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Lymphoma & related disorders

Mature B cell neoplasms

Large B cell lymphomas-special subtypes

Primary mediastinal


Isaac E. McCool, M.D.
Mahsa Khanlari, M.D.

Last author update: 19 November 2024
Last staff update: 19 November 2024

Copyright: 2001-2024, PathologyOutlines.com, Inc.

PubMed Search: Primary mediastinal large B cell lymphoma

Isaac E. McCool, M.D.
Mahsa Khanlari, M.D.
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Laboratory | Radiology description | Prognostic factors | Case reports | Treatment | Gross description | Frozen section description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Positive stains | Negative stains | Flow cytometry description | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2
Cite this page: McCool IE, Khanlari M. Primary mediastinal. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomamediastinal.html. Accessed December 26th, 2024.
Definition / general
  • Mature and clinically aggressive large B cell lymphoma
  • Probable thymic B cell origin
Essential features
  • Large B cell lymphoma in the anterior mediastinum
  • Mature B cell phenotype, accompanied by at least partial expression of CD23 and CD30
  • Desirable
    • Distinctive compartmentalized stromal sclerosis
    • Expression of at least 1 of the following markers: MAL, CD200, PDL1 and PDL2
    • Copy gain or rearrangement of CD274 / PDL2 / PDL1 locus or rearrangement involving CIITA (C2TA)
Terminology
  • Primary mediastinal clear cell lymphoma of B cell type (terminology no longer used)
  • Mediastinal diffuse large cell lymphoma with sclerosis (terminology no longer used)
ICD coding
  • ICD-O: 9679/3 - mediastinal large B cell lymphoma
  • ICD-11: 2A81.0 - primary mediastinal large B cell lymphoma
Epidemiology
  • Predominantly in young adults (median age: 35 years)
  • Female predominance (F:M = 2:1)
  • Familial predisposition in a subset of patients
  • Comprises 2 - 3% of non-Hodgkin lymphomas
  • Comprises 90 - 95% of anterior mediastinal non-Hodgkin lymphomas
  • References: Am J Surg Pathol 1986;10:176, Adv Anat Pathol 2019;26:346
Sites
  • Presents with a localized anterosuperior mediastinal mass arising in the thymic area
  • Regional supraclavicular and cervical lymph node involvement
Pathophysiology
  • Unknown
  • Possible pathways in lymphomagenesis
    • Activation of JAK-STAT and NFκB pathways
    • IL4R mutations (Blood 2018;131:2036)
    • Distinctive population of CD21- thymic B cells in the normal thymus are considered the normal counterpart for primary mediastinal large B cell lymphoma (PMBCL) (Int J Cancer 1989;43:10)
Etiology
  • Unknown
Clinical features
  • Symptoms: cough, dyspnea or superior vena cava syndrome (mass effect), effusions
  • Mass is often bulky (> 10 cm in 60 - 70% of patients)
  • Frequent direct extension invades adjacent structures, such as the lung, pleura and pericardium
    • Note that biopsy of the lung may be the first diagnostic biopsy, thus this differential diagnosis must be considered when making a diagnosis of large B cell lymphoma in the lung, particularly in young or female patients
  • Aside from direct extension into surrounding structures, extramediastinal involvement is unusual at the time of initial diagnosis (Am J Surg Pathol 2019;43:110, Am J Surg Pathol 2015;39:1322)
  • Bone marrow is not involved at the time of initial presentation; absence of systemic lymphadenopathy
  • At the time of relapse / progression, shows an unusual predilection for involvement of kidney, adrenal gland, liver and central nervous system; may involve bone marrow
Diagnosis
  • Fine needle aspiration (FNA) has a place as the first screening procedure
  • However, a tissue biopsy is recommended
Laboratory
  • Diagnosis of PMBCL usually does not require ancillary molecular studies
  • Gene expression profiling can identify PMBCL with high accuracy (85%) (Blood 2018;132:2401) 
  • Rearrangements of CIITA (C2TA)
  • Abnormalities of JAK2 / PDL1 (CD274) and PDL2 locus at 9p24.1
  • Rearrangements of BCL2, BCL6 and MYC are rare to absent
Radiology description
  • Computed tomography (CT) scan (AJR Am J Roentgenol 2019;213:W194)
    • Anterior mediastinal mass and less commonly as posterior mediastinal mass
    • Unilateral elevation of hemidiaphragm, pleural effusion and pericardial effusion
Prognostic factors
  • 70 - 90% chance of cure with appropriate therapy (Br J Haematol 2019;185:25)
  • Poor prognostic factors: pleural or pericardial effusion, extension beyond mediastinum, B symptoms, advanced clinical stage, high serum lactate dehydrogenase, relapse within the first 18 months, unsatisfactory response to induction (15 - 20% of patients)
  • While cases of relapsed / refractory PMBCL still portend a poor prognosis, chimeric antigen receptor T cell therapy and second line chemotherapy treatment regimens (leading to autologous stem cell transplant) have shown promise, including immune checkpoint inhibitors like pembrolizumab and nivolumab with brentuximab vedotin (N Engl J Med 2017;377:2531, J Clin Oncol 2019;37:3291, J Clin Oncol 2019;37:3081)
Case reports
  • 15 year old girl with rearrangements of MYC and BCL6 by fluorescent in situ hybridization (Am J Clin Pathol 2016;145:710)
  • 48 year old man, 72 year old woman and 80 year old man with nodal diffuse large B cell lymphoma with morphologic features of primary mediastinal large B cell lymphoma presenting in submandibular or supraclavicular lymph nodes (Am J Surg Pathol 2019;43:110)
  • 54 year old Chinese man, a renal recipient with Hashimoto thyroiditis, presented with an increasing neck mass and progressive dyspnea (Int J Clin Exp Pathol 2015;8:5944)
Treatment
  • R-EPOCH: rituximab, etoposide, prednisone, Oncovin (vincristine), cyclophosphamide and doxorubicin
    • Better than R-CHOP: rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone
    • Note that the treatment regimen is different than that of diffuse large B cell lymphoma, NOS and classic Hodgkin lymphoma, thus appropriate identification of this distinct lymphoma has immediate therapeutic implications

