Primary mediastinal large B-cell lymphoma

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Badria Munir M.B.B.S.[2] Sowminya Arikapudi, M.B,B.S. [3]

Synonyms and keywords:: Mediastinal B-cell lymphoma; Mediastinal large B-cell lymphoma, PMBCL, Primary mediastinal B-cell lymphoma.

Overview

Primary mediastinal large B-cell lymphoma (PMBCL) is a subtype of diffuse large B-cell lymphoma (DLBCL). It is also considered a distinct type of non-Hodgkin lymphoma (NHL) in the World Health Organization (WHO) classification system. It occurs in the thymus gland. The small gland in the centre of the chest behind the sternum where lymphocytes mature, multiply and become T cells. or lymph nodes in the center of the chest. On microscopic histopathological analysis, large-sized cells and alveolar fibrosis are characteristic findings of primary mediastinal large B-cell lymphoma. The incidence of primary mediastinal large B-cell lymphoma increases with age; the median age at diagnosis is 35 years. Symptoms of the primary mediastinal large B-cell lymphoma include fever, weight loss, night sweats, skin rash, facial swelling, cough, shortness of breath, and painless swelling in the neck, axilla, groin, thorax, or abdomen. Lymph node or mediastinal mass biopsy is diagnostic of primary mediastinal large B-cell lymphoma. The predominant therapy for primary mediastinal large B-cell lymphoma is chemotherapy. Adjunctive radiotherapy, stem cell transplant, and biological therapy may be required. The optimal therapy for primary mediastinal large B-cell lymphoma depends on the clinical presentation.[1][2]

Classification

  • Primary mediastinal B-cell lymphoma was recognized as a sub type of diffuse large B-cell lymphoma since the 1994 Revised European American Lymphoma Classification.[3]
  • It has been regarded as a unique clinical and biological entity since the 2001 World Health Organization classification.[4]

Pathophysiology

  • Primary mediastinal large B-cell lymphoma most likely arises within the thymus.[1][5]
  • Patients present with a localized anterosuperior mediastinal mass.
  • The mass is often bulky and frequently invades adjacent structures such as lungs, pleura, or pericardium.
  • Spread to supraclavicular and cervical lymph nodes can occur.
  • Pathophysiologically, tumor grows through constitutive STAT 6 phosphorylation and DNA-binding activity.[6]
  • STAT 6 phosphorylation activates Interleukin 4/ interleukin-13 signalling pathway.
  • Constitutive STAT6 phosphorylation and DNA-binding activity is detected is proved through immunohistochemical analysis.
  • Another proposed mechanism of autocrine pathway is amplification of JAK 2 pathway involves phosphorylation of IL-4 and IL-13.
  • The Janus kinase 2 (JAK2) is also constitutively phosphorylated in the primary mediastinal large B-cell lymphoma.
  • Primary mediastinal large B-cell lymphoma is treated with JAK2 inhibitor AG490, resulted in partially decreased STAT6 phosphorylation, which suggests that JAK2 is partially involved in STAT6 activation in these cells.

Genetics:

Genes involved in the pathogenesis of primary mediastinal large B-cell lymphoma include:

  • Comparative genomic hybridzation demonstrated gains in chromosome 9p24 and 2p15
  • Genomic hybridization in chromosome X-p11.4-21
  • Translocations involving the CIITA gene[7]
  • Amplification of the REL oncogene[8]
  • Hyperdiploid karyotypes, often with gains in the region on chromosome 9p containing the JAK2 gene and the genes encoding PD-L1 and PD-L2, ligands for the receptor PD-1[9]
  • The B cell leukemia/lymphoma 2 (BCL-2) gene and B cell leukemia 6 (BCL-6) gene rearrangements can occur.[10]
  • Gains of the proto-oncogene BCL11A and nuclear accumulation of BCL11A(XL) protein.[11]
  • Immunoglobulin genes clonally rearranged.

