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The intrathoracic manifestations of the malignant lymphomas and the leukemias
The Intrathoracic
Manifestations of the Malignant and the Leukemias
Lymphomas
Norman Blank and Ronald A. Castellino
classifications of HodgT HEkin HISTOLOGIC disease, non-Hodgkin lymphomas, and the acute and chronic leukemias as well as the current methods used in the clinical and pathologic staging of these diseasesis presented elsewhere in this issue.That information is essential to an understanding of prognosisand of modern methods of treatment, and to an appreciation of the need for precisely locating the sitesof disease in patients with malignant lymphoma. The intrathoracic manifestations of the malignant lymphomas may be considered from two standpoints: (1) those that are discovered at the time of initial diagnosis,and (2) those that occur with relapse or recurrence after one or more courses of treatment. It is not that the lesions themselves are significantly different at these times, but rather it is the incidence of the various lesions that is different. In this report we have placed emphasison the nature of the abnormalities seen at the time of initial diagnosis, with comments on similar lesions that may be seen after treatment. ANATOMY AND MEDIASTINAL
RADIOGRAPHY OF LYMPH NODES
Since mediastinal lymphadenopathy is such a common abnormality in this group of diseases,it is important to know the distribution of the lymph nodes and lymphatics in the thorax. Figure 1 is a schematic drawing of some of the key mediastinal lymph node chains. Our interpretation is based largely on the work of Rouviere,2’ buttressed by a small collection of our own casesin which mediastinal lymph nodes were fortuitously opacified at the time of lymphangiography. We have used Rouviere’s nomenclature in general, but also use the term tracheobronchial nodes to equate with those he labels nodes of the pulmonary root and the terms bronchopulmonary or hilar nodes to equate with the proximal groups of those nodes that he designatesas intrapulmonary. Whereas much of the mediastinal lymphadenopathy seen in day-to-day practice produces flagrant easily recognized abnormal shadows, a significant number of casespresent with subtle Seminars in Roentgenotogy,
Vol.
XV,
No.
3 (July),
1980
contour changes that can easily pass unrecognized. A clear understanding of normal radiographic mediastinal anatomy is invaluable in detecting these subtleties.“.13 In addition, in some areas of the mediastinum it is easier to locate and assess minimal departures from normal. These have been discussedin previous reports‘s3and we review them here. Nodes of the left prevascular chain, especially the ductus node or nodes, are located close to mediastinal pleural reflections and can produce recognizable changes when enlarged (Fig. 2).’ Normally, the pleural reflection between the aortic arch and the left pulmonary artery is either slightly concave, relatively straight towards the left lung (even though it is inclined like the side of a tent superomedially), or invisible. We consider any case in which this segment is clearly seen as a shadow convex towards the left lung highly suspect and worthy of further study. Adenopathy in the ductus and left prevascular nodes is the most common cause of this contour change, but any type of mediastinal mass, eg, a small thymoma, may produce this distortion if appropriately located. Distortion or effacement of portions of the aortic arch contours or the mediastinal pleura anterior to the arch may also be produced by lymphadenopathy in the left prevascular nodes(Fig. 3). On the right, the azygos node lies in variable relation to the azygos vein as it passesforward above the right main bronchus to enter the superior vena cava. This node is the lowest member of the right paratracheal chain. It lies
From the Division of Diagnostic Radiology, Stanford University School of Medicine, Stanford, Calif Supported in part by Grant CAO-5838. National Cancer Institute, National Institutes of Health. Norman Blank, M.D.: Professor of Radiology, Stanford University School of Medicine; Ronald A. Castellino, M.D.: Associate Professor of Radiology, Stanford University School of Medicine. Address reprint requests to Norman Blank, M.D., Division of Diagnostic Radiology, Stanford University School of Medicine, Stanford, Calif 94305. o 1980 by Grune & Stratton. Inc. 0037-198X/80/1503-0005$02.00/0
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Paratrrchea\ Nodes of
l
Interttachcobronchial
the
Pulmonary
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Roots (Subcrrinal)
PREVASCuLAR
l
Ptccaval Pre-aort
4 4
Para-aortic Paracsophagoal
a
PARIETAL
- Rt. ice- tarot
id
-
Lt.
NODES
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Paravartebral Diaphragmat I c - Per icardiac Internal Msmmafy - Not shown Xnt rrcost al - dot shown INTRAPULMONARY (HILAR) NODES 0 Note: The paratracheal and prcvascular nodes arc shown as interspersed in this Single plane. In actuality they are located in diCForrnt planes with the prcvascular (anterior msdiartinal) chains locrtd anterior to the paratrachaal chains. Fig. 1.
Schematic
diagram
of some I of the key lymph
close to a pleural reflection and when enlarged distorts or displaces that reflection. Any marginal shadow convex to the right that has the greater part of its arc above the level of the right main bronchus and is not clearly due to the image of the azygos vein itself we regard as probably abnormal (Fig. 4).2.3 Not every mass so situated will necessarily represent azygos adenopathy. Low nodes of the right prevascular chain (anterior to the superior vena cava) may produce a similar distortion of the mediastinal pleura (Fig. 5). Any small mediastinal tumor presenting in this region may also be indistinguishable. The distinction between an enlarged azygos vein and azygos adenopathy is not difficult. The vein responds to changes in posture and intrathoracic pressure. It is smaller on films made with the patient upright rather than supine, and it decreases in size during a sustained Valsalva maneuver. Subcarinal nodes are difficult to detect until they are large. Loss of the image of the outer wall of the bronchus intermedius on tomograms may be helpful. Subcarinal adenopathy com-
nodes of the mediastinum.
monly displaces the portion of the lung that normally permits visualization of this outer wall. Likewise, distortion and displacement of the azygoesophageal pleural reflection may also permit recognition of a subcarinal mass. It is important, however, not to mistake the confluence of pulmonary veins or the left atrium for subcarinal adenopathy particularly on the right side. Esophagography may be useful in establishing the presence of a subcarinal or retrotracheal mass that is large enough to alter the course or contour of the esophagus (Fig. 6). Posterior mediastinal paraesophageal adenopathy may also be recognized by impressions produced on the filled esophagus. Posterior mediastinal paraaortic adenopathy may appear as a small mass (with edges convex towards the left lung) that silhouettes out the adjacent segment of the edge of the descending thoracic aorta. Some nodes may also be interaorticoesophageal in position (Fig. 7). Paravertebral adenopathy may be detected when it produces distortions of paravertebral pleural reflections, resulting in relatively short
THE INTRATHORACIC
MANIFESTATIONS
OF THE MALIGNANT
Fig. 2. Prevascular nodes in a 44-yr-old woman with Hodgkin disease. Progressive alteration of the mediastinal pleural reflection between the aortic arch and left pulmonary artery caused by adenopathy in the region of the ductus node and left prevascular chain. The dashed line demarcates the left main bronchus. (A) The normal pleural reflection (dotted line) is concave to the left. (81 Seven months later, the pleural reflection has become straight. (C) Three months later, the pleural reflection is slightly convex to the left. (D) Two months later, there is increased convexity.
arc-like edges convex towards the lung (Fig. 7). Appropriate views of the thoracic spine will serve to prevent confusion with similar distortions produced by exuberant vertebra1 spurs. For purposes of chemotherapy, of course, it is not necessary to precisely locate these posterior nodes. Even for radiotherapy it is only important to know their approximate position. In planning an approach for biopsy, however, it may be useful to locate the mass as precisely as possible in relation to adjacent organs.
LYMPHOMAS
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Fig. 3. A 30-yr-old woman with Hodgkin disease involving the prevascular nodes. (A) Adenopathy on right side of mediastinum. probably of the right prevasculsr and peratracheal nodes (white arrow). fB1 Tomogram. Note sharp lateral edge of a mass anterior to the aortic arch on the left representing adenopathy in the left prevascular nodes (errowsl. In retrospect, this can also be seen in A.
Pericardiac-diaphragmatic adenopathy results in masses filling the cardiophrenic angles on the PA view. On the lateral view, they may lie either retrosternally or at the level of the inferior vena cava or phrenic nerve, depending on which nodes of the group are involved (Fig. S).’ When small, these nodes may simulate a pericardiac fat pad and pass unrecognized unless comparison
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Fig. 4. tymphadenopathy in a 41-yr-old man with nodular azygos node and higher nodes of the right paratracheal chain after treatment. Note the small azygos vein shadow. The right
with previous films show that they are a new finding. The internal mammary nodes are more numerous in the upper hemithorax and may be recognized on the lateral view as extrapleural masses anteriorly against the chest wall. Occasionally these nodes attain sufficient size to be seen as an ill-defined increase in density lateral
Fig. 5. Right prevascular lymphadenopathy. contour. (6) CT scan shows a mass (white adenopathy in the right prevascular chain.
arrow)
(A) Slightly projecting
mixed lymphocytic as well as right hilar lateral wall of trachea
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lymphoma. (A) Adenopathy involving nodes. [B) Regression of the adenopathy is now visible.
the
to the sternum on the PA film. On AP tomograms, only that portion of the mass tangential to lung demonstrates a well-defined margin. Care must be used to avoid mistaking the pleural reflections over the costochondral junctions or over the brachiocephalic vessels for internal mammary adenopathy in the lateral view. Enlarged mediastinal lymph nodes may signal
widened anterior
right mediastinum and lateral to the
without superior
a clear-cut distortion vene cava, consistent
of with
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Fig. 6. This 53-yr-old man with histiocytic lymphoma developed dysphagia. (A) Normal baseline film made 7 mo prior to admission. (6) Admission film. There is increased density corresponding to the subcarinal region. On the original film, a subtle “edge” shadow was seen on the right. Also, the left border of the descending thoracic aorta lies more lateral than in A. (C) Esophagram shows marked narrowing in the middle third of the esophagus associated with a soft-tissue mass extending both to the right and to the left. 6XE.F) Lateral views corresponding to A, B. and C, raspectively. (GI Tomogram shows the right edge of the mass in continuity with the azygoesophageal pleural reflection inferiorly. This places the mass in a prevertebral position. Its relationship to the major airways indicates that it is also retrotracheal and subcarinal.
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Fig. 7. Posterior mediastinal adenopathy in a !i4-yr-old woman with diffuse histiocytic lymphoma. There is a small mass adjacent to the lower thoracic spine on the right with an edge convex towards the right lung (arrowhead). This suggests origin in a paravertebral node. There is another small mass slightly lower in position on the left (arrow). The original films showed the left paravertebral stripe undisturbed and the descending aorta edge could be faintly seen. This suggests an origin in a paraesophageal node or in an interaorticoesophageal node.
