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Assessment and Significance of Mediastinal Bulk in Hodgkin's Disease: Comparison Between Computed Tomography and Chest Radiography

From the Departments of Diagnostic Radiology, Medical Statistics, and Medical Oncology, Christie Hospital National Health Science Trust, Manchester, United Kingdom.

Address reprint requests to A.J. Bradley, FRCR, Department of Radiology, Christie Hospital NHS Trust, Wilmslow Rd, Manchester, M20, 4BX, United Kingdom.

	ABSTRACT

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PURPOSE: In Hodgkin's disease (HD), mediastinal bulk is currently defined from chest radiograph (CXR) measurements as a ratio of the maximum transverse mass diameter to the internal thoracic diameter at T5/6 level 0.33. We evaluated how computed tomographic (CT) measurements of bulk correspond to those obtained from the CXR and correlated nodal mass long axis diameter with freedom from progression.

METHODS: Ninety-five adult patients who had a CXR thoracic ratio of greater than 0.3 and a CT scan within 28 days of the CXR were included in the study, provided that both investigations were performed before the start of treatment. Measurements of the widest mediastinal diameter and internal thoracic diameter were made on both CXR and CT scan. The thoracic ratio (TR) was calculated for each modality and compared using paired t tests. The longest diameter of the largest individual nodal mass (LIM_CT) was also measured from the CT and correlated with freedom from progression using Cox regression.

RESULTS: There was excellent correlation between CT and CXR for measurement of TR, with TR_CT greater than TR_CXR (mean difference of 2%). A TR_CT of 0.35 was found to be equivalent to a TR_CXR of 0.33. No single measurement of nodal size correlated with the current definition of bulk. However LIM_CT greater than 10 cm did correlate with increased risk of progressive HD (P = .03), even after adjustment for other prognostic variables (chemotherapy regimen and Hasenclever Prognostic Index).

CONCLUSION: Excellent correlation was observed between assessment of TR by CXR and CT scan. The longest diameter of the LIM_CT greater than 10 cm was found to be associated with an increased risk of disease progression.

	INTRODUCTION

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IN HODGKIN'S DISEASE, the presence of bulky mediastinal involvement at diagnosis is known to adversely affect prognosis.^1-6 This was initially documented in patients who received radiotherapy alone,^1-5 where the higher progression rate compared with nonbulky mediastinal disease was due to inadequate treatment. These studies suggested treatment of bulky disease by a combination of radiation therapy and chemotherapy, which is now part of accepted practice. Subsequent studies have demonstrated a reduced incidence of disease progression with the use of combined modality therapy,^7-10 and indeed, prognostic indices formulated in the last 10 years have found bulky disease to be of minor or no significance.^11,12 Therefore, combined modality therapy may be reducing the significance of the current definition of bulky disease. Bulky disease outside the thorax is defined as any lymph node mass measuring 10 cm or more in its largest dimension.¹³ Various definitions of mediastinal bulk have been proposed,^1,3,5,14-16 with agreement at the Cotswolds meeting to use the thoracic ratio of maximum transverse mass diameter one third (0.33) of the internal transverse thoracic diameter measured at the T5/6 intervertebral disc level.¹³ Inevitably, measurement of maximum transverse mass diameter by chest radiography (CXR) will often include adjacent normal mediastinal structures, which cannot be separated from the tumor mass on CXR but which can be seen separately on computed tomographic (CT) scans. Equally, the transverse mediastinal diameter may not reflect the true dimensions of any obliquely or sagittally positioned lymph node mass. The aims of this study were to evaluate (1) whether CT measurements of bulky disease corresponded to those obtained from the CXR, (2) whether a single measurement of the longest diameter of the largest individual nodal mass on the CT scan could be used as an indicator of bulky disease, and (3) how this latter measurement correlated with disease progression.

	METHODS

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The presentation CXRs performed on all adult patients (> 18 years) treated for Hodgkin's disease at the Christie Hospital between 1989 and 1996 were reviewed. Those that had a thoracic ratio of more than 0.30 (which included some patients whose disease was just below the criteria for bulk) were incorporated into this study, provided that a CT scan of the thorax performed within 28 days of the initial CXR was available and that both examinations were performed before the start of treatment.

Clinical Features
Patient details, including sex, age at presentation, treatment received (chemotherapy ± radiotherapy), and outcome (remission status, time to progression, survival), were obtained from the Manchester Lymphoma Group database. In addition, each patient's prognostic score according to the Hasenclever Prognostic Index¹¹ (Table 1) was calculated.

