Hodgkin's lymphoma

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Hodgkin lymphoma
Classification and external resources
Hodgkin lymphoma cytology large.jpg
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
NCI Hodgkin's lymphoma
Patient UK Hodgkin's lymphoma
MeSH D006689

Hodgkin lymphoma,[1] also known as Hodgkin's lymphoma or Hodgkin's disease,[2] is a type of lymphoma, which is a cancer originating from white blood cells called lymphocytes.

A history of infectious mononucleosis due to infection by Epstein–Barr virus (EBV) may increase risk of HL, but the precise contribution of Epstein–Barr virus remains largely unknown.[3][4] Hodgkin lymphoma is characterised 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 lymphoma may be treated with radiation therapy, chemotherapy, or hematopoietic stem cell transplantation, with the choice of treatment depending on the age and sex of the patient and the stage, bulk, and histological subtype of the disease. The overall five-year survival rate in the United States for 2004–2010 is 85%.[5] Since many people are young, they often live 40 years or more after treatment. However, few studies follow people as long as 25 years, and those studies are of older treatments with more life-threatening adverse effects. There is insufficient data available about the long-term outcomes of newer, less-toxic regimens and ones which limit radiation exposure. Radiation treatments, and some chemotherapy drugs, pose a risk of causing potentially fatal secondary cancers, heart disease, and lung disease 40 or more years later. Modern treatments greatly minimise the chances of these late effects.[6]

The disease occurrence shows two peaks: the first in young adulthood (age 15–35) and the second in those over 55 years old.[7] It was named after Thomas Hodgkin, who first described abnormalities in the lymph system in 1832.[8][9]

Classification[edit]

Types[edit]

Classical Hodgkin 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–Sternberg cell(s)).

Name Description ICD-10 ICD-O
Nodular sclerosing HL 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 degrees 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.[10] C81.3 M9653/3
Unspecified C81.9 M9650/3
Lymph node biopsy showing Hodgkin's lymphoma, mixed-cellularity type
CT image of a 46-year-old patient with Hodgkin's lymphoma, image at neck height. On the left side of the patient's neck enlarged lymph nodes are visible (marked in red).

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,[10] Reed–Sternberg cells are usually of B cell origin.[11][12] Although Hodgkin's is now frequently grouped with other B cell malignancies, some T cell markers (such as CD2 and CD4) are occasionally expressed.[13] However, this may be an artifact of the ambiguity inherent in the diagnosis.

Hodgkin 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.[14]

Staging[edit]

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

After Hodgkin 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 may include documentation of their histology, a physical examination, blood tests, chest X-ray radiographs, computed tomography (CT)/Positron emission tomography (PET)/magnetic resonance imaging (MRI) scans of the chest, abdomen and pelvis, and usually a bone marrow biopsy. Positron emission tomography (PET) scan is now used instead of the gallium scan for staging. On the PET scan, sites involved with lymphoma light up very brightly enabling accurate and reproducible imaging.[15] 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):

  • Stage I is involvement of a single lymph node region (I) (mostly the cervical region) or single extralymphatic site (Ie);
  • Stage II is involvement of two or more lymph node regions on the same side of the diaphragm (II) or of one lymph node region and a contiguous extralymphatic site (IIe);
  • Stage III is involvement of lymph node regions on both sides of the diaphragm, which may include the spleen (IIIs) and/or limited contiguous extralymphatic organ or site (IIIe, IIIes);
  • Stage IV is disseminated involvement of one or more extralymphatic organs.

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 localised extranodal extension from mass of nodes that does not advance the stage, subscript 'E' is added. Splenic involvement is signified by adding 'S' to the stage. The inclusion of "bulky disease" is signified by 'X'.

Signs and symptoms[edit]

