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=== Age: ===
=== Age: ===
The incidence of primary mediastinal large B-cell lymphoma increases with age; the median age at diagnosis is 35 years.<ref name="pmid10889382" />
The incidence of [[primary mediastinal large B-cell lymphoma]] increases with age; the median age at diagnosis is 35 years.<ref name="pmid10889382" />


=== Gender: ===
=== Gender: ===
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==Risk Factors==
==Risk Factors==
* There are no established risk factors for primary mediastinal large B-cell lymphoma.
There are no established risk factors for [disease name].
 
OR
 
The most potent risk factor in the development of [disease name] is [risk factor 1]. Other risk factors include [risk factor 2], [risk factor 3], and [risk factor 4].
 
OR
 
Common risk factors in the development of [disease name] include [risk factor 1], [risk factor 2], [risk factor 3], and [risk factor 4].
 
OR
 
Common risk factors in the development of [disease name] may be occupational, environmental, genetic, and viral.


==Screening==
==Screening==

Revision as of 17:36, 27 December 2018

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

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

There is no established system for the classification of primary mediastinal B-cell lymphoma.

Pathophysiology

  • Primary mediastinal large B-cell lymphoma most likely arises within the thymus.[1][3]
  • 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.[4]
  • 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[5]
  • Amplification of the REL oncogene[6]
  • 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[7]
  • The B cell leukemia/lymphoma 2 (BCL-2) gene and B cell leukemia 6 (BCL-6) gene rearrangements can occur.[8]
  • Gains of the proto-oncogene BCL11A and nuclear accumulation of BCL11A(XL) protein.[9]
  • 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.[8]
  • 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. [10]
  • Other markers that are relatively specific for PMBL are CD200 and MAL.[11][12]

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:[13]
    • 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

Causes

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

Differentiating ((Page name)) from Other Diseases

[Disease name] must be differentiated from other diseases that cause [clinical feature 1], [clinical feature 2], and [clinical feature 3], such as [differential dx1], [differential dx2], and [differential dx3].

OR

[Disease name] must be differentiated from [[differential dx1], [differential dx2], and [differential dx3].

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. [15]

Age:

The incidence of primary mediastinal large B-cell lymphoma increases with age; the median age at diagnosis is 35 years.[16]

Gender:

Females are more commonly affected with primary mediastinal large B-cell lymphoma than males.[16]

Risk Factors

There are no established risk factors for [disease name].

OR

The most potent risk factor in the development of [disease name] is [risk factor 1]. Other risk factors include [risk factor 2], [risk factor 3], and [risk factor 4].

OR

Common risk factors in the development of [disease name] include [risk factor 1], [risk factor 2], [risk factor 3], and [risk factor 4].

OR

Common risk factors in the development of [disease name] may be occupational, environmental, genetic, and viral.

Screening

There is insufficient evidence to recommend routine screening for [disease/malignancy].

OR

According to the [guideline name], screening for [disease name] is not recommended.

OR

According to the [guideline name], screening for [disease name] by [test 1] is recommended every [duration] among patients with [condition 1], [condition 2], and [condition 3].

Natural History, Complications, and Prognosis

If left untreated, [#]% of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].

OR

Common complications of [disease name] include [complication 1], [complication 2], and [complication 3].

OR

Prognosis is generally excellent/good/poor, and the 1/5/10-year mortality/survival rate of patients with [disease name] is approximately [#]%.

Diagnosis

Diagnostic Study of Choice

The diagnosis of [disease name] is made when at least [number] of the following [number] diagnostic criteria are met: [criterion 1], [criterion 2], [criterion 3], and [criterion 4].

OR

The diagnosis of [disease name] is based on the [criteria name] criteria, which include [criterion 1], [criterion 2], and [criterion 3].

OR

The diagnosis of [disease name] is based on the [definition name] definition, which includes [criterion 1], [criterion 2], and [criterion 3].

OR

There are no established criteria for the diagnosis of [disease name].

History and Symptoms

The majority of patients with [disease name] are asymptomatic.

OR

The hallmark of [disease name] is [finding]. A positive history of [finding 1] and [finding 2] is suggestive of [disease name]. The most common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3]. Common symptoms of [disease] include [symptom 1], [symptom 2], and [symptom 3]. Less common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3].

