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CT appearances of relapse of lymphoma in the lung
ClinicalRadiology (1990) 41,232-238
CT Appearances of Relapse of Lymphoma in the Lung M. COBBY, E. WHIPP*, J. BULLIMORE*, S. GOODMAN*, E. R. DAVIES and P. G O D D A R D
Department of Radiodiagnosis, Bristol Royal Infirmary and *Radiotherapy Centre, Bristol The patterns of pulmonary relapse were studied in 15 patients with Hodgkin's disease and one Patient with NonHodgkin's lymphoma. All the patients with Hodgkin's disease had mediastinal lymphadenopathy at initial diagnosis. For those patients with no prior episodes of relapse the mean time to pulmonary involvement was 2 years 11 months compared to over 8 years for those who first relapsed elsewhere. Thirteen patients are still alive; five have been followed up for more than 2 years. Pulmonary involvement consisted of." 1 nodules, either central (12 patients) or peripheral (10 patients), often with connection to the pleura or mediastinum, and sometimes with cavitation; 2 consolidation with or without cavitation (four patients); 3 mediastinal extension into the lung parenchyma (three patients). In seven patients there was evidence of newly enlarged mediastinal nodes. Pleural effusions or masses were seen in six patients and pericardiai involvement in one. The chest wall was involved in five. A combination of three or more of these signs were present in 11 patients. The pattern of involvement seen in the patient with Non-Hodgkin's lymphoma was indistinguishable from that seen in Hodgkin's disease. This study has demonstrated a variety of CT appearances useful in establishing or suggesting the diagnosis of pulmonary relapse. Enlarged mediastinal nodes were not a prerequisite but had been present in all patients at some stage in the course of the disease.
Relapse oflymphoma in the lung parenchyma is relatively uncommon. The radiological appearances have to be differentiated from infection, particularly with atypical organisms, radiotherapy changes and drug reactions. Routine use of computed tomography in the initial staging of Hodgkin's disease is well established. It is particularly useful in showing previously unrecognised mediastinal nodal involvement or parenchymal lung extension which may alter the proposed treatment (Meyer et al., 1984). We have examined its use in patients presenting with pulmonary opacities following treatment for lymphoma and have noted a number of typical patterns helpful in establishing a diagnosis of relapse. PATIENTS AND METHODS
Fifteen patients with Hodgkin's disease, eight male and seven female, with a mean age at diagnosis of 28 years (range 16-42), and one male patient with Non-Hodgkin's lymphoma aged 72 years were studied. CT scans of the chest were available for 12 patients from the time of their primary diagnosis. Subsequent CT Correspondence to: P. Goddard, Department of Radiodiagnosis, Bristol Royal Infirmary,MarlboroughStreet, BristolBS2 8HW.
scans were obtained on all patients to investigate possible or definite intrapulmonary opacities observed on follow. up chest radiographs. Most CT scans were performed using a Siemens Somatom D H R body scanner with contiguous 8 rnrn slices. An EMI 5005 body scanner with 13 mm slices and a Tomoscan 350 body scanner with 9 mm slices were used in some patients. Concurrent postero-anterior chest radio. graphs were also available. The diagnosis of pulmonary relapse was established by transbronchial biopsy in two patients (Case numbers 2 and 13) and open lung biopsy in three patients (Case numbers 11, 14 and 15). In the remaining patients a diagnosis of relapse was made on the basis of the clinical signs and symptoms, the CT findings, the exclusion of pulmonary infection by sputum culture and an appropriate response to radiotherapy or chemotherapy. In six of these patients CT demonstrated newly enlarged mediastinal nodes with parenchymal lung masses lying outside the previous radiation treatment field.
RESULTS The sites of initial involvement, of prior episodes of relapse, and the primary treatment given, are presented in Table 1. The time from initial diagnosis to pulmonary relapse and a ~summary of the CT findings of pulmonary involvement are also included. All the patients with Hodgkin's disease had mediastinal lymphadenopathy at initial presentation. Six were stage I or II and nine stage III or IV. The histological classifications were nodular sclerosing (13 patients), lymphocyte predominant (one patient), and mixed cellularity (one patient). The patient with Non-Hodgkin's lymphoma was classified as moderate to high grade. Seven patients received radiotherapy and nine chemotherapy as their initial treatment. One patient had Hodgkin's disease involving the mediastinum and extending into the adjacent lung parenchyma with multiple cavitating nodules attached by thickened bronchovascular bundles to the mediastinum at presentation (Case No 6). This patient relapsed 17 months after chemotherapy with new peripheral and central nodules, some of which were also cavitating. The mediastinal nodes and previous large central nodules had decreased in size. None of the remaining 14 patients with Hodgkin's disease had parenchymal lung involvement when they first presented. The mean time from the initial presentation with Hodgkin's disease to the occurrence of lung relapse for the whole group was five years (range 7 months to 17 years). For the seven patients with no prior episodes of relapse the mean was 2 years 11 months (range 7 months to 9 years) compared to 8 years 3 months for those who first relapsed elsewhere (range 4 years 9 months to 17 years). The difference in the times to relapse was significant at the 5% level (Mann-Whitney U test).
