Cancer, Hodgkin Lymphoma


Article Author:
Hatem Kaseb


Article Editor:
Hani Babiker


Editors In Chief:
Susan Johnson
Alexandra Caley


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes


Updated:
3/13/2019 4:19:25 PM

Introduction

Hodgkin lymphoma (HL), formerly called Hodgkin's disease, is a rare monoclonal lymphoid neoplasm with high cure rates. Biological and clinical studies have divided this disease entity into 2 distinct categories: classical Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma (NLP-HL). These 2 disease entities show differences in clinical picture and pathology. Classical Hodgkin lymphoma accounts for approximately 95% of all HL, and it is further subdivided into 4 subgroups: nodular sclerosis (NSHL), lymphocyte-rich (LRHL), mixed cellularity (MCHL), and lymphocyte-depleted (LDHL). Four features characterize Hodgkin lymphomas. They commonly arise in the cervical lymph nodes; the disease is more common in young adults; there are scattered large mononuclear Hodgkin and multinucleated cells (Reed-Sternberg) intermixed in a background of a mixture of non-neoplastic inflammatory cells; finally, T lymphocytes are often observed surrounding the characteristic neoplastic cells. Hodgkin lymphoma has an excellent overall prognosis with approximately 80% cure rate.[1][2][3]

Etiology

The exact etiology of Hodgkin lymphoma is unknown. However, there is increased risk of Hodgkin lymphoma in Epstein-Barr (EBV) infection, autoimmune diseases, and immunosuppression. There is also evidence of familial predisposition in Hodgkin lymphoma. EBV has been found to be more common in the mixed cellularity, and lymphocyte depleted subtypes of Hodgkin lymphoma. Loss of immune surveillance has been proposed as the possible disease etiology in EBV-positive disease. No other virus has been found to play a major contributing role in disease pathogenesis. Immunosuppression secondary to a solid organ or hematopoietic cell transplantation, therapy with immunosuppressive drugs, and human immunodeficiency (HIV) infection have all a higher risk of developing Hodgkin lymphoma. HIV patients commonly present with a more advanced stage, unusual lymph nodes sites and a poor prognosis. Studies found that there is a ten-fold increase of developing HL in same-sex siblings of patients with Hodgkin lymphoma suggesting a gene-environment interaction role in Hodgkin lymphoma predisposition.[4][5][6]

Epidemiology

Hodgkin lymphoma is a rare malignancy with an estimated incidence rate of 2.6 cases per 100,000 people in the United States. The disease represents 11% of all lymphomas seen in the United States. It has a bimodal distribution where most of the affected patients are between ages 20 to 40 years, and there is another peak from age 55 years and older. It affects males more than females especially in the pediatric population where 85% of cases occur in boys. Nodular sclerosis Hodgkin lymphoma is more common in young adults whereas mixed cellularity Hodgkin lymphoma tends to affect older adults. The incidence of classical Hodgkin lymphoma subtypes is as follows: nodular sclerosis classical Hodgkin lymphoma (70%), mixed cellularity classical HL (25%), lymphocyte-rich classical Hodgkin lymphoma (5%), and lymphocyte-depleted classical HL (less than 1%). NLPL represents approximately 5% of Hodgkin lymphoma in general.

