CASE REPORT

Hepatoid Adenocarcinoma of Small Intestine ComplicatingCrohn’s Disease: Second Reported Case

Kunal Kochar & Matthew Gawart & Janis Atkinson &

Matthew Hyser

Published online: 4 December 2012# Springer Science+Business Media New York 2012

Introduction

Hepatoid adenocarcinoma (HAC) is a rare tumor of extra-hepatic origin, which can present in the gastrointestinal (GI)tract as well as other anatomic sites. HAC consists of con-ventional adenocarcinoma combined with components thatshow both morphological and immunohistochemical evi-dence of hepatocellular differentiation. Many, but not all ofthese produce alpha-fetoprotein (AFP) and differentiationbetween HAC and hepatocellular carcinoma (HCC) can bedifficult, particularly when they rise in sites which mayeither be contiguous with the liver, such as, the gallbladderor in sites which commonly metastasize to the liver.

Since the first reported case of HAC by Ishikura et al. in1985 [1], numerous additional cases have been described,with the most frequent site being stomach followed by thefemale reproductive tract, lung, GI, and the urinary tract.HAC typically demonstrates extensive lymphovascular in-vasion, presents with metastatic disease to the liver, andcarries an overall poor prognosis [2].

HAC has also been described in patients with inflammatorybowel disease (IBD) [3–5]. IBD patients have an increasedrisk of developing GI tract malignancy with adenocarcinomabeing the most common associated cancer. In this report, wepresent the second known case of HAC of the small bowel,arising in a patient with long-standing Crohn’s disease.

Case Report

A 57-year-old female presented to her gastroenterologist with a2-month history of intermittent abdominal pain associated withconstipation, nausea, and vomiting. Her past medical historywas significant for hypothyroidism, depression, and Crohn’sdisease confined to the ileum. Her symptoms were well con-trolled with mesalamine, and her previous exacerbations hadresponded to steroid therapy. Her last colonoscopy, 3 years ago,was unremarkable. A comprehensive physical examination atthis time was normal, but her current symptoms were moreprominent than her usual Crohn’s exacerbations. An upper GIwith small bowel follow-through series and a computed tomog-raphy (CT) scan of the abdomen and pelvis were performed toevaluate her further (Figs. 1 and 2). These revealed numerousbilobar hypodense liver lesions with peripheral enhancement,which were highly suspicious for metastatic disease. Severalthickened loops of terminal ileum with inflammatory changesconsistent with Crohn’s ileitis were also seen in the mid-abdomen and right lower quadrant. The stomach was normaland there was no lymphadenopathy appreciated. A chest CTdemonstrated several 3-mm nodules in the lung apices bilater-ally, and a recent mammogram was normal. Serum level ofAFP was raised at 2,954 ng/ml. Other tumor makers includedcarcinoembryonic antitgen (CEA) of 1.4 ng/ml, carbohydrateantigen (CA) 125 of 12 U/ml, and CA19-9 level of 43.7 U/ml.Core needle liver biopsy demonstrated poorly differentiatedcarcinoma with pathologic features similar to a primary hep-atoma. However, immunohistochemical studies were negative

K. Kochar :M. Gawart :M. HyserMetropolitan Group Hospitals,Residency in General Surgery, UIC Chicago, Chicago, IL, USA

K. Kochare-mail: kocharkunal1@gmail.com

M. Gawarte-mail: mgawart@hotmail.com

J. AtkinsonDepartment of Pathology, St. Francis Hospital, 355 Ridge Avenue,Evanston, IL 60202, USAe-mail: jatkinson@presencehealth.org

M. Hyser (*)Surgical Associates, SC, St. Francis Hospital, 800 Austin Street,East Tower Suite 563,Evanston, IL 60202, USAe-mail: svmjhyser@sbcglobal.net

J Gastrointest Canc (2013) 44:357–361DOI 10.1007/s12029-012-9465-3

for hepatocyte marker Hep-Par 1, AFP, glypican 3(GPC3),CD10, and polyclonal CEA. Immunostains for CK7, CK20,and placental alkaline phosphatase (PLAP) were also nega-tive. Lack of GPC3 and PLAP, excluded a yolk sac tumor.

At this point, without a clear identification of the primarysite, chemotherapy was begun with oxaliplatin, fluorouracil,and leucovorin (FOLFOX). Ten days after her first cycle ofchemotherapy, she presented to the emergency department withfever, obstipation, and severe left lower and mid-abdominalpain. Her findings on examination were consistent with that oflocalized peritonitis. Repeat CT scan now demonstrated severesmall bowel inflammatory changes, thickening, and local per-foration in addition to multiple liver metastases (Fig. 3).