Physical Examination

Patients with [disease name] usually appear [general appearance]. Physical examination of patients with [disease name] is usually remarkable for [finding 1], [finding 2], and [finding 3].

OR

Common physical examination findings of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

The presence of [finding(s)] on physical examination is diagnostic of [disease name].

OR

The presence of [finding(s)] on physical examination is highly suggestive of [disease name].

Laboratory Findings

An elevated/reduced concentration of serum/blood/urinary/CSF/other [lab test] is diagnostic of [disease name].

OR

Laboratory findings consistent with the diagnosis of [disease name] include [abnormal test 1], [abnormal test 2], and [abnormal test 3].

OR

[Test] is usually normal among patients with [disease name].

OR

Some patients with [disease name] may have elevated/reduced concentration of [test], which is usually suggestive of [progression/complication].

OR

There are no diagnostic laboratory findings associated with [disease name].

Electrocardiogram

There are no ECG findings associated with [disease name].

OR

An ECG may be helpful in the diagnosis of [disease name]. Findings on an ECG suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

X-ray

There are no x-ray findings associated with [disease name].

OR

An x-ray may be helpful in the diagnosis of [disease name]. Findings on an x-ray suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

There are no x-ray findings associated with [disease name]. However, an x-ray may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

Echocardiography or Ultrasound

There are no echocardiography/ultrasound findings associated with [disease name].

OR

Echocardiography/ultrasound may be helpful in the diagnosis of [disease name]. Findings on an echocardiography/ultrasound suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

There are no echocardiography/ultrasound findings associated with [disease name]. However, an echocardiography/ultrasound may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

CT scan

There are no CT scan findings associated with [disease name].

OR

[Location] CT scan may be helpful in the diagnosis of [disease name]. Findings on CT scan suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

There are no CT scan findings associated with [disease name]. However, a CT scan may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

MRI

There are no MRI findings associated with [disease name].

OR

[Location] MRI may be helpful in the diagnosis of [disease name]. Findings on MRI suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

There are no MRI findings associated with [disease name]. However, a MRI may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

Other Imaging Findings

There are no other imaging findings associated with [disease name].

OR

[Imaging modality] may be helpful in the diagnosis of [disease name]. Findings on an [imaging modality] suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

Other Diagnostic Studies

There are no other diagnostic studies associated with [disease name].

OR

[Diagnostic study] may be helpful in the diagnosis of [disease name]. Findings suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

Other diagnostic studies for [disease name] include [diagnostic study 1], which demonstrates [finding 1], [finding 2], and [finding 3], and [diagnostic study 2], which demonstrates [finding 1], [finding 2], and [finding 3].

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 [strategy 3].

Causes

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

Differentiating type page name here from other Diseases

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

Epidemiology and Demographics

Age

The incidence of primary mediastinal large B-cell lymphoma increases with age; the median age at diagnosis is 35 years.[1]

Gender

Females are more commonly affected with primary mediastinal large B-cell lymphoma than males.[1]

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.[17]

Natural History, Complications and Prognosis

  • Primary mediastinal large B-cell lymphoma is usually a fast-growing (aggressive) 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, or chest pain as the mass grows in the chest.
  • 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.
  • 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.

Diagnosis

Staging

Staging for primary mediastinal large B-cell lymphoma is provided in the following table:[18]

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

Symptoms

Symptoms of the primary mediastinal large B-cell lymphoma include:[1]

  • 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[1]

Vitals

Skin

HEENT

Thorax

Abdomen

Extremities

Laboratory Findings

Laboratory tests for primary mediastinal large B-cell lymphoma include:[1]

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.[14]

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.

CT

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

MRI

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

Other Imaging Findings

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

Treatment

Medical Therapy

Treatment of primary mediastinal large B-cell lymphoma[2]
Therapy Description
Chemotherapy
Biological therapy
Radiation therapy
Stem cell transplant
  • A stem cell transplant may be offered to some people if their lymphoma returns or relapses after treatment.

References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 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. 2.0 2.1 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. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 8.0 8.1 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 14.00 14.01 14.02 14.03 14.04 14.05 14.06 14.07 14.08 14.09 14.10 Primary mediastinal large B-cell lymphoma.Hindawi Publishing Corporation. http://www.hindawi.com/journals/crihem/2012/197347/. Accessed on March 07, 2016
  15. "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.
  16. 16.0 16.1 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.
  17. 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
  18. 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.