LIVER TRANSPLANTATION 21:1169–1178, 2015
ORIGINAL ARTICLE
Pulmonary Nodules in Liver Transplant Candidates With Hepatocellular Carcinoma: Imaging Characteristics and Clinical Outcomes Christopher Lee,1 Lauren Ihde,1 Andrew Kim,1 Idoia Santos,4 Lea Matsuoka,2 Yong Cen,1 Melissa Wallman,3 and Edward Grant1 Departments of 1Radiology, 2Surgery, and 3Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA; and 4Department of Radiology, Parc Sanitari Sant Joan de Deu, Barcelona, Spain
No guidelines exist for the management of pulmonary nodules in patients with hepatocellular carcinoma (HCC) who are being evaluated for liver transplantation. The 172 patients with HCC who were listed for liver transplant at our institution received both pretransplant chest computed tomography (CT) and follow-up CT. Pulmonary nodules on CT were characterized and followed on subsequent scans by a blinded radiologist, with a consensus review with a second radiologist being performed for equivocal cases. Nodule characteristics and outcomes were examined with chi-square tests, and the posttransplant survival of patients with different nodule outcomes was compared. Cumulative probabilities of waiting-list removal for nontransplant patients and cumulative probabilities of undergoing transplantation for all patients were also compared between patients with and without pulmonary nodules. Of all the patients, 76.2% had at least 1 pulmonary nodule on pretransplant CT, with 301 total nodules characterized; 2.7% of nodules represented HCC metastases, 1.0% represented other bronchopulmonary malignancies, and 2.7% represented infections. None of the malignant nodules exhibited a triangular/lentiform shape or calcifications. There were no statistically significant differences in pulmonary nodule outcomes between patients who underwent transplantation and those who did not undergo transplantation. No significant differences in posttransplant survival were found between patients with different nodule outcomes. There was also no significant difference between patients with and without nodules in the cumulative probabilities of waiting-list removal. However, the cumulative probability of undergoing liver transplantation was borderline significantly higher in patients without pulmonary nodules. In conclusion, despite the low prevalence of malignant nodules, all pulmonary nodules besides triangular/lentiform-shaped or calcified nodules should be followed with serial CT while the patient is on the transplant list, with biopsy performed for new and/or enlarged nodules. Both malignancy and active infection must be excluded when one is confronted with enlarged pulmonary nodules. Clinicians should also be aware of the possibility of reactivation of a granulomatous infection after transC 2015 AASLD. plantation. Liver Transpl 21:1169-1178, 2015. V Received December 16, 2014; accepted March 30, 2015.
Abbreviations: CI, confidence interval; CIF, cumulative incidence function; CT, computed tomography; HCC, hepatocellular carcinoma; MELD, Model for End-Stage Liver Disease; MRSA, methicillin-resistant Staphylococcus aureus; NOS, not otherwise specified; UCSF, University of California San Francisco. Grants or other financial support: Nothing to report. Potential conflict of interest: Nothing to report. Neither the submitted material nor portions thereof have been published previously or are under consideration for publication elsewhere. Address reprint requests to Christopher Lee, M.D., Department of Radiology, Keck School of Medicine, University of Southern California, 1500 San Pablo Street, 2nd Floor Imaging, Los Angeles, CA 90033. Telephone: 323-442-8721; Fax: 323-442-8755; E-mail: [email protected] DOI 10.1002/lt.24133 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
C 2015 American Association for the Study of Liver Diseases. V
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Hepatocellular carcinoma (HCC) is the sixth most common tumor and the second most frequent contributor to cancer mortality worldwide.1 More than 750,000 cases of HCC were diagnosed in 2012.1 Liver transplantation can be curative in patients with HCC, and it results in favorable outcomes for those who fall within the Milan criteria (1 tumor of 5 cm or smaller or up to 3 tumors of less than 3 cm without vascular invasion or extrahepatic spread).2 Consequently, liver transplantation is now viewed as the treatment of choice for select patients with HCC who are not candidates for surgical resection.3 In patients with a synchronous primary extrahepatic malignancy, current guidelines recommend deferring transplantation after curative treatment with adequate tumor-free survival because of an increased risk of posttransplant recurrence.3 Because an extrahepatic malignancy (either metastatic HCC or a synchronous primary tumor) is a contraindication for liver transplantation, the detection of an extrahepatic malignancy is paramount when one is evaluating patients with HCC for possible transplantation. An autopsy meta-analysis reported that the lungs are the most common site of extrahepatic HCC, which occurs in 34% to 52% of cases.4 Katyal et al.5 evaluated computed tomography (CT) findings in patients with metastatic HCC and also found the lungs to be the most frequent site of extrahepatic disease, which occurred in 55% of patients. On the other hand, the prevalence of synchronous bronchopulmonary tumors in patients with HCC has not been well documented. Despite the frequency of metastatic spread to the lungs, no guidelines exist specifically for the management of pulmonary nodules in patients with HCC who are being evaluated for liver transplantation. The objectives of our study were to determine the prevalence of metastatic and nonmetastatic nodules in liver transplant candidates with HCC, to assess any correlation between the outcomes of pulmonary nodules and posttransplant survival, and to compare nodule outcomes between patients who underwent transplantation and those who did not.
PATIENTS AND METHODS This retrospective Health Insurance Portability and Accountability Act–compliant study was approved by our institutional review board with waiver of informed consent. In all, 310 patients with HCC were listed for liver transplantation at our institution from January 2004 through September 2011. Of these, 177 patients underwent both pretransplant chest CT scans and at least 1 follow-up chest CT scan; the remainder either received pretransplant imaging at an outside facility that was not uploaded into our imaging database or did not have a follow-up chest CT scan. Five patients were excluded because of an imaging follow-up of less than 3 months; the remaining 172 patients composed the study population.
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All CT scans performed at our institution were acquired on multidetector scanners with a minimum of 10 channels; reconstructed image thicknesses ranged from 1 to 5 mm. Both noncontrast and contrast-enhanced examinations were included. Thirteen baseline scans were performed at outside facilities, and all had a slice thickness of 5 mm or less; images were uploaded to our database for review. CT scans were retrospectively evaluated by a blinded radiologist (5 years of experience) on a digital workstation (Synapse, Fujifilm USA, Cypress, CA), with consensus review with a second radiologist (10 years of experience) performed for equivocal cases. All baseline CT examinations were reviewed for the presence of pulmonary nodules. A pulmonary nodule was defined as focal lung opacity of any shape and density that measured at least 2 mm in diameter. If the baseline study did not demonstrate any pulmonary nodules but a subsequent pretransplant scan showed interval development of a pulmonary nodule, these new nodules were also included. Up to 3 pulmonary nodules were characterized for each patient. If a patient had more than 3 pulmonary nodules on the baseline scan, the 3 nodules with the most suspicious features were chosen. Each pulmonary nodule was characterized according to size (long axis), shape, location, edge, density, and associated calcifications. All subsequent CT studies were reviewed to evaluate changes in the indexed pulmonary nodules as well as the development of new pulmonary nodules, the progression of the hepatic tumor burden, new sites of metastatic disease, infection, and other complications of liver transplantation. An increase or decrease in pulmonary nodule size was noted when the long-axis measurement changed by at least 20%. The mean imaging surveillance period for each patient was 33.5 months (range, 3-73 months). The clinical medical record was also reviewed for each patient with a mean follow-up of 59.7 months (range, 6-134 months). Pulmonary nodules with definitive diagnoses were classified into the following categories: infection, metastasis, other malignancy, and focal fibrosis/inflammation. Transplant status, posttransplant recurrence, and survival status were also recorded. For statistical analysis, a global chi-square test was used for testing differences in pulmonary nodule characteristics between the pathologic categories. To assess the relationship between transplant status and nodule outcomes, patients were first categorized as “all stable nodules,” “at least 1 nodule increased in size,” or “at least 1 nodule decreased in size,” and this was followed by a chi-square test of the 3 groups with respect to the transplant status. Kaplan-Meier survival curves and log-rank testing were used to compare posttransplant survival between patients within the 3 aforementioned categories. For patients who did not undergo transplantation, product-limit estimates and a log-rank test were used to compare the cumulative probabilities of waiting-list removal between patients with and without pulmonary nodules. For all patients, a nonparametric competing risk analysis
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TABLE 1. Patient Demographics (n 5 172) Characteristic Males, n (%) Mean age at listing for transplant, years Transplanted, n (%) Ethnicity, n (%) Hispanic Caucasian Asian African American Other Etiology of cirrhosis, n (%) Hepatitis C Alcohol Hepatitis C and Alcohol Hepatitis B Cryptogenic Autoimmune Nonalcoholic steatohepatitis Child-Pugh class at listing, n (%) A B C Mean MELD score at listing
TABLE 2. Distribution of Pulmonary Nodule Characteristics (n 5 301)
Value 125 (72.7) 56 109 (63.4) 100 (58.1) 28 (16.3) 38 (22.1) 3 (1.7) 3 (1.7) 60 (34.9) 27 (15.7) 41 (23.8) 19 (11.0) 10 (5.8) 5 (2.9) 7 (4.1) 64 (37.2) 78 (45.3) 28 (16.3) 10.7
was performed to estimate cumulative incidence functions; Gray’s test was used to compare cumulative probabilities of undergoing liver transplantation with competing risks of death and waiting-list removal. A P value < 0.05 was considered statistically significant. All statistical analyses were conducted with SAS 9.4 (SAS Institute, Inc., Cary, NC).
