Fever, Night Sweats, and Weight Loss

Peter W. Marks, MD

Yale University School of Medicine, New Haven, CT

Copyright of the American Society of Hematology, 2012. ISSN: 1931-6860.



Hodgkin lymphoma is less common than the group of non-Hodgkin lymphomas, with an incidence of about 8,500/year in the United States in 2010. There is a bimodal age distribution of cases. There is a peak in individuals 15 to 30 years of age, followed by another increase in incidence in persons over 55 years old.

A viral cause for Hodgkin disease has been suspected because of the association of Epstein Barr Virus (EBV) infection in about 30-40% of cases. However, the role of EBV infection remains controversial. Additional support for a viral cause or for susceptibility to the disease based on an immune mechanism comes from the observation that the disease is more common in individuals of higher socioeconomic status, suggesting that less exposure to certain infectious agents early in life may set the stage for the potential development of disease.

As for outcome, Hodgkin lymphoma and pediatric acute lymphoid leukemia were two of the first diseases to have their natural history dramatically altered by modern chemotherapy regimens. Today, even most relatively advanced cases of Hodgkin lymphoma are cured, resulting in rates of overall 5-year survival of 85% or more. As will be described in more detail below, a large focus of treatment today is on retaining a high rate of cure while reducing the toxicity of therapy.


The World Health Organization (WHO) describes two major categories of Hodgkin lymphoma: classical Hodgkin lymphoma, representing about 95% of cases, and nodular lymphocyte predominant Hodgkin disease, representing the remainder. Classical Hodgkin lymphoma is further divided into four subcategories: nodular sclerosis, mixed cellularity, lymphocyte-depleted, and lymphocyte-rich.

Classical Hodgkin lymphoma is characterized by the presence of Reed-Sternberg cells in a background of lymphocytes. Classic Reed-Sternberg cells are large binucleate cells. The nuclei each have prominent nucleoli, giving the cell a so-called “orphan Annie” or “owl eye” appearance. Over the past decades research has demonstrated that the Reed- Sternberg cells are the malignant cells in Hodgkin disease. These cells have a specific cell surface phenotype, and usually stain positive for CD30 and CD15. The different sub-types of classical Hodgkin lymphoma are distinguished by the context in which the Reed-Sternberg cells appear.

Sub-Types of Classical Hodgkin lymphoma
Nodular sclerosis
Nodular sclerosis classical Hodgkin lymphoma is the most common subtype of Hodgkin lymphoma in the West. It affects males and females with equal frequency and most commonly presents with cervical, axillary, and mediastinal lymphadenopathy. The pathology of the lymph node shows that there are broad collagen bands and some lymphocytes surrounding the Reed-Sternberg cells.
Mixed cellularity
Mixed cellularity Hodgkin lymphoma occurs more commonly in developing countries and in patients with HIV infection. It is about equally common in males as in females. It tends to present at a more advanced stage with involvement of peripheral lymph nodes and the spleen. The lymph node’s architecture is replaced with Reed-Sternberg cells, which appear in a mixed inflammatory background of eosinophils, plasma cells and histiocytes.
Lymphocyte-depleted Hodgkin lymphoma is also seen more commonly in developing countries. It is four times as common in males as in females and often presents with systemic symptoms (B symptoms) such as fevers, chills and night sweats). As with mixed cellularity disease, it often presents at a more advanced stage, in this case with retroperitoneal and abdominal disease. Pathology shows a hypocellular background with fibrosis and fewer lymphocytes than other types. Lymphocyte-depleted Hodgkin lymphoma has the most aggressive course and poorest prognosis of the Hodgkin lymphomas.
Lymphocyte-rich Hodgkin lymphoma is twice as common in males as in females. It tends to present with peripheral lymph node involvement at an early stage. The affected lymph nodes have few Reed-Sternberg cells in a lymphocytic infiltrate with some histiocytes but few eosinophils. Following treatment, lymphocyte-rich Hodgkin lymphoma is associated with a low incidence of relapse and an excellent prognosis.

The second major category of Hodgkin lymphoma described by WHO is nodular lymphocyte predominant Hodgkin disease, which represents about 5% of cases. This type is distinguished by the presence of “popcorn cells,” called LP cells according to the current WHO classification. The surface marker phenotype of these cells is distinctly different from that found in classical Hodgkin lymphoma: they are negative for CD30 and CD15, but positive for CD45 and CD20. It is about three times more common in males that in females. It tends to present with involvement of a single lymph node rather than a group of lymph nodes. The popcorn or LP cells occur with a background of small lymphocytes in a nodular pattern (at least partially). Nodular lymphocyte-predominant Hodgkin disease is associated with a good response to therapy, but tends to relapse. It also may appear to progress to other types of lymphoma, such as diffuse large B cell lymphoma (a non-Hodgkin lymphoma). The histology of nodular lymphocyte predominant Hodgkin lymphoma is shown below.


The Ann Arbor system is used for staging Hodgkin disease into four major categories. The utility of this staging system is that it has implications for both treatment and prognosis. Stages I – III may be associated with a single site of localized extralymphatic involvement, in which case an E is appended to that given stage. For this purpose, the spleen is considered to be equivalent to a large lymph node.

Each stage may also be associated with the absence or presence of systemic symptoms (called B symptoms). An A or B is routinely appended to the assigned stage in order to denote this, as the presence of systemic symptoms is generally associated with a poorer prognosis for any given stage.

Hodgkin Disease Staging
Stage Description
I Involvement of a single lymph node region
II Involvement of two or more lymph node regions on the same side of the diaphragm
III Involvement of lymph node regions on both sides of the diaphragm
IV Multifocal/disseminated involvement of one or more extralymphatic organs
A  No systemic symptoms present
B  Unexplained fevers >38oC, drenching night sweats, or weight loss >10% body weight

Unfavorable prognostic factors for stage I and II Hodgkin disease include the presence of B symptoms, more than three nodal sites of disease, or an ESR of 50 mm/hr or more, and mediastinal masses 10 cm in diameter or more.

For stage III and IV disease, seven adverse prognostic factors have been identified:

  • Age 45 years or older
  • Male gender
  • Stage IV disease
  • Albumin < 4 g/dL
  • Hemoglobin < 10.5 g/dL
  • WBC > 15,000/µL
  • Relative lymphocyte count < 8% of total WBC or absolute number < 600/µL

The International Prognostic Score for Hodgkin disease uses these to predict who might benefit from more intensive therapy; the presence of at least four indicates that this may be the case.

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