Hodgkin's lymphoma

Hodgkin's lymphoma
Classification and external resources

Micrograph showing Hodgkin's lymphoma (Field stain).
ICD-10 C81.
ICD-9 201
ICD-O: 9650/3-9667/3
DiseasesDB 5973
MedlinePlus 000580
eMedicine med/1022
MeSH D006689

Hodgkin's lymphoma, previously known as Hodgkin's disease, is a type of lymphoma, which is a cancer originating from white blood cells called lymphocytes. It was named after Thomas Hodgkin, who first described abnormalities in the lymph system in 1832.[1][2] Hodgkin's lymphoma is characterized by the orderly spread of disease from one lymph node group to another and by the development of systemic symptoms with advanced disease. When Hodgkins cells are examined microscopically, multinucleated Reed-Sternberg cells (RS cells) are the characteristic histopathologic finding. Hodgkin's lymphoma may be treated with radiation therapy or chemotherapy, the choice of treatment depending on the age and sex of the patient and the stage, bulk and histological subtype of the disease.

The disease occurrence shows two peaks: the first in young adulthood (age 15–35) and the second in those over 55 years old.[3]

The survival rate is generally 90% or higher when the disease is detected during early stages, making it one of the more curable forms of cancer.[4] Hodgkin's lymphoma is one of a handful of cancers that, even in its later stages, has a very high survival rate (~90% or better).[5] Most patients who are able to be successfully treated and thus enter remission generally go on to live long lives.

Patients with a history of infectious mononucleosis due to Epstein-Barr virus may have an increased risk of HL.

Contents

Classification

Types

Classical Hodgkin's lymphoma (excluding nodular lymphocyte predominant Hodgkin's lymphoma) can be subclassified into 4 pathologic subtypes based upon Reed-Sternberg cell morphology and the composition of the reactive cell infiltrate seen in the lymph node biopsy specimen (the cell composition around the Reed-Stenberg cell(s)).

Name Description ICD-10 ICD-O
Nodular sclerosing CHL Is the most common subtype and is composed of large tumor nodules showing scattered lacunar classical RS cells set in a background of reactive lymphocytes, eosinophils and plasma cells with varying degress of collagen fibrosis/sclerosis. C81.1 M9663/3
Mixed-cellularity subtype Is a common subtype and is composed of numerous classic RS cells admixed with numerous inflammatory cells including lymphocytes, histiocytes, eosinophils, and plasma cells. without sclerosis. This type is most often associated with EBV infection and may be confused with the early, so-called 'cellular' phase of nodular sclerosing CHL. C81.2 M9652/3.
Lymphocyte-rich or Lymphocytic predominance Is a rare subtype, show many features which may cause diagnostic confusion with nodular lymphocyte predominant B-cell Non-Hodgkin's Lymphoma (B-NHL). This form also has the most favorable prognosis. C81.0 M9651/3
Lymphocyte depleted Is a rare subtype, composed of large numbers of often pleomorphic RS cells with only few reactive lymphocytes which may easily be confused with diffuse large cell lymphoma. Many cases previously classified within this category would now be reclassified under anaplastic large cell lymphoma.[6] C81.3 M9653/3
Unspecified C81.9 M9650/3
Lymph node biopsy showing Hodgkin's lymphoma, mixed-cellularity type.

Nodular lymphocyte predominant Hodgkin's lymphoma expresses CD20, and is not currently considered a form of classical Hodgkin's.

For the other forms, although the traditional B cell markers (such as CD20) are not expressed on all cells,[6] Reed-Sternberg cells are usually of B cell origin.[7][8] Although Hodgkin's is now frequently grouped with other B cell malignancies, some T cell markers (such as CD2 and CD4) are occasionally expressed.[9] However, this may be an artifact of the ambiguity inherent in the diagnosis.

Hodgkin's cells produce Interleukin-21 (IL-21), which was once thought to be exclusive to T cells. This feature may explain the behavior of classical Hodgkin's lymphoma, including clusters of other immune cells gathered around HL cells (infiltrate) in cultures.[10]

Staging

The staging is the same for both Hodgkin's as well as non-Hodgkin's lymphomas.

After Hodgkin's lymphoma is diagnosed, a patient will be staged: that is, they will undergo a series of tests and procedures that will determine what areas of the body are affected. These procedures will include documentation of their histology, a physical examination, blood tests, chest X-ray radiographs, computed tomography (CT) scans or magnetic resonance imaging (MRI) scans of the chest, abdomen and pelvis, and a bone marrow biopsy. Positron emission tomography (PET) scan is now used instead of the gallium scan for staging. In the past, a lymphangiogram or surgical laparotomy (which involves opening the abdominal cavity and visually inspecting for tumors) were performed. Lymphangiograms or laparotomies are very rarely performed, having been supplanted by improvements in imaging with the CT scan and PET scan.