Exploratory laparotomy revealed a thickened terminal ile-um and dense adhesions in the base of small bowel mesenterywith a focal area of ileal perforation. The intraoperative ap-pearance of foreshortening of the mesentery, creeping fat, andchronic scarring was consistent with that of a perforated

segment of Crohn’s disease. The diseased terminal ileumand cecum were resected with formation of a primary ileo-ascending colostomy, and an excisional biopsy of a livernodule was performed. The stomach, colon, uterus, andovaries appeared normal, and no other intra-abdominalpathology was noted other than lymphadenopathy in theroot of the proximal jejunal mesentery. The small bowelspecimen was opened in the operating room and failedto reveal a distinct tumor mass or mucosal lesion.

Pathologic examination of the liver lesion confirmedmetastatic HAC. The primary lesion was identified with-in a narrowed ulcerated segment of small bowel, whichalso had chronic inflammatory changes consistent withCrohn’s disease. The tumor, measuring 7×4×1.2 cm,presented as a regional thickening rather than a masslesion and showed transmural invasion into subserosalfat, perforation, and serositis. Microscopically, the tumorrevealed a mixture of poorly differentiated adenocarci-noma including glandular differentiation within the ul-cerated superficial aspect and distinct hepatocellulardifferentiation with large polygonal cells arranged inplates infiltrating the muscle and subserosal fat(Fig. 4). Immunohistochemistry on the bowel specimenrevealed focal, patchy, positive staining for AFP (Fig. 4,inset), and Hep-Par 1. Discrepancy on immunohisto-chemistry results between the tumor primary and thecore biopsy of the liver metastasis is likely due totumor heterogeneity. Ten local lymph nodes were nega-tive for metastasis though vascular invasion was notedin the primary tumor. Genetic mutation testing on thetumor for PI3K, BRAF and K-RAS markers were neg-ative. A repeat AFP done after surgery measured2,173 ng/ml, which rose to 6,691 ng/ml by 1-monthpost-surgery. The patient convalesced, resumed chemo-therapy, and has completed nine cycles of FOLFOX.Disease in the liver has remained stable but neuropathymay limit use of additional oxaliplatin. Other drugs to

Fig. 1 Upper GI with small bowel follow through, December 2011demonstrating stricture in the terminal ileum

Fig. 2 February 2012 CT scandemonstrating multiple smallliver metastases

358 J Gastrointest Canc (2013) 44:357–361

be considered include cetuximab, irinotecan, regorafenib, andbevacizumab.

Discussion

Table 1 lists the sites of origin for the 352 cases of HACdescribed in the literature to date. It is evident that the GIand the female reproductive tract account for the majority ofcases. Lung, pancreas, hepatobiliary and urinary tract arealso relatively common along with a variety of additionalcase reports in various other individual organs or sites.

The diagnosis of HAC can be made when the appropriatemorphological and immunohistochemical or serological ev-idence occurs in a tumor outside the liver. The morphologyof the tumor may include a mixture of glandular adenocar-cinoma and tumor elements identical to HCC of liver origin.Confirmatory testing with either serological or immunohis-tochemical hepatic markers including AFP, Hep-Par 1, orGPC3 should be performed. GPC3 is an oncofetal protein,which is found to be present in many AFP-producing HCCas well as many HAC cancers [6]. It is also expressed ingerm cell tumors of the ovary, particularly yolk sac tumor.

AFP is a serum protein synthesized by fetal liver, yolk sac,and gastrointestinal tract, the production of which commonly

decreases after birth. AFP may be produced by germ celltumors and HCC as well. While the presence of increasedAFP levels are considered to be a characteristic feature ofHAC, increased serum AFP is not universal or necessary toestablish the diagnosis [2]. Additionally tumors usually stainpositive for AFP but this is not a uniform finding.

The clinical differentiation of HAC with unknown primary,from multifocal HCC may be difficult. The finding of adeno-carcinomatous and hepatocellular components, within the samespecimen, point to a diagnosis of HAC. The CTappearance of alarge liver mass with or without satellite lesions contrasted withdiffuse, multiple, and bilateral disease characteristic of metas-tases can be helpful in differentiating a primary from metastaticprocess. Finally, the development of HCC in a non-cirrhoticliver would be less commonly encountered [7].

