Journal of Clinical Pathology, 1978, 31, 990-995

Carcinoid tumour of the uterine cervixT. F. C. S. WARNER

From the Department ofPathology, Indiana University Medical Center, Indianapolis, Indiana, USA

SUMMARY A carcinoid tumour of the cervix in a 64-year-old woman is described. It is the firsttime that this rare tumour has been associated with carcinoma-in-situ.

Carcinoid tumours of the gastrointestinal tract andlung are well recognised yet relatively uncommonneoplasms. More unusual locations of carcinoids arethe ovary (Robboy et al., 1975), thymus (Rosai et al.,1976), pancreas (Hallwright et al., 1964; Patchefskyet al., 1974), liver (Primack et al., 1971), biliary tract(Shiffman and Juler, 1964), salivary gland (Nicod,1958), breast (Cubilla and Woodruff, 1977), and theuterine cervix (Tateishi et al., 1975; Albores-Saavedra et al., 1976). Argyrophilic precursor cellshave been demonstrated in most of these sites.In normal cervical mucosa these cells are very rare(Fox et al., 1964), and Tateishi et al. (1975) identifiedsmall numbers of them in 35% of instances. To date,17 carcinoid tumours of the cervix have been docu-mented (Tateishi et al., 1975; Albores-Saavedra etal.,1976). Another case is the subject of the presentreport.

Case report

A 64-year-old woman was admitted for investigationof intermittent vaginal spotting of five years' dura-tion. Bleeding became more profuse and frequenttwo months before admission. She had never hadgynaecological problems or a Papanicolaou smear.She had smoked one package of cigarettes per day forapproximately 30 years. Physical examination, chestx-ray, and an intravenous pyelogram were normal.However, a large fungating lesion of the cervix wasfound. Cervical biopsy showed 'epidermoid carci-noma-in-situ' (Figs 1 and 2). Pelvic examination,after referral for rebiopsy and staging, revealed a red,fungating, friable mass, approximately 4 x 4 cm,occupying most of the external cervical os, whichwas displaced to the left with minimal involvementof the vaginal apex. There was nodularity of theparametrium on the left side but the pelvic wall wasnormal. Neither organomegaly nor lymphadenopathywas found. No abnormalities were found on sig-

Received for publication 15 March 1978

moidoscopy and cystoscopy. The carcinoembryonicantigen level was 72-0 ng/ml. Microscopic examina-tion of cervical biopsy specimens was reported as'invasive, poorly differentiated epidermoid carci-noma, large-cell non-keratinising type; epidermoidcarcinoma-in-situ'.

Tentative clinical stage was JIB. However, atlaparotomy one week later, tumour was found in theuterine fundus, serosa of bladder, and left ovary.Metastatic 'poorly differentiated epidermoid carci-noma' was also found in a periaortic lymph node.During the following month 4000 rads externalradiation and two radium inserts (2000 rads each)were administered. On readmission two weeks latershe was cachectic, listless, and dehydrated. Ex-tension of the tumour to the lateral wall of thevagina was noted. Biopsy of slightly enlarged leftsupraclavicular lymph nodes under local anaes-thesia revealed 'metastatic poorly differentiatedepidermoid carcinoma'. Death occurred in hospital23 days later.

PATHOLOGICAL FINDINGSPostmortem examination revealed extensive meta-static disease in many organs. The pleural cavitiestogether contained 700 dl of clear yellow fluid;occasional 2-mm nodules were present on the visceraland parietal pleurae. The lungs together weighed1150 g; no obstruction or primary lesion was identi-fied in the bronchial tree. The liver weighed 2250 gand contained several 3-cm white tumour nodulesthroughout. The spleen weighed 210 g and harbouredseveral 1-5 cm tumour nodules. The heart containedan interatrial tumour nodule and several epicardialones but was otherwise normal. The combinedweight of the adrenal glands was 70 g, and both werealmost completely replaced by tumour. The uteruswas small, and subserosal tumour nodules werepresent; the endometrial surface was normal. Anecrotic mass of tissue, 10 cm in diameter, wasattached to the cervical remnant. Cervical, intra-thoracic, and intra-abdominal lymph nodes were

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Carcinoid tumour of the uterine cevix

Fig. 1 Carcinoma-in-situ of cervix.(Haematoxylin andeosin x 400)

Fig. 2 Severe cervicaldysplasia. (H and Ex 400)

enlarged. Tumour nodules were present in thekidneys, pancreas, ovary, thyroid, gastric mucosa,and vertebral bone marrow. Microscopic examina-tion confirmed the presence of tumour in theaforementioned sites.