On the basis of this staging, the patient will be classified according to a staging classification (the Ann Arbor staging classification scheme is a common one):

The absence of systemic symptoms is signified by adding 'A' to the stage; the presence of systemic symptoms is signified by adding 'B' to the stage. For localized extranodal extension from mass of nodes that does not advance the stage, subscript 'E' is added.

Signs and symptoms

Patients with Hodgkin's lymphoma may present with the following symptoms:

Cause

There are no guidelines for preventing Hodgkin's lymphoma because the cause is unknown or multifactorial. A risk factor is something that statistically increases your chance of getting a disease or condition. Risk factors include:

Pathogenesis

Mind map 3.jpg

Diagnosis

Hodgkin's lymphoma must be distinguished from non-cancerous causes of lymph node swelling (such as various infections) and from other types of cancer. Definitive diagnosis is by lymph node biopsy (Usually excisional biopsy with microscopic examination). Blood tests are also performed to assess function of major organs and to assess safety for chemotherapy. Positron emission tomography (PET) is used to detect small deposits that do not show on CT scanning. PET scans are also useful in functional imaging (by using a radiolabeled glucose to image tissues of high metabolism). In some cases a Gallium Scan may be used instead of a PET scan.

Pathology

Macroscopy

Affected lymph nodes (most often, laterocervical lymph nodes) are enlarged, but their shape is preserved because the capsule is not invaded. Usually, the cut surface is white-grey and uniform; in some histological subtypes (e.g. nodular sclerosis) a nodular aspect may appear.

A fibrin ring granuloma may be seen.

Microscopy
Reed-Sternberg lymphocyte nci-vol-7172-300.jpg

Microscopic examination of the lymph node biopsy reveals complete or partial effacement of the lymph node architecture by scattered large malignant cells known as Reed-Sternberg cells (RSC) (typical and variants) admixed within a reactive cell infiltrate composed of variable proportions of lymphocytes, histiocytes, eosinophils, and plasma cells. The Reed-Sternberg cells are identified as large often bi-nucleated cells with prominent nucleoli and an unusual CD45-, CD30+, CD15+/- immunophenotype. In approximately 50% of cases, the Reed-Sternberg cells are infected by the Epstein-Barr virus.

Characteristics of classic Reed-Sternberg cells include large size (20–50 micrometres), abundant, amphophilic, finely granular/homogeneous cytoplasm; two mirror-image nuclei (owl eyes) each with an eosinophilic nucleolus and a thick nuclear membrane (chromatin is distributed at the cell periphery).

Variants:

Hodgkin's lymphoma can be sub-classified by histological type. The cell histology in Hodgkin's lymphoma is not as important as it is in non-Hodgkin's lymphoma: the treatment and prognosis in classic Hodgkin's lymphoma usually depends on the stage of disease rather than the histotype.

Management

Patients with early stage disease (IA or IIA) are effectively treated with radiation therapy or chemotherapy. The choice of treatment depends on the age, sex, bulk and the histological subtype of the disease. Patients with later disease (III, IVA, or IVB) are treated with combination chemotherapy alone. Patients of any stage with a large mass in the chest are usually treated with combined chemotherapy and radiation therapy.

ABVD Stanford V BEACOPP
Currently, the ABVD chemotherapy regimen is the standard treatment of Hodgkin's disease in the US. The abbreviation stands for the four drugs Adriamycin, bleomycin, vinblastine, and dacarbazine. Developed in Italy in the 1970s, the ABVD treatment typically takes between six and eight months, although longer treatments may be required. The newer Stanford V regimen is typically only half as long as the ABVD but involves a more intensive chemotherapy schedule and incorporates radiation therapy. In a randomized controlled study in Italy, Stanford V was inferior to ABVD.[16] BEACOPP is a form of treatment for stages > II mainly used in Europe. The cure rate with the BEACOPP esc. regimen is approximately 10–15% higher than with standard ABVD in advanced stages. This was shown in a paper in The New England Journal of Medicine (Diehl et al.), but US physicians still favor ABVD, maybe because some physicians think that BEACOPP induces more secondary leukemia. However, this seems negligible compared to the higher cure rates. BEACOPP is more expensive because of the requirement for concurrent treatment with GCSF to increase production of white blood cells. Currently, the German Hodgkin Study Group tests 8 cycles (8x) BEACOPP esc vs. 6x BEACOPP esc vs. 8x BEACOPP-14 baseline (HD15-trial).[17]
Doxorubicin Doxorubicin Doxorubicin
Bleomycin Bleomycin Bleomycin
Vinblastine Vinblastine, Vincristine Vincristine
Dacarbazine Mechlorethamine Cyclophosphamide, Procarbazine
Etoposide Etoposide
Prednisone Prednisone