Pathophysiology

Hodgkin lymphoma has unique neoplastic cells in both the classical and NLP-HL types. Reed-Sternberg (RS) cell is a neoplastic, large multinucleated cell with 2 mirror-image nuclei (owl eyes) within a reactive cellular background. The RS cell is pathognomonic for classical HL. RS cells are derived from germinal center B cells with mutations of IgH-variable region segment. The RS secrete cytokines to recruit reactive cells that include IL-5 and transforming growth factor-beta (TGF-beta). The RS cell is usually aneuploid with no consistent cytogenetic abnormality. Clonal Ig gene rearrangements have been found in the majority of isolated RS cells. Immunohistochemistry stains for RS cells are positive for CD30, CD15, but typically negative for CD20 and CD45 that are positive only in neoplastic NLP-HL cells. In addition to CD15 and CD30, RS cells are usually positive for PAX5, CD25, HLA-DR, ICAM-1, Fascin, CD95 (apo-1/fas), TRAF1, CD40, and CD86. There are RS cells variants that include the Hodgkin cell, mummified cells, and lacunar cells. Hodgkin cells are mononuclear RS-cell variants. Mummified cells show condensed cytoplasm and pyknotic reddish nuclei with smudgy chromatin. Lacunar cells have multilobulated nuclei, small nucleoli, and abundant, pale cytoplasm that often retracts during tissue fixation and sectioning, leaving the nucleus in what appears to be empty space (lacune-like space). On the other hand, NLP-HL lacks the typical RS cells but has lymphocytic and histiocytic cells, which are characterized by larger cells with folded multilobulated nuclei (also known as “popcorn cells” or LP cells). The LP cells show a nucleus with multiple nucleoli that are basophilic and smaller than those seen in RS cells. LP cells show clonally rearranged immunoglobulin genes that are only detected in isolated single LP cells. The LP cells are usually positive for C020, CD45, EMA, CD79a, CD75, BCL6, BOB.1, OCT2, and J chain.

Histopathology

Morphology is used to determine Hodgkin lymphoma variants and NLP-HL. Nodular sclerosis HL shows a partially nodular growth pattern, with fibrous bands and inflammatory background. RS cells are rare. However, lacunar cells are more common. Mixed cellularity HL shows a diffuse or vaguely nodular growth pattern without sclerosis bands in an inflammatory background. Fine interstitial fibrosis may be present, and classical diagnostic Reed Sternberg cells are common. Lymphocyte-rich HL commonly shows a nodular growth pattern in an inflammatory background that consists predominantly of lymphocytes, with rare or no eosinophils or neutrophils. RS cells and mononuclear Hodgkin cells are usually present. Lymphocyte depleted HL has a diffuse hypocellular growth pattern with increased areas of fibrosis, necrosis, and uncommon inflammatory cells. RS cells are usually present. NLPHL is characterized by overall nodular architecture with LP cells in a background of small B lymphocytes, follicular dendritic cells, and follicular T lymphocytes. In conclusion, morphology and immunophenotype of both the neoplastic cells and the background infiltrate are crucial in diagnosing HL and its different subtypes. In summary, correct morphological and immunophenotypic assessment in HL is important for the correct diagnosis of the disease entity.

History and Physical

Hodgkin lymphoma patients frequently present with painless supra-diaphragmatic lymphadenopathy (one to two lymph node areas), B symptoms including unexplained profound weight loss, high fevers, and drenching night sweats. B symptoms are evident in up to 30% of patients and are generally more common in stage 3 to 4 of the disease, mixed cellularity, and lymphocyte depleted HL subtypes. Pain in lymph nodes may occur with alcohol consumption (paraneoplastic symptom). Chronic pruritus is another disease symptom that may be encountered. If mediastinal nodes enlargement is significant, the mass effect can produce chest pain and shortness of breath. If the patient has an extra-nodal disease, which is less common, related clinical manifestations may occur.

Each subtype of Hodgkin lymphoma has distinct clinical features. Nodular sclerosis subtype affects young adults and presents with early disease stage; while mixed cellularity HL is prevalent in both children and elderly patients and commonly presents with advanced disease stage. Lymphocyte depletion HL presents with the extensive extranodal disease, affects elderly patients and is associated with AIDS infection. Lymphocyte-rich classical HL presents with localized painless peripheral lymphadenopathy similar to NLP-HL. NLP-HL is a distinct, unique clinicopathological entity that is distinct from classical HL. It presents in males with localized painless peripheral lymphadenopathy in the neck that often spares the mediastinum. NLP-HL shows a more indolent course with a tendency for late relapses.[7][8][9]