Various theories exist to explain hepatoid features andAFP production by HAC. Hepatoid transformation or dif-ferentiation to a more fetal or primitive developmental stateis possible [8]. Additionally, a recent analysis of gastriccases producing AFP determined that early mucosal adeno-carcinomas are a common precursor lesion [9]. With tumorprogression and invasion, the ability to produce AFP paral-lels the development of hepatoid cellular features, alongwith AFP and GPC3 positivity on immunohistochemistry.Liver tropism by cells with similar histologic features may

Fig. 3 April 2012 CT scan withthickened loop of terminalileum and perforation in thesmall intestine, left lowerquadrant

Fig. 4 Left micrograph,terminal ileum adenocarcinoma,glandular area (×400). Rightmicrograph, terminal ileumhepatoid area with alphafetoprotein stain (inset; ×100)

J Gastrointest Canc (2013) 44:357–361 359

somehow relate to the propensity to develop liver metasta-ses, which is seen in most patients who develop HAC.

There is no known genetic basis for the development ofmalignancy in IBD. However, it is thought that chronicinflammation may lead to dysplasia and subsequent adeno-carcinoma formation. It is of note, that both cases nowdescribed of small intestinal HAC occurred in patients withCrohn’s disease [4]. Furthermore, in our patient, the tumordeveloped in a segment of the small intestine, which wasknown to be affected by Crohn’s disease.

HAC has been described in the colon more frequentlythan in the small intestine (Table 1). Eight of the 17 reportedcases of colon HAC were of rectal origin [3–5, 8, 10–22]. Ofthose eight, three patients had ulcerative colitis for 10 to15 years prior to developing HAC in the involved rectalsegment [3–5]. By contrast, in our review of patients whodeveloped gastric HAC, there was no associated history ofIBD. It appears that IBD may be a specific risk factor fordeveloping HAC in the small intestine and rectum.

The clinical presentation of our patient was rather abruptwith the onset of perforation and peritonitis. This occurredshortly after beginning chemotherapy, which may have beenresponsible for a partial tumor response resulting in perfo-ration of the affected bowel segment. Furthermore, the siteof ileal perforation was within the segment, which wasprominently involved with Crohn’s disease.

Extensive vascular invasion and a propensity for the devel-opment of liver metastases combine to signal a poor prognosis

in patients who develop HAC. Median survival is 11 months.Knowledge of this carcinoma variant can be important, par-ticularly when interpreting liver biopsies in patients withmetastatic lesions and a history of IBD. Additionally, the lackof clinical or radiologic improvement in a patient with long-standing IBD might lead towards a more aggressive evalua-tion of that segment of the GI tract, a serum AFPdetermination, and earlier surgical resection.

Conflict of interest The authors declare that they have no conflict ofinterest.

References

1. Ishikura H, Fukasawa Y, Ogasawara K, Natori T, Tsukada Y,Aizawa M. An AFP-producing gastric carcinoma with features ofhepatic differentiation: a case report. Cancer. 1985;56:840–8.

2. Metzgeroth G, Ströbel P, Baumbusch T, Reiter A, Hastka J.Hepatoid adenocarcinoma—review of the literature illustrated bya rare case originating in the peritoneal cavity. Onkologie. 2010;33(5):263–9.

3. Lattes C, Carella R, Faggioli S, Gabusi E, Grigioni WF. Hepatoidadenocarcinoma of the rectum arising in ulcerative colitis: report ofa case. Dis Colon Rectum. 2000;43(1):105–8.

4. Liu Q, Bannan M, Melamed J, Witkin GB, Nonaka D. Two casesof hepatoid adenocarcinoma of the intestine in association withinflammatory bowel disease. Histopathology. 2007;51(1):123–5.

Table 1 Distribution of all reported hepatoid adenocarcinomas

Tumor origin Total numberof cases

Malegender (% )

Age(years (range))

Patients with metastatic disease(liver, lung, and lymph nodes (%))

Median survival inmonths (range)

Stomach 219 157 (71) 67.2 (44–88) 170 (77) 8 (0.5–25)

Ovary 29 0 59 (35–78) 20 (68) 16 (4–60)

Colon/Rectum 17 4 (23.5) 55.45 (42–80) 14 (82.3) 8 (1–24)

Lung 16 16 (100) 61.8 (36–86) 4 (25) 4.5 (0.1–18)

Pancreas 16 10 (62.5) 57 (28–80) 12 (75) 14 (3–102)

Uterus 14 0 64 (55–89) 0 8 (3–32)

Gallbladder 13 3 (23) 74 (55–77) 11 (84.6) 20 (3–26)

Esophagus 7 3 (42.8) 47 (44–76) 4 (57.1) 4 (4–8)

Urinary bladder 7 5 (71) 68 (61–85) 4 (57.1) 14 (12–19)

Small intestine 2 0 40 and 57 2 (100) Unknown

Fallopian tube 2 0 52 and 79 1 (50) 10+ and 24+

Peritoneal cavity 3 3 (100) 21, 42, and 68 1 (33) 3, 6, and 36+

Papilla of Vater 1 0 61 0 Unknown

Renal pelvis 1 1 (100) 72 0 10+

Thymus 1 0 70 0 26+

Adrenal 1 1 (100) 57 0 Unknown

Ureter 1 0 80 1 (100) Unknown

Biliary tree 1 0 67 0 Unknown

Soft tissue 1 0 68 1 (100) 15+

360 J Gastrointest Canc (2013) 44:357–361

5. Borgonovo G, Razzetta F, Assalino M, Varaldo E, Puglisi M,Ceppa P. Rectal hepatoid carcinoma with liver metastases in apatient affected by ulcerative colitis. Hepatobiliary Pancreat DisInt. 2008;7(5):539–43.