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on chest films or tomograms most commonly when nodes have reached sufficient size to distort relationships of adjacent pleural reflections with lung. Based on plain film findings, we are usually dependent on recognizing distortions of the “wrapper” (the mediastinal pleura) in order to recognize the presence of a mediastinal mass. On CT scans of the chest, however, we can actually see the mediastinal contents independent of the wrapper (Fig. 5). This is due to the generous supply of mediastinal fat and the vastly superior capabilities of the CT scan technique to discriminate different tissue densities. From our brief experience, we have little doubt that CT scans will make recognition of mediastinal abnormalities an easier task in many patients. CT scans will be particularly useful in distinguishing fatty from solid masses, and thus solve such problems as distinguishing pericardiac fat pads from pericardiac adenopathy, or mediastinal lipomatosis from lymphadenopathy. We must nevertheless continue to develop our ability to detect mediastinal lesions on routine chest films, the study of first resort. INTRATHORACIC
their presence only because they impinge upon the esophagus, trachea, pulmonary arteries, or great veins, and produce signs and symptoms. Special studies directed towards evaluating the symptoms may lead to detection of these masses (Figs. 6 and 9). We emphasize that, as in all chest radiology, comparison with previous films may be the most rewarding exercise in detecting a mediastinal lesion. The abnormal overlaps the normal spectrum; that is to say, images that may still be within the range of normal may be abnormal for a given individual if they represent a change from a previous state. A straight mediastinal pleural edge between the aortic arch and the left pulmonary artery is part of the normal spectrum and yet may represent an early sign of adenopathy (or other mass) in a patient in whom this reflection was previously shown to be concave to the left (Fig. 2). However, we cannot rely on strict comparison between films made upright and supine, or in different degrees of inspiration, or in altered lordosis to evaluate subtle mediastinal contour changes. Mediastinal lymphadenopathy is detectable
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ADENOPATHY
Between 1971 and 1973, we analyzed the findings in 165 consecutive, untreated, newly diagnosed patients with Hodgkin disease.” Of these, 67% (11 O/ 164) had radiographic evidence of intrathoracic disease,and almost 99% of this subgroup had some evidence of intrathoracic lymphadenopathy. The incidence and distribution of involved lymph node groups in these patients is shown in Fig. 10. In general, basedon pretreatment radiographic study, involvement of only one intrathoracic lymph node group was not common ( 15%) in Hodgkin disease,but was relatively common (40%) in non-Hodgkin lymphoma. In the latter category, there were casesin which involvement of pericardiac, posterior mediastinal, or paravertebral nodes was the only recognizable sign of intrathoracic disease.In a seriesof 136 patients with non-Hodgkin lymphoma, 43% (58/ 136) showed evidence of intrathoracic diseaseat the time of diagnosis,and approximately 87% of this group had some radiographic evidence of intrathoracic lymphadenopathy.” Children aged l-10 yr who have Hodgkin lymphoma have a lower incidence (36%) of
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Pericardiac-diaphragmatic nodes. Fig. 8. (A) Diagrammatic presentation (modified (B) Pretreatment from Rouvibre). tomographic cut showing portions of a large mediastinal mass plus a mass in the region of the left anterior prepericardiac node (arrow). (C) Two years after treatment, the left-sided mass has resolved. There is recurrence in the right anterior prepericardiac node (arrow) plus recurrence in the lung anterior to the right hilum. Biopsy of the lung revealed Hodgkin disease. (Reproduced by permission of the American Journal of Roentgenology.5~
B
6- 68
Fig. 8. Pretracheal nodes involved by diffuse lymphoma. A 27-yr-old man presented with mediistinum on the chest film and a murmur pulmonic stenosis. A pulmonary arteriogram compression of the superior margin of the right artery (arrows) due to adenopathy. Courtesy of Finnegan, Santa Cruz, Calif. (Reproduced by from f?edio/ogy.‘“)
histiocytic a widened suggesting showed pulmonary Dr. Robert permission
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intrathoracic lymphadenopathy than do older children and adults at the time of initial diagnosis. This difference may be related to the fact that in the Stanford patient population, at least, there was a smaller number of young children with the nodular sclerosis histologic subtype and a larger number with the mixed cellularity type than in the group over age 10 yr.19 Hilar adenopathy in the absence of detectable mediastinal adenopathy was unusual in our cases of Hodgkin disease or non-Hodgkin lymphoma at initial diagnosis, but nevertheless did occur in both groups. In patients with leukemia, radiographically detectable hilar adenopathy may also be present with or without concomitant recognizable mediastinal adenopathy. Such adenopathy is most common in cases of acute or chronic lymphocytic leukemia and rare in cases of acute myelogenous leukemia.16 In any of these diseases, however, unilateral hilar lymphadenopathy as the only intrathoracic component occurs with enough frequency that we do not think it justifiable to omit malignant lymphoma or leukemia from the differential diagnosis. Intrathoracic lymphadenopathy is less commonly seen radiographically in leukemia than in malignant lymphoma. Intrathoracic lymphadenopathy is frequently present in the acute and chronic lymphocytic leukemia (Fig. 11) but is encountered on chest films in less than 40% of
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Fig. 10. Incidence of involvement of intrathoracic structures in a series of consecutive, previously untreated patients with Hodgkin and non-Hodgkin lymphoma. (Reproduced by permission from Radiology.‘“)
such cases.16 It is rare in acute myelogenous leukemia. We have not analyzed the specific sites of mediastinal adenopathy in patients with leukemia, nor could we find any other study that has. In general, these details are not as important in either treatment planning nor for prognosis for patients with leukemia, since the treatment is usually systemic rather than localized to specific disease sites.
Fig. 11. Massive lQyr-old with newly The mass regressed
anterior mediastinal diagnosed acute with antileukemic
adenopathy in a lymphatic leukemia. therapy.
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PULMONARY
MANIFESTATIONS
PARENCHYMAL
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LESIONS
Few reported series concerning pulmonary lesions in Hodgkin disease, non-Hodgkin lymphomas and leukemias separate lesions detected at the time of initial diagnosis from those discovered later after one or more courses of treatment. At least in the case of Hodgkin disease, this distinction is important. In our material, at the time of initial diagnosis, we did not have one case of pulmonary Hodgkin disease in the absence of some manifestation of hilar or mediastinal lymphadenopathy. Others have reported such cases,” but the occurrence must be rare. Therefore, a pulmonary lesion discovered in a newly diagnosed patient with Hodgkin disease who has no evidence of mediastinal or hilar adenopathy should be pursued to the point of a specific diagnosis and never assumed to be due to the underlying Hodgkin disease. Any of the histologic classifications of Hodgkin disease and non-Hodgkin lymphoma may have parenchymal involvement by the disease process, but in our material, this was more commonly the case in Hodgkin disease (11.6%) than in non-Hodgkin lymphoma (3.7%) at the time of initial diagnosis. If one relies on data from autopsy series or clinical reviews that include lung lesions that develop at any time during the course of the disease, then the incidence of lung involvement in both Hodgkin disease and non-Hodgkin lymphoma is much higher.‘,‘* There is widespread distribution of lymphoid aggregates along the course of pulmonary vessels and bronchi. These supply an ample basis to explain the development of lung lesions in malignant lymphomas. The spectrum of the parenchyma1 lesions is broad and there is much overlap in the radiographic appearances in Hodgkin and non-Hodgkin lymphomas.8~‘0~‘8*20~24 Extension of nodal disease into adjacent lung may be inferred when the pleural reflection over a mediastinal mass has lost its sharp margin and becomes shaggy and irregular. Likewise, when enlarged hilar nodes show contiguous irregular margins, extension into lung is presumed (Fig. 12). Sometimes peribronchial and perivascular lymphomatous deposits occur in a subsegmental or segmental distribution, producing a cluster or bands of poorly defined nodular shadows with
Fig. 12. Extension of nodal disease into adjacent lung in a 23-y-old woman with nodular sclerosing Hodgkin disease. (A) The tomogram shows obvious right mediastinal adenopathy. Note the bulge of the pleural reflection, convex to the right, beginning at the right tracheobronchial angle. Enlarged left hilar nodes have a shaggy irregular contour. consistent with extension into the LUL parenchyma.
intervening skip areas of relatively uninvolved lung. When such lesions are more extensive, there may be inhomogeneous involvement of larger areas and even the entirety of both lungs (Fig. 13). Localized areas of consolidation involving segments or lobes may be radiographitally indistinguishable from pneumonia. This is especially so when only one segment or lobe is involved. An air bronchogram may be seen in association with this type of massive consolidation in lymphoma, due to alveolar collapse or alveolar filling by malignant cells. Lymphomatous infiltration of bronchial walls may be so extensive as to cause endobronchial masses accompanied by collapse of lung peripherally. Unfortunately, it is not possible to know from the radiographic appearance how much of the peripheral parenchymal component is due to atelectasis alone or to concomitant lymphomatous deposits. Atelecatasis of lung may also occur from extrinsic pressure by enlarged lymph nodes about bronchi at the hilum, but is probably less common. Discrete parenchymal nodules or masses, either solitary or multiple, are also a common radiographic manifestation of pulmonary in-
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Fig. 13. Extensive hilar and parenchymal disease in a 28-yr-old man with mixed cellularity Hodgkin disease. Superior mediastinal adenopathy was confirmed on tomograms (not shown) but was the least conspicuous component. (Al Perenchymal involvement predominates in a peribronchial distribution interspersed with poorly defined nodular components. (8) Heavy involvement of the right middle lobe and lingula has produced an appearance of consolidation in the lateral view. (Cl A short time after 1500 rad had been delivered to the mediastinum. hila, and lungs. There is marked improvement. (D) CT scan of lung bases shortly after C. Note the distribution of the residual parenchymal disease in the form of irregular nodules and bands along the course of the bronchi and vessels.
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Fig. 14. Pulmonary nodules in a 16-yr-old girl with Hodgkin disease. (A) PA chest film shows bilateral mediastinal adenopathy and probable hilar enlargement. Note on the left side, lateral to the shadow of the aortic arch, a soft tissue shadow whose lateral edge extends from the level of the fifth posterior rib down to the left pulmonary artery (arrows). Tomograms showed this to lie far anterior just behind the level of the manubrium. This not uncommon finding in malignant lymphoma is a manifestation of involvement of internal mammary nodes. No parenchymal lesions are seen. (B) Composite of portions of lung seen on full lung tomograms. Both hila show adenopathy (medial arrows). Several fairly discrete low-density nodules are seen in the lungs (lateral arrows). (Reproduced by permission of Harvard University Press.‘?
volvement by the malignant lymphomas. The lesions vary in size from under 1 cm to several centimeters in diameter (Figs. 3, 14, and 15). They may be of low density with poorly defined margins. Tomographic identification of nodules that are invisible even on retrospective review of chest films is unusual, but occurs with enough frequency to warrant full lung tomography in all cases in which mediastinal or hilar adenopathy is suspect from plain films (Fig. 14). Tomograms may also show the marginal contours to be much sharper than anticipated from the plain film appearance. We know of no reliably useful crite-
ria of nodule size, marginal contours, or edge sharpness that permit lymphomatous nodules to be distinguished from noncalcified nodules of any other etiology. Cavitation may be seen in small nodules or larger masses and also fail to present distinguishing features. In some patients, particularly those with diffuse histiocytic lymphoma and less often those with Hodgkin disease, the evolution of pulmonary parenchymal disease may be surprisingly rapid. From a normal or near normal baseline appearance of the lung, widespread pulmonary disease may develop in a few days, including the
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Fig. 15. Mass in biopsyproved nodular sclerosing Hodgkin disease. (A) There is a mass occupying much of the LUL plus a small left pleural effusion. (B) Tomographic cut shows left hilar adenopathy. The air-filled apicoposterior segmental branch of the LUL courses into the mass.
appearance of thickened interlobar septa (Fig. 16). Sometimes this rapidity of change prompts a diagnosis of pulmonary edema or, in those patients who are febrile and toxic, of infection. Biopsy will reveal the true situation; appropriate chemotherapy will usually lead to rapid resolution of both the radiographic and clinical abnormalities. Primary Lymphoma and Pseudolymphoma of the Lung
Primary lymphoma of the lung seems to behave quite differently from other forms of non-Hodgkin lymphoma. It is a disease that
apparently originates in the lung, often has a long life history, usually produces few symptoms, and may be cured by surgical removal with perhaps additional survival following postoperative radiation therapy for those patients with involved hilar nodes. The radiographic manifestations are often described as massesor as areas of consolidation extending peripherally from the hilar region. Hilar nodesmay be involved but not mediastinal nodes or nodes at other sites if the case is to be considered a primary lymphoma of the lung. When followed over a long period of time (because of incorrect presumptive diagnosis), the pulmonary lesions have been noted to show slow progression. An interlobar fissure may
Fig. 16. Rapid appearance of diffuse pulmonary disease in a 13-yr-old girl with newly diagnosed Hodgkin disease. (AI Mediastinal adenopathy is present, although relatively subtle. (B) Two weeks later, the chest film shows a remarkable change. There ere peribronchial and perivascular cloaking shadows with small ill-defined nodular components. Septal B lines were also visible at the bases on the original films. Open lung biopsy showed perenchymal involvement by Hodgkin disease.