Radiologic Assessment
Examinations were allocated to one of two radiologists in a blinded randomized fashion to ensure that the CXR and CT for each patient were evaluated by a different radiologist. A third radiologist was present when all measurements were made to confirm that a standard approach was taken.

CXR assessment.
All CXRs were standard posteroanterior (PA) radiographs, taken on maximal inspiration, in the upright position with a 2-m source-to-skin distance. The following measurements and observations were made: (1) widest mediastinal diameter including the mass (WMD) (Fig 1A); if the mass projected to each side of the mediastinum asymmetrically (a minority of cases), then two separate measurements were made, each to the midline, and added together (Fig 1B); (2) internal thoracic diameter (ITD) at T5/6 vertebral disc space level (Fig 1A); (3) thoracic ratio (TR; WMD/ITD); and (4) the presence of hilar adenopathy, pulmonary infiltration, and pleural/pericardial involvement (Fig 1B).

View larger version (319K): [in this window] [in a new window]   Fig 1. (A) CXR with bulky mediastinal disease. WMDCXR was measured across the widest part of the mediastinum (between black arrows). ITDCXR was measured at the T5/6 intervertebral disc space (solid black line). (B) CXR with asymmetrical bulky mediastinal disease. To measure WMDCXR, two separate measurements of the widest part of each hemi-mediastinum were made to the midline (vertical solid black line) and added together. This patient also had pulmonary parenchymal involvement (black arrowheads) and right hilar adenopathy.

CT assessment.
Patients were scanned in the supine position, from the chest apices to the bases during dynamic infusion of intravenous contrast, with 10-mm contiguous sections. The scans were mostly performed on a Pace Plus (General Electric, Milwaukee, WI) scanner; technically comparable studies performed at other institutions were evaluated where necessary. Measurements were made using hard copy images, photographed on standard window levels and window widths optimized for soft tissues, using callipers that were then referred to the graduated centimeter scale provided at the side of each image. The same measurements and observations were made on CT as had been performed on the CXR (Fig 2A and 2B). In addition, the longest diameter of the largest individual or conglomerate nodal mass was also measured (LIM_CT) (Fig 2B). An evaluation of the scanograms of 20 consecutive patients without Hodgkin's disease who had attended for a CT of the thorax demonstrated the T5/6 disc level to be at or just above the carina in the majority of patients. Therefore, the internal thoracic diameter was measured on the section 1 cm above the carina.

View larger version (193K): [in this window] [in a new window]   Fig 2. (A) CT with bulky mediastinal disease. For WMDCT, the section with the widest mediastinal diameter was chosen and measured transversely (between the black arrows) using calipers, which were then referred to the graduated centimeter scale provided at the side of each image. (B) CT with bulky mediastinal disease. The section 1 cm above the carina was representative of the T5/6 intervertebral disc level, and used to measure ITDCT (white arrowheads). LIMCT was measured on the appropriate section (between black arrows). In this case, LIM CT lies obliquely and its value will differ from that of WMDCT.

Statistical Analysis
Simple techniques for method comparison studies as advocated by Bland and Altman¹⁷ were used. These methods are based on plots of differences between two measurements against the average of the two measurements. The significance of the mean difference in measurements was assessed with paired t tests, and the dependency of the magnitude of the difference on the size of the underlying measurement was gauged by the presence of a significant correlation in the Bland and Altman plot. The primary outcome measure chosen was freedom from progression (FFP). Kaplan-Meier plots were used to estimate FFP curves, and the contribution of features were considered using Cox regression.¹⁸ Interest was focused on the prognostic relevance of various measurements of the magnitude of mediastinal bulk after adjustment for two major prognostic features. We chose to adjust for the chemotherapy regimen (doxorubicin, cyclophosphamide, vincristine, bleomycin, etoposide, and prednisolone [VAPEC-B] or chlorambucil, vinblastine, procarbazine, prednisone, etoposide, vincristine, and doxorubicin [ChlVPP/EVA hybrid]) and the recently derived Hasenclever Prognostic Index¹¹ (Table 1). The LIM_CT measurements were initially entered into the model as continuous variables, and then scaled Martingale residual plots¹⁹ were used to see if some transformation was indicated (eg, grouping above and below a certain cut point on the scale).

