
2016, Diagnostic HistopathologyCitation Excerpt :A primary infection adolescent may manifest as mononucleosis (glandular fever). The histological picture of tissues such as lymph nodes and tonsils during a primary infection by EBV is the most relevant non-neoplastic mimicker of aggressive B-cell lymphoma in young patients.7,9 Histologic features of lymphoma are found in EBV infection such as tissue destruction and sheets of blasts.
Lessons we learn from hematopathology consultation in Taiwan
2013, Journal of the Formosan Medical AssociationCitation Excerpt :Clinical correlation, peripheral eosinophilia, and identification of necrotic foci help to establish the diagnosis.27 Other lesions that have been misdiagnosed as lymphoma include infectious mononucleosis,24 Kikuchi disease,28 Epstein–Barr virus (EBV)-associated lymphoid hyperplasia/reactivation,26 lupus lymphadenitis,28 and stromal-rich hyaline vascular Castleman disease.29 In patients with adult-onset immunodeficiency syndrome,30 systemic mycobacterial lymphadenopathy would also masquerade as peripheral T-cell lymphoma, NOS, or angioimmunoblastic T-cell lymphoma.31