Background: Hodgkin disease (HD) is a lymphoma, which is a cancer of the lymph system characterized by the presence of abnormal large Reed-Sternberg cells in a background of lymphocytes, macrophages, fibroblasts, and granulocytes. Dr Thomas Hodgkin first described HD in 1832.

The lymphatic system is composed of lymph nodes, lymphatic channels, spleen, bone marrow, and thymus. As a result of the widespread presence of the lymphatic system throughout the body, HD can start almost anywhere; however, in this article, only thoracic involvement is addressed.

In the thorax, mediastinal involvement is most common. The nodular sclerosing histologic subtype of HD is the most common, and it has a predilection for the anterior mediastinum, especially the thymus. The diagnosis of HD must be based on tissue biopsy results because treatment strategies are based on the histologic type, the stage of disease, and the age and performance status of the patient. Imaging is essential for staging, for assessing the response to treatment, for diagnosing relapse, and for evaluating treatment-related disorders.

Pathophysiology: Etiology of HD remains unknown, but a strong association with the Epstein-Barr virus (EBV) exists. However, the presence of EBV is not specific and can be found in other malignancies.

At present, HD is not preventable because no definite cause has been identified.

Frequency:

• In the US: According to the American Cancer Society, 7400 new cases of HD were estimated to occur in 2001 in the United States.

  The incidence of HD in families of patients is increased, but the genetic nature is not certain, and it may be the result of exposure of family members to identical environmental hazards. The incidence is increased in patients who are immunocompromised, for example, in patients with AIDS and in organ transplant recipients.

Mortality/Morbidity: The aim of the treatment of HD is to cure the disease. More than 75% of newly diagnosed cases of HD can be cured with chemotherapy and/or radiation therapy. The prognosis depends on various factors; a few of these important factors include the presence of systemic symptoms, the stage of disease at presentation, the presence of large masses, and the treatment administered. Effective treatment has led to 1-, 5-, 10-, and 15-year survival rates of 93%, 82%, 72%, and 63%, respectively.

Sex: The male-to-female ratio is 1:1.5. In nodular sclerosing HD, females are affected twice as often as men, but in patients with nodular sclerosing HD, thymic involvement is more common in men.

Age: HD has a bimodal incidence. It is seen in adults aged 15-40 years and in persons older than 55 years.

Anatomy: Because mediastinal involvement of the lymph nodes is the most common manifestation of thoracic HD, knowledge of lymph node distribution and lymphatics in the thorax is important. A clear understanding of normal findings in the radiographic anatomy by using chest radiography (CXR) is pivotal to recognizing subtle enlargement of the lymph nodes.

On CXR of the left side, the normal aortopulmonary window is slightly concave, straight, or invisible. Any departure from this should be viewed with suspicion, and further investigations are needed. In the prevascular area, adenopathy is the most common cause for convexity of the aortopulmonary bay toward left lung.

On CXR of the right side, the azygous node lies variably in relation to the azygous vein as the vein passes forward above the right bronchus to enter the superior vena cava (SVC). This node is the lowest member of the group of right paratracheal lymph nodes. Any convexity in this region that has a greater part of its curvature above the right main bronchus probably should be regarded as abnormal. Low right prevascular nodal enlargement also can distort this region.

Subcarinal lymph nodes are difficult to recognize until they are large. They can cause displacement of the azygoesophageal pleural reflection. Paravertebral adenopathy can be diagnosed by distortion of the paravertebral pleural reflections, which produces convexity toward the lungs.

Pericardiac and diaphragmatic lymph nodes can fill the cardiophrenic angle on posteroanterior (PA) CXR. On lateral views, these may lie retrosternally or at the level of the inferior vena cava or phrenic nerve. Smaller lymph nodes in these areas may simulate a pericardiac fat pad.

When sufficiently enlarged, internal mammary lymph nodes can produce ill-defined increased opacity lateral to the sternum on PA CXRs. On lateral views, these can appear as anterior extrapleural masses against the chest wall.

Clinical Details:

• Patients most commonly present with enlarged painless lymph nodes. Cervical lymph nodes are most common.

   

• HD can appear as an incidental finding on routine CXRs.

   

• An important feature of HD is its tendency to arise within lymph node areas and to spread in an orderly fashion to contiguous areas of lymph nodes.