Characteristic Shape, n (%) Oval Round Triangular/lentiform NOS Location (lobe), n (%) Central lower Central upper Peripheral lower Peripheral upper Right middle Edge, n (%) Irregular Lobulated Smooth Spiculated NOS Density, n (%) Cavitary Ground-glass Solid Partly-solid NOS Calcifications, n (%) Central Diffuse Peripheral No Size, n (%) 10 mm
Value 16 (5.3) 154 (51.2) 32 (10.6) 99 (32.9) 7 (2.3) 6 (2.0) 88 (29.2) 163 (54.2) 37 (12.3) 38 (12.6) 11 (3.7) 148 (49.2) 4 (1.3) 100 (33.2) 2 (0.7) 40 (13.3) 235 (78.1) 2 (0.7) 22 (7.3) 3 (1.0) 86 (28.6) 1 (0.3) 211 (70.1) 102 (33.9) 147 (48.8) 43 (14.3) 9 (3.0)
RESULTS Demographics for the 172 patients are shown in Table 1. Of the 172 patients, 131 (76.2%) had at least 1 pulmonary nodule on pretransplant CT scans; 107 of these patients met the Milan criteria at listing,2 whereas 24 patients met only the University of California San Francisco (UCSF) criteria.6 Five patients initially exceeded both the Milan criteria and the UCSF criteria, but after treatment and downstaging, they fulfilled the Milan criteria and were subsequently listed for transplant. In our study, 301 pulmonary nodules were identified and characterized for an average of 1.8 nodules (range, 1-17 nodules) per patient; 205 pulmonary nodules were recorded from the patients’ baseline scans, and 96 nodules were noted on follow-up pretransplant examinations. Overall, 244 of 301 pulmonary nodules (81.1%) were stable in size over at least 3-month follow-up, 2 (0.7%) nodules decreased in size, 32 (10.6%) resolved completely on follow-up CT, and 23 (7.6%) increased in size on follow-up imaging. The distribution of pulmonary nodule characteristics is summarized in Table 2. Pulmonary nodules were located most frequently within the peripheral upper
lobes and occurred within the peripheral right upper lobe 28.6% of the time and within the left upper lobe 25.6% of the time. The average length of a nodule was 4 mm (range, 2-40 mm); nearly half of the nodules were 3 to 5 mm, whereas only 3% of the nodules were greater than 10 mm in size. With respect to density, 78.1% of the pulmonary nodules were solid, 13.3% were ground glass, and 0.7% were partly solid. Round was the most common shape and occurred 51.2% of the time, whereas a triangular/lentiform shape occurred 10.6% of the time. With respect to edge, 49.2% of pulmonary nodules were smooth, 12.6% were irregular, 1.3% were spiculated, and 33.2% were not otherwise specified. Only 29.9% of nodules demonstrated calcification, which was diffuse in nearly all cases. The pulmonary nodule diagnoses are listed in Table 3. Eight nodules (2.7%) in 3 patients represented metastatic HCC; 1 patient’s nodules were pathologically confirmed, whereas the other 2 patients’ metastases were presumed because of their rapid growth and concomitant hepatic tumor progression. All 3 patients’ metastatic nodules were discovered before transplantation; none of the characterized pulmonary metastases
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TABLE 3. Pulmonary Nodule Diagnoses Size, Average Pathologic Category Infection* Tuberculosis Cryptococcosis MRSA Metastatic HCC† Other malignancy Carcinoid Lung adenocarcinoma Squamous cell carcinoma Focal fibrosis/inflammation
n
(Range), mm
Resolution
4 2 2 8
8 (2-13) 12 (5-19) 22 (4-40) 6 (3-8)
Increased Increased Resolved Increased
1 1 1 5
9 11 2 8 (5-17)
Increased Stable Increased 3 increased/2 stable
*Four tuberculosis nodules were in 2 patients; 2 cryptococcosis nodules were in 2 patients; and 2 MRSA nodules were in 1 patient. † Eight metastatic HCC nodules were in 3 patients.
TABLE 4. Distribution of Pulmonary Nodule Characteristics by Pathologic Outcomes Focal Fibrosis/
Shape, n (%) Oval Round NOS Location (lobe), n (%) Central lower Peripheral lower Peripheral upper Edge, n (%) Irregular Lobulated Smooth Spiculated NOS Density, n (%) Cavitary Ground-glass Solid Calcifications, n (%) Yes No Size, n (%) 10 mm Number, n (%) 1-5 6-10 >10 Outcome, n (%) Decreased Increased Resolved Stable
Other
Inflammation (n 5 5)
Infection (n 5 8)
Metastasis (n 5 6)
Malignancy (n 5 3)
1 (20.0) 4 (80.0) 0 (0)
0 (0) 2 (25.0) 6 (75.0)
0 (0) 5 (83.3) 1 (16.7)
0 (0) 0 (0) 3 (100)
0 (0) 3 (60.0) 2 (40.0)
0 (0) 6 (75.0) 2 (25.0)
0 (0) 3 (50.0) 3 (50.0)
1 (33.3) 0 (0) 2 (66.7)
3 (60.0) 0 (0) 2 (40.0) 0 (0) 0 (0)
4 (50.0) 0 (0) 1 (12.5) 1 (12.5) 2 (25.0)
0 (0) 2 (33.3) 4 (66.7) 0 (0) 0 (0)
1 (33.3) 1 (33.3) 0 (0) 0 (0) 1 (33.3)
0 (0) 1 (20.0) 4 (80.0)
1 (12.5) 1 (12.5) 6 (75.0)
0 (0) 0 (0) 6 (100)
0 (0) 1 (33.3) 2 (66.7)
0 (0) 5 (100)
1 (12.5) 7 (87.5)
0 (0) 6 (100)
0 (0) 3 (100)
(12.5) (25.0) (25.0) (37.5)
0 (0) 2 (33.3) 4 (66.7) 0 (0)
1 (33.3) 0 (0) 1 (33.3) 1 (33.3)
4 (80) 0 (0) 1 (20)
5 (62.5) 3 (37.5) 0 (0)
3 (50) 0 (0) 3 (50)
2 (66.7) 0 (0) 1 (33.3)
0 (0) 3 (60.0) 0 (0) 2 (40.0)
0 (0) 6 (75.0) 2 (25.0) 0 (0)
0 (0) 6 (100) 0 (0) 0 (0)
0 (0) 2 (66.7) 0 (0) 1 (33.3)
P Value 0.47
0.14
0.16
0.68
0.61
0.53 0 (0) 2 (40.0) 2 (40.0) 1 (20.0)
1 2 2 3
0.14
0.15
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were detected after transplantation. Three nodules (1.0%) were diagnosed as other bronchopulmonary malignancies by biopsy or resection; these nodules were typical carcinoid, lung adenocarcinoma in situ, and squamous cell carcinoma. Eight nodules (2.7%) in 4 patients represented culture-positive infections, including cryptococcosis and methicillin-resistant Staphylococcus aureus (MRSA) in 1 patient each before transplant and reactivation tuberculosis in 2 patients after transplant. Five pulmonary nodules represented pathologically proven focal fibrosis or inflammation. As shown in Table 4, there were no statistically significant differences in pulmonary nodule number, size, shape, location, edge, density, or calcifications between the various pathologic categories. However, none of the malignant nodules exhibited a triangular/lentiform shape or calcifications. All 8 metastatic nodules developed on surveillance CT examinations performed at 3-month intervals, with further growth on follow-up scans. The squamous cell carcinoma increased in size at 6-month follow-up. The adenocarcinoma in situ and carcinoid tumors were more indolent, with the adenocarcinoma in situ remaining stable for 6 months before resection and the carcinoid tumor only minimally increasing at the 12month follow-up CT scan. All calcified nodules were stable during the pretransplant period, but 1 calcified nodule developed a soft tissue component after transplantation, and this represented reactivation tuberculosis. All triangular/lentiform nodules either remained stable or resolved on follow-up examinations. Ten patients in our study population demonstrated posttransplant recurrence. Five of these patients had pulmonary metastases, and they included 3 patients without recurrence within the allograft liver. Seventeen pulmonary nodules in these 5 patients were characterized on pretransplant CT scans. After transplantation, 1 nodule decreased in size, 3 of the nodules resolved completely, and 13 nodules were stable. None of the posttransplant metastatic nodules corresponded to a preexisting nodule on the pretransplant CT scans. In addition, 1 patient developed posttransplant lymphoproliferative disease within the lungs, but none of the lymphomatous nodules corresponded to a nodule on pretransplant imaging. Of 172 patients, 109 (63.4%) had received a liver transplant at the time of this article’s submission, with the mean duration from listing to transplant being 16 months and the mean posttransplant followup being 58 months; 79 (72.5%) of these patients had pulmonary nodules on pretransplant CT scans, and 187 pretransplant nodules in these 79 patients were characterized. Of the 187 pulmonary nodules, 152 (81.3%) were stable after transplant, 24 (12.8%) decreased in size or resolved completely, 4 (2.1%) increased in size and were resected before transplant, and 7 (3.7%) increased in size after transplantation. None of the characterized nodules, including those that increased in size, represented metastases. Of 172 patients, 63 (36.6%) had not received a liver transplant with a mean clinical follow-up after trans-
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plant listing of 37 months. Of these patients who had not undergone transplantation, 27 were removed from the transplant list because of a progressive tumor burden, 11 were removed for reasons unrelated to HCC, 20 died before transplant, and 5 were still on the waiting list at the time of the article’s submission. The mean duration from listing to removal (with the exclusion of patients who died while awaiting transplantation) was 24 months, and the mean interval from listing to death without transplantation was 31 months. Of the patients with a progressive tumor burden, 17 patients exceeded the Milan and/or UCSF criteria; 3 patients had portal vein invasion by HCC; 2 patients had increasing alpha-fetoprotein levels; 3 patients had disseminated disease to the lungs; and 2 patients had disseminated disease to other organs. Of 63 patients who had not received a liver transplant, 52 (82.5%) demonstrated pulmonary nodules; 114 nodules in these 52 patients were identified and described. By the last follow-up CT scan, 92 (80.7%) remained stable, 10 (8.8%) decreased in size or resolved completely, and 12 (10.5%) increased in size, with 8 of these nodules representing metastases. There was no statistically significant difference between patients with and without nodules in the cumulative probabilities of waiting-list removal (P 5 0.58). For those patients with nodules, the cumulative probabilities of waiting-list removal at 1 and 2 years were 32.7% (95% confidence interval [CI], 19.9%-45.6%) and 53.9% (95% CI, 40.35-67.4%), respectively. For those without pulmonary nodules, the cumulative probabilities of waiting-list removal at 1 and 2 years were 40.0% (95% CI, 11.6%-68.4%) and 60.0% (95% CI, 29.6%-90.4%), respectively. Figure 1 illustrates the outcomes of pulmonary nodules on the basis of the transplant status. Among the 79 patients with pretransplant nodules who had undergone liver transplantation, 56 (70.9%) demonstrated stability of all their nodules, 7 (8.9%) had an increase in size in at least 1 nodule, and 16 (20.3%) had a decrease in size in at least 1 nodule. Of the 52 patients who had not undergone transplantation, 38 (73.1%) showed stability of all pulmonary nodules, 6 (11.5%) had an increase in size in at least 1 nodule, and 8 (15.4%) had a decrease in size in at least 1 nodule. There were no statistically significant differences in pulmonary nodule outcomes between patients who underwent transplantation and those who did not (P 5 0.72). Kaplan-Meier survival analysis revealed no significant differences in posttransplant survival between patients with different pulmonary nodule outcomes (P 5 0.52; Fig. 2). A nonparametric competing risk analysis of all patients revealed that the cumulative probability of undergoing liver transplantation was borderline significantly higher in patients without pulmonary nodules (P 5 0.07) after consideration of the competing risks of death and waiting-list removal (Fig. 3). For those patients without nodules, the cumulative probabilities of receiving a liver transplant at 1 and 2 years were 50.0% (95% CI, 33.5%-64.5%) and 65.0% (95%