All of the biopsy and necropsy material, with theexception of the block from the second biopsy, wasavailable for review. The metastatic tumour wascomposed of sheets, nests, and strands of tumourcells with pale eosinophilic cytoplasm and nuclei

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containing dense clumped chromatin. Mitoses wereplentiful and focal necrosis was not unusual.Clusters of rosettes were first noted among solidsheets of cells in the metastatic lesions (Fig. 3)and were identified in most deposits, but squamousdifferentiation was not found here. Close scrutiny ofthe second biopsy specimen and of most subsequentspecimens revealed the presence of rosettes, albeit insmall numbers (Fig. 4). Here tumour cells wereslightly larger than those of the necropsy material.Nuclear chromatin was stippled rather than clumped,and mitoses were numerous. These cytologicaldifferences may have been due to more immediatefixation and better viability of tissue. Rosettes werenot identified superficial to the limiting membrane inareas of dysplasia or carcinoma-in-situ. However,they were immediately subjacent to but not incontinuity with carcinoma-in-situ. There was amoderate lymphohistiocytic infiltrate in the sub-epithelial stroma. Foci of in-situ cancer and somefoci of microinvasive carcinoma were unmistakenlysquamous in type. Small foci of squamous differen-tiation and rosettes were also observed in separatefragments of a biopsy specimen from the uterinefundus (Fig. 5). Definite intermingling of rosettesand squamous elements was not seen. Isolated cellsthat reacted positively with a modified Grimeliusstain (Fernandez Pascual, 1976) and rosettes werefound in the supraclavicular lymph node (Fig. 6).

Discussion

Thispatient'ssymptomswere not unusual, and in viewof the long history of bleeding it is unfortunate thatshe never had cervical smears. The long survival afterthe onset of symptoms compares with two of thecases reported by Albores-Saavedra et al. (1976).Both were considered to have well differentiatedtumours and the patients survived five and six yearsas opposed to three to 24 months' survival for thosewith poorly differentiated carcinoids. Endocrinechanges were not found in this case, and estimationsof serum polypeptide hormones or amines were notperformed. Elevated levels of carcinoembryonicantigen have been reported in squamous cell car-cinoma of the cervix (DiSaia et al., 1975; Kjorstadand Orjaseter, 1977) but the level found in this caseis very high.

All carcinoid tumours, irrespective of the degreeof differentiation, are potentially lethal neoplasmsderived from the clear neurendocrine cells of Feyrter(1952), which are now commonly referred to asAPUD cells of Pearse (1974). The most benigntumours are those of the ileocaecal region with ahigh cure rate and very long survival (Moertel et al.,1961). Oat cell (small cell) carcinoma probablyrepresents the most malignant state of this cell type.Between these limits lie neoplasms of varying gradesof malignancy, depending on the degree of differen-

a..tX~~~~~~.Fig. 3 Metastatictumour in liver

40 showing rosetteformation. (H and

* E x400)

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Carcinoid tumour of the uterine cervix

Fig. 4 Rosetteformation in secondcervical biopsyspecimen. In otherfields the tumour wasmonotonous, andsevere dysplasia withcarcinoma-in-situ waspresent in thesuperficial epithelium.(H and E x 100)