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be crossed,so that the diseasemay involve adjacent lobes. Frequently, air bronchograms are seen within the consolidation. Although the latter sign is often inferred radiographically to indicate air-space consolidation, the histopathology sometimes indicates that the abnormal lymphoid tissue has primarily an interstitial distribution, with compressionrather than filling of alveoli. Cavitation is unusual but doesoccur.’ Pleural adhesions are reported as common, whereaspleural effusion is rare.22.2’ What is the relationship between primary lymphoma of the lung and pseudolymphoma? It seemsthat even following the strictest criteria it is not always possibleto separate one from the other on histopathologic grounds. The question is, does pseudolymphoma transform into lymphoma? Or is it simply that the pathologist’s interpretation transforms after viewing biopsy specimens obtained at different times, or that biopsies from different areas of the same lesion might prompt different diagnoses? Hopefully, techniques used to determine the monoclonal or polyclonal nature of the responsible cells will allow more reliable distinction between these lesions. Likewise, the diagnosis of lymphomatoid granulomatosis established by biopsy may subsequently be shown by study of further tissue specimensor by clinical events to have “evolved”
Fig. 17. A 60-yr-old man with chronic lymphocytic leukemia. There are bilateral pulmonary abnormalities with a reticulonodular appearance and peribronchial thickening as well. Lung biopsy showed extensive intersitial infiltration by leukemic cells. The consolidated area near the left heart border probably represents postoperative reaction at the lung biopsy site. The lesions cleared when the patient received antileukemic therapy.
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THE LEUKEMIAS
into a non-Hodgkin lymphoma. Whether this is evolution or confusion is uncertain. Leukemic
Pulmonary
Infiltrates
Leukemic infiltrates may be found in the lungs at autopsy in a high proportion of patients who die with either acute or chronic leukemia. These pulmonary infiltrates are most common in monocytic leukemia (46%) and least common in chronic myelogenousleukemia (15%1).‘~~‘~ In the vast majority of these cases,there are no roentgenographic manifestations of these infiltrates. In some, however, a diffuse peribronchial infiltrate not localized to a segment or lobe seemsto correspond to the autopsy findings (Fig. 17). Nodular lesions are most unusual and may represent pulmonary infarcts consequent to vascular occlusion by leukemic infiltrates. If these infarcts become confluent, they may present as massesor even resemble lobar consolidation. True leukemic consolidation of a lobe has not been reported to our knowledge, nor have cavitary lesionsbeen reported secondary only to the leukemic infiltrates. In the vast majority of our casesof acute or chronic leukemia, pulmonary lesions have proved to be manifestations of infection, pulmonary hemorrhage, or hemorrhagic infarction. Miliary lung lesionscaused by leukemic infil-
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trates have been reported, but rarely. Often in these cases the association is one of assumption rather than meticulous anatomic-pathologicradiologic correlation. The only case of this type that we have, is that of a young man who had miliary lesions and similiar foci of leukemic infiltrates at autopsy, but also had foci of inflammatory cells and inclusion bodies, so that it was not possible to exclude the contributions of an undiagnosed viral illness. It is our policy never to assume that miliary lesions in leukemia are due to the leukemia itself because there are far too many proved cases of disseminated tuberculosis, histoplasmosis, viruses (especially measles or cytomegalovirus, or even P. carinii that have caused miliary lesions in patients whose immune mechanisms have been compromised by the disease and its treatment. Patients with leukemia often have anemia, hypoproteinemia, fever, and infection, and are often treated with intravenous fluids, so interstitial pulmonary edema is common. The radiographic manifestations of the interstitial edema may antedate a clear-cut clinical picture of pulmonary edema and thus may be confused with the pattern of diffuse peribronchial infiltration caused by leukemic cells. The converse may also occur, but rarely. Fortunately, the radiographic signs of interstitial pulmonary edema clear rapidly with appropriate management and this will remove doubt about the diagnosis. Rapidity of onset of the pulmonary lesions is less reliable in differential diagnosis since diffuse pulmonary hemorrhage and interstitial leukemic infiltrates may also appear relatively rapidly, as may the pulmonary lesions of P. carinii pneumonia. Any of these may mimic the changes of interstitial pulmonary edema. Hemoptysis may not occur in patients with proved intrapulmonary hemorrhage, but usually there are other signs, such as petechiae or gastrointestinal bleeding, to alert one’s suspicion. PLEURAL
DISEASE
Pleural effusion is not common in either Hodgkin or non-Hodgkin lymphoma at the time of initial diagnosis. Seldom are patients subjected to either thoracoscopy or thoracotomy for inspection and biopsy of the pleura at this stage of their disease, so precise data as to the cause of these early effusions are not available.
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Certain conclusions can be drawn from clinical observations, however. A small to moderate effusion, unilateral or bilateral, may completely resolve following radiation therapy to the mediastinum alone.‘4,zs This sequence supports the theory that pleural effusion may occur as the result of partial obstruction of lymphatics by hilar or mediastinal adenopathy. In the case of bulky adenopathy, one may also invoke an element of obstruction of pulmonary venous return. Prominent septal lines may be found in conjunction with effusion from either mechanism. Thus, there need be no actual pleural invasion by tumor in these cases. However, pleural invasion along the border of the involved mediastinum may cause the effusion and account for its response to radiation treatment of the mediastinum. Pleural effusion as the only intrathoracic sign of Hodgkin disease at presentation is rare in adults (1 / 164). Not one example was found in a review of 105 consecutive patients less than 16 yr of age with newly diagnosed Hodgkin disease.” However, with non-Hodgkin lymphoma, pleural effusion may be found in previously untreated patients even in the absence of detectable intrathoracic lymphadenopathy. Pleural effusion occurred in 7 of 56 untreated children with non-Hodgkin lymphoma, and in 3 of the 7 it was the only radiographic manifestation of intrathoracic disease.4 Pleural or extrapleural masses may be apparent during the course of the disease, and subsequently proved by biopsy to be due to lymphomatous tissue (Fig. 18). Since there are parietal lymph nodes in the intercostal spaces, it is possible that they serve as the origin of some of these focal lesions. We are impressed with the fact that this type of focal pleural involvement is often unaccompanied by effusion. There may also be pleural lesions that have an irregular interface with adjacent lung, suggesting that lymphomatous involvement of subpleural pulmonary lymphatics have extended into the pleura, or vice versa. Cytologic study of pleural fluid removed from patients with any form of malignant lymphoma seldom shows malignant cells.*’ Even in the few that have positive cytologic study (about 15%), it is at least theoretically possible that the pleura itself is not invaded. However, in the cytologi-
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Fig. 18. Extrapleural involvement in a 25yr-old man with mixed cellularity Hodgkin disease. The patient was stage IV et the time of original diagnosis and had been successfully treated with a combination of radiotherapy end chemotherapy plus maintenance forms of chemotherapy over the prior 5 yr. (A) There is increased tissue density lateral to the right heart border lacking defined edges. The vascular shadows of the lung can be seen through the lesion. These findings raise the question of a pleural or extrapleural mass seen en face. Spot films made at fluoroscopy confirmed the extrapleural nature of the lesion. On the left, another mess convex to the left is seen through the heart (open arrowhead). Its medial extent abuts the vertebrae. (8) Coned view of the en face appearance of the lesion on the right side of the chest. (C) Lateral view shows the posterior location of the two extrapleural masses, but they overlap extensively. (Dj CT scan graphically demonstrates the crosssectional extent and position of the lesions. The extrapleural mound on the right (open arrows) is cradled against the posterior chest wall. The extrapleural mass on the left (closed arrows) is juxtavertebrel and sends e tongue of tissue posteriorly onto the chest wall. The lesion on the right was identified at thoracoscopy but the biopsy specimen was inadequate. A limited thoracotomy and biopsy on the left revealed extrapleural Hodgkin disease. There was no involvement of visceral pleura or lung over the lesion. (CT scan courtesy of Palo Alto Medical Clinic.)
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tally positive group, staging and treatment planning are usually based on the assumption that the pleura is involved in the neoplastic process. Chylothorax (pleural fluid having a fat content greater than 400 mg/ 100 ml) may be associated with a variety of benign and malignant conditions. In a Mayo Clinic series, 23 of 34 cases of chylothorax in patients having known malignant neoplasms were associated with is malignant lymphoma. 25 The mechanism usually obstruction of the upper abdominal or thoracic lymphatic ducts. Pleural effusion in leukemic patients may be caused by infiltration of the pleura by leukemic cells, which may on occasion be massive.‘2X’6 Thus, the effusion may result from involvement of the pleura by leukemic cells, by microscopic subpleural infarcts surrounded by leukemic infiltration, or from concomitant hilar and mediastinal lymphadenopathy. However, infections such as bacterial pneumonia or tuberculosis, pulmonary infarction, and heart failure may account for a greater number. Unfortunately, the precise cause is often not apparent radiographically. It is possible that CT examination of the chest of patients with malignant lymphoma or leukemia may enable us to identify plaques of pleural neoplasm that at present are not recognizable by conventional radiologic methods. CARDIAC
INVOLVEMENT
The pericardium, myocardium, and endocardium may be involved with neoplastic infiltrates of malignant lymphoma as well as by leukemia. This is especially true of the acute leukemias in children and the acute and chronic leukemias in the elderly. The most common radiographic sign of cardiac involvement is an enlarged cardiac silhouette. Fortunately, ultrasound has provided a safe, reliable, and noninvasive means of distinguishing pericardial effusion from other causes of apparent cardiac enlargement. There is also evidence to suggest that the incidence of pericardial effusion in patients with a large mediastinal mass is grossly underestimated. Many patients have a small- to moderate-sized pericardial effusion that is not detectable on routine radiographs, and goes undiagnosed unless echocardiographic examination is performed as part of the workup.17 Likewise, in autopsies of patients with leukemia, pericardial fluid in excess of 25 CC was
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found in 21%, but the amount of fluid seldom exceeded 100 cc and was rarely diagnosed (1%) on roentgenograms.‘6 There are patients with Hodgkin disease and non-Hodgkin lymphomas that may present with radiographic findings and ultrasound corroboration of pericardial effusion at the time of initial diagnosis. Seldom is direct evidence obtained as to whether these effusions are due to tumor invasion of the pericardium or myocardium or to lymphatic obstruction due to the massive mediastinal adenopathy that is almost invariably present. Resolution of the pericardial effusion along with resolution of the mediastinal masses after radiation therapy permits no easy choice as to cause, since a large portion of the pericardium is included in the radiation treatment ports.17 There are some patients with malignant lymphoma who may present initially with large mediastinal masses that extend inferiorly over the heart margins. Some of these most likely represent massive involvement of the thymus gland by neoplasm (so-called “granulomatous thymoma”). Most thymic gland involvement in lymphoma, however, is radiographically indistinguishable from massive anterior mediastinal lymphadenopathy. Occasionally, a mass may be seen projecting from either the right or left heart border. CT scans and ultrasound study may confirm that these are indeed solid masses such as would be expected with neoplasm (Fig. 19). Lack of a distinct cleavage plane between the heart and the mass is suspicious for direct myocardial invasion, but is not entirely reliable. These lesions respond to radiation treatment, but may recur. Rare cases of fatal arrhythmia secondary to involvement of the sinoatrial node by malignant lymphoma have been reported.’ In leukemia, enlargement of the heart itself due to involvement by the neoplastic process is uncommon. At autopsy, leukemic infiltrates of the heart have been found in 18% of casesI but there was no correlation with cardiomegaly or congestive failure. Cardiac enlargement and congestive failure recognized radiographically was more commonly associated with profound anemia. INTRATHORACIC RELAPSING
MANIFESTATIONS
OF
DISEASE
In the malignant lymphomas, extension of disease to sites that have not received prior
