Hodgkin lymphoma

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Hodgkin's lymphoma
)
Hodgkin lymphoma
Other namesHodgkin's lymphoma, Hodgkin's disease[1]
Micrograph showing Hodgkin lymphoma (Field stain)
SpecialtyHematology and oncology
SymptomsFever, night sweats, weight loss, nonpainful enlarged lymph nodes[2]
Risk factorsEpstein–Barr virus, family history, HIV/AIDS[2][3]
Diagnostic methodLymph node biopsy[2]
TreatmentChemotherapy, radiation therapy, stem-cell transplant,[4] immunotherapy
PrognosisFive-year survival rate 88% (US)[5]
Frequency574,000 (affected during 2015)[6]
Deaths23,900 (2015)[7]
Named afterThomas Hodgkin

Hodgkin lymphoma (HL) is a type of lymphoma in which cancer originates from a specific type of white blood cell called lymphocytes, where multinucleated Reed–Sternberg cells (RS cells) are present in the patient's lymph nodes.[2][8] The condition was named after the English physician Thomas Hodgkin, who first described it in 1832.[9][10] Symptoms may include fever, night sweats, and weight loss.[2] Often, nonpainful enlarged lymph nodes occur in the neck, under the arm, or in the groin.[2] Persons affected may feel tired or be itchy.[2]

The two major types of Hodgkin lymphoma are classic Hodgkin lymphoma and

Epstein–Barr virus-associated lymphoproliferative diseases.[12]

Hodgkin lymphoma may be treated with

heart disease, or lung disease over the subsequent decades.[9]

In 2015, about 574,000 people globally had Hodgkin lymphoma, and 23,900 (4.2%) died.[6][7] In the United States, 0.2% of people are affected at some point in their life.[5] Most people are diagnosed with the disease between the ages of 20 and 40.[5]

Signs and symptoms

People with Hodgkin lymphoma may present with these symptoms:

Diagnosis

Hodgkin lymphoma must be distinguished from noncancerous 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 safety for chemotherapy.[22] 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.[23]

Types

The two main types of Hodgkin lymphoma are classic Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma. The prevalence of classic Hodgkin lymphoma and nodular-lymphocyte Hodgkin lymphoma are about 90 and 10%, respectively.[24][25] The morphology, phenotype, molecular features, and, therefore, the clinical behaviour and presentation of the two types differ.[26]

Classic

Classic Hodgkin lymphoma (excluding nodular lymphocyte predominant Hodgkin lymphoma) can be subclassified into four 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)). Presence of EBV in Reed-Sternberg cells is most commonly found in the subtypes lymphocyte depleted HL (>70%) and mixed cellularity HL (70%), whilst being less prevalent in lymphocyte-rich HL (40%) and relatively uncommon by comparison in nodular sclerosing HL.[27][28]

Name Description ICD-10
ICD-O
Nodular sclerosing HL Is the most common subtype and is composed of large
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
Epstein-Barr virus infection
and may be confused with the early, so-called 'cellular' phase of the nodular sclerosing subtype. This type of Hodgkin lymphoma is most commonly seen in immunocompromised people.		 C81.2 M9652/3.
Lymphocyte-rich Is a rare subtype, show many features which may cause diagnostic confusion with nodular lymphocyte predominant B-cell non-Hodgkin 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
anaplastic large cell lymphoma.[29]
 C81.3 M9653/3
Unspecified C81.9 M9650/3
Lymph node biopsy showing Hodgkin lymphoma, mixed-cellularity type
CT image of a 46-year-old person with Hodgkin lymphoma, image at neck height. On the left side of the person's neck enlarged lymph nodes are visible (marked in red).