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Figure 1. Distribution of pulmonary nodule outcomes for patients who underwent transplantation and patients who did not undergo transplantation.
Figure 2. Kaplan-Meier survival curves for patients with pulmonary nodules detected before transplantation and survival after liver transplantation.
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Figure 3. Cumulative incidence function (CIF) curves of liver transplantation with competing risks of death and waiting-list removal.
CI, 47.6%-77.9%), respectively. For those with pulmonary nodules, the cumulative probabilities of receiving a liver transplant at 1 and 2 years were 40.0% (95% CI, 31.5%-48.3%) and 46.9% (95% CI, 38.1%-55.3%), respectively.
DISCUSSION Because metastatic disease is a contraindication for liver transplantation, the prospective diagnosis of extrahepatic spread is essential when one is evaluating patients with HCC for possible transplantation, particularly in the current era of organ shortages. Although HCC commonly metastasizes to the lungs, no guidelines specific to transplant candidacy exist for the management of pulmonary nodules in patients with HCC. Therefore, we sought to determine the prevalence of metastatic and nonmetastatic pulmonary nodules in liver transplant candidates with HCC, assess any correlation between pulmonary nodule outcomes and posttransplant survival, and compare nodule outcomes between patients who underwent transplantation and patients who did not. In our patient population, more than three-quarters of patients had at least 1 pulmonary nodule on the pretransplant CT scan, yet only 1.7% of patients harbored pulmonary metastases. There were no significant differences in posttransplant survival between patients with different pulmonary nodule outcomes. Moreover, there were no significant differences in nodule outcomes between patients who underwent transplantation and those who did not. Although the lungs are the most frequent site of metastatic disease, only 3 patients in our study population had pretransplant pulmonary metastases (Fig. 4). This is not surprising because metastases are far
Figure 4. HCC metastases. (A) Pretransplant axial CT image reveals a 4-mm pulmonary nodule (arrow) in the left lower lobe. (B) Follow-up CT 4 months later demonstrates interval enlargement of the left lower lobe nodule (arrowhead) as well as new nodules within the left upper and right middle lobes (open arrows). A right pleural effusion is also larger. The patient was subsequently removed from the transplant list.
more common in patients with an advanced intrahepatic tumor stage,5 which would likely preclude transplant eligibility. Moreover, patients with obvious pulmonary metastases during the initial transplant evaluation would not have been listed for liver transplant and thus would not have been included in our study. Interestingly, all 3 patients with pulmonary metastases met the Milan criteria at transplant listing. After confirmation of metastatic disease, the patients were removed from the transplant list. Careful scrutiny of the CT images did not reveal any distinguishing features of the nodules to suggest malignancy. However, all 3 patients also exhibited concurrent progression of their intrahepatic tumor burden. Five additional patients developed pulmonary metastases after transplantation, but none of the metastatic nodules corresponded to a pulmonary nodule on pretransplant CT scans. Notably, 2 of the 5
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Figure 5. Squamous cell carcinoma. (A) Pretransplant axial CT image demonstrates a tiny 2-mm nodule (arrowhead) in the peripheral right upper lobe. (B) Follow-up CT 6 months later shows that the nodule (arrow) has slightly increased in size. (C) The patient underwent a liver transplant, and surveillance CT 18 months later demonstrates significant interval growth of the nodule, which now exhibits a spiculated margin. Subsequent right upper lobectomy revealed squamous cell carcinoma.
patients exceeded the Milan criteria on liver explant pathology despite meeting the Milan criteria at listing; the remaining 3 patients met the Milan criteria both at listing and on explant. Three patients’ nodules represented other synchronous bronchopulmonary malignancies. The patients with adenocarcinoma in situ and typical carcinoid had their transplants deferred while they underwent further workup and treatment. The patient with squamous cell carcinoma had a 2-mm nodule that was not identified before transplant. This nodule grew significantly after transplantation and required resection (Fig. 5). A second squamous cell carcinoma also developed in the contralateral lung after transplantation, but this malignancy did not correspond to a pulmonary nodule on pretransplant CT. These events underscore the risk of developing and/or accelerating the growth of other malignancies during the posttransplant period secondary to chronic immunosuppressive therapy.7-9 Few studies have evaluated the significance of pulmonary nodules in liver transplant candidates with HCC. Concejero et al.10 investigated the prevalence and etiology of solitary pulmonary nodules in patients undergoing liver transplantation. In their study, 9 of 152 patients (5.9%) were diagnosed with a solitary nodule on preoperative chest radiography; further workup revealed cryptococcosis and tuberculosis in 2 patients each.10 Although no patient was diagnosed with pulmonary metastatic HCC or other lung neoplasm, chest radiography may have underdiagnosed these malignant nodules in comparison with CT. Paterson et al.11 examined the outcomes of pulmonary nodules diagnosed in liver transplant recipients. Pulmonary nodules were discovered on chest radiography or CT in 11 of 155 patients (7.1%) after transplantation. In 6 of the patients, the etiology of the pulmonary nodule was infectious, whereas in 5 patients, the etiology was neoplastic; this included 1 patient with metastatic HCC.11 The authors, however, did not correlate the nodules with the patients’ pre-
transplant imaging. Finally, Sotiropoulos et al.12 evaluated 10 liver transplant patients with pulmonary nodules on pretransplant CT; only 1 patient had a posttransplant pulmonary metastasis that corresponded to a pretransplant nodule. The major weaknesses of this study were the rather small study population and the absence of nodules that represented other malignancies or infection. None of the 3 studies evaluated pulmonary nodules in patients who did not undergo transplantation. In our study, all triangular/lentiform nodules either remained stable or resolved on follow-up CT examinations. These common but uniquely shaped nodules, particularly when located along a pleural surface, have a high probability of representing benign intrapulmonary lymph nodes.13-15 Of the triangular/lentiform nodules in our study, 94% (30/32) were peripheral in location. Although it is conceivable that malignancy may spread to intrapulmonary lymph nodes, none of the malignant nodules in our patient population demonstrated a triangular or lentiform shape. To our knowledge, this phenomenon has also not been reported in the literature. Similarly, calcified nodules have a high probability of being benign and likely represent sequelae of prior granulomatous disease. Once again, none of the malignant nodules in our study population demonstrated calcification. However, because many patients emigrate from regions where granulomatous infections are endemic, there is a potential for reactivation of infection when the patients are placed on immunosuppression after transplantation.16,17 The incidence of reactivation of granulomatous infection in our patient population was low, with only 2 patients developing reactivation tuberculosis after transplantation. In 1 patient, the reactivation occurred within a cluster of calcified nodules on pretransplant CT (Fig. 6); the other patient’s tuberculosis did not correspond to a preexisting nodule. Thus, though not a common occurrence, reactivation of infection should be considered in posttransplant patients with infectious
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Figure 6. Reactivation tuberculosis. (A) Pretransplant axial CT image shows a cluster of tiny calcified nodules (arrow) within the right lower lobe. (B) Posttransplant axial CT demonstrates interval development of a soft tissue nodule in the region of calcifications (open arrow). Subsequent CT-guided biopsy revealed reactivation tuberculosis.