It should be noted that the common non-Hodgkin's treatment, rituximab (which targets CD-20) is not used to treat Hodgkin's due to the lack of CD-20 surface antigens in Hodgkin's.

Although increased age is an adverse risk factor for Hodgkin's lymphoma, in general elderly patients without major comorbidities are sufficiently fit to tolerate standard therapy, and have a treatment outcome comparable to that of younger patients. However, the disease is a different entity in older patients and different considerations enter into treatment decisions.[18]

For Hodgkin's lymphomas, radiation oncologists typically use external beam radiation therapy (sometimes shortened to EBRT). Radiation oncologists deliver external beam radiation therapy to the lymphoma from a machine called a linear accelerator. Patients usually describe treatments as painless and similar to getting an X-ray. Treatments last less than 30 minutes each, every day but Saturday and Sunday.

For lymphomas, there are a few different ways radiation oncologists target the cancer cells. Involved field radiation is when the radiation oncologists give radiation only to the parts of your body known to have the cancer. Very often, this is combined with chemotherapy. Radiation therapy directed above the diaphragm to the neck, chest and/or underarms is called mantle field radiation. Radiation to below the diaphragm to the abdomen, spleen and/or pelvis is called inverted-Y field radiation. Total nodal irradiation is when your doctor gives radiation to all the lymph nodes in the body to destroy cells that may have spread.[19]

The high cure rates and long survival of many patients with Hodgkin's lymphoma has led to a high concern with late adverse effects of treatment, including cardiovascular disease and second malignancies such as acute leukemias, lymphomas, and solid tumors within the radiation therapy field. Most patients with early stage disease are now treated with abbreviated chemotherapy and involved-field radiation therapy rather than with radiation therapy alone. Clinical research strategies are exploring reduction of the duration of chemotherapy and dose and volume of radiation therapy in an attempt to reduce late morbidity and mortality of treatment while maintaining high cure rates. Hospitals are also treating those who respond quickly to chemotherapy with no radiation.

Prognosis

Treatment of Hodgkin's disease has been improving over the past few decades. Recent trials that have made use of new types of chemotherapy have indicated higher survival rates than have previously been seen. In one recent European trial, the 5-year survival rate for those patients with a favorable prognosis was 98%, while that for patients with worse outlooks was at least 85%.[4]

In 1998, an international effort[20] identified seven prognostic factors that accurately predict the success rate of conventional treatment in patients with locally extensive or advanced stage Hodgkin's lymphoma. Freedom from progression (FFP) at 5 years was directly related to the number of factors present in a patient. The 5-year FFP for patients with zero factors is 84%. Each additional factor lowers the 5-year FFP rate by 7%, such that the 5-year FFP for a patient with 5 or more factors is 42%.

The adverse prognostic factors identified in the international study are:

Other studies have reported the following to be the most important adverse prognostic factors: mixed-cellularity or lymphocyte-depleted histologies, male sex, large number of involved nodal sites, advanced stage, age of 40 years or more, the presence of B symptoms, high erythrocyte sedimentation rate, and bulky disease (widening of the mediastinum by more than one third, or the presence of a nodal mass measuring more than 10 cm in any dimension.)

Epidemiology

Age-standardized death from lymphomas and multiple myeloma per 100,000 inhabitants in 2004.[21]
     no data      less than 1.8      1.8–3.6      3.6–5.4      5.4–7.2      7.2–9      9–10.8      10.8–12.6      12.6–14.4      14.4–16.2      16.2–18      18–19.8      more than 19.8

Unlike some other lymphomas, whose incidence increases with age, Hodgkin's lymphoma has a bimodal incidence curve; that is, it occurs most frequently in two separate age groups, the first being young adulthood (age 15–35) and the second being in those over 55 years old although these peaks may vary slightly with nationality.[22] Overall, it is more common in males, except for the nodular sclerosis variant, which is slightly more common in females. The annual incidence of Hodgkin's lymphoma is about 1 in 25,000 people, and the disease accounts for slightly less than 1% of all cancers worldwide.

