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Lymphoma & related disorders

Mature B cell neoplasms

Large B cell lymphomas-special subtypes

Primary mediastinal


Mahsa Khanlari, M.D.
Jennifer Chapman, M.D.

Last author update: 10 December 2019
Last staff update: 22 December 2023 (update in progress)

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PubMed Search: Primary mediastinal large B cell lymphoma

Mahsa Khanlari, M.D.
Jennifer Chapman, M.D.
Page views in 2023: 14,456
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Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Etiology | Clinical features | 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: Khanlari M, Chapman J. Primary mediastinal. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomamediastinal.html. Accessed April 19th, 2024.
Definition / general
  • Mature and clinically aggressive large B cell lymphoma
  • Probable thymic B cell origin
  • Arising in mediastinum but may involve other sites (lung)
  • Characteristic clinical, immunophenotypic, genetic and molecular features
Essential features
  • Uncommon to arise outside of mediastinum (Am J Surg Pathol 2015;39:1322)
  • Occurs more frequently in young adults
  • Must be distinguished from systemic diffuse large B cell lymphoma with secondary mediastinal involvement, classic Hodgkin lymphoma and gray zone lymphoma with features intermediate between large B cell lymphoma and classic Hodgkin lymphoma
  • Genetic overlap based on gene expression profile between primary mediastinal large B cell lymphoma and classic Hodgkin lymphoma
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-10: C85.20 - mediastinal (thymic) large B cell lymphoma, unspecified site
  • ICD-10: C85.29 - mediastinal (thymic) large B cell lymphoma, extranodal and solid organ sites
Epidemiology
Sites
  • Presents with localized anterosuperior mediastinal mass arising in thymic area
  • Regional supraclavicular and cervical lymph node involvement
Etiology
  • Activation of JAK-STAT and NF-kB 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 (Int J Cancer 1989;43:10)
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 lung may be the first diagnostic biopsy, thus this differential diagnosis must be considered when making a diagnosis of large B cell lymphoma in 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 unusual predilection for involvement of kidney, adrenal gland, liver and central nervous system; may involve bone marrow
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)
  • Outcomes for patients with relapsed or refractory primary mediastinal large B cell lymphoma are generally poor (J Clin Oncol 1997;15:1646)
Case reports
  • 15 year old girl with rearrangements of MYC and BCL6 showed by fluorescent in situ hybridization (Am J Clin Pathol 2016;145:710)
  • 44 year old man presented with ileal perforation (BMJ Case Rep 2016 Jul 14;2016)
  • 54 year old Chinese man, a renal recipient with Hashimoto thyroiditis, presented with increased neck mass and progressive dyspnea (Int J Clin Exp Pathol 2015;8:5944)
  • 3 middle aged to elderly patients with nodal diffuse large B cell lymphoma with morphologic features of primary mediastinal large B cell lymphoma presenting in submandibular or supraclavicular lymph nodes; all 3 cases expressed cyclin D1 with copy number gains of CCND1 gene but without rearrangement (Am J Surg Pathol 2019;43:110)
Treatment
  • DA-EPOCH+R: etoposide, prednisone, Oncovin (vincristine), cyclophosphamide, doxorubicin plus rituximab
    • 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 PET evaluation may represent a tool to guide radiation therapy usage (Best Pract Res Clin Haematol 2018;31:241)
  • Disease management in relapse: intensive chemotherapy (DA-EPOCH+R) followed by an autologous stem cell transplantation (Br J Haematol 2019;185:25)
Gross description
  • Mass is often bulky (usually > 10 cm)
  • Most frequently diagnosed based on core biopsy of mediastinal mass or by biopsy of involved lung in patients with mediastinal mass
    • Because mediastinal masses may be lymphomas, which are generally not resected, it is unusual to have a resection specimen of this tumor
  • Reference: Jaffe: Hematopathology, 2nd Edition, 2016
Frozen section description
  • A definitive diagnosis should not be made at the time of frozen section given that required diagnostic features cannot be determined (immunophenotype, for example)
  • Diagnosis of lymphoma can be suspected if a population of intermediate to large sized and cytologically atypical lymphoid cells are seen
    • There is frequently 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
Microscopic (histologic) description
  • Characterized by a large spectrum of possible morphologic appearances
  • May mimic 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
    • Clear cell change (abundant pale cytoplasm)
    • Prominent sclerosis (compartmentalizing fibrosis)
    • Frequently, at least a subset of lymphoma cells are pleomorphic and may resemble Reed-Sternberg cells
  • Reference: Hum Pathol 1999;30:178
Microscopic (histologic) images

