The lymphatic system Pathology
Malignant lymphomas represent the most common neoplasm in patients between the ages of 20 and 40 years. The two major variances of malignant lymphoma are non-Hodgkin's lymphoma and Hodgkin's disease. Although both of these tumors infiltrate reticular endothelial organs, they are distinct from the biological and clinical standpoints.
Imaging is primarily required to detect nodal and extra nodal disease in regions inaccessible to physical examination. In two thirds of patients the disease is suspected by the presence of asymptomatic peripheral adenopathy that persists over 4 to 6 weeks. Constitutional symptoms such as fever and night sweats known as B symptoms occur in 25 to 30% of patients with Hodgkin's disease and in a lower percentage of patients with non-Hodgkin's lymphoma. Once the diagnosis is established by lymph node biopsy, imaging is required for full evaluation. Treatment of lymphomas can be highly effective if delivered properly with over 80% and 50% disease free survival being reported for Hodgkin's and non-Hodgkin's lymphomas, respectively. It is important to understand that imaging is primarily needed to determine whether the disease is at a localized stag e that could be treated with radiation therapy, a very effective approach. If the disease is at a more advanced stage, it is now established that radiotherapy is not indicated and chemotherapy alone entails a similar or better prognosis than radiotherapy or combination therapy in most cases. The Ann Arbor staging system is the most commonly used scheme and can serve as a guide for imaging interpretation (Table 2).
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Figure 8.
Examples of lymphadenopathy in lymphomas.
a) CT scan showing enlarged right and left anterior paracardiac nodes. This localization is very suggestive of Hodgkin's disease.
b) CT scan showing retro-crural adenopathy (arrows) in non Hodgkin's lymphoma. In the retroperitoneum, nodes larger than 6 mm are considered
abnormal.
c) CT scan of retroperitoneum, showing a common pitfall mimicking adneopathy, the crus of the right hemidiaphragm (arrow).
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Table 2.
Ann Arbor staging system for lymphomas
Stage 1: Involvement of a single node region or single extralymphatic site
Stage 2: Involvement of two or more nodal regions on the same side of the diaphragm; can include localized involvement in a single extralymphatic site
Stage 3: Involvement of nodal regions or extranodal sites on both sides of the diaphragm
Stage 4: Disseminated involvement to one or more extralymphatic organs with or without lymph node involvement
B: Denotes the presence of constitutional symptoms
E: Denotes involvement of extralymphatic sites
CT is the main method of imaging for staging lymphomas. Several differences in the natural history of Hodgkin's and non-Hodgkin's lymphomas need to be appreciated for the judicious use of imaging. Hodgkin's disease involves predominantly the axial lymph node groups such as mediastinal, paracardiac and paraaortic regions (Fig. 8). Over 60% of patients with Hodgkin's disease present with mediastinal lymphadenopathy. Non-Hodgkin's lymphomas predominantly involve peripheral nodal regions such as epitrochlear, mesenteric and Waldeyer's ring lymph nodes. Only 20 % of non-Hodgkin's lymphomas exhibit mediastinal lymph node involvement. In addition, Hodgkin's disease is more frequently localized and spreads by contiguity to adjacent nodal regions with infrequent "skipped" nodes. Non-Hodgkin's lymphoma is more frequently multifocal or diffuse and can easily spread to non-adjacent regions. Thus, in non-Hodgkin's lymphoma it is necessary to scan the entire body for accurate staging whereas in Hodgkin's disease involvement is generally contiguous. The great majority of involved nodes are enlarged and detectable with CT which exhibits accuracy's in the 80 to 90% range for staging of lymphomas. Microscopic disease and diffuse liver, spleen and marrow involvement, cannot be detected with CT. Gallium 67 scanning has been advocated for the detection of occult disease but does not seem to be useful except in the context of following up residual disease and detecting recurrence, however, it is indicated prior to therapy to determine if the lymphoma is Gallium avid. MRI has been advocated in the detection of liver and spleen involvement but does not appear efficacious without the use of contrast agents which are still under experimental development. On the other hand, MRI is sensitive to the presence of gross bone marrow involvement. When staging by imaging indicates localized disease in Hodgkin's lymphoma, staging laparoscopy may then be considered to exclude occult splenic or abdominal lymph node disease because no