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

  • Lymph nodes: the most common symptom of Hodgkin's is the painless enlargement of one or more lymph nodes, or lymphadenopathy. The nodes may also feel rubbery and swollen when examined. The nodes of the neck and shoulders (cervical and supraclavicular) are most frequently involved (80–90% of the time, on average). The lymph nodes of the chest are often affected, and these may be noticed on a chest radiograph.
  • Itchy skin
  • Night sweats
  • Unexplained weight loss
  • Splenomegaly: enlargement of the spleen occurs in about 30% of people with Hodgkin's lymphoma. The enlargement, however, is seldom massive and the size of the spleen may fluctuate during the course of treatment.
  • Hepatomegaly: enlargement of the liver, due to liver involvement, is present in about 5% of cases.
  • Hepatosplenomegaly: the enlargement of both the liver and spleen caused by the same disease.
  • Pain following alcohol consumption: classically, involved nodes are painful after alcohol consumption, though this phenomenon is very uncommon,[16] occurring in only two to three percent of people with Hodgkin's lymphoma,[17] thus having a low sensitivity. On the other hand, its specificity is high enough for it to be regarded as a pathognomonic sign of Hodgkin lymphoma.[17] The pain typically has an onset within minutes after ingesting alcohol, and is usually felt as coming from the vicinity where there is an involved lymph node.[17] The pain has been described as either sharp and stabbing or dull and aching.[17]
  • Back pain: nonspecific back pain (pain that cannot be localised or its cause determined by examination or scanning techniques) has been reported in some cases of Hodgkin's lymphoma. The lower back is most often affected.[citation needed]
  • Red-coloured patches on the skin, easy bleeding and petechiae due to low platelet count (as a result of bone marrow infiltration, increased trapping in the spleen etc.—i.e. decreased production, increased removal)
  • Systemic symptoms: about one-third of patients with Hodgkin's disease may also present with systemic symptoms, including low-grade fever; night sweats; unexplained weight loss of at least 10% of the patient's total body mass in six months or less, itchy skin (pruritus) due to increased levels of eosinophils in the bloodstream; or fatigue (lassitude). Systemic symptoms such as fever, night sweats, and weight loss are known as B symptoms; thus, presence of fever, weight loss, and night sweats indicate that the patient's stage is, for example, 2B instead of 2A.[18]
  • Cyclical fever: patients may also present with a cyclical high-grade fever known as the Pel-Ebstein fever,[19] or more simply "P-E fever". However, there is debate as to whether the P-E fever truly exists.[20]
  • Nephrotic syndrome can occur in individuals with Hodgkin's lymphoma and is most commonly caused by minimal change disease.[21]

Diagnosis[edit]

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[edit]

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
Micrograph of a classic Reed–Sternberg cell
Micrograph showing a "popcorn cell", the Reed–Sternberg cell variant seen in nodular lymphocyte predominant Hodgkin lymphoma. H&E stain

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.[citation needed]

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 close to the nuclear membrane).

Variants:

  • Hodgkin cell (atypical mononuclear RSC) is a variant of RS cell, which has the same characteristics, but is mononucleated.
  • Lacunar RSC is large, with a single hyperlobulated nucleus, multiple, small nucleoli and eosinophilic cytoplasm which is retracted around the nucleus, creating an empty space ("lacunae").
  • Pleomorphic RSC has multiple irregular nuclei.
  • "Popcorn" RSC (lympho-histiocytic variant) is a small cell, with a very lobulated nucleus, small nucleoli.
  • "Mummy" RSC has a compact nucleus with no nucleolus and basophilic cytoplasm.

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[edit]

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.[citation needed] Adding localised radiation therapy after the chemotherapy regimen controls the tumors better and provides a better chance for survival than chemotherapy alone.[22] 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.[citation needed]

MOPP ABVD Stanford V BEACOPP
The original treatment for Hodgkin's was MOPP (medicine). The abbreviation stands for the four drugs Mustargen, Oncovin (also known as Vincristine), Prednisone and Procarbazine (also known as Matulane). The treatment is usually administered in four week cycles, often for six cycles. MSD and VCR are administered intravenously, while procarbazine and prednisone are pills taken orally. MOPP was the first combination chemotherapy brought in that achieved a high success rate. It was developed at the National Cancer Institute in the 1960s by a team that included Vincent DeVita, Jr..

Although no longer the most effective combination, MOPP is still used after relapse or where the patient has certain allergies or lung or heart problems which prevents the use of another regimen.

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 randomised controlled study in Italy, Stanford V was inferior to ABVD;[23] however, this study has been heavily criticized due to its incorrect administration of radiotherapy, diverging from the original Stanford V protocol.[24] 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).[25]
Mustargen Doxorubicin Doxorubicin Doxorubicin
Oncovin Bleomycin Bleomycin Bleomycin
Vincristine Vinblastine Vinblastine, Vincristine Vincristine
Vinblastine Dacarbazine Mechlorethamine Cyclophosphamide, Procarbazine
Etoposide Etoposide
Prednisone Prednisone

It should be noted that the common non-Hodgkin's treatment, rituximab (which is a monoclonal antibody against CD20) is not routinely used to treat Hodgkin's lymphoma due to the lack of CD20 surface antigens in most cases. The use of rituximab in Hodgkin's lymphoma, including the lymphocyte predominant subtype has been reviewed recently.[26]

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.[27]

For Hodgkin's lymphomas, radiation oncologists typically use external beam radiation therapy (sometimes shortened to EBRT or XRT). 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 those parts of the patient's 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 the therapist gives radiation to all the lymph nodes in the body to destroy cells that may have spread.[28]

Adverse effects[edit]

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.