THE INTRATHORACIC
19. Pericardial Fig. in a 30-yr-old merit (Al Hodgk in disease.
MANIFESTATIONS
OF THE
MALIGNANT
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243
involveman with There is
adenopathy. In addition, the right heart border has an unusual configuration. At fluoroscopy. no abnormal cardiac pulsations were seen. (9) CT scans before (left) and after (right) contrast media injection. Note the contrast in the right heart. There is a nonopacified mass (arrows) along the anterolateral aspect of the right heart involving principally the pericar-
full-dose radiation treatment is far more common than recurrence in previously wellirradiated sites6 Relapse may occur in the mediastinum, hila, lung, pleura, or bones of the thorax. Evaluation of the mediastinum and hila after a patient has had these regions included in full-dose radiation treatment portals is totally dependent on having previous films available for comparison. The response of these regions to treatment is variable, regardless of whether there was disease present in the region initially, or if the treatment was only prophylactic. Following radiotherapy, even previously diseased areas may approach normal. Subsequent films may soon show loss of definition of perihilar vascular shadows, followed in weeks to months by upward and medial retraction of the hila, distortion of adjacent mediastinal contours, and reduction in volume of the paramediastinal portions of both lungs. There may be linear and ill-defined nodular shadows in the contracted
portions of the upper lobes with associated apical pleura1 thickening. Some patients may develop focal areas of contracted lung anterior and posterior to the hila that at times may simulate a paravertebral mass when viewed on the PA chest films. This postradiation reaction varies in severity from a barely perceptible shift in the position of hilar vessels and interlobar fissures to an extensive distortion of the mediastinal, hilar, and pulmonary structures in the irradiated volume. After several months, the process stabihzes, regardless of severity, and radiographs from then on must serve as baseline for each individual patient against which to measure the changes of relapse. Since a significant number of cases of relapsing disease is first detected on the chest films,’ careful comparison of follow-up films with a stabilized posttreatment film is mandatory. Relapse in mediastinal or hilar nodes may be impossible to assess without this comparison. It is worthwhile noting that in many treatment
244
plans the pericardiac, lower posterior mediastinal, and paravertebral nodes often receive lower radiation doses. When there is no evidence of disease at these sites at initial diagnosis, lead blocks may be interposed in the treatment beam in order to protect adjacent myocardium and pericardium from receiving a full dose.14 Therefore, relapses should especially be sought in these node groups, for otherwise they are easily overlooked. Involvement of pericardiac-diaphragmatic lymph nodes as the sole site of mediastinal Hodgkin disease at initial diagnosis did not occur in our series but may occur as a solitary site of nodal relapse. Whereas pulmonary parenchymal disease alone is rare in Hodgkin disease at initial diagnosis, it is not at all uncommon in relapsing Hodgkin or non-Hodgkin lymphomas. The various pulmonary patterns of disease seen in patients at the time of initial diagnosis may also be seen as patterns of relapse. Recurrent intrathoracic adenopathy may or may not accompany the parenchymal relapse. In newly diagnosed patients with Hodgkin or non-Hodgkin lymphomas who show pulmonary parenchymal involvement, the appropriate constellation of radiologic, clinical, and laboratory findings often suffices to allow rational treatment planning without lung biopsy. This is rarely the case in relapsing disease because the radiographic spectrum of the parenchymal lesions is so broad and so closely mimicked by other posttreatment complications that are known to occur commonly. Infection, druginduced pulmonary changes, or rarely a new neoplasm may produce radiographic changes similar to those of malignant lymphoma invading the lung. Therefore, we are dependent on biopsy proof in the majority of cases of disease relapse in the pulmonary parenchyma. When sputum studies, bronchoscopy, or needle aspiration specimens do not provide a clear answer, we feel open lung biopsy is needed. In Hodgkin disease we rarely use needle aspiration, because of the difficulty of establishing that diagnosis from cytologic specimens. Biopsy of these patients is justified because results of modern treatment indicate that parenchymal involvement by malignant lymphoma does not warrant the dismal prognosis it has been afforded in the past. Furthermore, there are frequent instances in which patients who have
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been treated for one unequivocally diagnosed form of malignant lymphoma are found to have a different histologic subtype upon relapse. Treatment strategy is dependent on precisely estabishing the nature of the lesion. Pleural effusion may also occur in patients a variable time after apparently successful radiotherapy, chemotherapy, or combined therapy; it may create a difficult clinical problem. If cytologic study of the fluid demonstrates malignant cells, rational treatment planning can be based on that finding. When, as is often the case, malignant cells are not recovered from thoracentesis, and needle biopsy of the pleura is also negative, a diagnostic and therapeutic dilemma may evolve. The pleural fluid may be due to otherwise inapparent relapsing disease, to benign disorders associated with dysfunction of mediastinal lymphatics from prior disease or irradiation, or to changes in pleural clearance mechanisms from prior therapy. Establishing whether the fluid meets the criteria of an exudate or transudate does not suffice to separate these possibilities. Each patient must be assessed carefully as to how aggressively the diagnostic workup should be pursued before undertaking treatment. At autopsy, many of the patients dying with malignant lymphoma have pleural invasion.*’ However, it is not wise to apply those data to the patient who has apparently been successfully treated and has no evidence of disease relapse other than a small to moderate pleural effusion. Pericardial effusion may also be encountered in patients in the posttreatment period. When there are no other findings to indicate disease relapse, it is critical to consider the possibility of radiation-induced pericarditis and myocarditis as the cause. Patients with constrictive pericarditis secondary to radiation may benefit from pericardiectomy if impaired cardiac function is not otherwise correctable.14 The radiographic intrathoracic manifestations of the malignant lymphomas and the leukemias cover a broad spectrum. They are frequently indistinguishable from abnormalities due to infection, anemia, or hemorrhage, or those consequent to treatment complications of the primary disease. Improvements in treatment, new drugs, and ever evolving treatment strategies, at least as pertain to Hodgkin disease, the non-Hodgkin lymphomas, and childhood lym-
THE
INTRATHORACIC
MANIFESTATIONS
OF THE
MALIGNANT
phocytic leukemia, have changed the prognoses even for patients with advanced stages of the disease. Recognizing that some histologic subtypes of the malignant lymphomas have a far better prognosis for survival than others, it is still important that we continue to approach each case with optimism and to employ procedures
LYMPHOMAS
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that help identify disease sites, infections, and complications of treatment with as much precision as necessary to undertake appropriate therapy. There has been continued improvement in survival in patients with advanced disease and with relapsing disease, so an aggressive approach is warranted.
REFERENCES 1. Blank N, Castellino RA: Patterns of pleural reflections of the left superior mediastinum: Normal anatomy and distortions produced by adenopathy. Radiology 1025855 589, 1972 2. Blank N, Castellino RA: Patterns of pleural reflections over the right side of the mediastinum. Presented at the meeting of the Association of University Radiologists, Kansas City, MO, 1977 3. Blank N, Castellino RA: Mediastinal lymphadenopathy. Semin Roentgenol 12:215-223,1977 4. Castellino RA, Bellani FF, Gasparini M, et al: Radiographic findings in previously untreated children with nonHodgkin’s lymphoma. Radiology 117:657-663, 1975 5. Castellino RA, Blank N: Adenopathy of the cardiophrenic angle (diaphragmatic) lymph nodes. Am J Roentgenol 114:5099515, 1972 6. Castellino RA, Blank N, Cassady JR, et al: Roentgenologic aspects of Hodgkin’s disease II. Role of routine radiographs in detecting initial relapse. Cancer 3 1:3 16-323, 1973 7. Dahlgren SE, Ovenfors C-O: Primary malignant lymphoma of the lung. Acta Radio1 (Diag) 8:401-408, 1969 8. Dunnick NR, Parker BR, Castellino RA: Rapid onset of pulmonary infiltration due to histiocytic lymphoma. Radiology 118:281-285, 1976 9. Feld R, Bodey GP, Rodriquez V, et al: Causes of death in patients with malignant lymphoma. Am J Med Sci 268:97-106.1974 10. Filly R, Blank N, Castellino RA: Radiographic distribution of intrathoracic disease in previously untreated patients with Hodgkin’s disease and non-Hodgkin’s lymphoma. Radiology 120:277728 1, 1976 Il. Gladnikoff H: A Radiographic Study of the Mediastinum in Health and in Pulmonary Carcinoma. Acta Radio1 (Suppl) no. 73, 1948
12. Green RA, Nichols NJ: Pulmonary involvement in leukemia. Am Rev Respir Dis 80:833-844, 1959 13. Heitzman ER: The Mediastinum: Radiologic correlations with Anatomy and Pathology. St. Louis, Mosby, 1977 14. Kaplan HS: Hodgkin’s Disease, Cambridge, Mass, Harvard University Press, 1972, pp 125, 129,294,334 15. Kern WH, Crepean AG, Jones JC: Primary Hodgkin’s disease of the lung. Cancer 14:1151-l 165, 1961 16. Klatte EC, Yardley J, Smith EB, et al: The pulmonary manifestations and complications of leukemia. Am J Roentgen01 89:598-609, 1963 17. Markiewicz W, Glatstein E, London EJ, et al: Echocardiographic detection of pericardial effusion and pericardial thickening in malignant lymphoma. Radiology 123: 16 I164,1977 18. McDonald JB: Lung involvement in Hodgkin’s disease. Thorax 32:664667, 1911 19. Parker BR, Castellino RA, Kaplan HS: Pediatric Hodgkin’s disease I. Radiographic evaluation. Cancer 37:243&2435,1976 20. Peckham MJ: Lung involvement in Hodgkin’s disease, in Smithers D (ed): Hodgkin’s Disease. London, Churchill Livingstone, 1973, pp 118-127 21. Rouviert H: Anatomy of the Human Lymphatic System. Ann Arbor, Edwards Bras, 1938 22. Rubin M: Primary lymphoma of the lung. J Thorac Cardiovasc Surg 56:293-303, 1968 23. Saltzstein SL: Pulmonary malignant lymphomas and pseudolymphomas: Classification, therapy, and prognosis. Cancer 16:928-955,1963 24. Stolberg HO, Patt NL, MacEwen KF, et al: Hodgkin’s disease of the lung. Roentgenologic-pathologic correlation. Am J Roentgen01 92:96-l 15, 1964 25. Weick JK, Kiely JM, Harrison EG Jr, et al: Pleural effusion in lymphoma. Cancer 31:848-853, 1973
Manifestations of the Malignant and the Leukemias
Lymphomas
Norman Blank and Ronald A. Castellino
classifications of HodgT HEkin HISTOLOGIC disease, non-Hodgkin lymphomas, and the acute and chronic leukemias as well as the current methods used in the clinical and pathologic staging of these diseasesis presented elsewhere in this issue.That information is essential to an understanding of prognosisand of modern methods of treatment, and to an appreciation of the need for precisely locating the sitesof disease in patients with malignant lymphoma. The intrathoracic manifestations of the malignant lymphomas may be considered from two standpoints: (1) those that are discovered at the time of initial diagnosis,and (2) those that occur with relapse or recurrence after one or more courses of treatment. It is not that the lesions themselves are significantly different at these times, but rather it is the incidence of the various lesions that is different. In this report we have placed emphasison the nature of the abnormalities seen at the time of initial diagnosis, with comments on similar lesions that may be seen after treatment. ANATOMY AND MEDIASTINAL
RADIOGRAPHY OF LYMPH NODES
Since mediastinal lymphadenopathy is such a common abnormality in this group of diseases,it is important to know the distribution of the lymph nodes and lymphatics in the thorax. Figure 1 is a schematic drawing of some of the key mediastinal lymph node chains. Our interpretation is based largely on the work of Rouviere,2’ buttressed by a small collection of our own casesin which mediastinal lymph nodes were fortuitously opacified at the time of lymphangiography. We have used Rouviere’s nomenclature in general, but also use the term tracheobronchial nodes to equate with those he labels nodes of the pulmonary root and the terms bronchopulmonary or hilar nodes to equate with the proximal groups of those nodes that he designatesas intrapulmonary. Whereas much of the mediastinal lymphadenopathy seen in day-to-day practice produces flagrant easily recognized abnormal shadows, a significant number of casespresent with subtle Seminars in Roentgenotogy,
Vol.