Fig. 5 Focus ofsquamousdifferentiation inuterus. (H andE x 1000)

tiation and on their location. Thus oat cell car-cinomas have been described in the same sites ascarcinoids with the interesting exception of the smallintestine and appendix. It is very likely that many;lundifferentiated small cell carcinomas of the cervix

are in reality types of carcinoid tumour. Morewidespread application of silver stains and ultra-structural examination should reveal more of thesetumours, especially in those cases that lack defini-tive histological features. Unfortunately in this case

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Fig. 6 Argyrophilgranules (arrows) inisolated cells ofsupraclavicular lymphnode. (ModifiedGrimelius x 1000)

the only tissue that might have been suitable forelectron microscopy was not available. Stains forargyrophilic cells also require excellent fixation, andtissue of borderline viability is obviously unsuitable.The histological pattern encountered in oat cell

carcinomas of the lung (Azzopardi, 1959) andcarcinoid tumours (Williams and Sandler, 1963;Soga and Tazawa, 1971) is distinctive and aids intheir recognition even without recourse to specialtechniques. Both may share common patterns, de-pending on their location, but generally oat cellcarcinomas are composed of small round or spindlecells. Cells may be arranged in ribbons, festoons,trabeculae or nests. Pseudorosettes and true rosettesmay also be present (Azzopardi, 1959; Soga andTazawa, 1971). The latter have been described incarcinoids of many sites, including the cervix(Albores-Saavedra et al., 1976), thymus (Rosai et al.,1976), and breast (Cubilla and Woodruff, 1977) andin oat cell carcinoma of the lung (Azzopardi, 1959);they correspond to the acini that are commonlyfound in midgut carcinoids. The presence of thesestructures lends a distinctive appearance to thesetumours. Morphologically they are distinguishablefrom glandular formation in adenocarcinoma(Azzopardi, 1959; Hattori et al., 1972). As in thepresent case, intracytoplasmic, intraluminal, andintercellular PAS-positive material has been found incarcinoids and oat cell tumours (Azzopardi, 1959;

Soga and Tazawa, 1971; Tateishi et al., 1975;Albores-Saavedra et al., 1976).

It is difficult to exclude the concurrence ofsquamous cell carcinoma and carcinoid tumour inthis case. Thus, this could be a collision tumour. Theclinical history and anatomical findings weigh heavilyagainst a primary tumour of the lung. Neoplasticchanges in the ectocervix were typically squamousand diffuse and did not resemble intraepithelialspread of the type seen in Paget's disease or malig-nant melanoma. Squamous metaplasia in the uteruscould be explained if the neural crest origin of theprecursor cell in this location was disregarded infavour of a mesodermal origin, that is, from endo-cervical glands. However, this is only because uterineadenocarcinomas may harbour benign or malignantsquamous elements. Microscopic foci of 'epidermoiddifferentiation' were found in three of the 12 cervicalcarcinoids reported by Albores-Saavedra et al.(1976), and Tateishi et al. (1975) found 'squamousmetaplasia' in two of five tumours. Squamous ele-ments are a rare but accepted feature of carcinoidtumours (Rosai et al., 1976). Carcinoma-in-situhas not been described in any of the 17 reportedcases of cervical carcinoid (Tateishi et al., 1975;Albores-Saavedra et al., 1976). This case is notwithout precedent as bimorphic features have beenrecognised in other carcinoid tumours, notably thoseof the gastrointestinal tract (Azzopardi and Pollock,

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Carcinoid tumour of the uterine cervix 995

1963; Hernandez and Reid, 1969). To explain thisone could postulate: (1) a common precursor cellwith metaplasia, (2) a collision effect with mixing oftwo elements, or (3) permanent phenotypic con-version with variable expressivity through genetransfer or cell hybridisation. All explanations arehighly speculative and lack experimental verification.

References

Albores-Saavedra, J., Larraza, 0., Poucell, S., andRodriguez-Martinez, H. A. (1976). Carcinoid of theuterine cervix. Cancer, 38, 2328-2342.

Azzopardi, J. G. (1959). Oat cell carcinoma of thebronchus. Journal of Pathology and Bacteriology, 78,513-519.