Evaluation

Definitive diagnosis for Hodgkin lymphoma is through biopsy from a lymph node or suspected organ. It is important to note that fine-needle aspiration or core-needle biopsy frequently show non-specific findings because of the low ratio of malignant cells and loss of architectural information. So excisional biopsy should be pursued if suspicion of Hodgkin lymphoma is high. An RS cell or LP cell need to be identified within the biopsy specimen to establish a definitive diagnosis. Further workup is essential to determine the stage, which guides treatment and provide prognostic information. Laboratory tests include complete blood count (CBC), complete metabolic panel (CMP), ESR, HBV, HBC, and HIV. Chest x-ray, CT chest/abdomen/pelvis, and PET/CT scans can help with staging. PET-CT scanning has now become a standard test for assessment of treatment response in HL and most lymphomas. Overall, a comprehensive workup is essential for both diagnosis and staging of Hodgkin lymphoma.

Treatment / Management

Treatment of Hodgkin lymphoma largely depends on the histologic characteristics, the stage of the disease, and the presence or absence of prognostic factors. The goal of treatment for patients with Hodgkin lymphoma is to cure the disease with control of short and long-term complications. There are several different staging systems for Hodgkin lymphoma, and the Cotswolds modified Ann Arbor classification is commonly used. The International Prognostic Factors Project on Advanced Hodgkin's lymphoma identified 7 variables for patients with advanced disease:

  1. Age older than 45 years
  2. Stage-IV disease
  3. Male gender
  4. WBC greater than 15,000/mL
  5. Lymphocyte less than 600/mL
  6. Albumin less than 4.0 g/dL
  7. Hemoglobin less than 10.5 g/dL

Risk stratification categorizes patients as low risk or high risk for recurrence. The response to therapy is determined by PET scan and is used to optimize therapy. Initial treatment of Hodgkin lymphoma depends on the subgroup treatment. There are 3 treatment subgroups: patients with the early-stage disease with favorable prognostic factors, patients with the limited-stage disease who have unfavorable prognostic factors, and those with advanced-stage disease. Patients who are in early-stage (stage I to IIA) with favorable prognostic features are treated with short duration of chemotherapy, typically 2 cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) followed by restricted involved-field radiation therapy (IFRT). Patients who are in limited-stage disease but with unfavorable features such as bulky mediastinal disease, elevated ESR and extra-nodal extension are treated with a longer course of chemotherapy (4 to 6 cycles) followed by a higher dose of IFRT. Patients with advanced-stage (stage IIB to IV) are risk stratified by a different scoring system, the International Prognostic Score (IPS). Depending on IPS, different chemotherapy regimen (for example, escalated BEACOPP and Stanford V) can be used, but the standard of care is ABVD for most patients. Radiation, in general, is not beneficial in these patients. Despite the high cure rate with initial therapy, approximately 10% of Hodgkin lymphoma patients are refractory to initial treatment, and up to 30% of patients will relapse after achieving an initial complete remission. High-dose chemotherapy followed by an autologous stem cell transplant is the standard of care for the majority of patients who are refractory or relapse post-initial therapy. For patients who fail autologous transplantation treatment options include: brentuximab vedotin, PD-1 blockade, non-myeloablative allogeneic transplantation or clinical trials. Future directions in the management of Hodgkin lymphoma will include the incorporation of frontline therapeutics that have shown efficacy in refractory/relapses disease setting as well as other possible novel therapeutics.[10][11][12][13]

Differential Diagnosis

  • Infectious mononucleosis
  • Peripheral T cell lymphoma
  • ALK1+ anaplastic (Ki-1) large cell lymphoma
  • Non-Hodgkin lymphoma
  • Diffuse large B cell lymphoma