In childhood cases of Hodgkin's lymphoma, long-term endocrine adverse effects are a major concern, mainly gonadal dysfunction and growth retardation. Gonadal dysfunction seems to be the most severe endocrine long-term effect, especially after treatment with alkylating agents and/or pelvic radiotherapy.[29]

Prognosis[edit]

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%.[30]

In 1998, an international effort[31] 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.)

More recently, use of positron emission tomography (PET) early after commencing chemotherapy has demonstrated to have powerful prognostic ability.[32] This enables assessment of an individuals response to chemotherapy as the PET activity switches off rapidly in patients who are responding. In this study,[32] after two cycles of ABVD chemotherapy, 83% of patients were free of disease at 3 years if they had a negative PET versus only 28% in those with positive PET scans. This prognostic power exceeds conventional factors discussed above. Several trials are underway to see if PET-based risk adapted response can be used to improve patient outcomes by changing chemotherapy early in patients who are not responding.

Epidemiology[edit]

Age-standardized death from lymphomas and multiple myeloma per 100,000 inhabitants in 2004[33]
  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.[34] 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 2.7 per 100,000 per persons per year, and the disease accounts for slightly less than 1% of all cancers worldwide.[35]

In 2010, globally it resulted in about 18,000 deaths down from 19,000 in 1990.[2]

The incidence of Hodgkin's lymphoma is increased in patients with HIV infection.[36] In contrast to many other lymphomas associated with HIV infection it occurs most commonly in patients with higher CD4 T cell counts.

UK[edit]

Hodgkin lymphoma accounts for less than 1% of all cancer cases and deaths in the UK. Around 1,800 people were diagnosed with the disease in 2011, and around 330 people died in 2012.[37]

History[edit]

Photograph from a 1938 medical textbook labeled "Hodgkin's Disease", (Essentials of medicine)

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.[8][9] 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.[8] Carswell's report of this seventh patient was accompanied by numerous illustrations that aided early descriptions of the disease.[38]

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.[8] Hodgkin's paper went largely unnoticed, however, even despite Bright highlighting it in an 1838 publication.[8] Indeed, Hodgkin himself did not view his contribution as particularly significant.[39]

In 1856, Samuel Wilks independently reported on a series of patients with the same disease that Hodgkin had previously described.[39] 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.[39]

Theodor Langhans and WS Greenfield first described the microscopic characteristics of Hodgkin's lymphoma in 1872 and 1878, respectively.[8] 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.[8]

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.[39] The remaining cases included non-Hodgkin lymphoma, tuberculosis, and syphilis.[39]

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.

Notable cases[edit]

  • Mario Lemieux, Hall of Fame NHL player, co-owner of the Pittsburgh Penguins and founder of the Mario Lemieux Foundation[40]
  • Howard Carter, Egyptologist and discoverer of the Tomb of Tutankhamun, died in 1939 from Hodgkin's disease.[41]
  • Lynden David Hall, British singer and songwriter, died on 14 February 2006, at the age of 31, from complications resulting from a stem cell transplant for Hodgkin's lymphoma. Hall was in remission at the time of his death.
  • Starchild Abraham Cherrix, a teenager whose refusal to undergo further conventional treatment after relapsing resulted in a court battle and a change to Virginia laws about medical neglect.[42]
  • Daniel Hauser, whose mother fled with him in order to prevent him from undergoing chemotherapy.[43]
  • American singer and guitarist Glen Goins died of the disease in 1978.
  • Australian singer Delta Goodrem was diagnosed in 2003. She was admitted to hospital to have treatment for the disease after having finished filming of T.V show Neighbors. The diagnosis caused mass hysteria around the world, with tabloid papers in the UK and Australia dubbing it the "Delta Affect". The year 2003 saw Delta have the highest selling, and longest running album at #1 on the charts in more than a decade. The year also saw her win an unprecedented 7 ARIA awards (Australian Grammy's) for her 15x Platinum Album Innocent Eyes. The album spawned 5 #1 singles, all reaching platinum or better certification.[44][45]
  • Irish actor Richard Harris, who portrayed Albus Dumbledore in the first two Harry Potter movies.[46]
  • Anthony Rizzo, MLB All-Star first baseman for the Chicago Cubs, May 2008 as a minor league player for the Red Sox.
  • Dinu Lipatti (1917–1950), Romanian classical pianist and composer.[47]

See also[edit]

References[edit]

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Further reading[edit]

  • Charlotte DeCroes Jacobs. Henry Kaplan and the Story of Hodgkin's Disease (Stanford University Press; 2010) 456 pages; combines a biography of the American radiation oncologist (1918–84) with a history of the lymphatic cancer whose treatment he helped to transform.

External links[edit]