XV,
No.
3 (July),
1980
contour changes that can easily pass unrecognized. A clear understanding of normal radiographic mediastinal anatomy is invaluable in detecting these subtleties.“.13 In addition, in some areas of the mediastinum it is easier to locate and assess minimal departures from normal. These have been discussedin previous reports‘s3and we review them here. Nodes of the left prevascular chain, especially the ductus node or nodes, are located close to mediastinal pleural reflections and can produce recognizable changes when enlarged (Fig. 2).’ Normally, the pleural reflection between the aortic arch and the left pulmonary artery is either slightly concave, relatively straight towards the left lung (even though it is inclined like the side of a tent superomedially), or invisible. We consider any case in which this segment is clearly seen as a shadow convex towards the left lung highly suspect and worthy of further study. Adenopathy in the ductus and left prevascular nodes is the most common cause of this contour change, but any type of mediastinal mass, eg, a small thymoma, may produce this distortion if appropriately located. Distortion or effacement of portions of the aortic arch contours or the mediastinal pleura anterior to the arch may also be produced by lymphadenopathy in the left prevascular nodes(Fig. 3). On the right, the azygos node lies in variable relation to the azygos vein as it passesforward above the right main bronchus to enter the superior vena cava. This node is the lowest member of the right paratracheal chain. It lies
From the Division of Diagnostic Radiology, Stanford University School of Medicine, Stanford, Calif Supported in part by Grant CAO-5838. National Cancer Institute, National Institutes of Health. Norman Blank, M.D.: Professor of Radiology, Stanford University School of Medicine; Ronald A. Castellino, M.D.: Associate Professor of Radiology, Stanford University School of Medicine. Address reprint requests to Norman Blank, M.D., Division of Diagnostic Radiology, Stanford University School of Medicine, Stanford, Calif 94305. o 1980 by Grune & Stratton. Inc. 0037-198X/80/1503-0005$02.00/0
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Paratrrchea\ Nodes of
l
Interttachcobronchial
the
Pulmonary
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Roots (Subcrrinal)
PREVASCuLAR
l
Ptccaval Pre-aort
4 4
Para-aortic Paracsophagoal
a
PARIETAL
- Rt. ice- tarot
id
-
Lt.
NODES
0 D
Paravartebral Diaphragmat I c - Per icardiac Internal Msmmafy - Not shown Xnt rrcost al - dot shown INTRAPULMONARY (HILAR) NODES 0 Note: The paratracheal and prcvascular nodes arc shown as interspersed in this Single plane. In actuality they are located in diCForrnt planes with the prcvascular (anterior msdiartinal) chains locrtd anterior to the paratrachaal chains. Fig. 1.
Schematic
diagram
of some I of the key lymph
close to a pleural reflection and when enlarged distorts or displaces that reflection. Any marginal shadow convex to the right that has the greater part of its arc above the level of the right main bronchus and is not clearly due to the image of the azygos vein itself we regard as probably abnormal (Fig. 4).2.3 Not every mass so situated will necessarily represent azygos adenopathy. Low nodes of the right prevascular chain (anterior to the superior vena cava) may produce a similar distortion of the mediastinal pleura (Fig. 5). Any small mediastinal tumor presenting in this region may also be indistinguishable. The distinction between an enlarged azygos vein and azygos adenopathy is not difficult. The vein responds to changes in posture and intrathoracic pressure. It is smaller on films made with the patient upright rather than supine, and it decreases in size during a sustained Valsalva maneuver. Subcarinal nodes are difficult to detect until they are large. Loss of the image of the outer wall of the bronchus intermedius on tomograms may be helpful. Subcarinal adenopathy com-
nodes of the mediastinum.
monly displaces the portion of the lung that normally permits visualization of this outer wall. Likewise, distortion and displacement of the azygoesophageal pleural reflection may also permit recognition of a subcarinal mass. It is important, however, not to mistake the confluence of pulmonary veins or the left atrium for subcarinal adenopathy particularly on the right side. Esophagography may be useful in establishing the presence of a subcarinal or retrotracheal mass that is large enough to alter the course or contour of the esophagus (Fig. 6). Posterior mediastinal paraesophageal adenopathy may also be recognized by impressions produced on the filled esophagus. Posterior mediastinal paraaortic adenopathy may appear as a small mass (with edges convex towards the left lung) that silhouettes out the adjacent segment of the edge of the descending thoracic aorta. Some nodes may also be interaorticoesophageal in position (Fig. 7). Paravertebral adenopathy may be detected when it produces distortions of paravertebral pleural reflections, resulting in relatively short
THE INTRATHORACIC
MANIFESTATIONS
OF THE MALIGNANT
Fig. 2. Prevascular nodes in a 44-yr-old woman with Hodgkin disease. Progressive alteration of the mediastinal pleural reflection between the aortic arch and left pulmonary artery caused by adenopathy in the region of the ductus node and left prevascular chain. The dashed line demarcates the left main bronchus. (A) The normal pleural reflection (dotted line) is concave to the left. (81 Seven months later, the pleural reflection has become straight. (C) Three months later, the pleural reflection is slightly convex to the left. (D) Two months later, there is increased convexity.
arc-like edges convex towards the lung (Fig. 7). Appropriate views of the thoracic spine will serve to prevent confusion with similar distortions produced by exuberant vertebra1 spurs. For purposes of chemotherapy, of course, it is not necessary to precisely locate these posterior nodes. Even for radiotherapy it is only important to know their approximate position. In planning an approach for biopsy, however, it may be useful to locate the mass as precisely as possible in relation to adjacent organs.
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Fig. 3. A 30-yr-old woman with Hodgkin disease involving the prevascular nodes. (A) Adenopathy on right side of mediastinum. probably of the right prevasculsr and peratracheal nodes (white arrow). fB1 Tomogram. Note sharp lateral edge of a mass anterior to the aortic arch on the left representing adenopathy in the left prevascular nodes (errowsl. In retrospect, this can also be seen in A.
Pericardiac-diaphragmatic adenopathy results in masses filling the cardiophrenic angles on the PA view. On the lateral view, they may lie either retrosternally or at the level of the inferior vena cava or phrenic nerve, depending on which nodes of the group are involved (Fig. S).’ When small, these nodes may simulate a pericardiac fat pad and pass unrecognized unless comparison
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Fig. 4. tymphadenopathy in a 41-yr-old man with nodular azygos node and higher nodes of the right paratracheal chain after treatment. Note the small azygos vein shadow. The right
with previous films show that they are a new finding. The internal mammary nodes are more numerous in the upper hemithorax and may be recognized on the lateral view as extrapleural masses anteriorly against the chest wall. Occasionally these nodes attain sufficient size to be seen as an ill-defined increase in density lateral
Fig. 5. Right prevascular lymphadenopathy. contour. (6) CT scan shows a mass (white adenopathy in the right prevascular chain.
arrow)
(A) Slightly projecting
mixed lymphocytic as well as right hilar lateral wall of trachea
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lymphoma. (A) Adenopathy involving nodes. [B) Regression of the adenopathy is now visible.
the
to the sternum on the PA film. On AP tomograms, only that portion of the mass tangential to lung demonstrates a well-defined margin. Care must be used to avoid mistaking the pleural reflections over the costochondral junctions or over the brachiocephalic vessels for internal mammary adenopathy in the lateral view. Enlarged mediastinal lymph nodes may signal
widened anterior
right mediastinum and lateral to the
without superior
a clear-cut distortion vene cava, consistent
of with
THE INTRATHORACIC
MANIFESTATIONS
OF THE
MALIGNANT
Fig. 6. This 53-yr-old man with histiocytic lymphoma developed dysphagia. (A) Normal baseline film made 7 mo prior to admission. (6) Admission film. There is increased density corresponding to the subcarinal region. On the original film, a subtle “edge” shadow was seen on the right. Also, the left border of the descending thoracic aorta lies more lateral than in A. (C) Esophagram shows marked narrowing in the middle third of the esophagus associated with a soft-tissue mass extending both to the right and to the left. 6XE.F) Lateral views corresponding to A, B. and C, raspectively. (GI Tomogram shows the right edge of the mass in continuity with the azygoesophageal pleural reflection inferiorly. This places the mass in a prevertebral position. Its relationship to the major airways indicates that it is also retrotracheal and subcarinal.
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Fig. 7. Posterior mediastinal adenopathy in a !i4-yr-old woman with diffuse histiocytic lymphoma. There is a small mass adjacent to the lower thoracic spine on the right with an edge convex towards the right lung (arrowhead). This suggests origin in a paravertebral node. There is another small mass slightly lower in position on the left (arrow). The original films showed the left paravertebral stripe undisturbed and the descending aorta edge could be faintly seen. This suggests an origin in a paraesophageal node or in an interaorticoesophageal node.