Staging

Treatment of Hodgkin lymphoma is based on clinical staging of the disease. The modified Ann Arbor staging system is the most common staging system. The staging system for Hodgkin lymphoma is based on the location of lymphadenopathy, the number, and size of lymph node, and whether the extranodal lymph node involvement is shown systemic. Commonly used staging system divides the disease into 4 stages:

  • Stage I: Involvement of single lymph node regions or lymphoid structure
  • Stage II: Involvement of 2 or more lymph node regions on the same side of the diaphragm; the number of anatomic sites should be indicated in a suffix (e.g., II2)
  • Stage III: Involvement of lymph nodes or structures on both sides of the diaphragm
  1. III1: With or without splenic, hilar, celiac or portal nodes
  2. III2: With paraaortic, iliac or mesenteric nodes
  • Stage IV: Involvement of extranodal sites beyond those designated as E (E: single extranodal site, or contiguous or proximal to the known nodal site of disease)

Prognosis

Prognosis depends on several prognostic factors including disease stage. Disease stage is currently only one factor in the prognostic indices used for pretreatment risk stratification and assessment. The 5-year overall survival (OS) in stage 1 or 2a is approximately 90%; on the other hand, stage 4 disease has a 5-year OS of approximately 60%.

Enhancing Healthcare Team Outcomes

The management of Hodgkin lymphoma is primarily by the oncologists. However, the patient may first present to the primary care provider or nurse practitioner with symptoms suggestive of the lymphoma. The key is prompt referral so that therapy can be initiated.  Treatment of Hodgkin lymphoma largely depends on the histologic characteristics, the stage of the disease, and the presence or absence of prognostic factors. The goal of treatment for patients with Hodgkin lymphoma is to cure the disease with control of short and long-term complications. 

Prognosis depends on several prognostic factors including disease stage. Disease stage is currently only one factor in the prognostic indices used for pretreatment risk stratification and assessment. The 5-year overall survival (OS) in stage 1 or 2a is approximately 90%; on the other hand, stage 4 disease has a 5-year OS of approximately 60%.[14][15](Level V)


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Cancer, Hodgkin Lymphoma - Questions

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A young woman presents with a 3 cm left neck mass. She does not report any other symptoms. Excisional biopsy of the mass reveals a uniform population of cells consisting of few large cells, lymphocytes, eosinophils, and plasma cells. Immunohistochemistry reveals positive CD 15 and CD 30 cells in the majority of the large cells. What is the most likely diagnosis?



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A patient presents with weight loss, fever, and night sweats. On physical, the patient is found to have enlarged cervical lymph nodes. Biopsy of the lymph nodes reveals the presence of Reed-Sternberg cells. What is the most likely diagnosis?



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What is the most common type of Hodgkin tumor?



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Which is least likely to cause postauricular adenopathy in children?



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Which of the following about Hodgkin disease is false?



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Which of the following is not included in the MOPP regime for Hodgkin lymphoma treatment?



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A male undergoes a needle biopsy of a mass in the neck. The pathologist mentions that there are Reed-Sternberg cells. The patient may have which of the following?



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A patient has a biopsy of an anterior chest wall mass and the pathologist reports Reed-Sternberg cells. What is the appropriate next step?



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A patient is receiving nitrogen mustard, vincristine, procarbazine, and prednisone (MOPP chemotherapy regimen) to treat Stage III Hodgkin disease. Which of the following should be monitored in this patient prior to receiving chemotherapy?



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Which of the following is not a subtype of Hodgkin lymphoma?



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Which histologic subtype of Hodgkin lymphoma is characterized by an indolent clinical course and a high 10-year survival rate in the early stage without treatment?



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What criteria are assessed during staging for Hodgkin lymphoma?



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What subtype of classical Hodgkin lymphoma (HL) is mostly associated with the finding of mediastinal adenopathy?



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Which of the following is a common histological finding in patients with Hodgkin lymphoma?