CT APPEARANCES OF RELAPSE OF LYMPHOMA IN THE LUNG
233
Table 1 - Site of initial involvement, areas of relapse prior to pulmonary involvement and number of months from initial diagnosis to lung involvement with lyrnphoma
Age at diagnosis
Sex
Initial involvement
Prior relapse
IT*
Months to pulmonary relapse
Findings on C T at time o f pulmonary relapse
1
26
M
m
Mediastinum, abdomen, thoracic spine
RT
204
Consolidation extending to pericardium resulting in effusion. Pleural effusion. Axillary & retro-crural nodes
2
16
F
m &a
Rt femur & Lt 2nd rib
RT
78
R T changes. No mediastinal nodes. Multiple central nodules with connections to mediastinum
3
34
M
m
No
CT
7
Mediastinal nodes. Multiple central nodules with connections to mediastinum one with cavitation. Peripheral nodules. Chest wall involvement. Pleural mass
4
39
F
m
No
CT
16
Mediastinal nodes with extension into lung parenchyma & chest wall. 'Cloudy' lungs following chemotherapy
5
28
F
m & a
~ No
CT
41
Mediastinal nodes (smaller than at presentation & some calcified). Multiple peripheral nodules. Central nodule with connection to mediastinum
6
29
F
m, a & p
Mediastinum
CT
17
P r e s e n t a t i o n - mediastinal nodes extending into lung parenchyma. Multiple cavitating central nodules with connections to mediastinum. 'Sausage shaped' area of collapse/consolidation. R e l a p s e - s m a l l residuum of mediastinal nodes. Peripheral nodules. Enlargement of previous small central nodules with cavitation. Decrease in size of previous large central nodules
7
20
F
m &a
Mediastinum
CT
76
Mediastinal nodes. Lt hilar nodes with central nodule and connection to mediastinum. Pleural masses. R T changes at apex. Possible anterior chest wall involvement
8
18
F
m &a
No
CT
14
R T changes. No mediastinal nodes. Multiple peripheral small nodules. Some central nodules, one with possible connection to hilum
9
72
M
e
No
RT
7
R T changes. Mediastinal nodes. Multiple central nodules some with connections to mediastinum. Peripheral nodules
10
31
M
a& m
Supraclavicular fossa, liver, mediastinum
CT
149
Mediastinal nodes, some calcified. Extension into lung parenchyma. Central nodules some with connections to mediastinum. Peripheral nodules. Consolidation with cavitation. Pleural mass with chest wall involvement
11
18
M
a &m
Mediastinum
RT
69
N o mediastinal nodes. Consolidation with subsequent development of nodules beyond the opacification. Multiple central nodules with connections to mediastinum. Bilateral effusions
12
42
F
a &m
No
CT
41
R T changes. Mediastinal nodes smaller than on presentation. One large central nodule connected to mediastinum. Other central nodules. One peripheral cavitating lesion. Pleural effusion. Chest wall involvement as at presentation
13
26
M
a & m
Cervical & axillary nodes
RT
74
Mediastinal nodes. Chest wall involvement. Multiple small peripheral nodules
14
42
M
m
No
RT
108
Marked emphysema in field of RT. Lobulated central nodule possibly with a connection to mediastinum
15
26
M
m
Supraclavicular mediastinum & para-aortic nodes
RT
57
Small inactive mediastinal nodes. Consolidation rt lower lobe with numerous small peripheral nodules. Generalised haziness in It lower and mid zones
16
22
M
m
No
CT
16
Mediastinal nodes. Central nodule with connection to rt hilum & separate nodule peripheral to this. RT changes
Case no.
*, initial treatment. CT, chemotherapy. RT, radiotherapy. a, abdominal lymph node involvement at diagnosis. m, mediastinal lymph node involvement at diagnosis. e, endobronchial involvement at diagnosis. P, lung parenchymal involvement at diagnosis. Case n u m b e r 9 had Non-Hodgkin's lymphoma, all other cases had Hodgkin's disease.
234
CLINICAL RADIOLOGY
Three patients died at 2, 4 a n d 16 months after the onset of pulmonary involvement (Case Nos 5, 12 and 15). The remaining patients have been followed up for between 2 months and 6 years. Five are alive more than 2 years after the onset of lung disease. The patient with Non-Hodgkin's lymphoma presented with collapse of the right lung caused by turnout involving the lateral wall of the trachea extending down the right main bronchus (case No 9). He relapsed 7 months after radiotherapy with a number of peripheral nodules, mediastinal adenopathy and central nodules attached to the mediastinum by thickened bronchovascular bundles.
CT Findings The CT findings of each case are summarised in Table I. At the time of pulmonary relapse, five patients had no
(a)
(b)
(a)
(b)
(c)
Fig. 1 - Case 2. Hodgkin's disease, relapse. (a) Chest radiograph. Radiation fibrosis adjacent to upper mediastinum and left apex with loss ofvolmne in both upper lobes. Hazy opacities both mid zones; no clearly defined nodules. (b) Concurrent CT. Multiple central nodules, some with connection to mediastinum (arrow). No mediastinal nodes present at any level.
Fig. 2 - Case 9. Non-Hodgkin's lymphoma, relapse. (a) Chest radiograph. Radiation changes adjacent to right upper mediastinum. Multiple nodules in both lungs. (b, e) Concurrent CT. Large central nodule with connection to mediastinum adjacent to the inferior pulmonary vein (arrow head). Smaller peripheral nodule with connection to pleura (arrow). Fibrotic changes in right lower lobe posteriorly.
235
CT APPEARANCES OF RELAPSE OF LYMPHOMA IN THE LUNG
current mediastinal lymphadenopathy. In four patients the nodes had decreased in size since a previous examination, and in seven there was evidence of newly enlarged nodes. In three of this latter group there was extension of disease from the mediastinum into the adjacent lung. Twelve patients had centrally sited lung nodules; they were multiple in 10 patients in whom at least one of the nodules appeared to have a connection to the mediastinum or hilum (Figs 1 and 2). The nodules were usually located in the fork of a bronchovascular division and in two patients they were cavitating (Fig. 3). Ten patients had peripherally sited lung nodules lying close to a pleural surface; in nine patients these were multiple. They tended to be smaller and more numerous than the centrally sited nodules (Figs 4 and 5). In four cases fine lines connected these nodules to the pleura (Figs 2 and 4). Cavitation was seen in one patient. Areas of consolidation were se~en in four patients. In three cases this was due to lymphoma (Fig. 6). The consolidation was initially unifocal but cavitation was present in one case and extension into the pericardium in another (Case no. 1). In the fourth patient multifocal
areas of consolidation were shown and at open lung biopsy both Pneumocystis carinii pneumonia and Hodgkin's disease were found (Case No 15). Five patients had chest wall involvement, in two patients this was probably due to enlarged internal mammary lymph nodes (Fig. 3)
(a)
(a)
n
(b)
(c) (b) Fig. 3 - Case 6. Hodgkin's disease, presentation. (a) Large mediastinal nodes which on the left extend into the lung parenchyma. Central area of focal consolidation in the right lung. Enlarged internal mammary lymph node (arrow). (b) Multiple central nodules and mediastinal lymphadenopathy. Cavitating nodule posteriorly on the left. 'Sausage shaped' area of presumed collapse and consolidation in the left mid-zone.