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on chest films or tomograms most commonly when nodes have reached sufficient size to distort relationships of adjacent pleural reflections with lung. Based on plain film findings, we are usually dependent on recognizing distortions of the “wrapper” (the mediastinal pleura) in order to recognize the presence of a mediastinal mass. On CT scans of the chest, however, we can actually see the mediastinal contents independent of the wrapper (Fig. 5). This is due to the generous supply of mediastinal fat and the vastly superior capabilities of the CT scan technique to discriminate different tissue densities. From our brief experience, we have little doubt that CT scans will make recognition of mediastinal abnormalities an easier task in many patients. CT scans will be particularly useful in distinguishing fatty from solid masses, and thus solve such problems as distinguishing pericardiac fat pads from pericardiac adenopathy, or mediastinal lipomatosis from lymphadenopathy. We must nevertheless continue to develop our ability to detect mediastinal lesions on routine chest films, the study of first resort. INTRATHORACIC
their presence only because they impinge upon the esophagus, trachea, pulmonary arteries, or great veins, and produce signs and symptoms. Special studies directed towards evaluating the symptoms may lead to detection of these masses (Figs. 6 and 9). We emphasize that, as in all chest radiology, comparison with previous films may be the most rewarding exercise in detecting a mediastinal lesion. The abnormal overlaps the normal spectrum; that is to say, images that may still be within the range of normal may be abnormal for a given individual if they represent a change from a previous state. A straight mediastinal pleural edge between the aortic arch and the left pulmonary artery is part of the normal spectrum and yet may represent an early sign of adenopathy (or other mass) in a patient in whom this reflection was previously shown to be concave to the left (Fig. 2). However, we cannot rely on strict comparison between films made upright and supine, or in different degrees of inspiration, or in altered lordosis to evaluate subtle mediastinal contour changes. Mediastinal lymphadenopathy is detectable
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ADENOPATHY
Between 1971 and 1973, we analyzed the findings in 165 consecutive, untreated, newly diagnosed patients with Hodgkin disease.” Of these, 67% (11 O/ 164) had radiographic evidence of intrathoracic disease,and almost 99% of this subgroup had some evidence of intrathoracic lymphadenopathy. The incidence and distribution of involved lymph node groups in these patients is shown in Fig. 10. In general, basedon pretreatment radiographic study, involvement of only one intrathoracic lymph node group was not common ( 15%) in Hodgkin disease,but was relatively common (40%) in non-Hodgkin lymphoma. In the latter category, there were casesin which involvement of pericardiac, posterior mediastinal, or paravertebral nodes was the only recognizable sign of intrathoracic disease.In a seriesof 136 patients with non-Hodgkin lymphoma, 43% (58/ 136) showed evidence of intrathoracic diseaseat the time of diagnosis,and approximately 87% of this group had some radiographic evidence of intrathoracic lymphadenopathy.” Children aged l-10 yr who have Hodgkin lymphoma have a lower incidence (36%) of
0
Int. mammary
*
Prepericardiao blat.
ericadac
group group 9rrxrp
cp uxtaphrenio)
Pericardiac-diaphragmatic nodes. Fig. 8. (A) Diagrammatic presentation (modified (B) Pretreatment from Rouvibre). tomographic cut showing portions of a large mediastinal mass plus a mass in the region of the left anterior prepericardiac node (arrow). (C) Two years after treatment, the left-sided mass has resolved. There is recurrence in the right anterior prepericardiac node (arrow) plus recurrence in the lung anterior to the right hilum. Biopsy of the lung revealed Hodgkin disease. (Reproduced by permission of the American Journal of Roentgenology.5~
B
6- 68
Fig. 8. Pretracheal nodes involved by diffuse lymphoma. A 27-yr-old man presented with mediistinum on the chest film and a murmur pulmonic stenosis. A pulmonary arteriogram compression of the superior margin of the right artery (arrows) due to adenopathy. Courtesy of Finnegan, Santa Cruz, Calif. (Reproduced by from f?edio/ogy.‘“)
histiocytic a widened suggesting showed pulmonary Dr. Robert permission
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intrathoracic lymphadenopathy than do older children and adults at the time of initial diagnosis. This difference may be related to the fact that in the Stanford patient population, at least, there was a smaller number of young children with the nodular sclerosis histologic subtype and a larger number with the mixed cellularity type than in the group over age 10 yr.19 Hilar adenopathy in the absence of detectable mediastinal adenopathy was unusual in our cases of Hodgkin disease or non-Hodgkin lymphoma at initial diagnosis, but nevertheless did occur in both groups. In patients with leukemia, radiographically detectable hilar adenopathy may also be present with or without concomitant recognizable mediastinal adenopathy. Such adenopathy is most common in cases of acute or chronic lymphocytic leukemia and rare in cases of acute myelogenous leukemia.16 In any of these diseases, however, unilateral hilar lymphadenopathy as the only intrathoracic component occurs with enough frequency that we do not think it justifiable to omit malignant lymphoma or leukemia from the differential diagnosis. Intrathoracic lymphadenopathy is less commonly seen radiographically in leukemia than in malignant lymphoma. Intrathoracic lymphadenopathy is frequently present in the acute and chronic lymphocytic leukemia (Fig. 11) but is encountered on chest films in less than 40% of
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Fig. 10. Incidence of involvement of intrathoracic structures in a series of consecutive, previously untreated patients with Hodgkin and non-Hodgkin lymphoma. (Reproduced by permission from Radiology.‘“)
such cases.16 It is rare in acute myelogenous leukemia. We have not analyzed the specific sites of mediastinal adenopathy in patients with leukemia, nor could we find any other study that has. In general, these details are not as important in either treatment planning nor for prognosis for patients with leukemia, since the treatment is usually systemic rather than localized to specific disease sites.
Fig. 11. Massive lQyr-old with newly The mass regressed
anterior mediastinal diagnosed acute with antileukemic
adenopathy in a lymphatic leukemia. therapy.
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LESIONS
Few reported series concerning pulmonary lesions in Hodgkin disease, non-Hodgkin lymphomas and leukemias separate lesions detected at the time of initial diagnosis from those discovered later after one or more courses of treatment. At least in the case of Hodgkin disease, this distinction is important. In our material, at the time of initial diagnosis, we did not have one case of pulmonary Hodgkin disease in the absence of some manifestation of hilar or mediastinal lymphadenopathy. Others have reported such cases,” but the occurrence must be rare. Therefore, a pulmonary lesion discovered in a newly diagnosed patient with Hodgkin disease who has no evidence of mediastinal or hilar adenopathy should be pursued to the point of a specific diagnosis and never assumed to be due to the underlying Hodgkin disease. Any of the histologic classifications of Hodgkin disease and non-Hodgkin lymphoma may have parenchymal involvement by the disease process, but in our material, this was more commonly the case in Hodgkin disease (11.6%) than in non-Hodgkin lymphoma (3.7%) at the time of initial diagnosis. If one relies on data from autopsy series or clinical reviews that include lung lesions that develop at any time during the course of the disease, then the incidence of lung involvement in both Hodgkin disease and non-Hodgkin lymphoma is much higher.‘,‘* There is widespread distribution of lymphoid aggregates along the course of pulmonary vessels and bronchi. These supply an ample basis to explain the development of lung lesions in malignant lymphomas. The spectrum of the parenchyma1 lesions is broad and there is much overlap in the radiographic appearances in Hodgkin and non-Hodgkin lymphomas.8~‘0~‘8*20~24 Extension of nodal disease into adjacent lung may be inferred when the pleural reflection over a mediastinal mass has lost its sharp margin and becomes shaggy and irregular. Likewise, when enlarged hilar nodes show contiguous irregular margins, extension into lung is presumed (Fig. 12). Sometimes peribronchial and perivascular lymphomatous deposits occur in a subsegmental or segmental distribution, producing a cluster or bands of poorly defined nodular shadows with
Fig. 12. Extension of nodal disease into adjacent lung in a 23-y-old woman with nodular sclerosing Hodgkin disease. (A) The tomogram shows obvious right mediastinal adenopathy. Note the bulge of the pleural reflection, convex to the right, beginning at the right tracheobronchial angle. Enlarged left hilar nodes have a shaggy irregular contour. consistent with extension into the LUL parenchyma.
intervening skip areas of relatively uninvolved lung. When such lesions are more extensive, there may be inhomogeneous involvement of larger areas and even the entirety of both lungs (Fig. 13). Localized areas of consolidation involving segments or lobes may be radiographitally indistinguishable from pneumonia. This is especially so when only one segment or lobe is involved. An air bronchogram may be seen in association with this type of massive consolidation in lymphoma, due to alveolar collapse or alveolar filling by malignant cells. Lymphomatous infiltration of bronchial walls may be so extensive as to cause endobronchial masses accompanied by collapse of lung peripherally. Unfortunately, it is not possible to know from the radiographic appearance how much of the peripheral parenchymal component is due to atelectasis alone or to concomitant lymphomatous deposits. Atelecatasis of lung may also occur from extrinsic pressure by enlarged lymph nodes about bronchi at the hilum, but is probably less common. Discrete parenchymal nodules or masses, either solitary or multiple, are also a common radiographic manifestation of pulmonary in-
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Fig. 13. Extensive hilar and parenchymal disease in a 28-yr-old man with mixed cellularity Hodgkin disease. Superior mediastinal adenopathy was confirmed on tomograms (not shown) but was the least conspicuous component. (Al Perenchymal involvement predominates in a peribronchial distribution interspersed with poorly defined nodular components. (8) Heavy involvement of the right middle lobe and lingula has produced an appearance of consolidation in the lateral view. (Cl A short time after 1500 rad had been delivered to the mediastinum. hila, and lungs. There is marked improvement. (D) CT scan of lung bases shortly after C. Note the distribution of the residual parenchymal disease in the form of irregular nodules and bands along the course of the bronchi and vessels.
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Fig. 14. Pulmonary nodules in a 16-yr-old girl with Hodgkin disease. (A) PA chest film shows bilateral mediastinal adenopathy and probable hilar enlargement. Note on the left side, lateral to the shadow of the aortic arch, a soft tissue shadow whose lateral edge extends from the level of the fifth posterior rib down to the left pulmonary artery (arrows). Tomograms showed this to lie far anterior just behind the level of the manubrium. This not uncommon finding in malignant lymphoma is a manifestation of involvement of internal mammary nodes. No parenchymal lesions are seen. (B) Composite of portions of lung seen on full lung tomograms. Both hila show adenopathy (medial arrows). Several fairly discrete low-density nodules are seen in the lungs (lateral arrows). (Reproduced by permission of Harvard University Press.‘?
volvement by the malignant lymphomas. The lesions vary in size from under 1 cm to several centimeters in diameter (Figs. 3, 14, and 15). They may be of low density with poorly defined margins. Tomographic identification of nodules that are invisible even on retrospective review of chest films is unusual, but occurs with enough frequency to warrant full lung tomography in all cases in which mediastinal or hilar adenopathy is suspect from plain films (Fig. 14). Tomograms may also show the marginal contours to be much sharper than anticipated from the plain film appearance. We know of no reliably useful crite-
ria of nodule size, marginal contours, or edge sharpness that permit lymphomatous nodules to be distinguished from noncalcified nodules of any other etiology. Cavitation may be seen in small nodules or larger masses and also fail to present distinguishing features. In some patients, particularly those with diffuse histiocytic lymphoma and less often those with Hodgkin disease, the evolution of pulmonary parenchymal disease may be surprisingly rapid. From a normal or near normal baseline appearance of the lung, widespread pulmonary disease may develop in a few days, including the
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Fig. 15. Mass in biopsyproved nodular sclerosing Hodgkin disease. (A) There is a mass occupying much of the LUL plus a small left pleural effusion. (B) Tomographic cut shows left hilar adenopathy. The air-filled apicoposterior segmental branch of the LUL courses into the mass.
appearance of thickened interlobar septa (Fig. 16). Sometimes this rapidity of change prompts a diagnosis of pulmonary edema or, in those patients who are febrile and toxic, of infection. Biopsy will reveal the true situation; appropriate chemotherapy will usually lead to rapid resolution of both the radiographic and clinical abnormalities. Primary Lymphoma and Pseudolymphoma of the Lung
Primary lymphoma of the lung seems to behave quite differently from other forms of non-Hodgkin lymphoma. It is a disease that
apparently originates in the lung, often has a long life history, usually produces few symptoms, and may be cured by surgical removal with perhaps additional survival following postoperative radiation therapy for those patients with involved hilar nodes. The radiographic manifestations are often described as massesor as areas of consolidation extending peripherally from the hilar region. Hilar nodesmay be involved but not mediastinal nodes or nodes at other sites if the case is to be considered a primary lymphoma of the lung. When followed over a long period of time (because of incorrect presumptive diagnosis), the pulmonary lesions have been noted to show slow progression. An interlobar fissure may
Fig. 16. Rapid appearance of diffuse pulmonary disease in a 13-yr-old girl with newly diagnosed Hodgkin disease. (AI Mediastinal adenopathy is present, although relatively subtle. (B) Two weeks later, the chest film shows a remarkable change. There ere peribronchial and perivascular cloaking shadows with small ill-defined nodular components. Septal B lines were also visible at the bases on the original films. Open lung biopsy showed perenchymal involvement by Hodgkin disease.