Immunophenotype:

  • The immunophenotype of PMBL is determined by histochemistry or flow cytometry.
  • The tumor cells express B cell-associated antigens (CD19, CD20, CD22, CD79a) and CD45.[10]
  • Weak expression of CD30 is often present
  • The tumor cells also stain for TRAF-1 and nuclear c-Rel. These two markers are also expressed by the Reed-Sternberg cells, but are not present in other forms of diffuse large B cell lymphoma. [12]
  • Other markers that are relatively specific for PMBL are CD200 and MAL.[13][14]

Microscopic Pathology:

  • On microscopic histopathological analysis, large-sized cells and alveolar fibrosis are characteristic findings of primary mediastinal large B-cell lymphoma.
  • The tumor is composed of large cells with variable nuclear features, cells may resemble:[15]
    • Centroblasts
    • Large centrocytes
    • Multilobated cells, often with pale or "clear" cytoplasm
    • Less frequently, the tumor cells resemble immunoblasts
    • Reed-Sternberg-like cells
    • Some cases have also presented with fine, compartmentalizing sclerosis
  • Hematoxylin and eosin (50X). Primary mediastinal B cells (PMBC) associated with delicate interstitial fibrosis.[16]

    Hematoxylin and eosin (50X). Primary mediastinal B cells (PMBC) associated with delicate interstitial fibrosis.[16]

  • Primary mediastinal large B-cell lymphoma immunoreactivity for B cell antigen on the membrane, CD20[16]

    Primary mediastinal large B-cell lymphoma immunoreactivity for B cell antigen on the membrane, CD20[16]

  • Primary mediastinal large B-cell lymphoma immunoreactivity for CD30[16]

    Primary mediastinal large B-cell lymphoma immunoreactivity for CD30[16]

Causes

There are no established causes of primary mediastinal B-cell lymphoma.

Differentiating ((Page name)) from Other Diseases

Primary mediastinal large B-cell lymphoma must be differentiated from other diseases such as:

Epidemiology and Demographics

Primary mediastinal large B-cell lymphoma comprises of 7% of overall diffuse large B cell lymphoma's and 2.4 % of all Non hodgkin lymphomas. [17]

Age:

The incidence of primary mediastinal large B-cell lymphoma increases with age; the median age at diagnosis is 35 years.[18]

Gender:

Females are more commonly affected with primary mediastinal large B-cell lymphoma than males.[18]

Risk Factors

  • There are no established risk factors for primary mediastinal large B-cell lymphoma.

Screening

According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for primary mediastinal large B-cell lymphoma.[19]

Natural History, Complications, and Prognosis

  • Primary mediastinal large B-cell lymphoma is usually a fast-growing lymphoma.
  • Patients often have localized disease in the chest at first.
  • If left untreated, primary mediastinal large B-cell lymphoma can cause:
    • shortness of breath
    • cough
    • chest pain
  • Primary mediastinal large B-cell lymphoma can also partially block the main vein (superior vena cava) that carries blood from the upper body to the heart and cause superior vena cava syndrome.

Common complications :

  • Compression of vessels in the neck often causes following symptoms :
    • Dyspnea
    • Facial swelling
    • Fullness of head on bending forwards
    • Arm swelling
    • Dysphagia
    • Cerebral edema
    • Headache
    • Confusion
    • Coma
  • Potential Oncologic emergencies are:
    • Acute airway obstruction
    • Pericardial tamponade
    • Hyperuricemia and tumor lysis syndrome
    • Thrombosis of major neck or superior thoracic veins
  • Patients with large mediastinal masses are at increased risk of respiratory or cardiac arrest during general anesthesia or heavy sedation.
  • Patients who present with cardiorespiratory symptoms or radiographic evidence of tracheal obstruction are at greatest risk of perioperative respiratory morbidity.

Less common complication :

  • Less common complication includes:
    • Tumor lysis syndrome is caused by massive tumor cell lysis and the release of large amounts of potassium, phosphate, and uric acid into the systemic circulation.
    • Deposition of uric acid and/or calcium phosphate crystals in the renal tubules results in acute renal failure.
  • The bone marrow is rarely affected by this type of lymphoma.
  • Recurrence or relapse often occurs in organs or tissues outside the lymph nodes (extranodal sites), such as the kidneys or central nervous system.

Prognosis:

  • Prognosis is generally good after aggressive therapy, which usually combines chemotherapy with mediastinal irradiation. However if relapse occurs , it depends on paucity of molecular level of tumor cells, and their ability to evade immune system.
  • Initial studies suggest that a more favorable course may be predicted by one of the following :
    • Low tumor metabolic activity which is determined by decreased total lesion glycolysis (a measure of FDG uptake) on FDG-PET imaging at baseline or after initial therapy. [20]
    • Further study is needed to confirm the prognostic value of PET before it can be used to modify initial treatment plans.