  • Adult treatment protocol may need to be considered in children (Blood 2013;121:278)
  • Postchemotherapy positron emission tomography (PET) evaluation may represent a tool to guide radiation therapy usage (Best Pract Res Clin Haematol 2018;31:241)
  • Primary refractory PMBCL might benefit from autologous hematopoietic stem cell transplant
  • Relapsed / refractory patients might benefit from chimeric antigen receptor T cell (CAR-T) cellular therapy and the use of PD1 inhibitors with or without brentuximab vedotin (N Engl J Med 2017;377:2531, Lancet Oncol 2019;20:31, J Clin Oncol 2019;37:3081)
Gross description
  • Mass is often bulky (usually > 10 cm)
  • Most frequently diagnosed based on core biopsy of mediastinal mass or by biopsy of the involved lung in patients with a mediastinal mass
    • Because mediastinal mass may be lymphoma, which is generally not resected, it is unusual to have a resection specimen of this tumor
  • Reference: Jaffe: Hematopathology, 2nd Edition, 2016
Frozen section description
  • Definitive diagnosis should not be made at the time of frozen section given that required diagnostic features cannot be determined (e.g., immunophenotype) but assessment of the quality and quantity of tissue for further diagnostic studies is essential
  • Diagnosis of lymphoma can be suspected if a population of intermediate to large sized and cytologically atypical lymphoid cells are seen
    • There is frequent associated sclerosis and may be necrosis, thus the differential diagnosis should include the possibility of classic Hodgkin lymphoma
  • Recommend that not all diagnostic tissue be frozen; save a portion of the sample for routine histology so that important morphologic features can be seen in permanent sections
  • Reference: Jaffe: Hematopathology, 2nd Edition, 2016
Microscopic (histologic) description
  • Characterized by a variety of possible morphologic appearances
  • May mimic nodular sclerosis classic Hodgkin lymphoma or diffuse large B cell lymphoma, NOS
  • Polymorphic background associated with classic Hodgkin lymphoma is usually absent
  • Neoplastic cells are usually intermediate sized lymphoma cells present in a diffuse or clustered distribution
    • Usually more numerous tumor cells than in classic Hodgkin lymphoma
    • Nuclei are round to oval and may be hyperchromatic or vesicular; some cases show a predominance of lobulated nuclei
    • Clear cell change (abundant pale cytoplasm)
    • Compartmentalizing fibrosis or prominent sclerosis
    • Frequently, at least a subset of lymphoma cells is pleomorphic and may resemble Reed-Sternberg cells
    • Remnants of thymus can be seen
  • Reference: Hum Pathol 1999;30:178
Microscopic (histologic) images