   

• Constitutional signs and symptoms include the following:

   

  • Fever

     

  • Fatigue

     

  • Decreased appetite

     

  • Coughing and breathlessness

     

  • Drenching night sweats

     

  • Itching

     

  • Weight loss

     

  • Bone pain

     

  • Pressure symptoms due to enlarged lymph nodes

     

  • SVC syndrome

     

  • Dysphagia

     

  • Paraneoplastic syndromes

     

  • Dermatologic manifestations

     

  • Renal and metabolic manifestations

     

  • Neurologic manifestations

Currently, HD is classified according to the World Health Organization/Revised European-American Lymphoma classification system. According to a number of characteristics—the appearance of cells, their genetic characteristics, chemistry, and clinical behavior—HD is classified into 2 types as follows:

• Nodular lymphocyte-predominant Hodgkin lymphoma (5% of cases of HD)

   

• Classic Hodgkin lymphoma (95% of cases of HD), which is subdivided further into 3 subtypes

   

  • Nodular sclerosis Hodgkin lymphoma

     

  • Mixed-cellularity Hodgkin lymphoma

     

  • Lymphocyte-depletion Hodgkin lymphoma

HD is staged according to the Ann Arbor, Michigan conference of 1971. Some modifications were made to this classification at the Cotswolds, United Kingdom, meeting. Staging of HD is important for planning the effective treatment, and for follow-up monitoring, and for comparing the trial treatment plans available in various centers.

Staging is as follows:

• Stage I - Involvement of a single lymph node region (I) or localized involvement of a single extralymphatic organ (IE)

   

• Stage II - Involvement of 2 or more lymph node regions on the same side of the diaphragm (II) or localized involvement of a single extralymphatic organ or site and its regional lymph node or nodes with or without involvement of the other lymph node region on the same side of the diaphragm (IIE)

   

• Stage III - Involvement of lymph node regions on both sides of the diaphragm (III) with or without localized involvement of an associated extralymphatic organ or site (IIIE) with or without involvement of the spleen (IIIS) or both (IIIE+S)

   

• Stage IV - Disseminated/multifocal involvement of 1 or more extralymphatic organs with or without associated lymph node involvement or isolated extralymphatic organ involvement with distal nodal involvement

Bulk disease or massive mediastinal disease is defined as a ratio of the maximum transverse diameter of mass to the internal transverse thoracic diameter of greater than or equal to 0.33, as measured on CXRs at the T5-T6 intervertebral disk level. Others have defined bulk disease as lymph node mass measuring 10 cm or more in its greatest dimension.

The presence of B symptoms (eg, fever, weight loss >10%, drenching night sweats) and bulk disease is associated with worse prognosis in clinical stage I or stage II HD.

Preferred Examination: A complete patient history should be elicited and a physical examination performed.

Procedures and laboratory studies

Lymph node biopsy is performed for pathologic analysis and classification.

Laboratory investigations are performed. The following are assessed: full blood count with erythrocyte sedimentation rate, liver function, biochemistry, and renal function biochemistry.

Radiologic examinations

CXRs are obtained at presentation, during therapy, and for follow-up monitoring. Mediastinal lymph node enlargement can be detected in 60-75% of patients.

CT scanning of the thorax, abdomen, and pelvis is performed for initial staging purposes. Compared with other methods, CT is more sensitive in detecting lymphadenopathy and extralymphatic involvement. CT scanning may be most useful in evaluating patients with lymphoma because it can depict the lymph nodes in the chest, abdomen, and pelvis.

MRI is performed in patients in whom chest wall involvement is suggested; MRI offers better tissue contrast.

Ultrasonography and echocardiography are useful in detecting pericardial effusion and for directing lymph node biopsy and pleural interventions.

Bone scan is useful in evaluating bone involvement in HD. Gallium-67 scans obtained at baseline, during therapy, and in the posttreatment period help in differentiating active HD from nonactive HD.

Positron emission tomography (PET) scanning with 2-[fluorine 18]-fluoro-2-deoxy-D-glucose (FDG) is most useful in detecting disease relapse.

Bilateral bone marrow aspirations and biopsy are performed to assess in stage III or IV disease with B symptoms.

Other investigations are directed to a particular clinical problem. For example, a superior venacavogram is obtained if the patient has clinical findings of SVC syndrome. Immunoscintigraphy is used on an experimental basis only.