Contributed by Jennifer Chapman, M.D.
 

Intermediate to large sized cytologically atypical lymphoid cells

 

Diffuse distribution of intermediate to large sized lymphoma cells

CD19

CD20


CD23

CD30

 

Endobronchial biopsy

 

Endobronchial biopsy

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

Positive stains
Negative stains
Flow cytometry description
  • Discordance in B cell receptor and sIg
  • CD79a+ and CD19 / CD20+, while light chain Ig-, CD10-, CD15-
  • CD30 frequently expressed (Cytometry B Clin Cytom 2018;94:459)
  • Variable loss of HLA classes I and II (HLA-DR) molecules
Molecular / cytogenetics description
  • Clonally rearranged immunoglobulin genes
  • Activation of JAK-STAT pathway (JAK2 amplification, STAT6 mutation, inactivating mutation of SOCS1 and PTPN1)
  • Activation of NF-κB 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 NF-κB
      • 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 NF-κB 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 female 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 ovoid nuclei, vesicular chromatin and occasionally prominent nucleoli. Mitotic figures and cellular apoptosis are increased. Associated granulation tissue is seen.
      • By immunohistochemistry, lymphoma cells are positive for CD20 (strong and diffuse), BCL2, CD30 (subset, heterogeneous 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 designation as primary mediastinal (thymic) large B cell lymphoma.
Differential diagnosis
  • Diffuse large B cell lymphoma, NOS (involving or arising in mediastinum):
    • Features favoring primary mediastinal large B cell lymphoma:
      • Young
      • F > M
      • Localized to mediastinum, absent systemic involvement on staging imaging
      • Intermediate sized cells with clear cytoplasm in a sclerotic stroma
      • Expression of CD23, nuclear NFKB (with cytoplasmic TRAF1) and MAL
  • Classic Hodgkin lymphoma:
    • Both express CD30 and have Reed-Sternberg cells
    • Features favoring primary mediastinal large B cell lymphoma:
      • Unlike classic Hodgkin lymphoma, primary mediastinal large B cell lymphoma expresses CD45, shows preservation of B cell program (expression of OCT2, BOB1, strong PAX5) and lacks strong expression of CD15
      • MAL expression (a small minority of cases of classic Hodgkin lymphoma [10 - 20%] express MAL) (Am J Clin Pathol 2006;125:776)
      • Polymorphic background that may be seen in classic Hodgkin lymphoma is absent in primary mediastinal large B cell lymphoma
  • Mediastinal gray zone lymphomas:
    • 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 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 positive), especially when associated with CD20 loss, favors the diagnosis of gray zone lymphoma (or classic Hodgkin lymphoma)
Board review style question #1
Which of the following genes / alterations is not considered part of the main landscape of primary mediastinal large B cell lymphoma genetic alteration?

  1. CARD11
  2. MAL
  3. PDL1
  4. PTPN1
  5. REL
Board review style answer #1
A. CARD11

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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 above morphology?

  1. BOB1
  2. CD20
  3. CD30
  4. LMP1 (EBV)
  5. MUM1
Board review style answer #2
D. LMP1 (EBV). The image shows primary mediastinal large B cell lymphoma.

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Reference: Primary mediastinal large B cell lymphoma
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