Title Elevated serum alpha-fetoprotein in a patient withundifferentiated carcinoma of the gall bladder

Author(s) Ng, WK; Ng, WF

Citation Journal of Clinical Pathology, 1995, v. 48 n. 11, p. 1061-1063

Issued Date 1995

URL http://hdl.handle.net/10722/46955

Rights Creative Commons: Attribution 3.0 Hong Kong License

Pseudoangiosarcomatous carcinoma of the genitourinary tract

Pathological findingsThe bladder showed diffuse thickening ofmostof its wall by infiltrating haemorrhagic tumour.Microscopically, the tumour was predomin-antly a typical high grade transitional cell car-cinoma showing focal keratinisation. In thedeeper aspect there was a spindle cell andpseudoangiosarcomatous pattern similar tothat seen in case 1, with cystic and slit-likespaces lined by tumour cells (fig 2). These werealso negative for factor VIII, QBEND 1 0, JC70,and S100 protein, but positive for Cam 5-2and AE1/3 (fig 2).Lymph nodes examined contained meta-

static tumour which also had a pseudo-angiosarcomatous pattern.

DiscussionSarcomas of the vulva and bladder are rareand are predominantly leiomyosarcomas andmalignant fibrous histiocytomas.6' Angio-sarcomas are exceedingly rare with only oc-casional cases reported.6 While examples ofso called spindle cell or pseudosarcomatouscarcinoma of the female genital tract and blad-der have been described,' 2 no case of pseudo-angiosarcomatous carcinoma has, to our know-ledge, been reported at these sites. Banerjee etal3 studied seven cases from skin, breast andlung, four of which were originally diagnosedas angiosarcoma, and Nappi et al45 reported asmall series from the skin and lung. The correctdiagnosis was established by a combination ofa careful search for focal keratinisation andatypical squamous epithelium, immuno-histochemistry and ultrastructural analysis. Inour cases the tumours had similar mor-phological features to those described by Baner-jee et al and Nappi et al, the diagnoses beingconfirmed by the presence of focal ker-atinisation and a vascular marker negative,cytokeratin positive immunophenotype.

It has been suggested that acantholysis is theunderlying pathogenic mechanism,3 possibly as

a consequence ofchanges in adhesion moleculeexpression by the tumour cells. There is evi-dence ofreduced E-cadherin expression in non-neoplastic acantholytic disorders of the skin8and a study of adhesion molecule expressionin these sarcomatoid tumours would be ofinterest.

Pseudoangiosarcomatous carcinoma seemsto behave in an aggressive manner reflectingthe high grade, poorly differentiated nature ofthe carcinoma.?5 Angiosarcomas of the vulvamay, however, behave in a more indolent fash-ion with recurrences and late metastases bythe haematogenous rather than the lymphaticroute.6

In conclusion, pseudoangiosarcomatous car-cinoma should be considered in the differentialdiagnosis of malignant angiomatoid tumours,particularly those that arise at sites, like thegenitourinary tract, where angiosarcoma is rare.Adequate sampling with careful examinationfor keratinisation, atypical squamous epi-thelium and areas of differentiated carcinomais advised and immunohistochemistry and pos-sibly electron microscopy performed.

1 Steeper TA, Piscioli F, Rosai J. Squamous cell carcinomawith sarcoma-like stroma of the female genital tract. Cancer1983;52:890-8.

2 Torenbeck R, Blomjous CEM, de Bruin PC, Newling DWW,Meijer CJLM. Sarcomatoid carcinoma of the urinary blad-der. Clinicopathologic analysis of 18 cases with imn-munohistochemical and electron microscopy findings. AmJ Surg Pathol 1994;18:241-9.

3 Banerjee SS, Eyden BP, Wells S, McWilliam U, Harris M.Pseudoangiosarcomatous carcinoma: A clinicopathologicalstudy of seven cases. Histopathology 1992;21:13-23.

4 Nappi 0, Wick MR, Pettinato G, Ghiselli RW, Swanson PE.Pseudovascular adenoid squamous cell carcinoma of theskin. A neoplasm that may be mistaken for angiosarcoma.Am J Surg Pathol 1992;16:429-38.