Limitations of Techniques: CXR is available everywhere and inexpensive; however, CXR is limited in evaluating soft tissue involvement of the chest wall. CXRs cannot be used to differentiate the various causes of lymph node enlargement. CT scanning is limited in its availability, especially in Third World countries. CT scans cannot be used to differentiate the various causes of lymph node enlargement or active tumor residue versus inactive tumor residue. MRI is limited in its availability because of its high cost. Some patients are claustrophobic and therefore cannot tolerate the MRI examination. Ultrasonography is limited in the thorax because the air contained in the lungs is not a suitable window through which the ultrasound waves can travel.

Nuclear medicine is limited because of its availability in expert centers only. At present, PET imaging is limited, and the studies are expensive.

DIFFERENTIALS

Aspergillosis, Thoracic
Blastomycosis, Thoracic
Coccidioidomycosis, Thoracic
Eosinophilic Granuloma, Thoracic
Histoplasmosis, Thoracic
Lung, Drug-induced Disease
Lung, Metastases
Lung, Postprimary Tuberculosis
Lung, Primary Tuberculosis
Non-Hodgkin Lymphoma, Thoracic
Wegener Granulomatosis, Thoracic

Other Problems to be Considered:

Leukemia
Pneumoconiosis
Histiocytosis X
Castleman disease
Agammaglobulinemia
Parasitic disorders
Connective tissue disorder

X-RAY

Findings: HD commonly appears as intrathoracic disease; therefore, PA and lateral CXRs are essential for clinical staging. Mediastinal adenopathy is the most common presentation, and direct extension of disease can be detected on chest radiographs. Chest images also allow evaluation of complications related to chemotherapy and radiation therapy. In follow-up studies for recurrent disease, along with history taking, physical examination, and laboratory investigations, CXR is the primary imaging modality.

• Among patients with HD, 67-74% have abnormal CXR findings at presentation.

   

• Of patients with abnormal CXR findings, 90% have bilateral asymmetric nodal disease.

   

• In HD, disease spreads contiguously along lymph node chains. Prevascular and paratracheal lymph nodes are most commonly affected.

   

• A single lymph node group is involved in only 15% of patients.

   

• Rarely, the posterior mediastinal or paracardiac lymph nodes are involved.

   

• The internal mammary chain of lymph nodes can be enlarged but not without other lymph node involvement.

   

• CXR can demonstrate either a single group with lymph node enlargement or a lobulated appearance resulting from multinodal involvement.

   

• Calcification is seen very rarely in untreated lymphoma.

   

• Direct invasion of the lungs can occur in 15-40% of patients and is associated nearly always with hilar adenopathy.

   

• Primary pulmonary involvement without hilar, mediastinal, or extrathoracic involvement is unusual; however, recurrent HD may appear in the absence of adenopathy, especially the nodular sclerosing type.

   

• Lung involvement can produce ill-defined or well-defined nodules, which can be unilateral or bilateral. These nodules may cavitate.

   

• Lung involvement can also appear as consolidation.

   

• Other findings in HD that can be detected on CXR include pleural effusions and skeletal lesions.

   

• In HD, two thirds of bone lesions are of the mixed lytic and sclerotic variety, few are lytic alone, and 10-15% are sclerotic alone. Sclerotic lesions tend to be confined to the vertebrae, demonstrating a typical appearance of ivory vertebrae.

   

• Anterior scalloping of vertebrae can be detected on lateral CXR, especially in the lower thoracic region.

   

• With CXR, HD can be quantified by calculating the mediastinal mass ratio (ratio of the maximum width of mediastinum to the maximum transverse thoracic diameter at the level of the diaphragm), by finding a mediastinal mass larger than one third of the transverse thoracic diameter at the T4-T5 level, or by determining an absolute transverse mediastinal diameter of 10 cm.

   

• In follow-up imaging of mediastinal bulk disease, 60% of CXRs demonstrate findings of residual adenopathy after treatment. This residual adenopathy may not contain active disease and may represent only residual scarring, but these can be seen at long-term follow-up.

Degree of Confidence: Most of the time, sufficiently enlarged lymph nodes in the thorax can be detected on CXR, but subtle enlargement can be missed; therefore, further imaging with CT is warranted.

False Positives/Negatives: A confluence of pulmonary veins, especially on the right, can be mistaken for subcarinal lymphadenopathy. Small pericardiac or diaphragmatic lymph nodes can mimic a fat pad. An enlarged azygous vein can mimic azygous adenopathy. When in doubt, repeat CXR by using the Valsalva maneuver. All of these false-positive CXR findings can be easily identified by performing CT.

Subtle enlargement of intrathoracic lymph nodes can be missed on CXR, and its detection greatly depends on the observer's experience as well as the type of CXR performed.