Fig. 4 - C a s e 8. Hodgkin's disease, relapse. (a) Chest radiograph. Radiation changes adjacent to upper mediastinum. Small ill-defined and pooly visualised nodules in both mid and lower zones. (b) Concurrent CT. Small peripheral nodules. Well marked radiation changes conforming with treatment portal. No mediastinal nodes present at any level. (c) CT at lower level. Multiple small, predominantly peripheral nodules, some with connecting septal lines to pleura (arrows).
236
CLINICAL RADIOLOGY
(a)
(a)
(b)
(b) Fig. 5 - Case 13. Hodgkin's disease, relapse. (a) CT at lung settings. Peripheral nodules. One is adjacent to the oblique fissure (arrow). Pleural thickening is demonstrated anteriorly on the right. (b) With mediastinal settings at the same level anterior chest wall involvement with Hodgkin's lymphoma is demonstrated (arrows). Mediastinal lymphadenopathy was present at other levels.
and in three patients to rib or soft tissue involvement (Fig. 5). Three patients had pleural masses and three pleural effusions (Fig. 6). A combination of three or more of these findings was present in 11 patients (Fig. 7). DISCUSSION At presentation 10 15% of patients with Hodgkin's disease, and 4% of those with Non-Hodgkin's disease, will have lung involvement (Filly et al., 1976; Colby et al., 1981b). Parenchymal disease in these patients is usually associated with mediastinal or hilar lymphadenopathy and is nearly always unilateral, tending to present as an ill-defined area of infiltration extending from the hilum peripherally (Filly et al., 1976). Single or multiple nodules, sometimes cavitating, are occasionally present and are usually accompanied by mediastinal or hilar lymphadenopathy (Fig. 3). These nodules may be poorly visualised on a chest radiograph or appear as hazy opacities. They are shown to be discrete lesions on
Fig. 6 - Case 11. Hodgkin's disease, relapse. (a) Focal area o f consolidation in right lung with bilateral pleural effusions. Open lung biopsy confirmed infiltration by Hodgkin's lymphoma. Multiple central nodules were present at other levels but there was no mediastinal adenopathy. (b) Subsequent CTscan shows the development of a nodule peripheral to the consolidation and resolution of the effusions.
tomography (Strickland, 1967; Filly et al., 1976) (Fig. 1). Primary pulmonary lymphoma, where lung involvement is seen without nodal disease, occurs rarely, usually presenting as one or more nodules with or without cavitation (Peterson et al., 1985; Yousem et al., 1986). The incidence of relapse within the lung parenchyma is difficult to estimate. In an early unselected series of patients with Hodgkin's disease approximately 30% had lung involvement, the incidence rising the longer the follow up (Fisher et al., 1962). None of these patients had parenchymal disease at presentation. Lung involvement was also found to be common in patients with evidence of Hodgkin's disease at post-mortem, occurring in 53% of cases (Colby et al., 1981a), and in another series, was estimated to involve the lung at some stage in 40% of patients (Macdonald, 1977). With more accurate staging and better methods of treatment these figures are likely to be far higher than those currently obtained, where overall relapse rates in Hodgkin's disease are now less than 20% (Selby and McElwain, 1987). Rosenberg and Kaplan (1966) demonstrated an orderly progression in the spread of Hodgkin's disease by contiguity from one lymph:node to the next; this mode of spread is thought to occur in over 90% of patients, with
237
CT APPEARANCES OF RELAPSE OF LYMPHOMA IN THE LUNG
(c) (a)
(d)
(b)
Fig. 7 - C a s e 3. Hodgkin's disease, relapse. (a) Chest radiograph. Mediastinal and right hilar lymphadenopathy. Mass adjacent to right heart boarded (arrow) and questionable consolidation in the right lower zone. (b) Concurrent CT. Mediastinal adenopathy is confirmed and anterior chest wall involvement is also demonstrated (arrow). (c) At a lower level a large central nodule is present in the azygo-oesophageal recess (arrow). Smaller nodules and ill-defined lung opacification is seen distal to this. A peripheral nodule lies adjacent to the right oblique fissure. (d) A subsequent CT scan after an interval of 12 months revealed a new area of consolidation with cavitation.