Diagnosis

Diagnostic Study of Choice

Biopsy:

  • The diagnosis of primary mediastinal large B cell lymphoma relies on the exclusion of adequate tissue, which offers most difficulty due to the location of the tumor, therefore an excisional tissue biopsy is usually not possible.
  • In context of these situations, surgical biopsy is highly preferred.[21]
  • Due to fibrosis (which is often extensive), needle aspirates are often paucicellular and fail to provide information about the tissue.
  • Small biopsies may be non-diagnostic because the lesion is not sampled adequately or because crush artifact or extensive necrosis, fibrosis, or cystic change obscures the diagnostic lesion.
  • Similarly, core biopsies often contain only fibrotic tissue or tumor cells that are disrupted and not diagnostically useful.
  • To obtain sufficient tissue for biopsy , patients usually undergo either one of the following techniques[21]
    • Cervical mediastinoscopy
    • Anterior mediastinotomy
    • Thoracoscopy

Staging

Staging for primary mediastinal large B-cell lymphoma is provided in the following table:[22]

Revised staging system for primary nodal lymphomas (Lugano classification)
Stage Involvement Extranodal (E) status
Limited
Stage I One node or a group of adjacent nodes Single extranodal lesions without nodal involvement
Stage II Two or more nodal groups on the same side of the diaphragm Stage I or II by nodal extent with limited contiguous extranodal involvement
Stage II bulky II as above with "bulky" disease Not applicable
Advanced
Stage III Nodes on both sides of the diaphragm; nodes above the diaphragm with spleen involvement Not applicable
Stage IV Additional noncontiguous extralymphatic involvement Not applicable

History and Symptoms

Symptoms of the primary mediastinal large B-cell lymphoma include:

  • Fever
  • Weight loss
  • Night sweats
  • Skin rash
  • Shortness of breath
  • Facial swelling
  • Cough
  • Painless swelling in the neck, axilla, groin, thorax, and abdomen

Physical Examination

Vitals

Skin

HEENT

Thorax

Abdomen

Extremities

Laboratory Findings

Laboratory tests for primary mediastinal large B-cell lymphoma include:

Electrocardiogram

There are no ECG findings associated with primary mediastinal large B-cell lymphoma.

Chest X-Ray

Chest X-ray may be helpful in the diagnosis of primary mediastinal large B-cell lymphoma. Finding on chest X-ray suggestive of primary mediastinal large B-cell lymphoma includes large anterior mediastinal mass.[16]

Biopsy

Lymph node or mediastinal mass biopsy is diagnostic of primary mediastinal large B-cell lymphoma.

Echocardiography

Echocardiography may be helpful in the diagnosis of primary mediastinal large B-cell lymphoma.

  • A comprehensive 2 dimensional M-mode color flow and Doppler echocardiography reveals a normal left ventricular systolic function (EF 60–69%). A large right atrial mass measuring  cm almost fills the right atrium and extends into the tricuspid valve causing tricuspid regurgitation.[16]

    A comprehensive 2 dimensional M-mode color flow and Doppler echocardiography reveals a normal left ventricular systolic function (EF 60–69%). A large right atrial mass measuring  cm almost fills the right atrium and extends into the tricuspid valve causing tricuspid regurgitation.[16]

CT

CT scan may be helpful in the diagnosis of primary mediastinal large B-cell lymphoma.

  • CT scan of the chest with contrast reveals a large lobulated anterior mediastinal solid mass (black arrow) with extension into the right hemithorax and the right atrium. There is displacement of the great vessels into the left hemithorax with significant mass effect on the right upper lobe. The tumor causes compression of the right pulmonary artery (red arrow) and right and left mainstem bronchi (white arrows).[16]

    CT scan of the chest with contrast reveals a large lobulated anterior mediastinal solid mass (black arrow) with extension into the right hemithorax and the right atrium. There is displacement of the great vessels into the left hemithorax with significant mass effect on the right upper lobe. The tumor causes compression of the right pulmonary artery (red arrow) and right and left mainstem bronchi (white arrows).[16]

  • Coronal CT scan image elucidates a mediastinal mass with extension into the right atrium (black arrow) with complete encasement and compression of the SVC. The tumor extends to the confluence of the IVC in the right atrium causing dilatation of the intraabdominal IVC and hepatic veins suggesting compromised cardiac return (red arrows). Tumor causes the displacement of great vessels into the left hemithorax.[16]

    Coronal CT scan image elucidates a mediastinal mass with extension into the right atrium (black arrow) with complete encasement and compression of the SVC. The tumor extends to the confluence of the IVC in the right atrium causing dilatation of the intraabdominal IVC and hepatic veins suggesting compromised cardiac return (red arrows). Tumor causes the displacement of great vessels into the left hemithorax.[16]

MRI

MRI scan may be helpful in the diagnosis of primary mediastinal large B-cell lymphoma.