symptomatology and calcified nodules on pretransplant imaging. Although the 2 patients with MRSA and cryptococcosis developed their infections before transplantation, these events serve to remind the transplant community that this patient population is at increased risk for a variety of infections. The presence of active infection in the body during liver transplantation can significantly affect perioperative morbidity and mortality. Furthermore, in the postoperative period, immunosuppressive medications can exacerbate preexisting infections and thus also affect posttransplant outcomes. Accordingly, it is critical to recognize and diagnose pretransplant nodules representing active infection and treat the patient sufficiently before transplantation.3 After liver transplantation, more than 90% of pulmonary nodules either remained stable or resolved on the follow-up CT scans. Nodule outcomes were similar in patients who did not undergo transplantation. This result indicates that pulmonary nodules developed in these patients regardless of their underlying liver disease and were not affected by replacement of the cirrhotic liver with a healthy liver. Furthermore, even though transplantation and subsequent immunosuppression may accelerate synchronous malignancy or reactivate granulomatous infection, these scenarios are actually quite rare. Importantly, pulmonary nodule outcomes do not appear to affect posttransplant survival. Thus, even though a tissue diagnosis was not obtained for most of the nodules, it is unlikely that a significant number of nodules harbored occult metastatic HCC or other life-threatening malignancy or infection. Our results suggest that triangular/lentiform or diffusely calcified nodules do not require further diagnostic workup while the patient is on the transplant list. All other nodules, regardless of size, may represent a metastasis or other bronchopulmonary malignancy.
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Although all liver transplant candidates with HCC are required to undergo baseline imaging of the liver to assess hepatic tumor burden and CT of the chest to exclude metastatic disease,18 there are no established guidelines for surveillance imaging of these anatomic sites. At our institution, CT scans of the chest, abdomen, and pelvis are repeated every 3 months while the patient is on the transplant list. We observed that all malignant nodules other than the carcinoid tumor and adenocarcinoma in situ demonstrated interval growth by 6 months, and all metastatic nodules had enlarged by 3-month follow-up CT examinations. Although the carcinoid and adenocarcinoma in situ were stable for at least 6 months, both nodules were large enough to be percutaneously biopsied early in the course of their workup. As expected, there was a trend toward decreased cumulative probability of undergoing liver transplantation in patients with pulmonary nodules versus those without nodules. This result demonstrates the impact of working up pulmonary nodules with respect to delays in transplantation. There were several limitations of this study. First, it was a retrospective analysis, and not all patients listed for transplantation received the necessary baseline and follow-up CT scans to be included. Furthermore, the range of follow-up imaging duration varied widely, and clinical follow-up was notably shorter for patients who had not undergone liver transplantation. Continued follow-up of patients who did not undergo transplantation may be of interest for further study of the natural history of HCC within the context of transplant eligibility. Less than 3% of the characterized pulmonary nodules represented metastatic HCC; with more metastatic cases, it may have been possible to derive CT predictors of metastatic disease. Finally, tissue diagnoses of most of the pulmonary nodules were not obtained, although the majority of nodules that increased in size were biopsied or resected. Regardless, nodule growth did not have any adverse impact on posttransplant survival. In conclusion, although small pulmonary nodules are extremely common in liver transplant candidates with HCC, the presence of metastatic disease in this patient population is rare. Liver transplantation, in general, does not affect pulmonary nodule outcomes, and posttransplant survival does not seem to be influenced by the presence and behavior of these nodules. Unfortunately, unless they demonstrate features characteristic of calcified granulomas or intrapulmonary lymph nodes, all detected pulmonary nodules should be followed with serial CT while the patient is on the transplant list, with biopsy of new and/or enlarged nodules, particularly if there is worsening hepatic tumor burden. The optimal frequency and duration of surveillance imaging remain uncertain, although our results suggest that metastatic progression can be detected within 3 months. Transplantation deferrals caused by working up pulmonary nodules—most of them benign—highlight the need to develop strict, universal surveillance protocols. Because an active infection needs to be adequately
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treated before transplantation, clinicians should also exclude pulmonary infections when they are confronted with enlarged nodules. Finally, clinicians must be aware of the possibility of accelerating growth of other bronchopulmonary malignancies after transplantation as well as reactivation of granulomatous infections.
REFERENCES 1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:E359-E386. 2. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693-699. 3. Martin P, DiMartini A, Feng S, Brown R Jr, Fallon M. Evaluation for liver transplantation in adults: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Hepatology 2014;59:1144-1165. 4. Lee YT, Geer DA. Primary liver cancer: pattern of metastases. J Surg Oncol 1987;36:26-31. 5. Katyal S, Oliver JH 3rd, Peterson MS, Ferris JV, Carr BS, Baron RL. Extrahepatic metastases of hepatocellular carcinoma. Radiology 2000;216:698-703. 6. Yao FY, Xiao L, Bass NM, Kerlan R, Ascher NL, Roberts JP. Liver transplantation for hepatocellular carcinoma: validation of the UCSF-expanded criteria based on preoperative imaging. Am J Transplant 2007;7:2587-2596. 7. Marqu es Medina E, Jim enez Romero C, G omez de la mara A, Rota Bernal A, Manrique Municio A, Moreno Ca Gonz alez E. Malignancy after liver transplantation: cumulative risk for development. Transplant Proc 2009; 41:2447-2449.
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8. Herrero JI. De novo malignancies following liver transplantation: impact and recommendations. Liver Transpl 2009;15(suppl 2):S90-S94. 9. Chandok N, Watt KD. Burden of de novo malignancy in the liver transplant recipient. Liver Transpl 2012;18: 1277-1289. 10. Concejero AM, Yong CC, Chen CL, Lu HI, Wang CC, Wang SH, et al. Solitary pulmonary nodule in the liver transplant candidate: importance of diagnosis and treatment. Liver Transpl 2010;16:760-766. 11. Paterson DL, Singh N, Gayowski T, Marino IR. Pulmonary nodules in liver transplant recipients. Medicine (Baltimore) 1998;77:50-58. 12. Sotiropoulos GC, Kuehl H, Sgourakis G, Molmenti EP, Beckebaum S, Cicinnati VR, et al. Pulmonary nodules at risk in patients undergoing liver transplantation for hepatocellular carcinoma. Transpl Int 2008;21:850-856. 13. Wang CW, Teng YH, Huang CC, Wu YC, Chao YK, Wu CT. Intrapulmonary lymph nodes: computed tomography findings with histopathologic correlations. Clin Imaging 2013;37:487-492. 14. Shaham D, Vazquez M, Bogot NR, Henschke CI, Yankelevitz DF. CT features of intrapulmonary lymph nodes confirmed by cytology. Clin Imaging 2010;34:185-190. 15. Hyodo T, Kanazawa S, Dendo S, Kobayashi K, Hayashi H, Kouno Y, et al. Intrapulmonary lymph nodes: thinsection CT findings, pathological findings, and CT differential diagnosis from pulmonary metastatic nodules. Acta Med Okayama 2004;58:235-240. 16. Kirsch S, Sester M. Tuberculosis in transplantation: diagnosis, prevention, and treatment. Curr Infect Dis Rep 2012;14:650-657. 17. John GT, Shankar V. Mycobacterial infections in organ transplant recipients. Semin Respir Infect 2002;17:274283. 18. Organ Procurement and Transplantation Network. Policies. http://optn.transplant.hrsa.gov/governance/policies. Accessed February 2015.