vessel invasion and haematological dissemination accounting for the remainder. This accounts for the observation that lung relapse is more common in Stage I or II Hodgkin's disease if it initially involves the mediastihum than if it does not (Young et al., 1978; North et al., 1982), and in our series, all except the patie0t with NonHodgkin's lymphoma had mediastinal involvement when first diagnosed. Relapse in the lung is also more likely to occur if the treatment portal fails to include unrecognised lateral extension from the mediastinum, or if there is bulky mediastinal involvement greater than 7.5 cm in diameter at presentation (North et al., 1982; Meyer et al., 1984). Computed tomography has been shown to be more sensitive than plain radiography in detecting recurrent rnediastinal and lung parenchymal disease as well as differentiating this from radiation changes (Heron et al., 1988). Pulmonary relapse usually occurs within four years of initial presentation with approximately 80% of cases occurring in the first two years (Fisher et al., 1962; Castellino et al., 1973; Costello and Mauch, 1979). The incidence may be reduced by combining chemotherapy with mantle radiotherapy in those with bulky disease, or by giving low dose irradiation to the lungs (Carmel and
Kaplan, 1976; North et al., 1982). The present series appears to be composed of two groups of patients with Hodgkin's disease, one in which there were no prior episodes of relapse before the development of lung disease, and the other where one or more relapses had occurred before the onset of lung involvement. In the first group pulmonary relapse occurred within 4 years of initial presentation in all but one of the seven patients with a mean of 2 years 11 months. The other group had a more indolent form of disease with lung involvement not seen for 5 or more years from the time of initial diagnosis with a mean of 8 years 3 months. The morphological patterns of relapse of Hodgkin's disease within the lung are summarised in Table 2. In this series three or more of these were present in 11 of the 16 patients so aiding the confidence with which a diagnosis of relapse could be made. The pattern of involvement seen in the patient with Non-Hodgkin's lymphoma was indistinguishable from that seen in Hodgkin's disease. Pulmonary nodules were present in all but two patients. They may be solitary or multiple with or without cavitation (Fisher et al., 1962; Strickland, 1967; Costello and Mauch, 1979; North et al., 1982). Nodules that are apparently single on plain films are usually found to be
238
CLINICAL RADIOLOGY
Table 2 - Radiologieal appearances of relapse within the lung
Nodules solitary/multiple central/peripheral with or without cavitation with or without lines to pleura or connection to mediastinum Consolidation with or without cavitation Mediastinal extension into lung parenchyrna Endobronchial diffuse submucosal solitary central airway mass Pleural effusion mass
multiple on CT. They tend to be larger if centrally sited, and in this series one or more were shown on computed tomography to be attached to the mediastinum by a thick bronchovascular or lymphatic 'stalk' (Figs 1 and 2). Peripherally sited nodules lie close to the pleura and in four cases computed tomography showed a thin line connecting a nodule to the pleural surface (Figs 2 and 4). The central nodules arise just outside any previous radiation field and lie in the fork of the bronchovascular bifurcations. This is where small pulmonary lymph nodes are located and the thick 'stalk' is probably due to centripetal spread of lymphoma into the peribronchial lymphatics. Consolidation is a well recognised pattern of pulmonary relapse and occurred in four patients from this series (Fig. 6). Infections, including tuberculosis, need to be excluded especially if cavitation is present. Open lung biopsy was required to confirm the diagnosis in two patients following negative transbronchial biopsies. In three patients the consolidation was initially unifocal. In the one patient with multifocal areas of consolidation open lung biopsy demonstrated active Hodgkin's disease and pneumocystis pneumonia. Other findings seen in this series included pleural masses and pleural effusions and extension from mediastinal lymphadenopathy into adjacent lung parenchyma, differentiated from coincidental consolidation distal to an obstructing lesion by its non-segmental or lobar distribution (Fisher et al., 1962; Costello and Mauch, 1979; North et al., 1982). Thoracic wall involvement can occur either in isolation or by spread from adjacent nodal invasion (Figs 3, 5 and 7) and is seen frequently in the sternum from anterior mediastinal adenopathy. Any of these patterns may be found at initial presentation (Filly et al., 1976). Endobronchial involvement occasionally occurs at presentation, as it did in one patient from this series, or with relapse. From the findings in three patients with Non-Hodgkin's lymphoma and a review of the literature, Rose et al. (1986) describe two patterns of involvement. In the first, diffuse submucosal infiltration is found in the presence ofintra- and extrathoracic lymphoma. The chest radiograph typically shows regional lymphadenopathy with or without parenchymal infiltrates. In the second pattern, the central airways are involved by a solitary mass in the absence of apparent systemic lymphoma. These patients present with airway obstruction and are usually first thought to have a bronchial carcinoma. A variety of radiation changes are also described, but are unlikely to cause confusion or misdiagnosis on computed tomography if the size and shape of the
previous radiation portal is considered (Fig. 4) (Libshitz and Shuman, 1984; Bell et al., 1988). Most of these appearances, if seen in isolation, can present problems in diagnosis. Infection, granulomatous disease, primary or secondary carcinoma, drug reactions, or incidental lung disease may cause similar abnormalities and making the correct diagnosis requires careful correlation of clinical, bacteriological, histological and radiological findings. In this study the demonstration by computed tomography of multiple abnormalities, frequently unsuspected or undetected on the chest radiograph, was most useful in establishing or suggesting the diagnosis of pulmonary relapse. Enlarged mediastinal nodes were not a prerequisite but had been present in all patients at some time in the course of the disease. Acknowledgement. Mark Cobby is supported by a grant from the Frances and Augustus Newman Foundation.
REFERENCES