5 Nappi 0, Swanson PE, Wick MR. Pseudovascular adenoidsquamous cell carcinoma of the lung: Clinicopathologicstudy of three cases and comparison with true pleuro-pulmonary angiosarcoma. Hum Pathol 1994;25:373-8.

6 Davos I, Abell MR. Soft tissue sarcomas of the vulva. GynecolOncol 1976;4:70-86.

7 Swartz DA, Johnson DE, Ayala AG, Watkins DL. Bladderleiomyosarcoma. A review of 10 cases with five year followup. Jf Urol 1985;133:200-2.

8 Burge SM, Schomberg KH. Adhesion molecules and relatedproteins in Dariers disease and Hailey-Hailey disease. BrJ Dermatol 1992;127:335-43.

J Clin Pathol 1995;48:1061-1063

Elevated serum cx-fetoprotein in a patient withundifferentiated carcinoma of the gall bladder

Department ofPathology,University of HongKong,Queen Mary HospitalCompound,Pokfulam Road,Hong KongW K Ng

Department ofPathology, RuttonjeeHospital, Hong KongW F Ng

Correspondence to:Dr W K Ng.Accepted for publication24 April 1995

W K Ng, W F Ng

AbstractAn uncommon case of undifferentiatedcarcinoma of the gall bladder in a 65 yearold Chinese man, who presented with anincreased serum a-fetoprotein con-centration, is reported. Histologically, thetumour had a primitive appearance andwas composed ofa pavement-like array ofpoorly differentiated columnar/polygonal

cells. Alpha-fetoprotein was demonstratedin some of the tumour cells using an im-munoperoxidase technique. Alpha-feto-protein secretion in this instance may haveoccurred because the gall bladder and theliver are of similar embryological origin.Alpha-fetoprotein may also be related tothe resurgent expression of oncofetal an-tigens. This tumour may represent an-

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other rare cause of increased serum a-fetoprotein concentrations.(_J Clin Pathol 1995;48:1061-1063)

Keywords: oa-fetoprotein, undifferentiated carcinoma,gall bladder.

Serum oa-fetoprotein concentrations are oftennoticeably increased in hepatocellular car-cinomas and yolk sac tumours. Such increaseshave also rarely been associated with carcinomaof the stomach,' colon, pancreas,2 and lung.3Many gall bladder malignancies are mucin se-creting adenocarcinomas and do not secrete a-fetoprotein; however, a rare type of gall bladdercarcinoma, previously known as pleomorphicgiant cell adenocarcinoma, has been reportedto be associated with intra- and/or extracellularoa-fetoprotein containing eosinophilic globules.'Recently, Vardaman et al5 described seven casesof clear cell carcinoma of the gall bladder.

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Figure 1 Photomicrograph of the gall bladder tumour showing the pavement-like arrayof tumour cells (haematoxylin and eosin, original magnification x 400).

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Figure 2 Photomicrograph of immunohistochemical staining showing cytoplasmicpositivity for a-fetoprotein in some of the tumour cells (original magnification x 1000).

One of their cases showed features of hepatoiddifferentiation and was associated with oa-feto-protein secretion. Here, we report a rare case ofundifferentiated carcinoma of the gall bladderpresenting with persistently increased serum oa-fetoprotein concentrations. The morphology ofthis tumour, however, was different from thatof clear cell carcinoma.

Case reportA 65 year old Chinese man first presented withepigastric pain of several days duration. Onadmission, the patient had an increased totalbilirubin concentration (124 jtmol/l) and slightderangement of liver function. His serum oa-fetoprotein concentration was 32 ng/ml. Ul-trasonogram of the biliary system and en-doscopic retrograde cholangiopancreatogramwere unremarkable. Four months after pre-sentation, the patient's serum oa-fetoproteinconcentration rose to 256 ng/ml. Liver functionremained normal. Hepatic arteriogram andlipoidal computed tomography were performedand did not reveal a definite tumour mass inthe liver. The gall bladder wall, however, wasthickened with a focal increase in density. Thepatient's serum oa-fetoprotein concentration re-mained high and was 425 ng/ml one monthlater. Seven months after initial presentation,the patient was readmitted because ofrecurrentepigastric pain. His serum cx-fetoprotein con-centration was 275 ng/ml at this time. Thepatient died suddenly two days after admissionof cardiac failure.A clinical postmortem examination was per-

