Hodgkin's disease

Hodgkin's lymphoma, formerly known as Hodgkin's disease, is a type of lymphoma described by Thomas Hodgkin in 1832, and characterized by the presence of Reed-Sternberg cells.

Epidemiology
Unlike other lymphomas, whose incidence increases with age, Hodgkin's lymphoma has a bimodal incidence  curve: that is, it occurs more frequently in two separate age groups, the first being young adulthood (age 15–35), the second being in those over 50 years old. Overall, it is more common in men, except for the nodular sclerosis variant (see below) of Hodgkin disease, which is more common in women.

The incidence of Hodgkin's disease is about 4/100,000 people/year, and accounts for slightly less than 1% of all cancers worldwide.

Symptoms
Swollen, but non-painful, lymph nodes are the most common sign of Hodgkin's lymphoma, often occurring in the neck. The lymph nodes of the chest are often affected and these may be noticed on a chest X-ray.

Splenomegaly, or enlargement of the spleen, occurs in about 30% of people with Hodgkin's lymphoma. The enlargement, however, is seldom massive. The liver may also be enlarged due to liver involvement in the disease in about 5% of cases.

About one-third of people with Hodgkin's disease may also notice some systemic symptoms, such as low-grade fever, night sweats, weight loss, itchy skin (pruritus), or fatigue. Patients may also present with a cyclic high-grade fever known as Pel-Ebstein fever, although there is debate as to whether or not this truly exists []. Systemic symptoms such as fever and weight loss are known as B symptoms.

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 (removal of a lymph node for pathological examination). Blood tests are also performed to assess function of major organs, to detect lymphoma deposits or to assess safety for chemotherapy. Positron emission tomography is used to detect small deposits that do not show on CT scanning. In some cases a Gallium Scan may be used instead of a PET scan.

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) may appear a nodular aspect.

Microscopy
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 (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 binucleated 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 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 hyperlobated 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, no nucleolus and basophilic cytoplasm. 1

Hodgkin's lymphoma can be subclassified 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 Hodgkin's lymphoma depend on the stage of disease rather than the histotype.

Classical
Classical Hodgkin's lymphoma (excluding nodular lymphocyte predominant Hodgkin's) 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. 

Classic Hodgkin's Lymphoma (CHL) subtypes:
 * 1) Nodular sclerosing CHL is the most common subtype and is composed of large tumor nodules with lacunar RS cells surrounded by fibrotic bands.
 * 2) Lymphocyte rich CHL is an uncommon subtype composed of numerous lymphocytes with admixed classic RSC and no fibrosis.
 * 3) Lymphocyte depleted subtype is also an uncommon subtype composed of numerous classic often pleomorphic RS cells with only few reactive lymphocytes which may easily be confused with diffuse large cell lymphoma.
 * 4) 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.

Other
Nodular lymphocyte predominant Hodgkin's lymphoma (NLPHL) is no longer classified as a form of classic Hodgkin's lymphoma. This is due to the fact that the RSC variants (popcorn cells) that characterize this form of the disease invariably express B lymphocyte markers such as CD20 (thus making NLPHL an unusual form of B cell lymphoma), and that (unlike classic HL) NLPHL may progress to diffuse large B cell lymphoma. There are small but clear differences in prognosis between the various forms.

Lymphocyte predominant HL is an uncommon subtype composed of vague nodules of numerous reactive lymphocytes admixed with large popcorn-shaped RSC. Unlike classic RSC, the non-classic popcorn-shaped RS cells of NLPHL are CD15 and CD30 negative while positive for the B cell marker CD20. 

Staging
After Hodgkin's lymphoma is diagnosed, a patient will be staged: that is, they will undergo a series of tests and procedures which 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, CT scans or MRI (magnetic resonance imaging) 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 lapartomy 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) 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.

In 1996, an international effort identified seven prognostic factors that accurately predict the success rate of conventional treatment in patients with locally extensive or advanced stage Hodgkin's disease. 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%.

Prognosis
The adverse prognostic factors identified in the international study are:
 * Age >= 45 years
 * Stage IV disease
 * Hemoglobin < 10.5 mg/dl
 * Lymphocyte count < 600/ul or < 8%
 * Male sex
 * Albumin < 4.0 mg/dl
 * White blood count >= 15,000/ul

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 10cm in any dimension.)

Treatment
Patients with early stage disease (IA or IIA) are effectively treated with radiation therapy although chemotherapy may also be advisable. 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.

Currently, the ABVD chemotherapy regimen is the gold standard for treatment of Hodgkin's disease. 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. Another form of treatment is the newer Stanford V regimen, which is typically only half as long as the ABVD but which involves a more intensive chemotherapy schedule and incorporates radiation therapy.

With appropriate treatment, over 85% of Hodgkin's lymphoma cases are curable.

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.