ORIGINAL ARTICLE
Pulmonary Nodules in Liver Transplant Candidates With Hepatocellular Carcinoma: Imaging Characteristics and Clinical Outcomes Christopher Lee,1 Lauren Ihde,1 Andrew Kim,1 Idoia Santos,4 Lea Matsuoka,2 Yong Cen,1 Melissa Wallman,3 and Edward Grant1 Departments of 1Radiology, 2Surgery, and 3Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA; and 4Department of Radiology, Parc Sanitari Sant Joan de Deu, Barcelona, Spain
No guidelines exist for the management of pulmonary nodules in patients with hepatocellular carcinoma (HCC) who are being evaluated for liver transplantation. The 172 patients with HCC who were listed for liver transplant at our institution received both pretransplant chest computed tomography (CT) and follow-up CT. Pulmonary nodules on CT were characterized and followed on subsequent scans by a blinded radiologist, with a consensus review with a second radiologist being performed for equivocal cases. Nodule characteristics and outcomes were examined with chi-square tests, and the posttransplant survival of patients with different nodule outcomes was compared. Cumulative probabilities of waiting-list removal for nontransplant patients and cumulative probabilities of undergoing transplantation for all patients were also compared between patients with and without pulmonary nodules. Of all the patients, 76.2% had at least 1 pulmonary nodule on pretransplant CT, with 301 total nodules characterized; 2.7% of nodules represented HCC metastases, 1.0% represented other bronchopulmonary malignancies, and 2.7% represented infections. None of the malignant nodules exhibited a triangular/lentiform shape or calcifications. There were no statistically significant differences in pulmonary nodule outcomes between patients who underwent transplantation and those who did not undergo transplantation. No significant differences in posttransplant survival were found between patients with different nodule outcomes. There was also no significant difference between patients with and without nodules in the cumulative probabilities of waiting-list removal. However, the cumulative probability of undergoing liver transplantation was borderline significantly higher in patients without pulmonary nodules. In conclusion, despite the low prevalence of malignant nodules, all pulmonary nodules besides triangular/lentiform-shaped or calcified nodules should be followed with serial CT while the patient is on the transplant list, with biopsy performed for new and/or enlarged nodules. Both malignancy and active infection must be excluded when one is confronted with enlarged pulmonary nodules. Clinicians should also be aware of the possibility of reactivation of a granulomatous infection after transC 2015 AASLD. plantation. Liver Transpl 21:1169-1178, 2015. V Received December 16, 2014; accepted March 30, 2015.
Abbreviations: CI, confidence interval; CIF, cumulative incidence function; CT, computed tomography; HCC, hepatocellular carcinoma; MELD, Model for End-Stage Liver Disease; MRSA, methicillin-resistant Staphylococcus aureus; NOS, not otherwise specified; UCSF, University of California San Francisco. Grants or other financial support: Nothing to report. Potential conflict of interest: Nothing to report. Neither the submitted material nor portions thereof have been published previously or are under consideration for publication elsewhere. Address reprint requests to Christopher Lee, M.D., Department of Radiology, Keck School of Medicine, University of Southern California, 1500 San Pablo Street, 2nd Floor Imaging, Los Angeles, CA 90033. Telephone: 323-442-8721; Fax: 323-442-8755; E-mail: [email protected] DOI 10.1002/lt.24133 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
C 2015 American Association for the Study of Liver Diseases. V
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Hepatocellular carcinoma (HCC) is the sixth most common tumor and the second most frequent contributor to cancer mortality worldwide.1 More than 750,000 cases of HCC were diagnosed in 2012.1 Liver transplantation can be curative in patients with HCC, and it results in favorable outcomes for those who fall within the Milan criteria (1 tumor of 5 cm or smaller or up to 3 tumors of less than 3 cm without vascular invasion or extrahepatic spread).2 Consequently, liver transplantation is now viewed as the treatment of choice for select patients with HCC who are not candidates for surgical resection.3 In patients with a synchronous primary extrahepatic malignancy, current guidelines recommend deferring transplantation after curative treatment with adequate tumor-free survival because of an increased risk of posttransplant recurrence.3 Because an extrahepatic malignancy (either metastatic HCC or a synchronous primary tumor) is a contraindication for liver transplantation, the detection of an extrahepatic malignancy is paramount when one is evaluating patients with HCC for possible transplantation. An autopsy meta-analysis reported that the lungs are the most common site of extrahepatic HCC, which occurs in 34% to 52% of cases.4 Katyal et al.5 evaluated computed tomography (CT) findings in patients with metastatic HCC and also found the lungs to be the most frequent site of extrahepatic disease, which occurred in 55% of patients. On the other hand, the prevalence of synchronous bronchopulmonary tumors in patients with HCC has not been well documented. Despite the frequency of metastatic spread to the lungs, no guidelines exist specifically for the management of pulmonary nodules in patients with HCC who are being evaluated for liver transplantation. The objectives of our study were to determine the prevalence of metastatic and nonmetastatic nodules in liver transplant candidates with HCC, to assess any correlation between the outcomes of pulmonary nodules and posttransplant survival, and to compare nodule outcomes between patients who underwent transplantation and those who did not.
PATIENTS AND METHODS This retrospective Health Insurance Portability and Accountability Act–compliant study was approved by our institutional review board with waiver of informed consent. In all, 310 patients with HCC were listed for liver transplantation at our institution from January 2004 through September 2011. Of these, 177 patients underwent both pretransplant chest CT scans and at least 1 follow-up chest CT scan; the remainder either received pretransplant imaging at an outside facility that was not uploaded into our imaging database or did not have a follow-up chest CT scan. Five patients were excluded because of an imaging follow-up of less than 3 months; the remaining 172 patients composed the study population.
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All CT scans performed at our institution were acquired on multidetector scanners with a minimum of 10 channels; reconstructed image thicknesses ranged from 1 to 5 mm. Both noncontrast and contrast-enhanced examinations were included. Thirteen baseline scans were performed at outside facilities, and all had a slice thickness of 5 mm or less; images were uploaded to our database for review. CT scans were retrospectively evaluated by a blinded radiologist (5 years of experience) on a digital workstation (Synapse, Fujifilm USA, Cypress, CA), with consensus review with a second radiologist (10 years of experience) performed for equivocal cases. All baseline CT examinations were reviewed for the presence of pulmonary nodules. A pulmonary nodule was defined as focal lung opacity of any shape and density that measured at least 2 mm in diameter. If the baseline study did not demonstrate any pulmonary nodules but a subsequent pretransplant scan showed interval development of a pulmonary nodule, these new nodules were also included. Up to 3 pulmonary nodules were characterized for each patient. If a patient had more than 3 pulmonary nodules on the baseline scan, the 3 nodules with the most suspicious features were chosen. Each pulmonary nodule was characterized according to size (long axis), shape, location, edge, density, and associated calcifications. All subsequent CT studies were reviewed to evaluate changes in the indexed pulmonary nodules as well as the development of new pulmonary nodules, the progression of the hepatic tumor burden, new sites of metastatic disease, infection, and other complications of liver transplantation. An increase or decrease in pulmonary nodule size was noted when the long-axis measurement changed by at least 20%. The mean imaging surveillance period for each patient was 33.5 months (range, 3-73 months). The clinical medical record was also reviewed for each patient with a mean follow-up of 59.7 months (range, 6-134 months). Pulmonary nodules with definitive diagnoses were classified into the following categories: infection, metastasis, other malignancy, and focal fibrosis/inflammation. Transplant status, posttransplant recurrence, and survival status were also recorded. For statistical analysis, a global chi-square test was used for testing differences in pulmonary nodule characteristics between the pathologic categories. To assess the relationship between transplant status and nodule outcomes, patients were first categorized as “all stable nodules,” “at least 1 nodule increased in size,” or “at least 1 nodule decreased in size,” and this was followed by a chi-square test of the 3 groups with respect to the transplant status. Kaplan-Meier survival curves and log-rank testing were used to compare posttransplant survival between patients within the 3 aforementioned categories. For patients who did not undergo transplantation, product-limit estimates and a log-rank test were used to compare the cumulative probabilities of waiting-list removal between patients with and without pulmonary nodules. For all patients, a nonparametric competing risk analysis
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TABLE 1. Patient Demographics (n 5 172) Characteristic Males, n (%) Mean age at listing for transplant, years Transplanted, n (%) Ethnicity, n (%) Hispanic Caucasian Asian African American Other Etiology of cirrhosis, n (%) Hepatitis C Alcohol Hepatitis C and Alcohol Hepatitis B Cryptogenic Autoimmune Nonalcoholic steatohepatitis Child-Pugh class at listing, n (%) A B C Mean MELD score at listing
TABLE 2. Distribution of Pulmonary Nodule Characteristics (n 5 301)
Value 125 (72.7) 56 109 (63.4) 100 (58.1) 28 (16.3) 38 (22.1) 3 (1.7) 3 (1.7) 60 (34.9) 27 (15.7) 41 (23.8) 19 (11.0) 10 (5.8) 5 (2.9) 7 (4.1) 64 (37.2) 78 (45.3) 28 (16.3) 10.7
was performed to estimate cumulative incidence functions; Gray’s test was used to compare cumulative probabilities of undergoing liver transplantation with competing risks of death and waiting-list removal. A P value < 0.05 was considered statistically significant. All statistical analyses were conducted with SAS 9.4 (SAS Institute, Inc., Cary, NC).