The incidence of Hodgkin's lymphoma is increased in patients with HIV infection.[23] In contrast to many other lymphomas associated with HIV infection it occurs most commonly in patients with higher CD4 T cell counts.

History

Hodgkin's lymphoma was first described in an 1832 report by Thomas Hodgkin, although Hodgkin noted that perhaps the earliest reference to the condition was provided by Marcello Malpighi in 1666.[1][2] While occupied as museum curator at Guy's Hospital, Hodgkin studied seven patients with painless lymph node enlargement. Of the seven cases, two were patients of Richard Bright, one was of Thomas Addison, and one was of Robert Carswell.[1] Carswell's report of this seventh patient was accompanied by numerous illustrations that aided early descriptions of the disease.[24]

Hodgkin's report on these seven patients, entitled "On some morbid appearances of the absorbent glands and spleen", was presented to the Medical and Chirurgical Society in London in January 1832 and was subsequently published in the society's journal, Medical-Chirurgical Society Transactions.[1] Hodgkin's paper went largely unnoticed, however, even despite Bright highlighting it in an 1838 publication.[1] Indeed, Hodgkin himself did not view his contribution as particularly significant.[25]

In 1856, Samuel Wilks independently reported on a series of patients with the same disease that Hodgkin had previously described.[25] Wilks, a successor to Hodgkin at Guy's Hospital, was unaware of Hodgkin's prior work on the subject. Bright made Wilks aware of Hodgkin's contribution and in 1865, Wilks published a second paper, entitled "Cases of enlargement of the lymphatic glands and spleen", in which he called the disease "Hodgkin's disease" in honor of his predecessor.[25]

Theodor Langhans and WS Greenfield first described the microscopic characteristics of Hodgkin's lymphoma in 1872 and 1878, respectively.[1] In 1898 and 1902, respectively, Carl Sternberg and Dorothy Reed independently described the cytogenetic features of the malignant cells of Hodgkin's lymphoma, now called Reed-Sternberg cells.[1]

Tissue specimens from Hodgkin's seven patients remained at Guy's Hospital for a number of years. Nearly 100 years after Hodgkin's initial publication, histopathologic reexamination confirmed Hodgkin's lymphoma in only three of seven of these patients.[25] The remaining cases included non-Hodgkin lymphoma, tuberculosis, and syphilis.[25]

Hodgkin's lymphoma was one of the first cancers which could be treated using radiation therapy and, later, it was one of the first to be treated by combination chemotherapy.