	RESULTS

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One hundred seven patients from a total population of 309 fulfilled the selection criteria, for whom radiologic data were available for 95. The majority of patients (74%) had a CXR performed first, followed by a CT scan within the next 21 days. When the difference between the mediastinal diameter on CT (WMD_CT) and the mediastinal diameter on CXR (WMD_CXR) was evaluated against the days from CXR to CT, it was seen that there was no significant alteration in the magnitude of the average difference across the time interval. This means that the effects of tumor growth in the interval of up to 28 days between the two modalities is unlikely to be a source of error in our data. The WMD_CT was smaller than the WMD_CXR in most cases (P < .0001). Similarly, the internal thoracic diameter measured on CT (ITD_CT) was considerably smaller than the CXR measurements (ITD_CXR), with a mean difference of 2.61 cm (P < .0001). The TRs calculated from the CT measurements (TR_CT) were consistently slightly larger than those on the CXRs (TR_CXR), with a mean difference of 0.02 arbitrary units (P < .001), which corresponds to 2% (Fig 3). The magnitude of this difference does not significantly alter between smaller TRs, such as 0.33, and larger TRs, such as 0.66 (P = .65).

View larger version (14K): [in this window] [in a new window]   Fig 3. Graph to show comparison of TRs. TRCTs were slightly larger than TRCXRs, with most of the points lying just above the line of equality (solid black line). The mean difference of 0.02 units is constant across the graph.

When LIM_CT was compared with TR_CXR, there was marked variation between the values, and no single measurement of nodal size could be correlated with the current definition of bulk.

CT provided useful additional information over the CXR in a number of cases, as listed in Table 2. In patients with pulmonary, chest wall, or pericardial infiltration, this led to an increase in stage of disease. The patients in whom pulmonary infiltration was not recognized on CXR all had direct lung invasion from the mediastinal mass. Three patients had pulmonary nodules that were considered to be caused by disease; these were all correctly identified on the CXRs.

Forty-four patients had hilar disease on CT; 13 of these were not detected on the CXRs due to small volume disease, with nodes smaller than 2 cm. A further six patients were considered to have involvement of one or both hila on CXR, but this was not confirmed by CT.

Outcome
Follow-up data were available for 93 of 95 patients (median duration of follow-up for survivors was 3.9 years; range, 1 to 8 years). Thirty-eight patients were from the mustine, vinblastine, procarbazine, prednisolone (MVPP) versus ChlVPP/EVA hybrid trial²⁰ (1989 to 1992) and 55 patients were from the later ChlVPP/EVA hybrid versus VAPEC-B trial²¹ (1993 to 1997). Details of the chemotherapy regimens are given in Table 3. In total, there were 16 cases of disease progression and five deaths. Eleven of the 16 cases of disease progression occurred in the 30 patients who had received the weekly VAPEC-B therapy, and the other five cases occurred in the 63 patients who had received the ChlVPP/EVA hybrid chemotherapy. Seventy-nine patients had also received mantle radiotherapy; of the 14 who did not, seven had experienced disease progression early (before the end of planned chemotherapy) and the other seven had mediastinal disease that was not quite bulk.

Cox regression analysis (Table 4) demonstrated that the incidence of disease progression was significantly increased after VAPEC-B chemotherapy (P < .0001) and increasing score in the Hasenclever Index (P = .05). After adjustment for the above two factors, LIM_CT greater than 10 cm was also associated with a significant increase in disease progression compared with measurements of 10 cm (P = .03) (Fig 4). It is of note, however, that TR_CXR (the current method by which mediastinal bulk is assessed) did not have similar prognostic relevance after adjustment for the same two features.

View larger version (15K): [in this window] [in a new window]   Fig 4. Kaplan-Meier curves of FFP by the longest diameter of the largest individual nodal mass (LIMCT). There was a significant increase in disease progression with values of LIMCT greater than 10 cm (P = .03).

	DISCUSSION

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In Hodgkin's disease, large mediastinal masses at presentation are more likely to be associated with residual abnormalities after treatment.^3,22,23 Furthermore, there is a higher progression rate after treatment with radiotherapy alone, and it is now routine for patients with mediastinal bulk to receive both radiotherapy and chemotherapy.^7-10,24 North et al⁵ have suggested that mediastinal masses greater than 7.5 cm confer an increased risk of intrathoracic relapse, and Willett et al²⁵ demonstrated an increased mediastinal relapse rate with masses greater than 200 mL in patients treated with both radiotherapy alone and combination therapy. Volumetric assessment is the most accurate way of assessing the extent of disease, but calculating volumes is time-consuming and beyond the scope of routine radiologic reporting. On the other hand, measurement of LIM_CT is a quick and easily reproducible method of assessing the extent of mediastinal disease, and in this study, LIM_CT greater than 10 cm at presentation did confer an increased risk of disease progression. LIM_CT was evaluated as a continuous variable in the Cox regression analysis; when compared with the cumulative incidence of disease progressions, there was an increase in the slope of the graph at 10 cm with relative plateaus above and below the 10 cm level. No other level (eg, 5 or 15 cm) was associated with a significantly increased number of disease progressions. It is of note that LIM_CT greater than 10 cm also correlates with the current definition of bulky disease at extrathoracic sites (longest diameter of nodal mass 10 cm).