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be crossed,so that the diseasemay involve adjacent lobes. Frequently, air bronchograms are seen within the consolidation. Although the latter sign is often inferred radiographically to indicate air-space consolidation, the histopathology sometimes indicates that the abnormal lymphoid tissue has primarily an interstitial distribution, with compressionrather than filling of alveoli. Cavitation is unusual but doesoccur.’ Pleural adhesions are reported as common, whereaspleural effusion is rare.22.2’ What is the relationship between primary lymphoma of the lung and pseudolymphoma? It seemsthat even following the strictest criteria it is not always possibleto separate one from the other on histopathologic grounds. The question is, does pseudolymphoma transform into lymphoma? Or is it simply that the pathologist’s interpretation transforms after viewing biopsy specimens obtained at different times, or that biopsies from different areas of the same lesion might prompt different diagnoses? Hopefully, techniques used to determine the monoclonal or polyclonal nature of the responsible cells will allow more reliable distinction between these lesions. Likewise, the diagnosis of lymphomatoid granulomatosis established by biopsy may subsequently be shown by study of further tissue specimensor by clinical events to have “evolved”
Fig. 17. A 60-yr-old man with chronic lymphocytic leukemia. There are bilateral pulmonary abnormalities with a reticulonodular appearance and peribronchial thickening as well. Lung biopsy showed extensive intersitial infiltration by leukemic cells. The consolidated area near the left heart border probably represents postoperative reaction at the lung biopsy site. The lesions cleared when the patient received antileukemic therapy.
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into a non-Hodgkin lymphoma. Whether this is evolution or confusion is uncertain. Leukemic
Pulmonary
Infiltrates
Leukemic infiltrates may be found in the lungs at autopsy in a high proportion of patients who die with either acute or chronic leukemia. These pulmonary infiltrates are most common in monocytic leukemia (46%) and least common in chronic myelogenousleukemia (15%1).‘~~‘~ In the vast majority of these cases,there are no roentgenographic manifestations of these infiltrates. In some, however, a diffuse peribronchial infiltrate not localized to a segment or lobe seemsto correspond to the autopsy findings (Fig. 17). Nodular lesions are most unusual and may represent pulmonary infarcts consequent to vascular occlusion by leukemic infiltrates. If these infarcts become confluent, they may present as massesor even resemble lobar consolidation. True leukemic consolidation of a lobe has not been reported to our knowledge, nor have cavitary lesionsbeen reported secondary only to the leukemic infiltrates. In the vast majority of our casesof acute or chronic leukemia, pulmonary lesions have proved to be manifestations of infection, pulmonary hemorrhage, or hemorrhagic infarction. Miliary lung lesionscaused by leukemic infil-
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trates have been reported, but rarely. Often in these cases the association is one of assumption rather than meticulous anatomic-pathologicradiologic correlation. The only case of this type that we have, is that of a young man who had miliary lesions and similiar foci of leukemic infiltrates at autopsy, but also had foci of inflammatory cells and inclusion bodies, so that it was not possible to exclude the contributions of an undiagnosed viral illness. It is our policy never to assume that miliary lesions in leukemia are due to the leukemia itself because there are far too many proved cases of disseminated tuberculosis, histoplasmosis, viruses (especially measles or cytomegalovirus, or even P. carinii that have caused miliary lesions in patients whose immune mechanisms have been compromised by the disease and its treatment. Patients with leukemia often have anemia, hypoproteinemia, fever, and infection, and are often treated with intravenous fluids, so interstitial pulmonary edema is common. The radiographic manifestations of the interstitial edema may antedate a clear-cut clinical picture of pulmonary edema and thus may be confused with the pattern of diffuse peribronchial infiltration caused by leukemic cells. The converse may also occur, but rarely. Fortunately, the radiographic signs of interstitial pulmonary edema clear rapidly with appropriate management and this will remove doubt about the diagnosis. Rapidity of onset of the pulmonary lesions is less reliable in differential diagnosis since diffuse pulmonary hemorrhage and interstitial leukemic infiltrates may also appear relatively rapidly, as may the pulmonary lesions of P. carinii pneumonia. Any of these may mimic the changes of interstitial pulmonary edema. Hemoptysis may not occur in patients with proved intrapulmonary hemorrhage, but usually there are other signs, such as petechiae or gastrointestinal bleeding, to alert one’s suspicion. PLEURAL
DISEASE
Pleural effusion is not common in either Hodgkin or non-Hodgkin lymphoma at the time of initial diagnosis. Seldom are patients subjected to either thoracoscopy or thoracotomy for inspection and biopsy of the pleura at this stage of their disease, so precise data as to the cause of these early effusions are not available.
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Certain conclusions can be drawn from clinical observations, however. A small to moderate effusion, unilateral or bilateral, may completely resolve following radiation therapy to the mediastinum alone.‘4,zs This sequence supports the theory that pleural effusion may occur as the result of partial obstruction of lymphatics by hilar or mediastinal adenopathy. In the case of bulky adenopathy, one may also invoke an element of obstruction of pulmonary venous return. Prominent septal lines may be found in conjunction with effusion from either mechanism. Thus, there need be no actual pleural invasion by tumor in these cases. However, pleural invasion along the border of the involved mediastinum may cause the effusion and account for its response to radiation treatment of the mediastinum. Pleural effusion as the only intrathoracic sign of Hodgkin disease at presentation is rare in adults (1 / 164). Not one example was found in a review of 105 consecutive patients less than 16 yr of age with newly diagnosed Hodgkin disease.” However, with non-Hodgkin lymphoma, pleural effusion may be found in previously untreated patients even in the absence of detectable intrathoracic lymphadenopathy. Pleural effusion occurred in 7 of 56 untreated children with non-Hodgkin lymphoma, and in 3 of the 7 it was the only radiographic manifestation of intrathoracic disease.4 Pleural or extrapleural masses may be apparent during the course of the disease, and subsequently proved by biopsy to be due to lymphomatous tissue (Fig. 18). Since there are parietal lymph nodes in the intercostal spaces, it is possible that they serve as the origin of some of these focal lesions. We are impressed with the fact that this type of focal pleural involvement is often unaccompanied by effusion. There may also be pleural lesions that have an irregular interface with adjacent lung, suggesting that lymphomatous involvement of subpleural pulmonary lymphatics have extended into the pleura, or vice versa. Cytologic study of pleural fluid removed from patients with any form of malignant lymphoma seldom shows malignant cells.*’ Even in the few that have positive cytologic study (about 15%), it is at least theoretically possible that the pleura itself is not invaded. However, in the cytologi-
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Fig. 18. Extrapleural involvement in a 25yr-old man with mixed cellularity Hodgkin disease. The patient was stage IV et the time of original diagnosis and had been successfully treated with a combination of radiotherapy end chemotherapy plus maintenance forms of chemotherapy over the prior 5 yr. (A) There is increased tissue density lateral to the right heart border lacking defined edges. The vascular shadows of the lung can be seen through the lesion. These findings raise the question of a pleural or extrapleural mass seen en face. Spot films made at fluoroscopy confirmed the extrapleural nature of the lesion. On the left, another mess convex to the left is seen through the heart (open arrowhead). Its medial extent abuts the vertebrae. (8) Coned view of the en face appearance of the lesion on the right side of the chest. (C) Lateral view shows the posterior location of the two extrapleural masses, but they overlap extensively. (Dj CT scan graphically demonstrates the crosssectional extent and position of the lesions. The extrapleural mound on the right (open arrows) is cradled against the posterior chest wall. The extrapleural mass on the left (closed arrows) is juxtavertebrel and sends e tongue of tissue posteriorly onto the chest wall. The lesion on the right was identified at thoracoscopy but the biopsy specimen was inadequate. A limited thoracotomy and biopsy on the left revealed extrapleural Hodgkin disease. There was no involvement of visceral pleura or lung over the lesion. (CT scan courtesy of Palo Alto Medical Clinic.)
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tally positive group, staging and treatment planning are usually based on the assumption that the pleura is involved in the neoplastic process. Chylothorax (pleural fluid having a fat content greater than 400 mg/ 100 ml) may be associated with a variety of benign and malignant conditions. In a Mayo Clinic series, 23 of 34 cases of chylothorax in patients having known malignant neoplasms were associated with is malignant lymphoma. 25 The mechanism usually obstruction of the upper abdominal or thoracic lymphatic ducts. Pleural effusion in leukemic patients may be caused by infiltration of the pleura by leukemic cells, which may on occasion be massive.‘2X’6 Thus, the effusion may result from involvement of the pleura by leukemic cells, by microscopic subpleural infarcts surrounded by leukemic infiltration, or from concomitant hilar and mediastinal lymphadenopathy. However, infections such as bacterial pneumonia or tuberculosis, pulmonary infarction, and heart failure may account for a greater number. Unfortunately, the precise cause is often not apparent radiographically. It is possible that CT examination of the chest of patients with malignant lymphoma or leukemia may enable us to identify plaques of pleural neoplasm that at present are not recognizable by conventional radiologic methods. CARDIAC
INVOLVEMENT
The pericardium, myocardium, and endocardium may be involved with neoplastic infiltrates of malignant lymphoma as well as by leukemia. This is especially true of the acute leukemias in children and the acute and chronic leukemias in the elderly. The most common radiographic sign of cardiac involvement is an enlarged cardiac silhouette. Fortunately, ultrasound has provided a safe, reliable, and noninvasive means of distinguishing pericardial effusion from other causes of apparent cardiac enlargement. There is also evidence to suggest that the incidence of pericardial effusion in patients with a large mediastinal mass is grossly underestimated. Many patients have a small- to moderate-sized pericardial effusion that is not detectable on routine radiographs, and goes undiagnosed unless echocardiographic examination is performed as part of the workup.17 Likewise, in autopsies of patients with leukemia, pericardial fluid in excess of 25 CC was
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found in 21%, but the amount of fluid seldom exceeded 100 cc and was rarely diagnosed (1%) on roentgenograms.‘6 There are patients with Hodgkin disease and non-Hodgkin lymphomas that may present with radiographic findings and ultrasound corroboration of pericardial effusion at the time of initial diagnosis. Seldom is direct evidence obtained as to whether these effusions are due to tumor invasion of the pericardium or myocardium or to lymphatic obstruction due to the massive mediastinal adenopathy that is almost invariably present. Resolution of the pericardial effusion along with resolution of the mediastinal masses after radiation therapy permits no easy choice as to cause, since a large portion of the pericardium is included in the radiation treatment ports.17 There are some patients with malignant lymphoma who may present initially with large mediastinal masses that extend inferiorly over the heart margins. Some of these most likely represent massive involvement of the thymus gland by neoplasm (so-called “granulomatous thymoma”). Most thymic gland involvement in lymphoma, however, is radiographically indistinguishable from massive anterior mediastinal lymphadenopathy. Occasionally, a mass may be seen projecting from either the right or left heart border. CT scans and ultrasound study may confirm that these are indeed solid masses such as would be expected with neoplasm (Fig. 19). Lack of a distinct cleavage plane between the heart and the mass is suspicious for direct myocardial invasion, but is not entirely reliable. These lesions respond to radiation treatment, but may recur. Rare cases of fatal arrhythmia secondary to involvement of the sinoatrial node by malignant lymphoma have been reported.’ In leukemia, enlargement of the heart itself due to involvement by the neoplastic process is uncommon. At autopsy, leukemic infiltrates of the heart have been found in 18% of casesI but there was no correlation with cardiomegaly or congestive failure. Cardiac enlargement and congestive failure recognized radiographically was more commonly associated with profound anemia. INTRATHORACIC RELAPSING
MANIFESTATIONS
OF
DISEASE
In the malignant lymphomas, extension of disease to sites that have not received prior