For the other forms, although the traditional

T-cell markers (such as CD2 and CD4) are occasionally expressed.[32]
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 classic Hodgkin lymphoma, including clusters of other immune cells gathered around HL cells (infiltrate) in cultures.[33]

Nodular lymphocyte predominant

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is another subtype of Hodgkin lymphoma distinct from classic Hodgkin lymphoma and is characterized by the presence of popcorn cells which express CD20.[25][34] Due to these differences, among others, NLPHL is often treated differently from classic Hodgkin lymphoma, including using rituximab in combination with AVBD chemotherapy, though individual cases vary and clinical trials are ongoing.[25]

Staging

The staging is the same for both Hodgkin and non-Hodgkin lymphomas.

After Hodgkin lymphoma is diagnosed, a person will be

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.[18]

On the basis of this staging, the person will be classified according to a staging classification (the

Ann Arbor staging classification scheme is a common one):[36]

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".[37]

  • Stage 1 Hodgkin lymphoma
    Stage 1 Hodgkin lymphoma
  • Stage 2 Hodgkin lymphoma
    Stage 2 Hodgkin lymphoma
  • Stage 3 Hodgkin lymphoma
    Stage 3 Hodgkin lymphoma
  • Stage 4 Hodgkin lymphoma
    Stage 4 Hodgkin lymphoma

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.[38]

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

CD15+/− immunophenotype. In approximately 50% of cases, the Reed–Sternberg cells are infected by the Epstein–Barr virus.[39]

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). Almost all of these cells have an increased copy number of chromosome 9p/9p24.1.[40]

Variants:

  • Hodgkin cell (atypical mononuclear RSC) is a variant of RS cell, which has the same characteristics but is mononucleated.[41]
  • 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 lymphoma can be sub-classified by histological type. The cell histology in Hodgkin lymphoma is not as important as it is in non-Hodgkin lymphoma: the treatment and prognosis in classic Hodgkin lymphoma usually depends on the stage of disease rather than the histotype.[42]

Management

The current approach for treatment aims to reduce the acute and long-term toxicities associated with Hodgkin lymphoma (e.g. cardiac damage and secondary cancers) and increase overall survival.[43]

People with early stage disease (IA or IIA) can be treated effectively with radiation therapy or chemotherapy. The choice of treatment depends on the age, sex, bulk and the histological subtype of the disease.[42] Adding localised radiation therapy after the chemotherapy regimen may provide a longer

combination chemotherapy alone. People of any stage with a large mass in the chest are usually treated with combined chemotherapy and radiation therapy.[45]

MOPP ABVD Stanford V BEACOPP
The original treatment for Hodgkin's was
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 person has certain allergies or lung or heart problems which prevents the use of another regimen.

Currently, the
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;[46] however, this study has been heavily criticized due to its incorrect administration of radiotherapy, diverging from the original Stanford V protocol.[47]
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).[48]
Chlormethine Doxorubicin Doxorubicin Doxorubicin
Oncovin
 Bleomycin Bleomycin Bleomycin
Prednisone Vinblastine Vinblastine, Vincristine Vincristine
Procarbazine Dacarbazine Chlormethine Cyclophosphamide, Procarbazine
Etoposide Etoposide
Prednisone Prednisone

The common non-Hodgkin treatment, rituximab (which is a monoclonal antibody against CD20) is not routinely used to treat Hodgkin lymphoma due to the lack of CD20 surface antigens in most cases. The use of rituximab in Hodgkin lymphoma, including the lymphocyte predominant subtype has been recently reviewed.[49] The evidence is very uncertain about the effect of Nivolumab for patients with a Hodgkin's lymphoma e.g. on the overall survival.[50]

Increased age is an adverse risk factor for Hodgkin lymphoma, but in general elderly people (≥ 60 years of age) without major comorbidities are sufficiently fit to tolerate therapy with curative intent. Despite this, treatment outcome in the elderly patient is not comparable to that of younger people and the disease is a different entity in older people where different considerations enter into treatment decisions.[51][52]

Recently, two novel targeted drugs have been developed for relapsing and refractory HL patients; Brentuximab vedotin, a CD30 antibody conjugated with a cytotoxic component MMAE,[53] and the checkpoint inhibitors, Nivolumab and Pembrolizumab.[54][55][56][57] This has been an important step in the treatment for the few, but still existing refractory patients.