Prognostic indices have been devised with the aim of identifying patients at risk for disease progression.^12,26 Gobbi et al¹² studied several clinical characteristics in a group of 586 patients with Hodgkin's disease; multiple regression analysis demonstrated that erythrocyte sedimentation rate, stage, histologic subtype, and age were the most important factors, in decreasing order of significance. Sex, albumin, and mediastinal bulky disease were found to have minor value. The Hasenclever Prognostic Index was recently derived as a result of a multicenter collaboration involving 5,023 patients,¹¹ using freedom from progression as the main end point. The seven factors that have been shown to adversely affect prognosis are listed in Table 1, and include albumin, hemoglobin, male sex, and stage IV disease. Interestingly, in Hasenclever's study, bulky mediastinal disease did not have a significant effect on prognosis, except in a small subgroup of patients with very large masses with TR greater than 0.45. It is possible that this subgroup consisted of patients with LIM_CT greater than 10 cm, although in our study, no relationship could be established between LIM_CT and TR_CXR, and no single measurement of nodal size could be correlated with the current definition of bulky disease.

Increasing score in the Hasenclever Index was associated with an increasing risk of disease progression in the present study as well. Our findings of worse outcome in the VAPEC-B group reflect the findings in the ChlVPP/EVA hybrid versus VAPEC-B trial as a whole, which was terminated early because of the high incidence of disease progression in the VAPEC-B arm.²¹

The selection criteria for this study meant that all patients had bulky or near bulky disease by conventional assessment, and the majority, therefore, received combined modality therapy. Within this group, TR did not have any prognostic significance when correlated with outcome. A limitation of this study was that only patients with TR_CXR 0.3 were evaluated. It would be interesting to assess the outcome of patients with a TR_CXR of less than 0.3, particularly to see if any had a value of LIM_CT more than 10 cm, and we look forward to other groups examining the effect of LIM_CT in their patient populations.

For mediastinal diameter and internal thoracic diameter, the discrepancies between the CXR and CT measurements can at least in part be explained by a magnification factor of the order of 5% for the CXRs,²⁷ whereas CT measurements are absolute with no magnification error.²⁸ A few patients in Fig 3 were noted to have TR_CT measurements smaller than TR _CXR. A possible explanation for this is postural variation in the value of WMD, because CT scans are performed with the patient in a supine position, and CXRs are performed with the patient in an erect position. The alteration from the erect to supine position has been noted to produce an increase in the width of the mediastinal mass when erect CXRs are compared with supine simulation films.²⁹ In addition to CT providing much more information about the size and orientation of the nodal masses than is available from the CXR, previous studies have established that CT is more sensitive and specific for evaluating chest disease than plain radiography.^25,30-32 In the present study, CT demonstrated previously unsuspected hilar lymphadenopathy in 13.7% and excluded its presence in 6.3%; thus we confirm that CXR is not an accurate method for assessment of hilar adenopathy, with false-positive or false-negative results in 19 patients (20%). Pericardial or pleural effusions and direct involvement of structures adjacent to the nodal mass, including the lung, pericardium, and chest wall, were also only detected by CT in some patients (Table 2).

Assessment of mediastinal bulk is an important part of the staging process in Hodgkin's disease, and this study shows that, using the methods described, there is a high degree of correlation between TR calculated from CXR and CT scan (with TR_CXR of 0.33 equivalent to TR_CT of 0.35). Furthermore, we have shown that although no single CT-derived measurement of nodal size correlated with the current definition of bulky disease, an LIM_CT greater than 10 cm conferred an increased risk of disease progression in the study population. Thus, in addition to providing information about hilar, pericardial, lung, and chest wall involvement, the CT scan can now be used to define bulky disease, either on the basis of conventional criteria (thoracic ratio) or by permitting measurement of the LIM, which, when greater than 10 cm, seems to carry additional prognostic significance. For all of these reasons, we suggest that although CXR is useful for monitoring response during treatment, it no longer has a specific role in the staging of Hodgkin's disease where, in all circumstances, the CT scan provides equivalent or superior data.

	NOTES

 
Results presented at the Fourth International Symposium on Hodgkin's Lymphoma, Cologne, Germany, March 28-April 1, 1998.

	REFERENCES

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Submitted September 11, 1998; accepted March 30, 1999.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bradley, A. J. Articles by Radford, J. A. Search for Related Content PubMed PubMed Citation Articles by Bradley, A. J. Articles by Radford, J. A.