THE INTRATHORACIC
19. Pericardial Fig. in a 30-yr-old merit (Al Hodgk in disease.
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involveman with There is
adenopathy. In addition, the right heart border has an unusual configuration. At fluoroscopy. no abnormal cardiac pulsations were seen. (9) CT scans before (left) and after (right) contrast media injection. Note the contrast in the right heart. There is a nonopacified mass (arrows) along the anterolateral aspect of the right heart involving principally the pericar-
full-dose radiation treatment is far more common than recurrence in previously wellirradiated sites6 Relapse may occur in the mediastinum, hila, lung, pleura, or bones of the thorax. Evaluation of the mediastinum and hila after a patient has had these regions included in full-dose radiation treatment portals is totally dependent on having previous films available for comparison. The response of these regions to treatment is variable, regardless of whether there was disease present in the region initially, or if the treatment was only prophylactic. Following radiotherapy, even previously diseased areas may approach normal. Subsequent films may soon show loss of definition of perihilar vascular shadows, followed in weeks to months by upward and medial retraction of the hila, distortion of adjacent mediastinal contours, and reduction in volume of the paramediastinal portions of both lungs. There may be linear and ill-defined nodular shadows in the contracted
portions of the upper lobes with associated apical pleura1 thickening. Some patients may develop focal areas of contracted lung anterior and posterior to the hila that at times may simulate a paravertebral mass when viewed on the PA chest films. This postradiation reaction varies in severity from a barely perceptible shift in the position of hilar vessels and interlobar fissures to an extensive distortion of the mediastinal, hilar, and pulmonary structures in the irradiated volume. After several months, the process stabihzes, regardless of severity, and radiographs from then on must serve as baseline for each individual patient against which to measure the changes of relapse. Since a significant number of cases of relapsing disease is first detected on the chest films,’ careful comparison of follow-up films with a stabilized posttreatment film is mandatory. Relapse in mediastinal or hilar nodes may be impossible to assess without this comparison. It is worthwhile noting that in many treatment
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plans the pericardiac, lower posterior mediastinal, and paravertebral nodes often receive lower radiation doses. When there is no evidence of disease at these sites at initial diagnosis, lead blocks may be interposed in the treatment beam in order to protect adjacent myocardium and pericardium from receiving a full dose.14 Therefore, relapses should especially be sought in these node groups, for otherwise they are easily overlooked. Involvement of pericardiac-diaphragmatic lymph nodes as the sole site of mediastinal Hodgkin disease at initial diagnosis did not occur in our series but may occur as a solitary site of nodal relapse. Whereas pulmonary parenchymal disease alone is rare in Hodgkin disease at initial diagnosis, it is not at all uncommon in relapsing Hodgkin or non-Hodgkin lymphomas. The various pulmonary patterns of disease seen in patients at the time of initial diagnosis may also be seen as patterns of relapse. Recurrent intrathoracic adenopathy may or may not accompany the parenchymal relapse. In newly diagnosed patients with Hodgkin or non-Hodgkin lymphomas who show pulmonary parenchymal involvement, the appropriate constellation of radiologic, clinical, and laboratory findings often suffices to allow rational treatment planning without lung biopsy. This is rarely the case in relapsing disease because the radiographic spectrum of the parenchymal lesions is so broad and so closely mimicked by other posttreatment complications that are known to occur commonly. Infection, druginduced pulmonary changes, or rarely a new neoplasm may produce radiographic changes similar to those of malignant lymphoma invading the lung. Therefore, we are dependent on biopsy proof in the majority of cases of disease relapse in the pulmonary parenchyma. When sputum studies, bronchoscopy, or needle aspiration specimens do not provide a clear answer, we feel open lung biopsy is needed. In Hodgkin disease we rarely use needle aspiration, because of the difficulty of establishing that diagnosis from cytologic specimens. Biopsy of these patients is justified because results of modern treatment indicate that parenchymal involvement by malignant lymphoma does not warrant the dismal prognosis it has been afforded in the past. Furthermore, there are frequent instances in which patients who have
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been treated for one unequivocally diagnosed form of malignant lymphoma are found to have a different histologic subtype upon relapse. Treatment strategy is dependent on precisely estabishing the nature of the lesion. Pleural effusion may also occur in patients a variable time after apparently successful radiotherapy, chemotherapy, or combined therapy; it may create a difficult clinical problem. If cytologic study of the fluid demonstrates malignant cells, rational treatment planning can be based on that finding. When, as is often the case, malignant cells are not recovered from thoracentesis, and needle biopsy of the pleura is also negative, a diagnostic and therapeutic dilemma may evolve. The pleural fluid may be due to otherwise inapparent relapsing disease, to benign disorders associated with dysfunction of mediastinal lymphatics from prior disease or irradiation, or to changes in pleural clearance mechanisms from prior therapy. Establishing whether the fluid meets the criteria of an exudate or transudate does not suffice to separate these possibilities. Each patient must be assessed carefully as to how aggressively the diagnostic workup should be pursued before undertaking treatment. At autopsy, many of the patients dying with malignant lymphoma have pleural invasion.*’ However, it is not wise to apply those data to the patient who has apparently been successfully treated and has no evidence of disease relapse other than a small to moderate pleural effusion. Pericardial effusion may also be encountered in patients in the posttreatment period. When there are no other findings to indicate disease relapse, it is critical to consider the possibility of radiation-induced pericarditis and myocarditis as the cause. Patients with constrictive pericarditis secondary to radiation may benefit from pericardiectomy if impaired cardiac function is not otherwise correctable.14 The radiographic intrathoracic manifestations of the malignant lymphomas and the leukemias cover a broad spectrum. They are frequently indistinguishable from abnormalities due to infection, anemia, or hemorrhage, or those consequent to treatment complications of the primary disease. Improvements in treatment, new drugs, and ever evolving treatment strategies, at least as pertain to Hodgkin disease, the non-Hodgkin lymphomas, and childhood lym-
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phocytic leukemia, have changed the prognoses even for patients with advanced stages of the disease. Recognizing that some histologic subtypes of the malignant lymphomas have a far better prognosis for survival than others, it is still important that we continue to approach each case with optimism and to employ procedures
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that help identify disease sites, infections, and complications of treatment with as much precision as necessary to undertake appropriate therapy. There has been continued improvement in survival in patients with advanced disease and with relapsing disease, so an aggressive approach is warranted.
REFERENCES 1. Blank N, Castellino RA: Patterns of pleural reflections of the left superior mediastinum: Normal anatomy and distortions produced by adenopathy. Radiology 1025855 589, 1972 2. Blank N, Castellino RA: Patterns of pleural reflections over the right side of the mediastinum. Presented at the meeting of the Association of University Radiologists, Kansas City, MO, 1977 3. Blank N, Castellino RA: Mediastinal lymphadenopathy. Semin Roentgenol 12:215-223,1977 4. Castellino RA, Bellani FF, Gasparini M, et al: Radiographic findings in previously untreated children with nonHodgkin’s lymphoma. Radiology 117:657-663, 1975 5. Castellino RA, Blank N: Adenopathy of the cardiophrenic angle (diaphragmatic) lymph nodes. Am J Roentgenol 114:5099515, 1972 6. Castellino RA, Blank N, Cassady JR, et al: Roentgenologic aspects of Hodgkin’s disease II. Role of routine radiographs in detecting initial relapse. Cancer 3 1:3 16-323, 1973 7. Dahlgren SE, Ovenfors C-O: Primary malignant lymphoma of the lung. Acta Radio1 (Diag) 8:401-408, 1969 8. Dunnick NR, Parker BR, Castellino RA: Rapid onset of pulmonary infiltration due to histiocytic lymphoma. Radiology 118:281-285, 1976 9. Feld R, Bodey GP, Rodriquez V, et al: Causes of death in patients with malignant lymphoma. Am J Med Sci 268:97-106.1974 10. Filly R, Blank N, Castellino RA: Radiographic distribution of intrathoracic disease in previously untreated patients with Hodgkin’s disease and non-Hodgkin’s lymphoma. Radiology 120:277728 1, 1976 Il. Gladnikoff H: A Radiographic Study of the Mediastinum in Health and in Pulmonary Carcinoma. Acta Radio1 (Suppl) no. 73, 1948
12. Green RA, Nichols NJ: Pulmonary involvement in leukemia. Am Rev Respir Dis 80:833-844, 1959 13. Heitzman ER: The Mediastinum: Radiologic correlations with Anatomy and Pathology. St. Louis, Mosby, 1977 14. Kaplan HS: Hodgkin’s Disease, Cambridge, Mass, Harvard University Press, 1972, pp 125, 129,294,334 15. Kern WH, Crepean AG, Jones JC: Primary Hodgkin’s disease of the lung. Cancer 14:1151-l 165, 1961 16. Klatte EC, Yardley J, Smith EB, et al: The pulmonary manifestations and complications of leukemia. Am J Roentgen01 89:598-609, 1963 17. Markiewicz W, Glatstein E, London EJ, et al: Echocardiographic detection of pericardial effusion and pericardial thickening in malignant lymphoma. Radiology 123: 16 I164,1977 18. McDonald JB: Lung involvement in Hodgkin’s disease. Thorax 32:664667, 1911 19. Parker BR, Castellino RA, Kaplan HS: Pediatric Hodgkin’s disease I. Radiographic evaluation. Cancer 37:243&2435,1976 20. Peckham MJ: Lung involvement in Hodgkin’s disease, in Smithers D (ed): Hodgkin’s Disease. London, Churchill Livingstone, 1973, pp 118-127 21. Rouviert H: Anatomy of the Human Lymphatic System. Ann Arbor, Edwards Bras, 1938 22. Rubin M: Primary lymphoma of the lung. J Thorac Cardiovasc Surg 56:293-303, 1968 23. Saltzstein SL: Pulmonary malignant lymphomas and pseudolymphomas: Classification, therapy, and prognosis. Cancer 16:928-955,1963 24. Stolberg HO, Patt NL, MacEwen KF, et al: Hodgkin’s disease of the lung. Roentgenologic-pathologic correlation. Am J Roentgen01 92:96-l 15, 1964 25. Weick JK, Kiely JM, Harrison EG Jr, et al: Pleural effusion in lymphoma. Cancer 31:848-853, 1973