Hodgkin's disease

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

Contents

1 Epidemiology

2 Symptoms

3 Diagnosis

4 Pathology

4.1 Macroscopy
4.2 Microscopy

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 males, 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 a bit less than 1% of all cancers worldwide.

Symptoms

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

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, or fatigue.

Diagnosis

Hodgkin's disease 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.

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) may appear a nodular aspect.

Microscopy

Microscopic examination of the lymph node biopsy reveals the completely or partially 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 CD15+, CD30+ immunophenotype. In approximately 50% of cases, the Reed-Sternberg cells are infected by the Epstein-Barr virus.

Characteristics of typical Reed-Sternberg cell: 20-50 micrometres, abundant, amphofilic, finely granular/homogenous 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. "Pop-corn" 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 (http://www.pathologyatlas.ro/Reed%20Sternberg%20Cell%20Hodgkin%20Lymphoma.html)

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

Types

Hodgkin's disease (now also known as Hodgkin's 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. There are small but clear differences in prognosis between the various forms.

1. Nodular sclerosing subtype is the most common subtype and is composed of large tumor nodules with lacunar RS cells surrounded by fibrotic bands.

2. Lymphocyte predominant subtype is an uncommon subtype and is composed of vague nodules with numerous reactive lymphocytes. Unlike the other forms of Hodgkin lymphoma, the non-classic RS cells are CD15 and CD30 negative while positive for the B cell marker CD20.

3. Lymphocyte depleted subtype is also an uncommon subtype and is composed of numerous classic RS cells with only few reactive lymphocytes.

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.

Staging

After Hodgkin's disease 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 always 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. Some patients will also require liver biopsy, lymphangiograms, gallium scans, bone scans, and surgical laparotomy, which involves opening the abdominal cavity and visually inspecting for tumors. Surgical laparotomy is now largely of historical significance only.

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%.

The 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

Treatment

Patients with early stage disease (IA or IIA) are effectively treated with radiation therapy. 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.

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

The high cure rates and long survival of many patients with Hodgkin's disease 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.

External link

Hodgkin's Lymphoma Home Page (http://www.cancer.gov/cancertopics/types/hodgkinslymphoma) at the American National Cancer Institute.
Timeline of discovery and treatment of Hodgkin's Lymphoma (http://www.lymphomainfo.net/hodgkins/timeline.html)
Photos at: Atlas of Pathology (http://www.pathologyatlas.ro/Reed%20Sternberg%20Cell%20Hodgkin%20Lymphoma.html)