Bell, J, McGivern, D, Bullimore, J, Hill, J, Davies, ER & Goddard, P (1988). Diagnostic imaging of post-irradiation changes in the chest. Clinical Radiology, 39, 109 119. Carmel, RT & Kaplan, HS (1976). Mantle irradiation in Hodgkin's disease, an analysis of technique, tumour eradication and complications. Cancer, 37, 2813-2825. Castellino, RA, Blank, N, Cassady, JR & Kaplan, HS (1973). Roentgenologic aspects of Hodgkin's disease. Cancer, 31, 316 323. Colby, TV, Hoppe, RT & Warnicke, RA (1981a). Hodgkin's disease at autopsy, 1972-1977. Cancer, 47, 1852 1862. Colby, TV, Hoppe, RT & Warnicke, RA (1981b). Hodgkin's disease, a clinicopathologic study of 659 cases. Cancer, 49, 1848-1858. Costello, P & Mauch, P (1979). Radiographic features of recurrent Hodgkin's disease following radiation therapy. American Journal of Roentgenology, 133, 201-206. Filly, R, Blank, N & Casellino, RA (1976). Radiographic distribution of intrathoracic disease in previously untreated patients with Hodgkin's disease and non-Hodgkin's lymphoma. Radiology, 120, 277281. Fisher, AM, Kendal, B & Van Leuven, BD (1962). Hodgkin's disease, a radiological survey. Clinical Radiology, 13, 115-127. Heron, CW, Husband, JE, Williams, MP & Cherryman, GR (1988). The value of thoracic computed tomography in the detection of recurrent Hodgkin's disease. British Journal of Radiology, 61, 567-572. Libshitz, HI & Shuman, LS (1984). Radiation-induced pulmonary change, CT findings. Journal of Computer Assisted Tomography, 8, 15 19. Macdonald, JS (1977). Lung involvement in Hodgkin's disease. Thorax, 32, 664 667. Meyer, JE, Linggood, RM, Lindfords, KK, McLoud, TC & Stomper, PC (1984). Impact of thoracic computed tomography on radiation therapy planning in Hodgkin's disease. Journalof Computer Assisted Tomography, 8, 892-894. North, LB, Fuller, LM, Hagemeister, FB, Rodger, RW, Butler, JJ & Shullenberger, CC (1982). Importance of initial mediastinal adenopathy in Hodgkin disease. American Journal of Roentgenology, 138, 229 235. Peterson, H, Snider, HL, Yam, LT, Bowlds, CF, Arnn, EH & Li, CY (1985). Primary pulmonary lymphoma. Cancer, 56, 805 813. Rose, RM, Grigas, D, Strattemeir, E, Harris, NL & Linggood, RM (1986). Endobronchial involvement with non-Hodgkin's Lymphoma. A clinical radiologic analysis. Cancer, 57, 1750-1755. Rosenberg, SA & Kaplan, HS (1966). Evidence for an orderly progression in the spread of Hodgkin's disease. CancerResearch, 26, 1225 1235. Selby, P & McElwain, TJ (1987). Clinical features of Hodgkin's disease. In Hodgkin's Disease, Ed. P. Selby & T. J. McElwain. pp. 94-125. Blackwell Scientific Publications, Oxford. Srickland, B (1967). Intra-thoracic Hodgkin's disease. Part II. Peripheral manifestations of Hodgkin's disease in the chest. British Journal of Radiology, 40, 930-938. Young, RC, Canellos, GP, Chabner, BA, Hubbard, SM & DeVita, VT (1978). Patterns of relapse in advanced Hodgkin's disease treated with combination chemotherapy. Cancer, 42, 1001-1007. Yousem, SA, Weiss, LM & Colby, TV (1986). Primary pulmonary Hodgkin's disease. Cancer, 57, 1217-1224.
CT Appearances of Relapse of Lymphoma in the Lung M. COBBY, E. WHIPP*, J. BULLIMORE*, S. GOODMAN*, E. R. DAVIES and P. G O D D A R D
Department of Radiodiagnosis, Bristol Royal Infirmary and *Radiotherapy Centre, Bristol The patterns of pulmonary relapse were studied in 15 patients with Hodgkin's disease and one Patient with NonHodgkin's lymphoma. All the patients with Hodgkin's disease had mediastinal lymphadenopathy at initial diagnosis. For those patients with no prior episodes of relapse the mean time to pulmonary involvement was 2 years 11 months compared to over 8 years for those who first relapsed elsewhere. Thirteen patients are still alive; five have been followed up for more than 2 years. Pulmonary involvement consisted of." 1 nodules, either central (12 patients) or peripheral (10 patients), often with connection to the pleura or mediastinum, and sometimes with cavitation; 2 consolidation with or without cavitation (four patients); 3 mediastinal extension into the lung parenchyma (three patients). In seven patients there was evidence of newly enlarged mediastinal nodes. Pleural effusions or masses were seen in six patients and pericardiai involvement in one. The chest wall was involved in five. A combination of three or more of these signs were present in 11 patients. The pattern of involvement seen in the patient with Non-Hodgkin's lymphoma was indistinguishable from that seen in Hodgkin's disease. This study has demonstrated a variety of CT appearances useful in establishing or suggesting the diagnosis of pulmonary relapse. Enlarged mediastinal nodes were not a prerequisite but had been present in all patients at some stage in the course of the disease.
Relapse oflymphoma in the lung parenchyma is relatively uncommon. The radiological appearances have to be differentiated from infection, particularly with atypical organisms, radiotherapy changes and drug reactions. Routine use of computed tomography in the initial staging of Hodgkin's disease is well established. It is particularly useful in showing previously unrecognised mediastinal nodal involvement or parenchymal lung extension which may alter the proposed treatment (Meyer et al., 1984). We have examined its use in patients presenting with pulmonary opacities following treatment for lymphoma and have noted a number of typical patterns helpful in establishing a diagnosis of relapse. PATIENTS AND METHODS
Fifteen patients with Hodgkin's disease, eight male and seven female, with a mean age at diagnosis of 28 years (range 16-42), and one male patient with Non-Hodgkin's lymphoma aged 72 years were studied. CT scans of the chest were available for 12 patients from the time of their primary diagnosis. Subsequent CT Correspondence to: P. Goddard, Department of Radiodiagnosis, Bristol Royal Infirmary,MarlboroughStreet, BristolBS2 8HW.
scans were obtained on all patients to investigate possible or definite intrapulmonary opacities observed on follow. up chest radiographs. Most CT scans were performed using a Siemens Somatom D H R body scanner with contiguous 8 rnrn slices. An EMI 5005 body scanner with 13 mm slices and a Tomoscan 350 body scanner with 9 mm slices were used in some patients. Concurrent postero-anterior chest radio. graphs were also available. The diagnosis of pulmonary relapse was established by transbronchial biopsy in two patients (Case numbers 2 and 13) and open lung biopsy in three patients (Case numbers 11, 14 and 15). In the remaining patients a diagnosis of relapse was made on the basis of the clinical signs and symptoms, the CT findings, the exclusion of pulmonary infection by sputum culture and an appropriate response to radiotherapy or chemotherapy. In six of these patients CT demonstrated newly enlarged mediastinal nodes with parenchymal lung masses lying outside the previous radiation treatment field.