Contributed by Jennifer Chapman, M.D.
Intermediate to large sized cytologically atypical lymphoid cells   Intermediate to large sized cytologically atypical lymphoid cells

Intermediate to large sized cytologically atypical lymphoid cells

Diffuse distribution of intermediate to large sized lymphoma cells   Diffuse distribution of intermediate to large sized lymphoma cells

Diffuse distribution of intermediate to large sized lymphoma cells

Endobronchial biopsy   Endobronchial biopsy

Endobronchial biopsy


Endobronchial biopsy   Endobronchial biopsy

Endobronchial biopsy

CD19

CD19

CD20

CD20

CD23

CD23

CD30

CD30

Cytology description
  • Predominantly single, intermediate to large lymphoid cells
    • Round to oval nuclei
    • Smooth to irregular nuclear contours
    • One or more visible nucleoli
    • Scant to abundant cytoplasm (may be clear)
    • Oval / elongated nuclei due to fibrosis
  • In some cases, the atypical lymphoid cells show markedly lobulated nuclei and may resemble Reed-Sternberg cells
  • Background may contain connective tissue fragments admixed with single lymphocytes or groups of lymphocytes
  • Reference: Jaffe: Hematopathology, 2nd Edition, 2016
Cytology images

Contributed by Mahsa Khanlari, M.D.
Papanicolaou   Papanicolaou

Papanicolaou

Positive stains
Negative stains
Flow cytometry description
Molecular / cytogenetics description
  • Clonally rearranged immunoglobulin genes
  • Activation of JAK-STAT pathway (JAK2 amplification, STAT6 mutation, inactivating mutation of SOCS1 and PTPN1)
  • Activation of NFκB pathway
    • Nuclear translocation of c-REL: target gene of tumor necrosis factor receptor associated factor 1 (TRAF1) (Am J Surg Pathol 2007;31:106)
      • Combination of nuclear c-REL with cytoplasmic TRAF1 reflects activation of NFκB
      • Useful to distinguish primary mediastinal large B cell lymphoma from other subtypes of diffuse large B cell lymphoma
    • Loss of TNFAIP3 (A20) by coding sequence mutation (J Exp Med 2009;206:981)
      • A20 is a ubiquitin modifying enzyme that inhibits NFκB activation in succession of TNF receptor and toll-like receptor induced signals
  • Immune privilege / evasion of immune surveillance (CIITA gene translocation leading to loss of MHC class II expression, PDL1 and PDL2 amplification and translocation)
  • Note: BCL2 and BCL6 genes usually not rearranged but high frequency of BCL6 gene mutations (~70%)
    • Rare / no translocations involving CCND1 and MYC
    • MAL gene (myelin and lymphocyte protein [MAL]) frequently expressed (70%) (Br J Haematol 2019;185:25)
  • Genomic landscape / comparative genomic hybridization (PLoS One 2015;10:e0139663)
    • 2p15 (REL / COMMD1)
    • 9p24 (JAK2, CD274: locus for PD1 ligand)
    • 16p13 (SOCS1, LITAF, CIITA)
    • 2p16 (MSH6)
    • 6q23 (TNFAIP3)
    • 9p22 (CDKN2A / B)
    • 20p12 (PTPN1)
Sample pathology report
  • Lung, right upper lobe anterior tumor, endobronchial biopsies:
    • Diffuse large B cell lymphoma partially expressing CD23 and CD30, most consistent with primary mediastinal (thymic) large B cell lymphoma (see comment)
    • Comment:
      • The patient is a 35 year old woman who presented with fatigue and was found to have an anterior mediastinal mass with extension into the upper lobe of the right lung.
      • Histologic sections consist of endobronchial biopsies of the lung mass and show respiratory mucosa that is involved by lymphoma. Lymphoma cells are present in a diffuse distribution and consist of intermediate to large sized neoplastic cells with round to oval nuclei, vesicular chromatin and occasionally prominent nucleoli. Mitotic figures and karyorrhexis are increased. Associated granulation tissue is seen.
      • By immunohistochemistry, lymphoma cells are positive for CD20 (strong and diffuse), BCL2, CD30 (subset, variable intensity) and CD23 (subset) and are negative for CD10, BCL6 and CD3. The proliferative index based on Ki67 immunostain is 70%. MYC expression by immunohistochemistry is detected in 30% of tumor cell nuclei. In situ hybridization for EBER is negative.
      • The overall findings are those of diffuse large B cell lymphoma with histologic, immunophenotypic and clinical features compatible with primary mediastinal (thymic) large B cell lymphoma.
Differential diagnosis
  • Diffuse large B cell lymphoma, NOS (involving or arising in mediastinum):
    • Older adults but it also occurs in children and young adults
    • Diffuse growth pattern
    • Immunophenotype
    • Molecular genetic features
      • Monoclonal IGH rearrangements
      • t(14;18)(q32;q21) / IGH::BCL2+
      • t(3;14)(q27;q32) or other partners with BCL6
      • MYC translocations
  • Nodular sclerosis classic Hodgkin lymphoma:
    • Young patients
    • Mediastinal involvement in a large subset of cases
    • Nodular growth pattern with thick sclerotic bands
    • Variable numbers of large Hodgkin / lacunar cells
    • Many inflammatory cells present
    • Immunophenotype
    • Molecular genetic features
      • Monoclonal IGH rearrangements are usually negative
  • Mediastinal gray zone lymphomas:
    • Formerly designated as B cell lymphoma, unclassifiable, with features intermediate between diffuse large B cell lymphoma and classic Hodgkin lymphoma
    • Most frequent histologic finding is a variable microscopic appearance in different areas (some areas look like classic Hodgkin lymphoma, some areas look like primary mediastinal large B cell lymphoma)
    • Mediastinal gray zone lymphoma is characterized by a heterogenous immunophenotype among lymphoma cells in an individual case or the immunophenotype of the lymphoma cells does not match the morphologic appearance (for example, cells look like classic Hodgkin lymphoma but have preserved B cell program; cells do not look like classic Hodgkin lymphoma but show classic Hodgkin lymphoma immunophenotype)
    • Variable expression of B cell antigens (primary mediastinal large B cell lymphoma consistently express the B cell antigens in a homogenous pattern)
    • Although both mediastinal gray zone lymphomas and primary mediastinal large B cell lymphoma usually express CD30, coexpression of CD15 or presence of EBV (EBER+), especially when associated with CD20 negativity, favors the diagnosis of gray zone lymphoma (or classic Hodgkin lymphoma)
Board review style question #1
Which of the following biomarkers has both high sensitivity and specificity for the diagnosis of primary mediastinal large B cell lymphoma (PMBCL) as compared to expression in other subtypes of diffuse large B cell lymphoma?