  • Cardiac MRI short axis T1 at the level of mitral valve reveals a large mediastinal mass infiltrating and obliterating the SVC causing SVC obstruction. The tumor extends into the right atrium (red arrow) and invades the tricuspid valve.[16]

    Cardiac MRI short axis T1 at the level of mitral valve reveals a large mediastinal mass infiltrating and obliterating the SVC causing SVC obstruction. The tumor extends into the right atrium (red arrow) and invades the tricuspid valve.[16]

Other Imaging Findings

  • PET scan may be helpful in the diagnosis of primary mediastinal large B-cell lymphoma.
  • In contrast to CT imaging, FDG-PET is a functional imaging tool that can distinguish between viable tumor and necrosis or fibrosis in a residual mass.[23]

Other diagnostic studies

  • Monoclonal anti-MAL antibody is now commercially used in order to identify PMBL. It provides good sensitivity and high specificity fot diagnosis of primary mediastinal large B-cell lymphoma. [24]

Treatment

Medical Therapy

There is no treatment for [disease name]; the mainstay of therapy is supportive care.

OR

Supportive therapy for [disease name] includes [therapy 1], [therapy 2], and [therapy 3].

OR

The majority of cases of [disease name] are self-limited and require only supportive care.

OR

[Disease name] is a medical emergency and requires prompt treatment.

OR

The mainstay of treatment for [disease name] is [therapy].

OR

The optimal therapy for [malignancy name] depends on the stage at diagnosis.

OR

[Therapy] is recommended among all patients who develop [disease name].

OR

Pharmacologic medical therapy is recommended among patients with [disease subclass 1], [disease subclass 2], and [disease subclass 3].

OR

Pharmacologic medical therapies for [disease name] include (either) [therapy 1], [therapy 2], and/or [therapy 3].

OR

Empiric therapy for [disease name] depends on [disease factor 1] and [disease factor 2].

OR

Patients with [disease subclass 1] are treated with [therapy 1], whereas patients with [disease subclass 2] are treated with [therapy 2].

Surgery

Surgical intervention is not recommended for the management of [disease name].

OR

Surgery is not the first-line treatment option for patients with [disease name]. Surgery is usually reserved for patients with either [indication 1], [indication 2], and [indication 3]

OR

The mainstay of treatment for [disease name] is medical therapy. Surgery is usually reserved for patients with either [indication 1], [indication 2], and/or [indication 3].

OR

The feasibility of surgery depends on the stage of [malignancy] at diagnosis.

OR

Surgery is the mainstay of treatment for [disease or malignancy].

Primary Prevention

There are no established measures for the primary prevention of [disease name].

OR

There are no available vaccines against [disease name].

OR

Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3].

OR

[Vaccine name] vaccine is recommended for [patient population] to prevent [disease name]. Other primary prevention strategies include [strategy 1], [strategy 2], and [strategy 3].

Secondary Prevention

There are no established measures for the secondary prevention of [disease name].

OR

Effective measures for the secondary prevention of [disease name] include [strategy 1], [strategy 2], and