RESULTS The sites of initial involvement, of prior episodes of relapse, and the primary treatment given, are presented in Table 1. The time from initial diagnosis to pulmonary relapse and a ~summary of the CT findings of pulmonary involvement are also included. All the patients with Hodgkin's disease had mediastinal lymphadenopathy at initial presentation. Six were stage I or II and nine stage III or IV. The histological classifications were nodular sclerosing (13 patients), lymphocyte predominant (one patient), and mixed cellularity (one patient). The patient with Non-Hodgkin's lymphoma was classified as moderate to high grade. Seven patients received radiotherapy and nine chemotherapy as their initial treatment. One patient had Hodgkin's disease involving the mediastinum and extending into the adjacent lung parenchyma with multiple cavitating nodules attached by thickened bronchovascular bundles to the mediastinum at presentation (Case No 6). This patient relapsed 17 months after chemotherapy with new peripheral and central nodules, some of which were also cavitating. The mediastinal nodes and previous large central nodules had decreased in size. None of the remaining 14 patients with Hodgkin's disease had parenchymal lung involvement when they first presented. The mean time from the initial presentation with Hodgkin's disease to the occurrence of lung relapse for the whole group was five years (range 7 months to 17 years). For the seven patients with no prior episodes of relapse the mean was 2 years 11 months (range 7 months to 9 years) compared to 8 years 3 months for those who first relapsed elsewhere (range 4 years 9 months to 17 years). The difference in the times to relapse was significant at the 5% level (Mann-Whitney U test).
CT APPEARANCES OF RELAPSE OF LYMPHOMA IN THE LUNG
233
Table 1 - Site of initial involvement, areas of relapse prior to pulmonary involvement and number of months from initial diagnosis to lung involvement with lyrnphoma
Age at diagnosis
Sex
Initial involvement
Prior relapse
IT*
Months to pulmonary relapse
Findings on C T at time o f pulmonary relapse
1
26
M
m
Mediastinum, abdomen, thoracic spine
RT
204
Consolidation extending to pericardium resulting in effusion. Pleural effusion. Axillary & retro-crural nodes
2
16
F
m &a
Rt femur & Lt 2nd rib
RT
78
R T changes. No mediastinal nodes. Multiple central nodules with connections to mediastinum
3
34
M
m
No
CT
7
Mediastinal nodes. Multiple central nodules with connections to mediastinum one with cavitation. Peripheral nodules. Chest wall involvement. Pleural mass
4
39
F
m
No
CT
16
Mediastinal nodes with extension into lung parenchyma & chest wall. 'Cloudy' lungs following chemotherapy
5
28
F
m & a
~ No
CT
41
Mediastinal nodes (smaller than at presentation & some calcified). Multiple peripheral nodules. Central nodule with connection to mediastinum
6
29
F
m, a & p
Mediastinum
CT
17
P r e s e n t a t i o n - mediastinal nodes extending into lung parenchyma. Multiple cavitating central nodules with connections to mediastinum. 'Sausage shaped' area of collapse/consolidation. R e l a p s e - s m a l l residuum of mediastinal nodes. Peripheral nodules. Enlargement of previous small central nodules with cavitation. Decrease in size of previous large central nodules
7
20
F
m &a
Mediastinum
CT
76
Mediastinal nodes. Lt hilar nodes with central nodule and connection to mediastinum. Pleural masses. R T changes at apex. Possible anterior chest wall involvement
8
18
F
m &a
No
CT
14
R T changes. No mediastinal nodes. Multiple peripheral small nodules. Some central nodules, one with possible connection to hilum
9
72
M
e
No
RT
7
R T changes. Mediastinal nodes. Multiple central nodules some with connections to mediastinum. Peripheral nodules
10
31
M
a& m
Supraclavicular fossa, liver, mediastinum
CT
149
Mediastinal nodes, some calcified. Extension into lung parenchyma. Central nodules some with connections to mediastinum. Peripheral nodules. Consolidation with cavitation. Pleural mass with chest wall involvement
11
18
M
a &m
Mediastinum
RT
69
N o mediastinal nodes. Consolidation with subsequent development of nodules beyond the opacification. Multiple central nodules with connections to mediastinum. Bilateral effusions
12
42
F
a &m
No
CT
41
R T changes. Mediastinal nodes smaller than on presentation. One large central nodule connected to mediastinum. Other central nodules. One peripheral cavitating lesion. Pleural effusion. Chest wall involvement as at presentation
13
26
M
a & m
Cervical & axillary nodes
RT
74
Mediastinal nodes. Chest wall involvement. Multiple small peripheral nodules
14
42
M
m
No
RT
108
Marked emphysema in field of RT. Lobulated central nodule possibly with a connection to mediastinum
15
26
M
m
Supraclavicular mediastinum & para-aortic nodes
RT
57
Small inactive mediastinal nodes. Consolidation rt lower lobe with numerous small peripheral nodules. Generalised haziness in It lower and mid zones
16
22
M
m
No
CT
16
Mediastinal nodes. Central nodule with connection to rt hilum & separate nodule peripheral to this. RT changes
Case no.
*, initial treatment. CT, chemotherapy. RT, radiotherapy. a, abdominal lymph node involvement at diagnosis. m, mediastinal lymph node involvement at diagnosis. e, endobronchial involvement at diagnosis. P, lung parenchymal involvement at diagnosis. Case n u m b e r 9 had Non-Hodgkin's lymphoma, all other cases had Hodgkin's disease.
234
CLINICAL RADIOLOGY
Three patients died at 2, 4 a n d 16 months after the onset of pulmonary involvement (Case Nos 5, 12 and 15). The remaining patients have been followed up for between 2 months and 6 years. Five are alive more than 2 years after the onset of lung disease. The patient with Non-Hodgkin's lymphoma presented with collapse of the right lung caused by turnout involving the lateral wall of the trachea extending down the right main bronchus (case No 9). He relapsed 7 months after radiotherapy with a number of peripheral nodules, mediastinal adenopathy and central nodules attached to the mediastinum by thickened bronchovascular bundles.
CT Findings The CT findings of each case are summarised in Table I. At the time of pulmonary relapse, five patients had no
(a)
(b)
(a)
(b)
(c)
Fig. 1 - Case 2. Hodgkin's disease, relapse. (a) Chest radiograph. Radiation fibrosis adjacent to upper mediastinum and left apex with loss ofvolmne in both upper lobes. Hazy opacities both mid zones; no clearly defined nodules. (b) Concurrent CT. Multiple central nodules, some with connection to mediastinum (arrow). No mediastinal nodes present at any level.