  1. CD23
  2. CD30
  3. MUM1
  4. STAT6
Board review style answer #1
A. CD23. MAL, CD23, CD200, PDL1 and PDL2 are all biomarkers with > 70% sensitivity and specificity. Answer B is incorrect because, even though > 80% of cases stain weakly / heterogeneously for CD30, it does not have both high sensitivity and high specificity. Answer C is incorrect because, in spite of 75 - 95% of cases expressing this biomarker, MUM1 is not both highly sensitive and highly specific for PMBCL. Answer D is incorrect because, even though activation of the JAK / STAT pathway results in perpetually expressed phosphorylated STAT6 and thus, immunopositivity, STAT6 is not both highly sensitive and highly specific for PMBCL.

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Reference: Primary mediastinal large B cell lymphoma
Board review style question #2


Which of the following immunohistochemical markers is least likely to be positive in the mediastinal mass of a 26 year old woman with the morphology shown in the image above?

  1. BOB1
  2. CD20
  3. CD30
  4. LMP1 (EBV)
  5. MUM1
Board review style answer #2
D. LMP1 (EBV). Very rare cases of primary mediastinal large B cell lymphoma (PMBCL) demonstrate evidence of EBV. The presence of EBV does not preclude rendering a diagnosis of PMBCL; however, when EBV is present, this finding favors another entity, such as classic Hodgkin lymphoma (CHL). Answer A is incorrect because this B lineage program transcription regulator is commonly expressed and aids in ruling out other entities, like CHL. Answer B is incorrect because PMBCL is expected to express pan-B cell markers, including CD20. Answer C is incorrect because the majority of PMBCL cases are positive for weak / heterogeneous staining of CD30. Answer E is incorrect because IRF4 / MUM1 expression can be seen in 75 - 95% of cases of PMBCL.

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Reference: Primary mediastinal large B cell lymphoma
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