For Hodgkin 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 which produces high energy X-rays and electrons. People usually describe treatments as painless and similar to getting an X-ray. Treatments last less than 30 minutes each.

For lymphomas, there are a few different ways radiation oncologists target the cancer cells. Involved site radiation is when the radiation oncologists give radiation only to those parts of the person's body known to have the cancer.[58] Very often, this is combined with chemotherapy. Radiation therapy directed above the diaphragm to the neck, chest or underarms is called mantle field radiation. Radiation to below the diaphragm to the abdomen, spleen 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.[59]

Adverse effects

The high cure rates and long survival of many people with Hodgkin lymphoma has led to a high concern with late adverse effects of treatment, including cardiovascular disease and second malignancies such as acute

solid tumors within the radiation therapy field. Most people with early-stage disease are now treated with abbreviated chemotherapy and involved site 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.[60]

In childhood cases of Hodgkin lymphoma, long-term endocrine adverse effects are a major concern, mainly gonadal dysfunction and

alkylating agents or pelvic radiotherapy.[61]

It is possible that patients undergoing a chemotherapy need a platelet transfusion.[62][63] If a stem cell transplantation is necessary for the treatment of a relapse, graft-versus-host diseases might occur.[64]

Supportive treatment

Adding physical exercises to the standard treatment for adult patients with haematological malignancies like Hodgkin lymphoma may result in little to no difference in the mortality, the quality of life and the physical functioning. These exercises may result in a slight reduction in depression. Furthermore, aerobic physical exercises probably reduce fatigue. The evidence is very uncertain about the effect on anxiety and serious adverse events.[65] 

Prognosis

Treatment of Hodgkin's disease has been improving over the past few decades. Recent[when?] 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 five-year survival rate for those people with a favorable prognosis (FFP) was 98%, while that for people with worse outlooks was at least 85%.[66]

In 1998, an international effort[67] identified seven prognostic factors that accurately predict the success rate of conventional treatment in people with locally extensive or advanced-stage Hodgkin lymphoma. Freedom from progression (FFP) at five years was directly related to the number of factors present in a person. The five-year FFP for people with zero factors is 84%. Each additional factor lowers the five-year FFP rate by 7%, such that the five-year FFP for a person with five or more factors is 42%.[68]

The adverse prognostic factors identified in the international study are:

  • Age ≥ 45 years
  • Stage IV disease
  • Hemoglobin < 10.5 g/dl
  • Lymphocyte count
    < 600/µl or < 8%
  • Male
  • Albumin < 4.0 g/dl
  • White blood count
    ≥ 15,000/µl

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.)[69]

More recently, the use of positron emission tomography (PET) early after commencing chemotherapy has demonstrated to have powerful prognostic ability.[70] This enables assessment of an individual's response to chemotherapy as the PET activity switches off rapidly in people who are responding. In this study,[70] after two cycles of ABVD chemotherapy, 83% of people were free of disease at 3 years if they had a negative PET versus only 28% in those with positive PET scans. This prognostic method improves on FFP estimates based on the seven conventional factors. Several trials are underway to see if PET-based risk adapted response can be used to improve a person's outcomes by changing chemotherapy early in people who are not responding.