Fig. 2 - Case 9. Non-Hodgkin's lymphoma, relapse. (a) Chest radiograph. Radiation changes adjacent to right upper mediastinum. Multiple nodules in both lungs. (b, e) Concurrent CT. Large central nodule with connection to mediastinum adjacent to the inferior pulmonary vein (arrow head). Smaller peripheral nodule with connection to pleura (arrow). Fibrotic changes in right lower lobe posteriorly.
235
CT APPEARANCES OF RELAPSE OF LYMPHOMA IN THE LUNG
current mediastinal lymphadenopathy. In four patients the nodes had decreased in size since a previous examination, and in seven there was evidence of newly enlarged nodes. In three of this latter group there was extension of disease from the mediastinum into the adjacent lung. Twelve patients had centrally sited lung nodules; they were multiple in 10 patients in whom at least one of the nodules appeared to have a connection to the mediastinum or hilum (Figs 1 and 2). The nodules were usually located in the fork of a bronchovascular division and in two patients they were cavitating (Fig. 3). Ten patients had peripherally sited lung nodules lying close to a pleural surface; in nine patients these were multiple. They tended to be smaller and more numerous than the centrally sited nodules (Figs 4 and 5). In four cases fine lines connected these nodules to the pleura (Figs 2 and 4). Cavitation was seen in one patient. Areas of consolidation were se~en in four patients. In three cases this was due to lymphoma (Fig. 6). The consolidation was initially unifocal but cavitation was present in one case and extension into the pericardium in another (Case no. 1). In the fourth patient multifocal
areas of consolidation were shown and at open lung biopsy both Pneumocystis carinii pneumonia and Hodgkin's disease were found (Case No 15). Five patients had chest wall involvement, in two patients this was probably due to enlarged internal mammary lymph nodes (Fig. 3)
(a)
(a)
n
(b)
(c) (b) Fig. 3 - Case 6. Hodgkin's disease, presentation. (a) Large mediastinal nodes which on the left extend into the lung parenchyma. Central area of focal consolidation in the right lung. Enlarged internal mammary lymph node (arrow). (b) Multiple central nodules and mediastinal lymphadenopathy. Cavitating nodule posteriorly on the left. 'Sausage shaped' area of presumed collapse and consolidation in the left mid-zone.
Fig. 4 - C a s e 8. Hodgkin's disease, relapse. (a) Chest radiograph. Radiation changes adjacent to upper mediastinum. Small ill-defined and pooly visualised nodules in both mid and lower zones. (b) Concurrent CT. Small peripheral nodules. Well marked radiation changes conforming with treatment portal. No mediastinal nodes present at any level. (c) CT at lower level. Multiple small, predominantly peripheral nodules, some with connecting septal lines to pleura (arrows).
236
CLINICAL RADIOLOGY
(a)
(a)
(b)
(b) Fig. 5 - Case 13. Hodgkin's disease, relapse. (a) CT at lung settings. Peripheral nodules. One is adjacent to the oblique fissure (arrow). Pleural thickening is demonstrated anteriorly on the right. (b) With mediastinal settings at the same level anterior chest wall involvement with Hodgkin's lymphoma is demonstrated (arrows). Mediastinal lymphadenopathy was present at other levels.
and in three patients to rib or soft tissue involvement (Fig. 5). Three patients had pleural masses and three pleural effusions (Fig. 6). A combination of three or more of these findings was present in 11 patients (Fig. 7). DISCUSSION At presentation 10 15% of patients with Hodgkin's disease, and 4% of those with Non-Hodgkin's disease, will have lung involvement (Filly et al., 1976; Colby et al., 1981b). Parenchymal disease in these patients is usually associated with mediastinal or hilar lymphadenopathy and is nearly always unilateral, tending to present as an ill-defined area of infiltration extending from the hilum peripherally (Filly et al., 1976). Single or multiple nodules, sometimes cavitating, are occasionally present and are usually accompanied by mediastinal or hilar lymphadenopathy (Fig. 3). These nodules may be poorly visualised on a chest radiograph or appear as hazy opacities. They are shown to be discrete lesions on
Fig. 6 - Case 11. Hodgkin's disease, relapse. (a) Focal area o f consolidation in right lung with bilateral pleural effusions. Open lung biopsy confirmed infiltration by Hodgkin's lymphoma. Multiple central nodules were present at other levels but there was no mediastinal adenopathy. (b) Subsequent CTscan shows the development of a nodule peripheral to the consolidation and resolution of the effusions.
tomography (Strickland, 1967; Filly et al., 1976) (Fig. 1). Primary pulmonary lymphoma, where lung involvement is seen without nodal disease, occurs rarely, usually presenting as one or more nodules with or without cavitation (Peterson et al., 1985; Yousem et al., 1986). The incidence of relapse within the lung parenchyma is difficult to estimate. In an early unselected series of patients with Hodgkin's disease approximately 30% had lung involvement, the incidence rising the longer the follow up (Fisher et al., 1962). None of these patients had parenchymal disease at presentation. Lung involvement was also found to be common in patients with evidence of Hodgkin's disease at post-mortem, occurring in 53% of cases (Colby et al., 1981a), and in another series, was estimated to involve the lung at some stage in 40% of patients (Macdonald, 1977). With more accurate staging and better methods of treatment these figures are likely to be far higher than those currently obtained, where overall relapse rates in Hodgkin's disease are now less than 20% (Selby and McElwain, 1987). Rosenberg and Kaplan (1966) demonstrated an orderly progression in the spread of Hodgkin's disease by contiguity from one lymph:node to the next; this mode of spread is thought to occur in over 90% of patients, with
237
CT APPEARANCES OF RELAPSE OF LYMPHOMA IN THE LUNG
(c) (a)
(d)
(b)
Fig. 7 - C a s e 3. Hodgkin's disease, relapse. (a) Chest radiograph. Mediastinal and right hilar lymphadenopathy. Mass adjacent to right heart boarded (arrow) and questionable consolidation in the right lower zone. (b) Concurrent CT. Mediastinal adenopathy is confirmed and anterior chest wall involvement is also demonstrated (arrow). (c) At a lower level a large central nodule is present in the azygo-oesophageal recess (arrow). Smaller nodules and ill-defined lung opacification is seen distal to this. A peripheral nodule lies adjacent to the right oblique fissure. (d) A subsequent CT scan after an interval of 12 months revealed a new area of consolidation with cavitation.