Treatment

References

  1. ↑ 1.0 1.1 Primary mediastinal large B-cell lymphoma. Surveillance, Epidemiology, and End Results Program. http://seer.cancer.gov/seertools/hemelymph/51f6cf56e3e27c3994bd5318/. Accessed on March 7, 2016
  2. ↑ Primary mediastinal large B-cell lymphoma. Canadian Cancer Society. http://www.cancer.ca/en/cancer-information/cancer-type/non-hodgkin-lymphoma/non-hodgkin-lymphoma/types-of-nhl/primary-mediastinal-large-b-cell-lymphoma/?region=nb. Accessed on March 7, 2016
  3. ↑ Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, Delsol G, De Wolf-Peeters C, Falini B, Gatter KC (September 1994). "A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group". Blood. 84 (5): 1361–92. PMID 8068936.
  4. ↑ Liu PP, Wang KF, Xia Y, Bi XW, Sun P, Wang Y, Li ZM, Jiang WQ (July 2016). "Racial patterns of patients with primary mediastinal large B-cell lymphoma: SEER analysis". Medicine (Baltimore). 95 (27): e4054. doi:10.1097/MD.0000000000004054. PMC 5058818. PMID 27399089.
  5. ↑ Addis BJ, Isaacson PG (April 1986). "Large cell lymphoma of the mediastinum: a B-cell tumour of probable thymic origin". Histopathology. 10 (4): 379–90. PMID 2423430.
  6. ↑ Guiter C, Dusanter-Fourt I, Copie-Bergman C, Boulland ML, Le Gouvello S, Gaulard P, Leroy K, Castellano F (July 2004). "Constitutive STAT6 activation in primary mediastinal large B-cell lymphoma". Blood. 104 (2): 543–9. doi:10.1182/blood-2003-10-3545. PMID 15044251.
  7. ↑ Steidl C, Shah SP, Woolcock BW, Rui L, Kawahara M, Farinha P, Johnson NA, Zhao Y, Telenius A, Neriah SB, McPherson A, Meissner B, Okoye UC, Diepstra A, van den Berg A, Sun M, Leung G, Jones SJ, Connors JM, Huntsman DG, Savage KJ, Rimsza LM, Horsman DE, Staudt LM, Steidl U, Marra MA, Gascoyne RD (March 2011). "MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers". Nature. 471 (7338): 377–81. doi:10.1038/nature09754. PMC 3902849. PMID 21368758.
  8. ↑ Joos S, Otaño-Joos MI, Ziegler S, Brüderlein S, du Manoir S, Bentz M, Möller P, Lichter P (February 1996). "Primary mediastinal (thymic) B-cell lymphoma is characterized by gains of chromosomal material including 9p and amplification of the REL gene". Blood. 87 (4): 1571–8. PMID 8608249.
  9. ↑ Twa DD, Chan FC, Ben-Neriah S, Woolcock BW, Mottok A, Tan KL, Slack GW, Gunawardana J, Lim RS, McPherson AW, Kridel R, Telenius A, Scott DW, Savage KJ, Shah SP, Gascoyne RD, Steidl C (March 2014). "Genomic rearrangements involving programmed death ligands are recurrent in primary mediastinal large B-cell lymphoma". Blood. 123 (13): 2062–5. doi:10.1182/blood-2013-10-535443. PMID 24497532.
  10. ↑ 10.0 10.1 Lamarre L, Jacobson JO, Aisenberg AC, Harris NL (September 1989). "Primary large cell lymphoma of the mediastinum. A histologic and immunophenotypic study of 29 cases". Am. J. Surg. Pathol. 13 (9): 730–9. PMID 2788371.
  11. ↑ Weniger MA, Pulford K, Gesk S, Ehrlich S, Banham AH, Lyne L, Martin-Subero JI, Siebert R, Dyer MJ, Möller P, Barth TF (October 2006). "Gains of the proto-oncogene BCL11A and nuclear accumulation of BCL11A(XL) protein are frequent in primary mediastinal B-cell lymphoma". Leukemia. 20 (10): 1880–2. doi:10.1038/sj.leu.2404324. PMID 16871282.
  12. ↑ Rodig SJ, Savage KJ, Nguyen V, Pinkus GS, Shipp MA, Aster JC, Kutok JL (February 2005). "TRAF1 expression and c-Rel activation are useful adjuncts in distinguishing classical Hodgkin lymphoma from a subset of morphologically or immunophenotypically similar lymphomas". Am. J. Surg. Pathol. 29 (2): 196–203. PMID 15644776.
  13. ↑ Dorfman DM, Shahsafaei A, Alonso MA (December 2012). "Utility of CD200 immunostaining in the diagnosis of primary mediastinal large B cell lymphoma: comparison with MAL, CD23, and other markers". Mod. Pathol. 25 (12): 1637–43. doi:10.1038/modpathol.2012.129. PMID 22899296.