Society and culture

Notable cases

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Cultural references

See also

Further reading

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Hellman S (2007). "Brief Consideration of Thomas Hodgkin and His Times". In Hoppe RT, Mauch PT, Armitage JO, Diehl V, Weiss LM. Hodgkin Lymphoma (2nd ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. pp. 3–6. ISBN 0-7817-6422-X. 
  2. ↑ 2.0 2.1 Hodgkin T (1832). "On some morbid experiences of the absorbent glands and spleen". Med Chir Trans 17: 69–97. 
  3. ↑ Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) Caner.gov
  4. ↑ 4.0 4.1 Fermé C, Eghbali H, Meerwaldt JH, et al. (November 2007). "Chemotherapy plus involved-field radiation in early-stage Hodgkin's disease". The New England Journal of Medicine 357 (19): 1916–27. doi:10.1056/NEJMoa064601. PMID 17989384. http://content.nejm.org/cgi/pmidlookup?view=short&pmid=17989384&promo=ONFLNS19. 
  5. ↑ Stein RS, Morgan D (2003). Handbook of cancer chemotherapy (6th ed.). Hagerstown, MD: Lippincott Williams & Wilkins. p. 493. ISBN 0-7817-3629-3. 
  6. ↑ 6.0 6.1 "HMDS: Hodgkin's Lymphoma". http://www.hmds.org.uk/hl.html. Retrieved February 1, 2009. 
  7. ↑ Küppers R, Schwering I, Bräuninger A, Rajewsky K, Hansmann ML (2002). "Biology of Hodgkin's lymphoma". Ann. Oncol. 13 Suppl 1: 11–8. PMID 12078890. http://annonc.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=12078890. 
  8. ↑ Bräuninger A, Schmitz R, Bechtel D, Renné C, Hansmann ML, Küppers R (April 2006). "Molecular biology of Hodgkin's and Reed/Sternberg cells in Hodgkin's lymphoma". Int. J. Cancer 118 (8): 1853–61. doi:10.1002/ijc.21716. PMID 16385563. 
  9. ↑ Tzankov A, Bourgau C, Kaiser A, et al. (December 2005). "Rare expression of T-cell markers in classical Hodgkin's lymphoma". Mod. Pathol. 18 (12): 1542–9. doi:10.1038/modpathol.3800473. PMID 16056244. 
  10. ↑ Lamprecht B, Kreher S, Anagnostopoulos, I, Johrens k, Monteleone G, Junt F, Stein H, Janz M, Dorken B, Mathas S (2008). "Aberrant expression of the Th2 cytokine IL-21 in Hodgkin lymphoma cells regulates STAT3 signaling and attracts Treg cells via regulation of MIP-3a". Blood 112 (Oct 2008): 3339–3347. doi:10.1182/blood-2008-01-134783. PMID 18684866. http://bloodjournal.hematologylibrary.org/cgi/content/abstract/112/8/3339. 
  11. ↑ Bobrove AM (June 1983). "Alcohol-related pain and Hodgkin's disease". The Western Journal of Medicine 138 (6): 874–5. PMID 6613116. 
  12. ↑ Portlock CS (July 2008). "Hodgkin Lymphoma". Merck Manual Professional. http://www.merck.com/mmpe/sec11/ch143/ch143b.html. Retrieved June 18, 2009. 
  13. ↑ {Hodgon DC, Gospodarowicz MK (2007). "Clinical Evaluation and Staging of Hodgkin Lymphoma". In Hoppe RT, Mauch PT, Armitage JO, Diehl V, Weiss LM. Hodgkin’s disease. Lippincott Williams & Wilkins. pp. 123–132. ISBN 978-0-7817-6422-3. 
  14. ↑ Asher, Richard (July 6, 1995). "Making Sense". The New England Journal of Medicine 333 (1): 66–67. doi:10.1056/NEJM199507063330118. PMID 7777006. 
  15. ↑ 15.0 15.1 15.2 15.3 15.4 15.5 Hodgkin's disease (Hodgkin's lymphoma) at Mount Sinai Hospital
  16. ↑ Gobbi PG, Levis A, Chisesi T, et al. (2005). "ABVD versus modified stanford V versus MOPPEBVCAD with optional and limited radiotherapy in intermediate- and advanced-stage Hodgkin's lymphoma: final results of a multicenter randomized trial by the Intergruppo Italiano Linfomi". J. Clin. Oncol. 23 (36): 9198–207. doi:10.1200/JCO.2005.02.907. PMID 16172458. 
  17. ↑ Home | German Hodgkin Study Group
  18. ↑ Klimm B, Diehl V, Engert A (2007). "Hodgkin's Lymphoma in the Elderly: A Different Disease in Patients Over 60". Oncology 21 (8). http://www.cancernetwork.com/display/article/10165/59443. 
  19. ↑ RTanswers.com
  20. ↑ Hasenclever D, Diehl V (November 19, 1998). "A Prognostic Score for Advanced Hodgkin's Disease". New England Journal of Medicine 339 (21): 1506–14. doi:10.1056/NEJM199811193392104. PMID 9819449. 
  21. ↑ "WHO Disease and injury country estimates". World Health Organization. 2009. http://www.who.int/healthinfo/global_burden_disease/estimates_country/en/index.html. Retrieved Nov. 11, 2009. 
