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Intrapulmonary ectopic liver after orthotopic heart transplantation.

The patient was a 54-year-old woman with a history of hypertension and dilated cardiomyopathy who underwent orthotopic heart transplantation on March 13, 2004. The organ donor was a 21-year-old man, who died following a gunshot wound to the head. The liver, kidneys, and both lungs were also harvested for use in other patients. Following the procedure, the patient developed an enlarging pericardial effusion and was taken to the operating room on May 7. Pericardiectomy, drainage of 900 cc of yellow effusion, and tube thoracostomy were performed, and a pericardial window was constructed to the right side of the heart. A right anterior minithoracotomy was also performed at that time.

The patient did well postoperatively with an ejection fraction of 55%. On routine screening, a basilar opacity was identified by x-ray on the right side of the chest (December 21, 2006). Subsequent noncontrast computed tomography of the chest was performed (January 18,2007) and showed multiple (approximately 20) peribronchial and centrilobular micronodules and macronodules, ranging in size from less than 1 cm to 3 cm in greatest dimension. The lesions were present in all lobes of both lungs and were more frequent in the basal segments of the right lower lobe (Figure, A). No significant pericardial or pleural effusions were identified, and there was no lymphadenopathy. Visualized portions of the liver were unremarkable. The origin of the multiple pulmonary nodules was unclear. No previous computed tomography scans were available for comparison. Because of concern about infection or neoplasm in this patient with a compromised immune system, a tissue biopsy was undertaken.

Computed tomography-guided needle biopsy of one nodule of the right lower lobe of the lung was performed on February 16, 2007. The histologic sections showed unremarkable hepatic parenchyma. Pulmonary tissue was not identified within the sampled material. Although imaging confirmed that the proper site was biopsied, based on the histology, it was suspected that perhaps the liver was biopsied inadvertently. So, an additional biopsy of a separate, discrete, more superior nodule was performed 1 month later. Histologic sections of this right, middle lobe nodule also revealed unremarkable hepatic parenchyma with no pulmonary tissue. All findings indicated that the nodules corresponded to discrete foci of ectopic liver tissue situated within the lung.

Fluorescent in situ hybridization for the Y chromosome was performed in hopes of further elucidating the origin of the liver tissue. Because the donor was male, positivity would indicate that the tissue was of donor origin. Fluorescent in situ hybridization performed on both biopsy specimens ultimately proved negative for the Y chromosome, indicating that the liver tissue was not of donor origin.

The patient, who was reliable in reporting her past medical history, denied history of alcohol use and admitted to only brief, remote use of tobacco. She remains alive and well more than 5 years after orthotopic heart transplantation. A repeat computed tomography scan, performed 6 months after the original scan, again showed multiple pulmonary nodules with no detectable increase in size. A query made to the United Network for Organ Sharing revealed that all other organ recipients associated with her donor are alive and well more than 5 years after transplantation procedures.


Sections from 2 discrete nodules, sampled from the right middle and right lower lobes of the lung, revealed unremarkable hepatic parenchyma with hepatic plates up to 2 cells wide. The well-preserved hepatocytes displayed abundant eosinophilic, granular cytoplasm with occasional nuclear to cytoplasmic ratio within reference range, consistent with a healthy liver (Figure, B). Portal areas, consisting of bile ducts and hepatic arteries, were present in both biopsies. A few central veins were also seen situated at regular intervals from portal areas. There was no nuclear atypia. No lung parenchyma was identified. Some nuclei featured glycogenation. The edge of one biopsy showed minimal periportal fibrous tissue. No steatosis or inflammation was seen. Healthy endotheliallined sinusoids were present. Minimal lipofuscin was seen in scattered hepatocytes. No Mallory bodies or degenerative changes were appreciated.


Reticulin stains performed on both biopsies highlighted findings of normal architecture with no regenerative activity (Figure C). Immunohistochemical staining with appropriate positive and negative controls for HepPar1 showed strong, diffuse positivity for cytoplasmic granular material; findings from a stain for Glypican-3 were negative.


The findings in this case confirm the presence of 2 discrete intrapulmonary nodules of ectopic liver in a female orthotopic heart recipient. Imaging studies showed no connection of the nodules to the native liver (or to each other) and suggest that multiple, additional, unsampled nodules of liver tissue were present throughout both lungs. The benign nature of the liver tissue was confirmed by histopathologic examination and subsequent clinical behavior of the nodules.

Possible etiologies for the patient's "misplaced" liver tissue included congenital accessory liver and/or ectopia, dissemination resulting from previous trauma, and hematogenous dispersal of donor and/or recipient tissue following the orthotopic heart transplantation procedure.

Congenital ectopic liver seems unlikely in this case considering (1) the intrapulmonary location, (2) the multiplicity of the lesions, and (3) the age at diagnosis. The patient denied any history of prior trauma to the thorax or abdomen, making dissemination from prior trauma unfounded. Negativity of fluorescent in situ hybridization for Y chromosome obviates introduction of donor hepatocytes as a tissue origin, assuming that all nodules share a common origin. It seems probable, therefore, that the multiple nodules originated from dissemination of native (ie, recipient) liver during the orthotopic heart transplantation procedure.

Several reported cases of congenital and acquired ectopic liver have been published. However, the occurrence is notably rare, far less frequent than ectopia of the pancreas or spleen. Most commonly, ectopic and accessory liver has been described within the abdominal cavity, often seen adjacent to the pancreas, gallbladder, spleen, or native liver. Liver ectopic to the thorax is unusual. (1) Rare cases of pleural and pericardial involvement have been described, including acquired intrathoracic masses noted after trauma and diaphragmatic hernia repair. (2,3) Only one case, to our knowledge, of intrapulmonary involvement has been reported, identified during autopsy of an infant with a complex congenital heart disease. (4) Similarly, thoracic splenosis (including intrapulmonary splenosis) is a rare condition occurring in patients following splenic laceration, sometimes resulting in several (or hundreds) of ectopic nodules because of hematogenous dispersal of native tissue.