imaging technique is accurate enough to exclude such eventuality if the disease is adjacent to abdominal structures. For non-Hodgkin's lymphoma the incidence of localized disease is less than 10% and except for low and intermediate grade types, systemic therapy is almost always used. A common problem in the management of lymphoma is the frequent occurrence of partial regression of tumor masses raising the possibility of incompletely treated active disease versus residual masses. MRI can help evaluate and monitor such residual masses by virtue of the different signal intensity of fibrosis and active tumor on T2-weighted image sequences. It has been shown that residual fibrosis exhibits uniform low signal intensity because of its low T2 relaxation times whereas residual tumor exhibits high or mixed signal intensity due to its higher water content and longer T2 relaxation times (Figs. 6 and 7). Thus, MRI can help monitor response to therapy in such cases and help assess early recurrence in residual masses which are commonly the site of relapsing lymphoma. Gallium 67 scanning is also us ed extensively for this purpose with fibrotic lesions exhibiting no activity. Both MRI and Gallium 67 scanning suffer from false positive results in the first 6 months following initiation of therapy because of necrosis and inflammatory reactions. More recently, PET scanning with FDG-glucose as a marker for assessment of non-aerobic metabolism has been proposed for the evaluation of the problem of partial regression in lymphoma and is still being investigated.
Hodgkin's disease involves the thorax in over 60% of cases with the anterior medastinum, tracheo-bronchial, paratracheal and hilar nodes involved in 50%, 45 %,40% and 25 % of cases, respectively. Non-Hodgkin's lymphoma involves the same nodal groups in less than 15 % of cases. Paraesophageal, posterior mediastinal and pleural involvement are, however, more common in non-Hodgkin's than in Hodgkin's lymphoma. Calcification of lymphomatous masses is distinctly unusual in untreated lymphoma but can be present in post treatment CT studies most particularly after radiation therapy. Non-Hodgkin's lymphoma are more common in the abdomen and involve intestinal structures and other extra nodal sites in a higher proportion of cases. It is, however, unusual to detect extra nodal masses without some associated lymphadenopathy in lymphoma, whereas other types of focal masses do not exhibit significant adenopathy. Thus, when confronted with a mass associated with significant adenopathy and the possibility of lymphoma, surgical excisional biopsy rather than image guided needle biopsy should be undertaken because diagnosis and cell typing of lymphoma usually requires larger tissue samples.
Metastatic nodal disease
In every neoplasm, involvement of loco-regional and distant lymph nodes is associated with a worsened prognosis. In several cancers, the presence of lymph node metastasis is a critical element of staging and determines in many cases the feasibility of surgical resection. The impact of imaging on the most commonly encountered cancers will be reviewed here.
Primary lung cancer
Except for small cell lung cancer which is almost always disseminated by the time of initial diagnosis, nodal staging is a critical element in the staging of lung cancer. To facilitate assessment of mediastinal lymph nodes, a standardized map of the different nodal stations has be en developed by the American Thoracic Society and is used as part of the new International Lung Cancer TNM staging system (Fig. 9). CT and MRI have been investigated extensively as staging modalities. CT and MRI exhibit similar accuracy in assessing mediastinal lymph nodes. Initially, high sensitivities and specificities in the 80 to 90% range were reported with CT scanning but with increasing experience and better designed multi at best are now observed. This is primarily due to the higher than suspected incidence of microscopic disease, the existence of skipped nodal regions and, the higher incidence of enlarged reactive lymph nodes simulating metastatic disease most particularly in patients with associated pneumonitis or prior granulomatous infection. MRI signal intensities have not proven helpful in the differentiation of metastatic versus reactive nodes. Recent and still preliminary data with FTG-glucose PET scanning suggests that such differentiation may be achievable in lung cancer. Nonetheless, despite these limitations, CT remains important for the management of the lung cancer patient because the current surgical staging scheme adopted in 1984 no longer considers low ipsilateral or subcarinal adenopathy a cause for non-resectability. Only positive contralateral, high
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Figure 10.