The evidence is very uncertain about the effect of negative (= good prognosis) or positive (= bad prognosis) interim PET scan results for patients with a Hodgkin's lymphoma on the progression-free survival. Negative interim PET scan results may result in an increase in progression-free survival compared if the adjusted result was measured. Negative interim PET scan results probably result in a large increase in the overall survival compared to those with a positive interim PET scan result,[43]

Epidemiology

lymphomas and multiple myeloma per 100,000 inhabitants in 2004[71]
  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

bimodal curve for the number of cases; 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.[72] Overall, it is more common in males, except for the nodular sclerosis variant, which is slightly more common in females. The annual number of cases of Hodgkin lymphoma is 2.7 per 100,000 per persons per year, and the disease accounts for slightly less than 1% of all cancers worldwide.[73]

In 2010, globally it resulted in about 18,000 deaths down from 19,000 in 1990.[1] In 2012, there were an estimated 65,950 cases and 25,469 deaths from Hodgkin lymphoma worldwide, with 28,852 and 37,098 cases occurring in developed and developing countries, respectively.[74] However, the age-standardized rates were higher in developed regions, with the greatest rates in the Americas (1.5 per 100,000), East Mediterranean Region (1.5 per 100,000), and Europe (2.0 per 100,000).[74] The East Mediterranean Region also has the highest age-standardized mortality rate of 1.0 per 100,000, which is mainly attributed to lifestyle and environmental risk factors associated with transitional economies such as smoking, obesity, physical inactivity, and reproductive behaviors, as well as availability of diagnostic practices and awareness of the disease.[74]

The number of cases of Hodgkin lymphoma is increased in people with HIV infection.[75] In contrast to many other lymphomas associated with HIV infection it occurs most commonly in people with higher CD4 T cell counts.

Canada

Hodgkin lymphoma accounts for 0.6% of all male cancer cases, and 0.4% of all female cancer cases in Canada. In 2017, approximately 990 Canadians will be diagnosed with Hodgkin lymphoma, and 140 will die of the disease.[76]

UK

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.[77]

United States

In 2016, there were 8,389 new cases and 1,000 mortalities attributed to Hodgkin lymphoma, a decrease from the 8,625 new cases and 1,120 mortalities in 2015.[78] As of January 1, 2016, the 5-year limited duration prevalence of Hodgkin lymphoma was 37,513 representing 0.71% of all diagnosed cancers in the U.S.[78]

History

Photograph of Hodgkin's disease from a 1938 medical textbook

Hodgkin lymphoma was first described in an 1832 report by Thomas Hodgkin, although Hodgkin noted that perhaps an earlier reference to the condition was provided by Marcello Malpighi in 1666.[79][10] While occupied as museum curator at Guy's Hospital, London, Hodgkin studied seven people with painless lymph node enlargement. Of the seven cases, two were under the care of Richard Bright, one was of Thomas Addison, and one was of Robert Carswell.[79] Carswell's report of the seventh case was accompanied by numerous illustrations that aided early descriptions of the disease.[80]

Hodgkin's report on the seven cases, entitled "On some morbid appearances of the absorbent glands and spleen", was presented to the Medical and Chirurgical Society of London in January 1832 and was subsequently published in the society's journal, Medical-Chirurgical Society Transactions.[79] Hodgkin's paper went largely unnoticed, however, even though Bright highlighted it in an 1838 publication.[79] Indeed, Hodgkin himself did not view his contribution as particularly significant.[81]

In 1856, Samuel Wilks independently reported on a series of patients with the same disease that Hodgkin had previously described.[81] Wilks, a successor to Hodgkin at Guy's Hospital, was unaware of Hodgkin's prior work on the subject. Bright informed Wilks 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 named the illness "Hodgkin's disease" in honor of his predecessor.[81]

Dorothy Reed independently described the cytogenetic features of the malignant cells of Hodgkin lymphoma, now called Reed–Sternberg cells.[79]

Tissue specimens from Hodgkin's seven cases were preserved at Guy's Hospital. Nearly 100 years after Hodgkin's initial publication, histopathologic reexamination confirmed Hodgkin lymphoma in only three of seven of these people.[81] The remaining cases included non-Hodgkin lymphoma, tuberculosis, and syphilis.[81]

Hodgkin lymphoma was one of the first cancers to be treated successfully with

combination chemotherapy
.

Notable cases

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Further reading

  • 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

Wikimedia Commons has media related to Hodgkin's lymphoma.
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