Characteristic Shape, n (%) Oval Round Triangular/lentiform NOS Location (lobe), n (%) Central lower Central upper Peripheral lower Peripheral upper Right middle Edge, n (%) Irregular Lobulated Smooth Spiculated NOS Density, n (%) Cavitary Ground-glass Solid Partly-solid NOS Calcifications, n (%) Central Diffuse Peripheral No Size, n (%) 10 mm
Value 16 (5.3) 154 (51.2) 32 (10.6) 99 (32.9) 7 (2.3) 6 (2.0) 88 (29.2) 163 (54.2) 37 (12.3) 38 (12.6) 11 (3.7) 148 (49.2) 4 (1.3) 100 (33.2) 2 (0.7) 40 (13.3) 235 (78.1) 2 (0.7) 22 (7.3) 3 (1.0) 86 (28.6) 1 (0.3) 211 (70.1) 102 (33.9) 147 (48.8) 43 (14.3) 9 (3.0)
RESULTS Demographics for the 172 patients are shown in Table 1. Of the 172 patients, 131 (76.2%) had at least 1 pulmonary nodule on pretransplant CT scans; 107 of these patients met the Milan criteria at listing,2 whereas 24 patients met only the University of California San Francisco (UCSF) criteria.6 Five patients initially exceeded both the Milan criteria and the UCSF criteria, but after treatment and downstaging, they fulfilled the Milan criteria and were subsequently listed for transplant. In our study, 301 pulmonary nodules were identified and characterized for an average of 1.8 nodules (range, 1-17 nodules) per patient; 205 pulmonary nodules were recorded from the patients’ baseline scans, and 96 nodules were noted on follow-up pretransplant examinations. Overall, 244 of 301 pulmonary nodules (81.1%) were stable in size over at least 3-month follow-up, 2 (0.7%) nodules decreased in size, 32 (10.6%) resolved completely on follow-up CT, and 23 (7.6%) increased in size on follow-up imaging. The distribution of pulmonary nodule characteristics is summarized in Table 2. Pulmonary nodules were located most frequently within the peripheral upper
lobes and occurred within the peripheral right upper lobe 28.6% of the time and within the left upper lobe 25.6% of the time. The average length of a nodule was 4 mm (range, 2-40 mm); nearly half of the nodules were 3 to 5 mm, whereas only 3% of the nodules were greater than 10 mm in size. With respect to density, 78.1% of the pulmonary nodules were solid, 13.3% were ground glass, and 0.7% were partly solid. Round was the most common shape and occurred 51.2% of the time, whereas a triangular/lentiform shape occurred 10.6% of the time. With respect to edge, 49.2% of pulmonary nodules were smooth, 12.6% were irregular, 1.3% were spiculated, and 33.2% were not otherwise specified. Only 29.9% of nodules demonstrated calcification, which was diffuse in nearly all cases. The pulmonary nodule diagnoses are listed in Table 3. Eight nodules (2.7%) in 3 patients represented metastatic HCC; 1 patient’s nodules were pathologically confirmed, whereas the other 2 patients’ metastases were presumed because of their rapid growth and concomitant hepatic tumor progression. All 3 patients’ metastatic nodules were discovered before transplantation; none of the characterized pulmonary metastases
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TABLE 3. Pulmonary Nodule Diagnoses Size, Average Pathologic Category Infection* Tuberculosis Cryptococcosis MRSA Metastatic HCC† Other malignancy Carcinoid Lung adenocarcinoma Squamous cell carcinoma Focal fibrosis/inflammation
n
(Range), mm
Resolution
4 2 2 8
8 (2-13) 12 (5-19) 22 (4-40) 6 (3-8)
Increased Increased Resolved Increased
1 1 1 5
9 11 2 8 (5-17)
Increased Stable Increased 3 increased/2 stable
*Four tuberculosis nodules were in 2 patients; 2 cryptococcosis nodules were in 2 patients; and 2 MRSA nodules were in 1 patient. † Eight metastatic HCC nodules were in 3 patients.
TABLE 4. Distribution of Pulmonary Nodule Characteristics by Pathologic Outcomes Focal Fibrosis/
Shape, n (%) Oval Round NOS Location (lobe), n (%) Central lower Peripheral lower Peripheral upper Edge, n (%) Irregular Lobulated Smooth Spiculated NOS Density, n (%) Cavitary Ground-glass Solid Calcifications, n (%) Yes No Size, n (%) 10 mm Number, n (%) 1-5 6-10 >10 Outcome, n (%) Decreased Increased Resolved Stable
Other
Inflammation (n 5 5)
Infection (n 5 8)
Metastasis (n 5 6)
Malignancy (n 5 3)
1 (20.0) 4 (80.0) 0 (0)
0 (0) 2 (25.0) 6 (75.0)
0 (0) 5 (83.3) 1 (16.7)
0 (0) 0 (0) 3 (100)
0 (0) 3 (60.0) 2 (40.0)
0 (0) 6 (75.0) 2 (25.0)
0 (0) 3 (50.0) 3 (50.0)
1 (33.3) 0 (0) 2 (66.7)
3 (60.0) 0 (0) 2 (40.0) 0 (0) 0 (0)
4 (50.0) 0 (0) 1 (12.5) 1 (12.5) 2 (25.0)
0 (0) 2 (33.3) 4 (66.7) 0 (0) 0 (0)
1 (33.3) 1 (33.3) 0 (0) 0 (0) 1 (33.3)
0 (0) 1 (20.0) 4 (80.0)
1 (12.5) 1 (12.5) 6 (75.0)
0 (0) 0 (0) 6 (100)
0 (0) 1 (33.3) 2 (66.7)
0 (0) 5 (100)
1 (12.5) 7 (87.5)
0 (0) 6 (100)
0 (0) 3 (100)
(12.5) (25.0) (25.0) (37.5)
0 (0) 2 (33.3) 4 (66.7) 0 (0)
1 (33.3) 0 (0) 1 (33.3) 1 (33.3)
4 (80) 0 (0) 1 (20)
5 (62.5) 3 (37.5) 0 (0)
3 (50) 0 (0) 3 (50)
2 (66.7) 0 (0) 1 (33.3)
0 (0) 3 (60.0) 0 (0) 2 (40.0)
0 (0) 6 (75.0) 2 (25.0) 0 (0)
0 (0) 6 (100) 0 (0) 0 (0)
0 (0) 2 (66.7) 0 (0) 1 (33.3)
P Value 0.47
0.14
0.16
0.68
0.61
0.53 0 (0) 2 (40.0) 2 (40.0) 1 (20.0)
1 2 2 3
0.14
0.15
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were detected after transplantation. Three nodules (1.0%) were diagnosed as other bronchopulmonary malignancies by biopsy or resection; these nodules were typical carcinoid, lung adenocarcinoma in situ, and squamous cell carcinoma. Eight nodules (2.7%) in 4 patients represented culture-positive infections, including cryptococcosis and methicillin-resistant Staphylococcus aureus (MRSA) in 1 patient each before transplant and reactivation tuberculosis in 2 patients after transplant. Five pulmonary nodules represented pathologically proven focal fibrosis or inflammation. As shown in Table 4, there were no statistically significant differences in pulmonary nodule number, size, shape, location, edge, density, or calcifications between the various pathologic categories. However, none of the malignant nodules exhibited a triangular/lentiform shape or calcifications. All 8 metastatic nodules developed on surveillance CT examinations performed at 3-month intervals, with further growth on follow-up scans. The squamous cell carcinoma increased in size at 6-month follow-up. The adenocarcinoma in situ and carcinoid tumors were more indolent, with the adenocarcinoma in situ remaining stable for 6 months before resection and the carcinoid tumor only minimally increasing at the 12month follow-up CT scan. All calcified nodules were stable during the pretransplant period, but 1 calcified nodule developed a soft tissue component after transplantation, and this represented reactivation tuberculosis. All triangular/lentiform nodules either remained stable or resolved on follow-up examinations. Ten patients in our study population demonstrated posttransplant recurrence. Five of these patients had pulmonary metastases, and they included 3 patients without recurrence within the allograft liver. Seventeen pulmonary nodules in these 5 patients were characterized on pretransplant CT scans. After transplantation, 1 nodule decreased in size, 3 of the nodules resolved completely, and 13 nodules were stable. None of the posttransplant metastatic nodules corresponded to a preexisting nodule on the pretransplant CT scans. In addition, 1 patient developed posttransplant lymphoproliferative disease within the lungs, but none of the lymphomatous nodules corresponded to a nodule on pretransplant imaging. Of 172 patients, 109 (63.4%) had received a liver transplant at the time of this article’s submission, with the mean duration from listing to transplant being 16 months and the mean posttransplant followup being 58 months; 79 (72.5%) of these patients had pulmonary nodules on pretransplant CT scans, and 187 pretransplant nodules in these 79 patients were characterized. Of the 187 pulmonary nodules, 152 (81.3%) were stable after transplant, 24 (12.8%) decreased in size or resolved completely, 4 (2.1%) increased in size and were resected before transplant, and 7 (3.7%) increased in size after transplantation. None of the characterized nodules, including those that increased in size, represented metastases. Of 172 patients, 63 (36.6%) had not received a liver transplant with a mean clinical follow-up after trans-
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plant listing of 37 months. Of these patients who had not undergone transplantation, 27 were removed from the transplant list because of a progressive tumor burden, 11 were removed for reasons unrelated to HCC, 20 died before transplant, and 5 were still on the waiting list at the time of the article’s submission. The mean duration from listing to removal (with the exclusion of patients who died while awaiting transplantation) was 24 months, and the mean interval from listing to death without transplantation was 31 months. Of the patients with a progressive tumor burden, 17 patients exceeded the Milan and/or UCSF criteria; 3 patients had portal vein invasion by HCC; 2 patients had increasing alpha-fetoprotein levels; 3 patients had disseminated disease to the lungs; and 2 patients had disseminated disease to other organs. Of 63 patients who had not received a liver transplant, 52 (82.5%) demonstrated pulmonary nodules; 114 nodules in these 52 patients were identified and described. By the last follow-up CT scan, 92 (80.7%) remained stable, 10 (8.8%) decreased in size or resolved completely, and 12 (10.5%) increased in size, with 8 of these nodules representing metastases. There was no statistically significant difference between patients with and without nodules in the cumulative probabilities of waiting-list removal (P 5 0.58). For those patients with nodules, the cumulative probabilities of waiting-list removal at 1 and 2 years were 32.7% (95% confidence interval [CI], 19.9%-45.6%) and 53.9% (95% CI, 40.35-67.4%), respectively. For those without pulmonary nodules, the cumulative probabilities of waiting-list removal at 1 and 2 years were 40.0% (95% CI, 11.6%-68.4%) and 60.0% (95% CI, 29.6%-90.4%), respectively. Figure 1 illustrates the outcomes of pulmonary nodules on the basis of the transplant status. Among the 79 patients with pretransplant nodules who had undergone liver transplantation, 56 (70.9%) demonstrated stability of all their nodules, 7 (8.9%) had an increase in size in at least 1 nodule, and 16 (20.3%) had a decrease in size in at least 1 nodule. Of the 52 patients who had not undergone transplantation, 38 (73.1%) showed stability of all pulmonary nodules, 6 (11.5%) had an increase in size in at least 1 nodule, and 8 (15.4%) had a decrease in size in at least 1 nodule. There were no statistically significant differences in pulmonary nodule outcomes between patients who underwent transplantation and those who did not (P 5 0.72). Kaplan-Meier survival analysis revealed no significant differences in posttransplant survival between patients with different pulmonary nodule outcomes (P 5 0.52; Fig. 2). A nonparametric competing risk analysis of all patients revealed that the cumulative probability of undergoing liver transplantation was borderline significantly higher in patients without pulmonary nodules (P 5 0.07) after consideration of the competing risks of death and waiting-list removal (Fig. 3). For those patients without nodules, the cumulative probabilities of receiving a liver transplant at 1 and 2 years were 50.0% (95% CI, 33.5%-64.5%) and 65.0% (95%