formed one day after his death. There was a 4cm, tan coloured, fungating tumour over thefundus of the gall bladder. The distal part ofthe common bile duct was obstructed by a 2cm, cylindrical, necrotic tumour mass whichhad detached from the main tumour bulk inthe gall bladder. Local destruction of adjacentorgans was not seen. Gallstones and lymphnode enlargement were not present. The liverwas mildly enlarged and there was no evidenceof hepatocellular carcinoma. Thorough ex-amination of the testes, mediastinum and brainrevealed no evidence of germ cell tumours.

Multiple tissue blocks were sampled fromthe gall bladder tumour, promptly fixed in 10%neutral buffered formalin and embedded inparaffin wax. Sections, 3 jtm thick, were cutand stained with haematoxylin and eosin, mu-cicarmine, periodic acid-Schiff (PAS), alcianblue, Grimelius, and Fontana-Masson. Im-munohistochemical studies were carried outusing the Streptavidin biotin complex tech-nique using antibodies directed against cx-feto-protein (Dako), AE 1/3 (BioGenex), Cam 5.2(Becton Dickinson), vimentin (Dako), mono-clonal carcinoembryonic antigen (Dako),neuron-specific enolase (BioGenex), chro-mogranin (BioGenex), and synaptophysin(Boehringer Mannheim).

Histological examination of the gall bladdertumour revealed a superficially invasive car-cinoma infiltrating the inner part of the musclecoat. The tumour was composed of a pave-ment-like array of columnar/polygonal cells (fig

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Undifferentiated carcinoma of the gall bladder

1) which contained a moderately pleomorphicvesicular nucleus, inconspicuous nucleoli, fre-quent mitotic figures, and foamy to granularamphophilic cytoplasm. Occasional tumourgiant cell formation was evident. There wereno sarcomatoid or clear cell changes. Focalareas with a microtrabecular pattern and pal-isaded nuclei were identified, but true papillaryconfigurations or hepatoid differentiation wasnot found. In some of the sections the tumourcells were associated with clumps of acellu-lar eosinophilic squame-like material. Truesquamous cell components, however, were notidentified. The tumour cells were negative formucicarmine, PAS and alcian blue. They werealso non-argyrophilic and non-argentaffinic.On immunohistochemistry, oa-fetoprotein wasdetected in the cytoplasm of some tumourcells (fig 2) as well as among extracellulareosinophilic material. The tumour cells did notexpress vimentin, carcinoembryonic antigen,neuron-specific enolase, chromogranin, or sy-naptophysin.

DiscussionAlpha-fetoprotein is a serum glycoprotein pro-duced by embryonic liver cells and yolk sactissues. It has no confirmed biological functionin humans. The serum oa-fetoprotein con-centration is of particular value in the diagnosisand follow up of hepatocellular carcinomas oryolk sac tumours. It has been proposed that aserum concentration of400 ng/m in adults maybe a useful threshold for diagnosing hepa-tocellular carcinoma. Other tumour types andnon-neoplastic conditions such as viral hep-atitis and inflammatory bowel disease are rarelyassociated with this degree of elevation. Thispatient represents a rare case of carcinoma ofgall bladder associated with a persistent in-crease in serum oa-fetoprotein concentrations.

Histologically, the tumour was an un-differentiated carcinoma of the gall bladder,previously referred to as pleomorphic giant celladenocarcinoma. This group of neoplasms ischaracterised by a wide spectrum of mor-phology and various proportions of polygonal,round, spindle, and multinucleated giant cells.4Areas of well differentiated adenocarcinomaare found in about two thirds of the tumours,representing a transition from pleomorphiccomponents to well differentiated elements.Foci of squamoid differentiation may also bepresent in a small number of cases. The finalthird, including the case presented here, con-sists exclusively of undifferentiated elements.Eosinophilic hyaline globules are present inabout 10% of the tumours, and some are posi-tive for oa-1-antitrypsin or ca-fetoprotein. Thewide spectrum ofmorphological features ofthisgroup of tumours illustrates their potential todifferentiate along different lines includingglandular, squamous and hepatoid. In contrastto most of the previously reported cases ofoa-fetoprotein producing gall bladder car-

cinomas,5" this case did not show any evidenceof clear cell differentiation. It is possible thatthe present case and the a-fetoprotein secretingclear cell carcinomas simply represent two ex-tremes of a spectrum with different degreesand stages of hepatoid differentiation.