Coronal T1-weighted MRl showing extensive metastastic peribronchial and paratracheal adenopathy in patient with right upper lobe carcinoma. |
mediastinal or distant nodes contraindicate surgery. Thus, CT is important in identifying such nodes and prompts nodal sampling with mediastinoscopy prior to curative surgery if distant or contralateral disease is found. On the other hand, most surgeons consider a negative CT scan sufficient to proceed directly to surgical exploration since full ipsilateral nodal resection is routinely undertaken in most cases. Technically, the use of thinner 4-5 mm sections from the arch of the aorta to the lower lobar bifurcations are important in detecting enlarged nodes and avoid partial volume averaging of vascular structures and nodes. Likewise, contrast enhancement most particularly with rapid or single breath-hold continuous spiral scanning is also preferable whenever possible and necessary when mediastinal fat is limited in amount. Although no specific nodal size can be reliable, it is generally agreed that sharply marginated nodes smaller than 1 cm are considered normal, nodes between 1 and 1.5 cm are suspicious and larger nodes are definitely abnormal. The appearance of lymph nodes is sometimes useful with nodes exhibiting a central lucency and sharp margins considered benign and those appearing irregular, adherent to adjacent clustered nodes considered probably malignant. In the patient with allergy to contrast and in patients with lesions suspected of invading critical structures such as the heart, great vessels, esophagus, vertebral bodies or superior sulcus, MRI is indicated because blood vessels, airways and adjacent masses can easily be differentiated in multiple imaging planes (Figs. 3 and 10).
Breast cancer
Despite the critical importance of lymph node dissemination in this disease, no method of imaging has been effective in staging cancerous nodes in breast cancer. Most surgeons do not feel that axillary lymph node imaging is necessary. However, for advanced lesions, CT scanning of the chest to assess internal mammary lymph nodes has been advocated. More recently, research using PET scanning and labelled metabolites such as FDG-glucose or MRI with lymph node specific contrast agents have been investigated. In the absence of are liable method for detecting microscopic disease in lymph nodes, it is doubtful that imaging methods can obviate the need for surgical nodal sampling.
Head and neck tumors
In head and neck tumors, assessment of deep lymph nodes is essential. Both CT and MRI are being extensively used for such purposes. With CT, contrast enhancement is essential in assessing nodes of the neck region. Some investigators report that the pattern of enhancement of lymph nodes may be helpful in differentiating benign from malignant nodes with rim enhancement being suggestive of malignant disease. In the neck, nodes greater than 1 cm are considered abnormal.
Colorectal cancer
The presence of more than 4 malignant lymph nodes has a significant detrimental effect on the prognosis of the patient with colorectal cancer. A recently conducted prospective multi-institutional clinical trial in the United States comparing CT and MRI in the staging of colorectal cancers showed that both modalities are not very accurate in staging lymph node extension with CT showing a slightly better performance albeit not statistically significant. Normal nodes are smaller in the mesentery and retroperitoneum than in the mediastinum. Nodes larger than 6 mm should be considered suspicious especially if clustered and with ill defined margins. Peripancreatic and portocaval nodes are commonly involved in more advanced stages of colonic cancer and should be specifically sought by using thinner sections in the pancreatic regions as well as excellent intestinal opacification throughout the bowel. At least 16 ounces of oral contrast should be administered prior to CT examination. Although, monoclonal antibody imaging has been experimentally successful in the detection and staging of colorectal malignancies it has not gained widespread acceptance.
Prostate cancer
Extension of pro state cancer to the regional nodes most commonly in the internal iliac chain is an absolute contraindication to prostatectomy for cancer. Imaging methods, however, have had limited success in reliably detecting nodal invasion preoperatively except in the most advanced cases. Imaging may be useful in staging the transcapsular extent of the prostatic tumor and the possible involvement of the neurovascular bundles which, optimally, should be spared at surgery. During such imaging evaluation, iliac lymph nodes can be visualized and nodes larger than 1 cm are considered highly suspicious for metastatic disease. Needle biopsy can then be used to assess these lymph nodes. In practice, however, because of the high rate of false negative nodal examinations, surgical sampling with immediate frozen section diagnosis remains the preferred approach.
Elias Zerhouni