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Figure 1. Distribution of pulmonary nodule outcomes for patients who underwent transplantation and patients who did not undergo transplantation.
Figure 2. Kaplan-Meier survival curves for patients with pulmonary nodules detected before transplantation and survival after liver transplantation.
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Figure 3. Cumulative incidence function (CIF) curves of liver transplantation with competing risks of death and waiting-list removal.
CI, 47.6%-77.9%), respectively. For those with pulmonary nodules, the cumulative probabilities of receiving a liver transplant at 1 and 2 years were 40.0% (95% CI, 31.5%-48.3%) and 46.9% (95% CI, 38.1%-55.3%), respectively.
DISCUSSION Because metastatic disease is a contraindication for liver transplantation, the prospective diagnosis of extrahepatic spread is essential when one is evaluating patients with HCC for possible transplantation, particularly in the current era of organ shortages. Although HCC commonly metastasizes to the lungs, no guidelines specific to transplant candidacy exist for the management of pulmonary nodules in patients with HCC. Therefore, we sought to determine the prevalence of metastatic and nonmetastatic pulmonary nodules in liver transplant candidates with HCC, assess any correlation between pulmonary nodule outcomes and posttransplant survival, and compare nodule outcomes between patients who underwent transplantation and patients who did not. In our patient population, more than three-quarters of patients had at least 1 pulmonary nodule on the pretransplant CT scan, yet only 1.7% of patients harbored pulmonary metastases. There were no significant differences in posttransplant survival between patients with different pulmonary nodule outcomes. Moreover, there were no significant differences in nodule outcomes between patients who underwent transplantation and those who did not. Although the lungs are the most frequent site of metastatic disease, only 3 patients in our study population had pretransplant pulmonary metastases (Fig. 4). This is not surprising because metastases are far
Figure 4. HCC metastases. (A) Pretransplant axial CT image reveals a 4-mm pulmonary nodule (arrow) in the left lower lobe. (B) Follow-up CT 4 months later demonstrates interval enlargement of the left lower lobe nodule (arrowhead) as well as new nodules within the left upper and right middle lobes (open arrows). A right pleural effusion is also larger. The patient was subsequently removed from the transplant list.
more common in patients with an advanced intrahepatic tumor stage,5 which would likely preclude transplant eligibility. Moreover, patients with obvious pulmonary metastases during the initial transplant evaluation would not have been listed for liver transplant and thus would not have been included in our study. Interestingly, all 3 patients with pulmonary metastases met the Milan criteria at transplant listing. After confirmation of metastatic disease, the patients were removed from the transplant list. Careful scrutiny of the CT images did not reveal any distinguishing features of the nodules to suggest malignancy. However, all 3 patients also exhibited concurrent progression of their intrahepatic tumor burden. Five additional patients developed pulmonary metastases after transplantation, but none of the metastatic nodules corresponded to a pulmonary nodule on pretransplant CT scans. Notably, 2 of the 5
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Figure 5. Squamous cell carcinoma. (A) Pretransplant axial CT image demonstrates a tiny 2-mm nodule (arrowhead) in the peripheral right upper lobe. (B) Follow-up CT 6 months later shows that the nodule (arrow) has slightly increased in size. (C) The patient underwent a liver transplant, and surveillance CT 18 months later demonstrates significant interval growth of the nodule, which now exhibits a spiculated margin. Subsequent right upper lobectomy revealed squamous cell carcinoma.
patients exceeded the Milan criteria on liver explant pathology despite meeting the Milan criteria at listing; the remaining 3 patients met the Milan criteria both at listing and on explant. Three patients’ nodules represented other synchronous bronchopulmonary malignancies. The patients with adenocarcinoma in situ and typical carcinoid had their transplants deferred while they underwent further workup and treatment. The patient with squamous cell carcinoma had a 2-mm nodule that was not identified before transplant. This nodule grew significantly after transplantation and required resection (Fig. 5). A second squamous cell carcinoma also developed in the contralateral lung after transplantation, but this malignancy did not correspond to a pulmonary nodule on pretransplant CT. These events underscore the risk of developing and/or accelerating the growth of other malignancies during the posttransplant period secondary to chronic immunosuppressive therapy.7-9 Few studies have evaluated the significance of pulmonary nodules in liver transplant candidates with HCC. Concejero et al.10 investigated the prevalence and etiology of solitary pulmonary nodules in patients undergoing liver transplantation. In their study, 9 of 152 patients (5.9%) were diagnosed with a solitary nodule on preoperative chest radiography; further workup revealed cryptococcosis and tuberculosis in 2 patients each.10 Although no patient was diagnosed with pulmonary metastatic HCC or other lung neoplasm, chest radiography may have underdiagnosed these malignant nodules in comparison with CT. Paterson et al.11 examined the outcomes of pulmonary nodules diagnosed in liver transplant recipients. Pulmonary nodules were discovered on chest radiography or CT in 11 of 155 patients (7.1%) after transplantation. In 6 of the patients, the etiology of the pulmonary nodule was infectious, whereas in 5 patients, the etiology was neoplastic; this included 1 patient with metastatic HCC.11 The authors, however, did not correlate the nodules with the patients’ pre-
transplant imaging. Finally, Sotiropoulos et al.12 evaluated 10 liver transplant patients with pulmonary nodules on pretransplant CT; only 1 patient had a posttransplant pulmonary metastasis that corresponded to a pretransplant nodule. The major weaknesses of this study were the rather small study population and the absence of nodules that represented other malignancies or infection. None of the 3 studies evaluated pulmonary nodules in patients who did not undergo transplantation. In our study, all triangular/lentiform nodules either remained stable or resolved on follow-up CT examinations. These common but uniquely shaped nodules, particularly when located along a pleural surface, have a high probability of representing benign intrapulmonary lymph nodes.13-15 Of the triangular/lentiform nodules in our study, 94% (30/32) were peripheral in location. Although it is conceivable that malignancy may spread to intrapulmonary lymph nodes, none of the malignant nodules in our patient population demonstrated a triangular or lentiform shape. To our knowledge, this phenomenon has also not been reported in the literature. Similarly, calcified nodules have a high probability of being benign and likely represent sequelae of prior granulomatous disease. Once again, none of the malignant nodules in our study population demonstrated calcification. However, because many patients emigrate from regions where granulomatous infections are endemic, there is a potential for reactivation of infection when the patients are placed on immunosuppression after transplantation.16,17 The incidence of reactivation of granulomatous infection in our patient population was low, with only 2 patients developing reactivation tuberculosis after transplantation. In 1 patient, the reactivation occurred within a cluster of calcified nodules on pretransplant CT (Fig. 6); the other patient’s tuberculosis did not correspond to a preexisting nodule. Thus, though not a common occurrence, reactivation of infection should be considered in posttransplant patients with infectious
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Figure 6. Reactivation tuberculosis. (A) Pretransplant axial CT image shows a cluster of tiny calcified nodules (arrow) within the right lower lobe. (B) Posttransplant axial CT demonstrates interval development of a soft tissue nodule in the region of calcifications (open arrow). Subsequent CT-guided biopsy revealed reactivation tuberculosis.