6. Kakar S, Gown AM, Goodman ZD, Ferrell LD. Best practicesin diagnostic immunohistochemistry: hepatocellular carcinomaversus metastatic neoplasms. Arch Pathol Lab Med. 2007;13(11):1648–54.

7. Ellouze S, Slim C, Ahmad G, Naourez G, Ali A, Héla M, MariemK, Mohamed BA, Tahia B. Hepatoid adenocarcinoma of the gall-bladder. World J Surg Oncol. 2011;9:103.

8. Taguchi J, Yano H, Sueda J, Yamaguchi R, Kojiro M, Shirouzu G,Hashimoto K. Alpha-fetoprotein-producing rectal carcinoma—acase report. Kurume Med J. 1997;44(4):339–48.

9. Kinjo T, Taniguchi H, Kushima R, Sekine S, Oda I, Saka M,Gotoda T, Kinjo F, Fujita J, Shimoda T. Histologic and immuno-histochemical analyses of α-fetoprotein-producing cancer of thestomach. Am J Surg Pathol. 2012;36(1):56–65.

10. Nakajima T, Okazaki N, Morinaga S, Tsumuraya M, Shimosato Y,Saiki S. A case of alpha-fetoprotein-producing rectal carcinoma.Jpn J Clin Oncol. 1985;15(4):679–85.

11. Yu YY, Ogino T, Okada S. An alpha-fetoprotein-producingcarcinoma of the rectum. Acta Pathol Jpn. 1992;42(9):684–7.

12. Sato Y, Sekine T, Ohwada S. Alpha-fetoprotein-producing rectalcancer: calculated tumor marker doubling time. J Surg Oncol.1994;55(4):265–8.

13. Narita T, Sekiguchi H, Kajikawa M. A case of alpha-fetoprotein rectalcarcinoma. Shokaki Geka (Gastroenterol Surg). 1989;12:2009–13.

14. Hocking GR, Shembrey M, Hay D, Ostör AG. Alpha-fetoprotein-producing adenocarcinoma of the sigmoid colon with possiblehepatoid differentiation. Pathology. 1995;27(3):277–9.

15. Ishikura H, Kishimoto T, Andachi H, Kakuta Y, Yoshiki T.Gastrointestinal hepatoid adenocarcinoma: venous permeationand mimicry of hepatocellular carcinoma, a report of four cases.Histopathology. 1997;31(1):47–54.

16. Yachida S, Fukushima N, Nakanishi Y, Akasu T, Kitamura H,Sakamoto M, Shimoda T. Alpha-fetoprotein-producing carcinomaof the colon: report of a case and review of the literature. Dis ColonRectum. 2003;46(6):826–31.

17. Zhang J, Li XJ, Teng HH. Colon hepatoid adenocarcinoma with livermetastasis. Zhonghua Bing Li Xue Za Zhi. 2005;34(4):249–50.

18. Cappetta A, Bergamo F, Mescoli C, Lonardi S, Rugge M, ZagonelV. Hepatoid adenocarcinoma of the colon: what should we target?Pathol Oncol Res. 2012;18(1):93–6.

19. Hsu KF, Hsieh CB, Chang YM, Yu JC, Chan DC, Jin JS, Jao SW.An unusual submucosal tumor of the cecum presenting a palpableabdominal mass: hepatoid carcinoma. Rev Esp Enferm Dig.2011;103(1):43–4.

20. Kurihara K, Konishi F, Kanazawa K, Fujii T, Saito K. Alpha-fetoprotein-producing carcinoma of the colon: report of a case.Surg Today. 1997;27(5):453–6.

21. Slotta JE, Jüngling B, Kim YJ, Wagner M, Igna D, Schilling MK.Hepatoid adenocarcinoma of the transverse colon. Int J ColorectalDis. 2012;27(7):989–91.

22. Kato K, Matsuda M, Ingu A, Imai M, Kasai S, Mito M, KobayashiT. Colon cancer with a high serum alpha-fetoprotein level. Am JGastroenterol. 1996;91(5):1045–6.

J Gastrointest Canc (2013) 44:357–361 361