vessel invasion and haematological dissemination accounting for the remainder. This accounts for the observation that lung relapse is more common in Stage I or II Hodgkin's disease if it initially involves the mediastihum than if it does not (Young et al., 1978; North et al., 1982), and in our series, all except the patie0t with NonHodgkin's lymphoma had mediastinal involvement when first diagnosed. Relapse in the lung is also more likely to occur if the treatment portal fails to include unrecognised lateral extension from the mediastinum, or if there is bulky mediastinal involvement greater than 7.5 cm in diameter at presentation (North et al., 1982; Meyer et al., 1984). Computed tomography has been shown to be more sensitive than plain radiography in detecting recurrent rnediastinal and lung parenchymal disease as well as differentiating this from radiation changes (Heron et al., 1988). Pulmonary relapse usually occurs within four years of initial presentation with approximately 80% of cases occurring in the first two years (Fisher et al., 1962; Castellino et al., 1973; Costello and Mauch, 1979). The incidence may be reduced by combining chemotherapy with mantle radiotherapy in those with bulky disease, or by giving low dose irradiation to the lungs (Carmel and
Kaplan, 1976; North et al., 1982). The present series appears to be composed of two groups of patients with Hodgkin's disease, one in which there were no prior episodes of relapse before the development of lung disease, and the other where one or more relapses had occurred before the onset of lung involvement. In the first group pulmonary relapse occurred within 4 years of initial presentation in all but one of the seven patients with a mean of 2 years 11 months. The other group had a more indolent form of disease with lung involvement not seen for 5 or more years from the time of initial diagnosis with a mean of 8 years 3 months. The morphological patterns of relapse of Hodgkin's disease within the lung are summarised in Table 2. In this series three or more of these were present in 11 of the 16 patients so aiding the confidence with which a diagnosis of relapse could be made. The pattern of involvement seen in the patient with Non-Hodgkin's lymphoma was indistinguishable from that seen in Hodgkin's disease. Pulmonary nodules were present in all but two patients. They may be solitary or multiple with or without cavitation (Fisher et al., 1962; Strickland, 1967; Costello and Mauch, 1979; North et al., 1982). Nodules that are apparently single on plain films are usually found to be
238
CLINICAL RADIOLOGY
Table 2 - Radiologieal appearances of relapse within the lung
Nodules solitary/multiple central/peripheral with or without cavitation with or without lines to pleura or connection to mediastinum Consolidation with or without cavitation Mediastinal extension into lung parenchyrna Endobronchial diffuse submucosal solitary central airway mass Pleural effusion mass
multiple on CT. They tend to be larger if centrally sited, and in this series one or more were shown on computed tomography to be attached to the mediastinum by a thick bronchovascular or lymphatic 'stalk' (Figs 1 and 2). Peripherally sited nodules lie close to the pleura and in four cases computed tomography showed a thin line connecting a nodule to the pleural surface (Figs 2 and 4). The central nodules arise just outside any previous radiation field and lie in the fork of the bronchovascular bifurcations. This is where small pulmonary lymph nodes are located and the thick 'stalk' is probably due to centripetal spread of lymphoma into the peribronchial lymphatics. Consolidation is a well recognised pattern of pulmonary relapse and occurred in four patients from this series (Fig. 6). Infections, including tuberculosis, need to be excluded especially if cavitation is present. Open lung biopsy was required to confirm the diagnosis in two patients following negative transbronchial biopsies. In three patients the consolidation was initially unifocal. In the one patient with multifocal areas of consolidation open lung biopsy demonstrated active Hodgkin's disease and pneumocystis pneumonia. Other findings seen in this series included pleural masses and pleural effusions and extension from mediastinal lymphadenopathy into adjacent lung parenchyma, differentiated from coincidental consolidation distal to an obstructing lesion by its non-segmental or lobar distribution (Fisher et al., 1962; Costello and Mauch, 1979; North et al., 1982). Thoracic wall involvement can occur either in isolation or by spread from adjacent nodal invasion (Figs 3, 5 and 7) and is seen frequently in the sternum from anterior mediastinal adenopathy. Any of these patterns may be found at initial presentation (Filly et al., 1976). Endobronchial involvement occasionally occurs at presentation, as it did in one patient from this series, or with relapse. From the findings in three patients with Non-Hodgkin's lymphoma and a review of the literature, Rose et al. (1986) describe two patterns of involvement. In the first, diffuse submucosal infiltration is found in the presence ofintra- and extrathoracic lymphoma. The chest radiograph typically shows regional lymphadenopathy with or without parenchymal infiltrates. In the second pattern, the central airways are involved by a solitary mass in the absence of apparent systemic lymphoma. These patients present with airway obstruction and are usually first thought to have a bronchial carcinoma. A variety of radiation changes are also described, but are unlikely to cause confusion or misdiagnosis on computed tomography if the size and shape of the
previous radiation portal is considered (Fig. 4) (Libshitz and Shuman, 1984; Bell et al., 1988). Most of these appearances, if seen in isolation, can present problems in diagnosis. Infection, granulomatous disease, primary or secondary carcinoma, drug reactions, or incidental lung disease may cause similar abnormalities and making the correct diagnosis requires careful correlation of clinical, bacteriological, histological and radiological findings. In this study the demonstration by computed tomography of multiple abnormalities, frequently unsuspected or undetected on the chest radiograph, was most useful in establishing or suggesting the diagnosis of pulmonary relapse. Enlarged mediastinal nodes were not a prerequisite but had been present in all patients at some time in the course of the disease. Acknowledgement. Mark Cobby is supported by a grant from the Frances and Augustus Newman Foundation.
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