symptomatology and calcified nodules on pretransplant imaging. Although the 2 patients with MRSA and cryptococcosis developed their infections before transplantation, these events serve to remind the transplant community that this patient population is at increased risk for a variety of infections. The presence of active infection in the body during liver transplantation can significantly affect perioperative morbidity and mortality. Furthermore, in the postoperative period, immunosuppressive medications can exacerbate preexisting infections and thus also affect posttransplant outcomes. Accordingly, it is critical to recognize and diagnose pretransplant nodules representing active infection and treat the patient sufficiently before transplantation.3 After liver transplantation, more than 90% of pulmonary nodules either remained stable or resolved on the follow-up CT scans. Nodule outcomes were similar in patients who did not undergo transplantation. This result indicates that pulmonary nodules developed in these patients regardless of their underlying liver disease and were not affected by replacement of the cirrhotic liver with a healthy liver. Furthermore, even though transplantation and subsequent immunosuppression may accelerate synchronous malignancy or reactivate granulomatous infection, these scenarios are actually quite rare. Importantly, pulmonary nodule outcomes do not appear to affect posttransplant survival. Thus, even though a tissue diagnosis was not obtained for most of the nodules, it is unlikely that a significant number of nodules harbored occult metastatic HCC or other life-threatening malignancy or infection. Our results suggest that triangular/lentiform or diffusely calcified nodules do not require further diagnostic workup while the patient is on the transplant list. All other nodules, regardless of size, may represent a metastasis or other bronchopulmonary malignancy.
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Although all liver transplant candidates with HCC are required to undergo baseline imaging of the liver to assess hepatic tumor burden and CT of the chest to exclude metastatic disease,18 there are no established guidelines for surveillance imaging of these anatomic sites. At our institution, CT scans of the chest, abdomen, and pelvis are repeated every 3 months while the patient is on the transplant list. We observed that all malignant nodules other than the carcinoid tumor and adenocarcinoma in situ demonstrated interval growth by 6 months, and all metastatic nodules had enlarged by 3-month follow-up CT examinations. Although the carcinoid and adenocarcinoma in situ were stable for at least 6 months, both nodules were large enough to be percutaneously biopsied early in the course of their workup. As expected, there was a trend toward decreased cumulative probability of undergoing liver transplantation in patients with pulmonary nodules versus those without nodules. This result demonstrates the impact of working up pulmonary nodules with respect to delays in transplantation. There were several limitations of this study. First, it was a retrospective analysis, and not all patients listed for transplantation received the necessary baseline and follow-up CT scans to be included. Furthermore, the range of follow-up imaging duration varied widely, and clinical follow-up was notably shorter for patients who had not undergone liver transplantation. Continued follow-up of patients who did not undergo transplantation may be of interest for further study of the natural history of HCC within the context of transplant eligibility. Less than 3% of the characterized pulmonary nodules represented metastatic HCC; with more metastatic cases, it may have been possible to derive CT predictors of metastatic disease. Finally, tissue diagnoses of most of the pulmonary nodules were not obtained, although the majority of nodules that increased in size were biopsied or resected. Regardless, nodule growth did not have any adverse impact on posttransplant survival. In conclusion, although small pulmonary nodules are extremely common in liver transplant candidates with HCC, the presence of metastatic disease in this patient population is rare. Liver transplantation, in general, does not affect pulmonary nodule outcomes, and posttransplant survival does not seem to be influenced by the presence and behavior of these nodules. Unfortunately, unless they demonstrate features characteristic of calcified granulomas or intrapulmonary lymph nodes, all detected pulmonary nodules should be followed with serial CT while the patient is on the transplant list, with biopsy of new and/or enlarged nodules, particularly if there is worsening hepatic tumor burden. The optimal frequency and duration of surveillance imaging remain uncertain, although our results suggest that metastatic progression can be detected within 3 months. Transplantation deferrals caused by working up pulmonary nodules—most of them benign—highlight the need to develop strict, universal surveillance protocols. Because an active infection needs to be adequately
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treated before transplantation, clinicians should also exclude pulmonary infections when they are confronted with enlarged nodules. Finally, clinicians must be aware of the possibility of accelerating growth of other bronchopulmonary malignancies after transplantation as well as reactivation of granulomatous infections.
REFERENCES 1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:E359-E386. 2. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693-699. 3. Martin P, DiMartini A, Feng S, Brown R Jr, Fallon M. Evaluation for liver transplantation in adults: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Hepatology 2014;59:1144-1165. 4. Lee YT, Geer DA. Primary liver cancer: pattern of metastases. J Surg Oncol 1987;36:26-31. 5. Katyal S, Oliver JH 3rd, Peterson MS, Ferris JV, Carr BS, Baron RL. Extrahepatic metastases of hepatocellular carcinoma. Radiology 2000;216:698-703. 6. Yao FY, Xiao L, Bass NM, Kerlan R, Ascher NL, Roberts JP. Liver transplantation for hepatocellular carcinoma: validation of the UCSF-expanded criteria based on preoperative imaging. Am J Transplant 2007;7:2587-2596. 7. Marqu es Medina E, Jim enez Romero C, G omez de la mara A, Rota Bernal A, Manrique Municio A, Moreno Ca Gonz alez E. Malignancy after liver transplantation: cumulative risk for development. Transplant Proc 2009; 41:2447-2449.
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8. Herrero JI. De novo malignancies following liver transplantation: impact and recommendations. Liver Transpl 2009;15(suppl 2):S90-S94. 9. Chandok N, Watt KD. Burden of de novo malignancy in the liver transplant recipient. Liver Transpl 2012;18: 1277-1289. 10. Concejero AM, Yong CC, Chen CL, Lu HI, Wang CC, Wang SH, et al. Solitary pulmonary nodule in the liver transplant candidate: importance of diagnosis and treatment. Liver Transpl 2010;16:760-766. 11. Paterson DL, Singh N, Gayowski T, Marino IR. Pulmonary nodules in liver transplant recipients. Medicine (Baltimore) 1998;77:50-58. 12. Sotiropoulos GC, Kuehl H, Sgourakis G, Molmenti EP, Beckebaum S, Cicinnati VR, et al. Pulmonary nodules at risk in patients undergoing liver transplantation for hepatocellular carcinoma. Transpl Int 2008;21:850-856. 13. Wang CW, Teng YH, Huang CC, Wu YC, Chao YK, Wu CT. Intrapulmonary lymph nodes: computed tomography findings with histopathologic correlations. Clin Imaging 2013;37:487-492. 14. Shaham D, Vazquez M, Bogot NR, Henschke CI, Yankelevitz DF. CT features of intrapulmonary lymph nodes confirmed by cytology. Clin Imaging 2010;34:185-190. 15. Hyodo T, Kanazawa S, Dendo S, Kobayashi K, Hayashi H, Kouno Y, et al. Intrapulmonary lymph nodes: thinsection CT findings, pathological findings, and CT differential diagnosis from pulmonary metastatic nodules. Acta Med Okayama 2004;58:235-240. 16. Kirsch S, Sester M. Tuberculosis in transplantation: diagnosis, prevention, and treatment. Curr Infect Dis Rep 2012;14:650-657. 17. John GT, Shankar V. Mycobacterial infections in organ transplant recipients. Semin Respir Infect 2002;17:274283. 18. Organ Procurement and Transplantation Network. Policies. http://optn.transplant.hrsa.gov/governance/policies. Accessed February 2015.