Secretion of ot-fetoprotein by gall bladdercarcinomas may occur because the gall bladderand the liver are of similar embryological origin,as well as because ofthe resurgence ofoncofetalantigens. Embryologically, the gall bladder ori-ginates from the hepatic diverticulum, whichis a ventral outgrowth from the caudal part ofthe foregut and later divides to form the gallbladder and the liver. In laboratory animalschemically induced liver tumours can differ-entiate morphologically and biochemicallytowards either liver tissues or intestinal epi-thelium.'0 Similarly, because the gall bladderand the liver are closely related at the em-bryological level, multipotential uncommittedtumour cells in undifferentiated carcinoma ofthe gall bladder may undergo primitive hepa-toid differentiation and acquire the ability toproduce a-fetoprotein. Alternatively, re-surgence of oncofetal antigen expression by thetumour cells may also explain this phe-nomenon.The present case represents another

uncommon cause of increased serum oa-fetoprotein concentrations. While this phe-nomenon may help in the understanding ofembryological differentiation of undiffer-entiated gall bladder carcinomas, it may alsoserve to remind clinicians that increased serumoa-fetoprotein concentrations in adults are notalways diagnostic of hepatocellular carcinoma.Analysis of follow up serum oa-fetoprotein con-centrations can also be useful for assessingtumour recurrence.

1 Matsunou H, Konishi F, Jalal RE, Yamamichi N, MukawaA. Alpha-fetoprotein-producing gastric carcinoma withenteroblastic differentiation. Cancer 1994;73:534-40.

2 McIntire KR, Waldmann TA, Moertel CG, Go VL. Serumalpha-fetoprotein in patients with neoplasms of the gas-trointestinal tract. Cancer Res 1975;35:991-6.

3 Ishikura H, Kanda M, Ito M, Nosaka K, Mizuno K. Hepa-toid adenocarcinoma. A distinctive histological subtypeof alpha-fetoprotein-producing lung carcinoma. VirchowsArch A Pathol Anat Histopathol 1990;417:73-80.

4 Albores-Saavedra J, Henson DE. Tumors of the gallbladderand extrahepatic bile ducts. Atlas oftumorpathology, fascicle22. 2nd series. Washington DC: Armed Forces Instituteof Pathology, 1986.

5 Vardaman C, Albores-Saavedra J. Clear cell carcinomas ofthe gallbladder and extrahepatic bile ducts. Am J SurgPathol 1995;19:91-9.

6 Brown JA, Roberts CS. Elevated serum alpha-fetoproteinlevels in primary gallbladder carcinoma without hepaticinvolvement. Cancer 1992;70: 1838-40.

7 Haruta J, Kanayama K, Tachino F, Hayakawa M, KusakabeA, Kurokawa S, et al. A clinicopathological evaluation ofAFP-positive gallbladder cancer. With special referenceto two autopsy cases investigated by an immunologicalmethod. Gan No Rinsho 1987;33:1839-45.

8 Sugaya Y, Sugaya H, Kuronuma Y, Hisauchi T, Harada T.A case of gallbladder carcinoma producing both alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA).Gastroenteroljpn 1989;24:325-31.

9 Watanabe M, Hori Y, Nojima T, Kato H, Taketa K, IsogawaS, et al. Alpha-fetoprotein-producing carcinoma of thegallbladder. Dig Dis Sci 1993;38:561-4.

10 Yoshida Y, Kaneko A, Chisaka N, Onoe T. Appearance ofintestinal type oftumor cells in hepatoma tissue induced by3'-methyl-4-dimethylaminoazobenzene. Cancer Res 1978;38:2753-8.

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