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An 17-year-old underwent a cervical neck biopsy, which reveals presence of Reed Sternberg cells. His prognosis depends on which factor?



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A 24-year-old male presents with multiple painless, rubbery, enlarged cervical nodes. For the past few weeks, he has also been complaining of fever, night sweats, weight loss, and generalized itching. Biopsy of the nodes reveals cellular infiltrates with large nuclei. Which of the following is the most likely diagnosis?



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Which of the following is not a histological type of Hodgkin disease?



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A 17-year-old male has just been diagnosed with Hodgkin lymphoma. The best prognosis is with which histology?



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Which of the following is most likely to cause clonal immunoglobulin gene rearrangements?



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A young patient with Hodgkin disease is treated with a multi-drug regimen called "ABVD". What does the "B" stand for in this group?



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Which of the following is not a subtype of Hodgkin's disease?



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What is the ideal therapy in a 44-year-old male with newly diagnosed Hodgkin lymphoma localized to the mediastinum?



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What is the most common subtype of Hodgkin lymphoma seen in the mediastinum?



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What tumor is seen when Reed Sternberg cells are seen?



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Which group of lymph nodes is most commonly involved in Hodgkin lymphoma (HL)?



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A patient with Hodgkin lymphoma is treated with the multi-drug regimen AVBD. The B stands for:



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A female presents with a one month history of an enlarged anterior cervical node. She denies weight loss, fever, or sweats but has had generalized pruritus for 3 weeks. The patient has a 3 cm lymph node and the rest of the physical is normal. Biopsy is positive for sclerosing Hodgkin disease. CT of the chest, abdomen, and pelvis are normal. Laparotomy is normal. According to the Ann Arbor classification the patient's stage is which of the following?



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Which feature is most commonly seen in Hodgkin lymphoma?



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Which is true regarding treatment of Hodgkin lymphoma?



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A 17-year-old female without significant past medical history presents with cervical, axillary, supraclavicular, and inguinal lymphadenopathy. She has had some generalized pruritus, undocumented fevers, and night sweats. She started coughing about 10 days ago but produces no sputum. The lungs are clear and there is no hepatosplenomegaly. Select the next step in management.



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According to the Ann Arbor staging system, what stage is Hodgkin lymphoma with affected lymph nodes on both sides of the diaphragm?



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The most common presenting manifestation of Hodgkin's disease is:



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A 17-year-old male presents with a 3-week history general malaise, low- grade fever, night sweats, and loss of appetite. Last week he developed itching all over his body and vague muscle pain. Physical exam reveals the presence of painless lymphadenopathy. An excisional biopsy reveals the presence of cells with an "owl's eye nuclei." In which part of the body will the adenopathy be most common?



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Which is not a typical feature of Hodgkin lymphoma?



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Cancer, Hodgkin Lymphoma - References