  14. ↑ Copie-Bergman C, Plonquet A, Alonso MA, Boulland ML, Marquet J, Divine M, Möller P, Leroy K, Gaulard P (November 2002). "MAL expression in lymphoid cells: further evidence for MAL as a distinct molecular marker of primary mediastinal large B-cell lymphomas". Mod. Pathol. 15 (11): 1172–80. doi:10.1097/01.MP.0000032534.81894.B3. PMID 12429796.
  15. ↑ De Paepe P, Achten R, Verhoef G, Wlodarska I, Stul M, Vanhentenrijk V, Praet M, De Wolf-Peeters C (October 2005). "Large cleaved and immunoblastic lymphoma may represent two distinct clinicopathologic entities within the group of diffuse large B-cell lymphomas". J. Clin. Oncol. 23 (28): 7060–8. doi:10.1200/JCO.2005.15.503. PMID 16129841.
  16. ↑ 16.0 16.1 16.2 16.3 16.4 16.5 16.6 16.7 Primary mediastinal large B-cell lymphoma.Hindawi Publishing Corporation. http://www.hindawi.com/journals/crihem/2012/197347/. Accessed on March 07, 2016
  17. ↑ "A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project". Blood. 89 (11): 3909–18. June 1997. PMID 9166827.
  18. ↑ 18.0 18.1 Nguyen LN, Ha CS, Hess M, Romaguera JE, Manning JT, Cabanillas F, Cox JD (July 2000). "The outcome of combined-modality treatments for stage I and II primary large B-cell lymphoma of the mediastinum". Int. J. Radiat. Oncol. Biol. Phys. 47 (5): 1281–5. PMID 10889382.
  19. ↑ Recommendations. U.S Preventive Services Task Force. http://www.uspreventiveservicestaskforce.org/BrowseRec/Search?s=Primary+mediastinal+large+B-cell+lymphoma+. Accessed on March 7, 2016
  20. ↑ Martelli M, Ceriani L, Zucca E, Zinzani PL, Ferreri AJ, Vitolo U, Stelitano C, Brusamolino E, Cabras MG, Rigacci L, Balzarotti M, Salvi F, Montoto S, Lopez-Guillermo A, Finolezzi E, Pileri SA, Davies A, Cavalli F, Giovanella L, Johnson PW (June 2014). "[18F]fluorodeoxyglucose positron emission tomography predicts survival after chemoimmunotherapy for primary mediastinal large B-cell lymphoma: results of the International Extranodal Lymphoma Study Group IELSG-26 Study". J. Clin. Oncol. 32 (17): 1769–75. doi:10.1200/JCO.2013.51.7524. PMID 24799481.
  21. ↑ 21.0 21.1 Sun W, Song K, Zervos M, Pass H, Cangiarella J, Bizekis C, Crawford B, Wang BY (May 2010). "The diagnostic value of endobronchial ultrasound-guided needle biopsy in lung cancer and mediastinal adenopathy". Diagn. Cytopathol. 38 (5): 337–42. doi:10.1002/dc.21195. PMID 19890836.
  22. ↑ Cheson, Bruce D.; Fisher, Richard I.; Barrington, Sally F.; Cavalli, Franco; Schwartz, Lawrence H.; Zucca, Emanuele; Lister, T. Andrew; Alliance, Australasian Leukaemia and Lymphoma Group; Eastern Cooperative Oncology Group; European Mantle Cell Lymphoma Consortium; Italian Lymphoma Foundation; European Organisation for Research; Treatment of Cancer/Dutch Hemato-Oncology Group; Grupo Español de Médula Ósea; German High-Grade Lymphoma Study Group; German Hodgkin's Study Group; Japanese Lymphorra Study Group; Lymphoma Study Association; NCIC Clinical Trials Group; Nordic Lymphoma Study Group; Southwest Oncology Group; United Kingdom National Cancer Research Institute (2014-09-20). "Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 32 (27): 3059–3068. doi:10.1200/JCO.2013.54.8800. ISSN 1527-7755. PMID 25113753.
  23. ↑ Nagle SJ, Chong EA, Chekol S, Shah NN, Nasta SD, Glatstein E, Plastaras JP, Torigian DA, Schuster SJ, Svoboda J (January 2015). "The role of FDG-PET imaging as a prognostic marker of outcome in primary mediastinal B-cell lymphoma". Cancer Med. 4 (1): 7–15. doi:10.1002/cam4.322. PMC 4312112. PMID 25205600.
  24. ↑ Traverse-Glehen A, Pittaluga S, Gaulard P, Sorbara L, Alonso MA, Raffeld M, Jaffe ES (November 2005). "Mediastinal gray zone lymphoma: the missing link between classic Hodgkin's lymphoma and mediastinal large B-cell lymphoma". Am. J. Surg. Pathol. 29 (11): 1411–21. PMID 16224207.
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