Azzopardi, J. G., and Pollock, D. J. (1963). Argentaffinand argyrophil cells in gastric carcinoma. Journal ofPathology and Bacteriology, 86, 443-451.

Cubilla, A. L., and Woodruff, J. M. (1977). Primarycarcinoid tumour of the breast. American Journal ofSurgical Pathology, 1, 283-292.

DiSaia, P. J., Haverback, B. J., Dyce, B. J., and Morrow,C. P. (1975). Carcinoembryonic antigen in patientswith gynaecologic malignancies. American Journal ofObstetrics and Gynaecology, 121, 159-163.

Fernandez Pascual, J. S. (1976). A new method for easydemonstration of argyrophil cells. Stain Technology,51, 231-235.

Feyrter, F. (1952). Zum Begriff der Helle-Zellen-Systeme.Frankfurter Zeitschrift fur Pathologie, 63, 259-266.

Fox, H., Kazzaz, B., and Langley, F. A. (1964). Argyro-phil and argentaffin cells in the female genital tract andin ovarian mucinous cysts. Journal of Pathology andBacteriology, 88, 479-488.

Hallwright, G. P., North, K. A. K., and Reid, J. D.(1964). Pigmentation and Cushing's syndrome due tomalignant tumour of the pancreas. Journal of ClinicalEndocrinology and Metabolism, 24, 496-500.

Hattori, S., Matsuda, M., Tateishi, R., Nishihara, H., andHorai, T. (1972). Oat-cell carcinoma of the lung:clinical and morphological studies in relation to itshistogenesis. Cancer, 30, 1014-1024.

Hernandez, F. J., and Reid, J. D. (1969). Mixed carci-noid and mucus-secreting intestinal tumors. ArchivesofPathology, 88, 489-496.

Kjorstad, K. E., and Orjaseter, H. (1977). Studies oncarcinoembryonic antigen levels in patients withadenocarcinoma of the uterus. Cancer, 40, 2953-2956.

Moertel, C. G., Sauer, W. G., Dockerty, M. B., andBaggenstoss, A. H. (1961). Life history of the carcinoidtumour of the small intestine. Cancer, 14, 901-912.

Nicod, J. L. (1958). Carcinoide de la parotide. Bulletin del'Association FranCaise pour l'Ttude du Cancer, 45,214-222.

Patchefsky, A. S., Gordon, G., Harrer, W. V., and Hoch,W. S. (1974). Carcinoid tumour of the pancreas.Cancer, 33, 1349-1354.

Pearse, A. G. E. (1974). The APUD cell concept and itsimplications in pathology. Pathology Annual, 9, 27-41.

Primack, A., Wilson, J., O'Connor, G. T., Engelman, K.,Hull, E., and Canellos, G. P. (1971). Hepatocellularcarcinoma with the carcinoid syndrome. Cancer, 27,1182-1189.

Robboy, S. J., Norris, H. J., and Scully, R. E. (1975).Insular carcinoid primary in the ovary. Cancer, 36,404-418.

Rosai, J., Levine, G., Weber, W. R., and Higa, E. (1976).Carcinoid tumours and oat cell carcinomas of thethymus. Pathology Annual, 11, 201-226.

Shiffman, M. A., and Juler, G. (1964). Carcinoid of thebiliary tract. Archives of Surgery, 89, 1113-1115.

Soga, J., and Tazawa, K. (1971). Pathologic analysis ofcarcinoids: Histologic reevaluation of 62 cases. Cancer,28, 990-998.

Tateishi, R., Wada, A., Hayakawa, K., Hongo, J.,Ishii, S., and Terakawa, N. (1975). Argyrophil cellcarcinomas (Apudomas) of the uterine cervix. VirchowsArchiv A Pathological Anatomy and Histology, 366,257-274.

Williams, E. D., and Sandler, M. (1963). The classificationof carcinoid tumours. Lancet, 1, 238-239.

Requests for reprints to: Dr T. F. C. S. Warner,Department of Pathology, Indiana School of Medicine,1100 West Michigan Street, Indianapolis, Indiana 46202,USA.

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