References

Lees C,Keane C,Gandhi MK,Gunawardana J, Biology and therapy of primary mediastinal B-cell lymphoma: current status and future directions. British journal of haematology. 2019 Feb 10;     [PubMed]
Amraee A,Evazi MR,Shakeri M,Roozbeh N,Ghazanfarpour M,Ghorbani M,Ansari J,Darvish L, Efficacy of nivolumab as checkpoint inhibitor drug on survival rate of patients with relapsed/refractory classical Hodgkin lymphoma: a meta-analysis of prospective clinical study. Clinical     [PubMed]
Metzger ML,Mauz-Körholz C, Epidemiology, outcome, targeted agents and immunotherapy in adolescent and young adult non-Hodgkin and Hodgkin lymphoma. British journal of haematology. 2019 Feb 6;     [PubMed]
Childhood Hodgkin Lymphoma Treatment (PDQ®): Health Professional Version 2002;     [PubMed]
Milgrom SA,Elhalawani H,Lee J,Wang Q,Mohamed ASR,Dabaja BS,Pinnix CC,Gunther JR,Court L,Rao A,Fuller CD,Akhtari M,Aristophanous M,Mawlawi O,Chuang HH,Sulman EP,Lee HJ,Hagemeister FB,Oki Y,Fanale M,Smith GL, A PET Radiomics Model to Predict Refractory Mediastinal Hodgkin Lymphoma. Scientific reports. 2019 Feb 4;     [PubMed]
Lyapichev KA,You MJ, Unusual presentation of classic Hodgkin lymphoma. Blood. 2019 Jan 31;     [PubMed]
Justiz Vaillant AA,Stang CM, Lymphoproliferative Disorders 2018 Jan;     [PubMed]
Gaut D,Schiller GJ, Hematopoietic stem cell transplantation in primary central nervous system lymphoma: a review of the literature. International journal of hematology. 2019 Jan 22;     [PubMed]
Cai Q,Fang Y,Young KH, Primary Central Nervous System Lymphoma: Molecular Pathogenesis and Advances in Treatment. Translational oncology. 2019 Mar;     [PubMed]
Hoppe RT,Advani RH,Ai WZ,Ambinder RF,Aoun P,Armand P,Bello CM,Benitez CM,Bierman PJ,Chen R,Dabaja B,Dean R,Forero A,Gordon LI,Hernandez-Ilizaliturri FJ,Hochberg EP,Huang J,Johnston PB,Kaminski MS,Kenkre VP,Khan N,Maddocks K,Maloney DG,Metzger M,Moore JO,Morgan D,Moskowitz CH,Mulroney C,Rabinovitch R,Seropian S,Tao R,Winter JN,Yahalom J,Burns JL,Ogba N, NCCN Guidelines Insights: Hodgkin Lymphoma, Version 1.2018. Journal of the National Comprehensive Cancer Network : JNCCN. 2018 Mar;     [PubMed]
Gordon LI, Strategies for Management of Relapsed or Refractory Hodgkin Lymphoma. Journal of the National Comprehensive Cancer Network : JNCCN. 2017 May;     [PubMed]
Klimm B,Goergen H,Fuchs M,von Tresckow B,Böll B,Meissner J,Glunz A,Diehl V,Eich HT,Engert A,Borchmann P, Impact of risk factors on outcomes in early-stage Hodgkin's lymphoma: an analysis of international staging definitions. Annals of oncology : official journal of the European Society for Medical Oncology. 2013 Dec;     [PubMed]
Hoppe RT,Advani RH,Ai WZ,Ambinder RF,Aoun P,Bello CM,Bierman PJ,Blum KA,Chen R,Dabaja B,Duron Y,Forero A,Gordon LI,Hernandez-Ilizaliturri FJ,Hochberg EP,Maloney DG,Mansur D,Mauch PM,Metzger M,Moore JO,Morgan D,Moskowitz CH,Poppe M,Pro B,Winter JN,Yahalom J,Sundar H, Hodgkin lymphoma, version 2.2012 featured updates to the NCCN guidelines. Journal of the National Comprehensive Cancer Network : JNCCN. 2012 May;     [PubMed]
Chihara D,Oki Y,Fanale MA,Westin JR,Nastoupil LJ,Neelapu S,Fayad L,Fowler NH,Cheah CY, Stage I non-Hodgkin lymphoma: no plateau in disease-specific survival ? Annals of hematology. 2019 Jan 8;     [PubMed]
Ramchandren R,Advani RH,Ansell SM,Bartlett NL,Chen R,Connors JM,Feldman T,Forero-Torres A,Friedberg JW,Gopal AK,Gordon LI,Kuruvilla J,Savage KJ,Younes A,Engley G,Manley TJ,Fenton K,Straus DJ, Brentuximab Vedotin plus Chemotherapy in North American Subjects with Newly Diagnosed Stage III or IV Hodgkin Lymphoma. Clinical cancer research : an official journal of the American Association for Cancer Research. 2019 Jan 7;     [PubMed]

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