  22. ↑ Mauch, Peter; James Armitage, Volker Diehl, Richard Hoppe, Laurence Weiss (1999). Hodgkin's Disease. Lippincott Williams & Wilkins. pp. 62–64. ISBN 0-7817-1502-4. 
  23. ↑ Biggar RJ, Jaffe ES, Goedert JJ, Chaturvedi A, Pfeiffer R, Engels EA (2006). "Hodgkin lymphoma and immunodeficiency in persons with HIV/AIDS". Blood 108 (12): 3786–91. doi:10.1182/blood-2006-05-024109. PMID 16917006. 
  24. ↑ Dawson PJ (December 1999). "The original illustrations of Hodgkin's disease". Annals of Diagnostic Pathology 3 (6): 386–93. doi:10.1053/ADPA00300386 (inactive 2010-01-09). PMID 10594291. http://linkinghub.elsevier.com/retrieve/pii/00300386. 
  25. ↑ 25.0 25.1 25.2 25.3 25.4 Geller SA (August 1984). "Comments on the anniversary of the description of Hodgkin's disease". Journal of the National Medical Association 76 (8): 815–7. PMID 6381744. 
  26. ↑ Call of the ancient mariner: Reese ... - Google Books. Books.google.com. 2003-10-03. ISBN 9780071388818. http://books.google.com/?id=5bVBhLBis1UC&pg=PA229&lpg=PA229&dq=%22don+cohan%22&q=%22don%20cohan%22. Retrieved June 6, 2010. 
  27. ↑ James, TGH (2004). "Carter, Howard (1874–1939)". Oxford Dictionary of National Biography. Oxford University Press. doi:10.1093/ref:odnb/32312. http://www.oxforddnb.com/view/article/32312. Retrieved June 18, 2009. 
  28. ↑ "Prithviraj Kapoor and the Prithvi Theatres". Shammi Kapoor. http://www.junglee.org.in/ptheatre.html. Retrieved March 3, 2010. 
  29. ↑ "Jane Austen's Illness". http://www.orchard-gate.com/bmj.htm. Retrieved 2010-06-22. 
  30. ↑ "#41 Paul Allen". The World's Billionaires. Forbes. March 5, 2008. http://www.forbes.com/lists/2008/10/billionaires08_Paul-Allen_1217.html. 
  31. ↑ "Investor Paul Allen Diagnosed With Non-Hodgkin's Lumphoma". The Wall Street Journal. Dow Jones & Company Inc.. November 17, 2009. http://online.wsj.com/article/SB10001424052748704431804574540513683976836.html?mod=googlenews_wsj. 
  32. ↑ "Soul star dies after cancer fight". BBC News. February 15, 2006. http://news.bbc.co.uk/1/hi/entertainment/4716060.stm. Retrieved December 27, 2008. 
  33. ↑ "Singer Goodrem has cancer". BBC News. July 11, 2003. http://news.bbc.co.uk/1/hi/entertainment/music/3057991.stm. Retrieved December 27, 2008. 
  34. ↑ Ainley, Mark (2002). "Dinu Lipatti". http://www.markainley.com/music/classical/lipatti/prince_of_pianists.html. 
  35. ↑ "Making a transition into pop simplicity". MSNBC News. http://www.msnbc.msn.com/id/9927566/. Retrieved December 22, 2009. 
  36. ↑ Terry, MJ (2002). "Mario Lemieux". Celebrity Survivor Biographies. CureHodgkins. http://www.curehodgkins.com/hodgkins_resources/celebrity_survivors.html. 
  37. ↑ "Former 'Idol' Contestant Luke Menard Has Hodgkin's Lymphoma". Fox News. http://www.foxnews.com/story/0,2933,356961,00.html. Retrieved December 22, 2009. 
  38. ↑ "Teen, court reach agreement over cancer care". Associated Press. MSNBC. September 5, 2006. http://www.msnbc.msn.com/id/14371567/. Retrieved June 18, 2009. 
  39. ↑ Matzke-Fawcett, Amy (December 31, 2009). "Musicians rally for cancer victim". The Roanoke Times. http://www.roanoke.com/news/nrv/nrventertainment/wb/231393. 
  40. ↑ "Big John Studd". Hall of Fame. WWE. http://www.wwe.com/superstars/halloffame/bigjohnstudd/bio/. 
  41. ↑ Carter B (August 28, 1997). "Brandon Tartikoff, Former NBC Executive Who Transformed TV in the 80's, Dies at 48". New York Times. http://www.nytimes.com/1997/08/28/arts/brandon-tartikoff-former-nbc-executive-who-transformed-tv-in-the-80-s-dies-at-48.html?pagewanted=1. Retrieved December 22, 2009. 
  42. ↑ Shanahan M; Goldstein M (May 19, 2009). "Time for 'Grown Ups'". Boston Globe. http://www.boston.com/ae/celebrity/articles/2009/05/19/time_for_grown_ups/. Retrieved June 18, 2009. 
  43. ↑ "Minnesota: Evaluation Ordered for a 13-Year-Old With Cancer". Associated Press. NY Times. May 16, 2009. http://www.nytimes.com/2009/05/16/us/16brfs-EVALUATIONOR_BRF.html?_r=1&scp=4&sq=daniel%20hauser&st=cse. Retrieved June 18, 2009. 
  44. ↑ News-briefs.ew.com
  45. ↑ Kubatko, Justin. "Wesley Coe Biography and Olympic Results". Olympics at Sports-Reference.com - Olympic Statistics and History.. http://www.sports-reference.com/olympics/athletes/co/wesley-coe-1.html. Retrieved June 12, 2010. 

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