Embryologically, the endodermal diverticula of the foregut gives rise to both the lungs and the liver, which are in close proximity to one another between weeks 3 and 8 of development (during which time a connection between the thoracic and abdominal cavities is usually present). The phenomenon of congenital ectopic liver could be explained by an incomplete closure of this canal or an abnormal cellular migration during its formation. However, most described congenital cases relate a single hepatic focus of variable size. The incidence is reportedly equal in males and females. (5)

According to the literature, ectopic hepatocellular carcinoma (defined as extrahepatic hepatocellular carcinoma arising in patients without native liver lesions) is uncommon in humans and other mammals. Some researchers have suggested that ectopic liver is associated with an increased risk of malignancy. (6,7) However, as light has gradually been shed on this unusual entity, incidental findings of benign ectopic liver have occurred more frequently. These authors propose that benign ectopia may be more common than originally put forward. Furthermore, malignant cases may simply be identified more readily as they tend to become symptomatic.

It is not difficult to speculate how tissue seeding could theoretically occur during transplantation procedures. Intraoperative mechanical considerations, including possible central cannulation during cardiopulmonary bypass and manipulation of viscera, could cause moderate internal injury, thereby initiating microscopic dispersal of various native tissues into the bloodstream or otherwise causing internal tissue displacement. Additionally, donor organs for transplantation could potentially harbor foreign, nongraft tissue, including liver parenchyma, which is then introduced to the recipient. This may be particularly relevant in cases where several organs are harvested for multiple uses or where the donor endured significant premortem trauma. Additional pericardial and diaphragmatic manipulation may have been contributory in this patient who developed postoperative pericardial effusion necessitating further surgery. Moreover, postoperative immunosuppression may contribute by decreasing the usual scavenging function, thereby permitting circulation of foreign materials (including hepatocytes) to go unchecked.

It is well known that liver is a regenerative tissue that is able to survive within the vascular system, implant within other tissues, and subsequently proliferate. It is, therefore, conceivable how donor and/or recipient hepatocytes released into the vascular system during transplantation could perhaps endure the changed environment. In fact, it has been shown that mature hepatocytes can be derived from circulating (extrahepatic) stem cells in patients who receive therapeutic bone marrow transplantations. (8) Moreover, infusions of exogenous hepatocytes, which have been successfully used to treat patients suffering from various enzyme deficiencies, have been shown to implant and induce hepatization of native tissues. (9,10)

It is concluded that hematogenous dispersal of native liver is the most likely cause for the development of multiple, stable lung nodules in this 54-year-old orthotopic heart recipient.


(1.) Luoma R, Raboei E. Supradiaphragmatic accessory liver: a rare cause of respiratory distress in a neonate. Journal of Pediatric Surgery. 2003;38(9):1413-1414.

(2.) Kinnunen P, Kulmala P, Kaarteenaho-Wiik R, Vuopala K. Ectopic liver in the human pericardium. Histopathology. 1997;30(3):277-279.

(3.) Lasser A, Wilson, GL. Ectopic liver tissue mass in the thoracic cavity. Cancer. 1975;36(5):1823-1826.

(4.) Mendoza A, Voland J, Wolf P, Benirschke K. Supradiaphragmatic liver in the lung. Arch Pathol Lab Med. 1986;110(11):1085-1086.

(5.) Huang CS, Hsu WH, Hsia CY. Supradiaphragmatic ectopic liver: delayed traumatic hepatic hernia mimics pulmonary tumor. Thorac Cardiovasc Surg. 2007;55(4):271-278.

(6.) Arakawa M, Kimura Y, Sakata K, Kubo Y, Fukushima T, Okuda K. Propensity of ectopic liver to hepatocarcinogenesis: case reports and a review of the literature. Hepatology. 1999;29(1):57-61.

(7.) Kim KA, Park CM, Kim CH, et al. Hepatocellular carcinoma in an ectopic liver: CT findings. Eur Radiol. 2003;13(suppl 4):L45-L47.

(8.) Theise ND, Nimmakayalu M, Gardner R, et al. Liver from bone marrow in humans. Hepatology. 2000;32(1):11-16.

(9.) Fisher RA, Strom SC. Human hepatocyte transplantation: worldwide results. Transplantation. 2006;82(4):441-449.

(10.) Ponder KP, Gupta S, Leland F, et al. Mouse hepatocytes migrate to liver parenchyma and function indefinitely after intrasplenic transplantation. Proc Natl Acad Sci U S A. 1991;88(4):1217-1221.

Rupal I. Mehta, MD; Chi K. Lai, MD; Stephen Kee, MD; Michael C. Fishbein, MD

Accepted for publication October 27, 2009.

From the Departments of Pathology and Laboratory Medicine (Drs Mehta, Lai, and Fishbein) and Radiology (Dr Kee), University of California, Los Angeles.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Rupal I. Mehta, MD, Department of Pathology and Laboratory Medicine, University of California, Los Angeles, 10833 Le Conte Ave, 18-126 Center for Health Science, Los Angeles, CA 90095 (e-mail:
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Author:Mehta, Rupal I.; Lai, Chi K.; Kee, Stephen; Fishbein, Michael C.
Publication:Archives of Pathology & Laboratory Medicine
Date:Jul 1, 2010
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