Histopathology 1992. 21, 371-374

Small cell (neuroendocrine) carcinoma of the vagina J.R.MILIAUSKAS & A.S-Y.LEONG* Division of Tissue Pathology, Gribbles Pathology and *Division of Tissue Pathology, Znstitute of Medical 6 Veterinary Science, Adelaide, Australia Date of submisslon 20 December 1991 Accepted for publication 13 March 1992

MILIAUSKAS J.R. & LBONG A.S-Y.

(1992) Histopathology 21, 371-374

Small cell (neuroendocrine)carcinoma of the vagina We report a case of vaginal smail cell (neuroendocrine)carcinoma. Immunostaining for neuron-specific enolase, PGP 9.5, chromogranin, synaptophysin, Leu 7 and cytokeratin was positive. Neurosecretory granules were found by electronmicroscopy.There was local recurrence and regional lymph node metastases. The patient survived for 10 months following local surgical therapy only. Keywords: small cell carcinoma, vagina, neuroendocrine, immunohistochemistry

Introduction Small cell carcinoma occurs most commonly in the lung. However, up to 5% arise in extrapulmonary sites. Regardless of the site of origin, small cell carcinoma is an aggressive tumour with a propensity to early metastasis. Small cell carcinoma of the female genital tract occurs most frequently in the cervix, but may also develop in the endometrium and vulva’-’. There are seven reported cases of small cell carcinoma of the vagina*-12.and six other cases have been mentioned in two separate studies on vaginal and cervical We present the light and electroamicroscopic features of a case of primary small cell carcinoma of the vagina, with associated immunohistochemical characteristics and a review of the literature.

Case report

scan of the abdomen, chest and pelvis was clear of disease. The chest X-ray was normal. Local excision of the polypoid lesions revealed a small cell malignant neoplasm. A modified right hemivaginovulvectomy and right-sided inguinal node dissection was performed. This revealed minute residual islands of tumour and one inguinal lymph node contained metastatic carcinoma. Five months later, there was tumour recurrence in the paravaginal and pararectal regions, Once again CT scan of the abdomen and chest were clear of tumour. Left vagino-vulvectomy and antero-posterior resection of rectum were performed. No radiotherapy or chemotherapy was utiliid. The patient died 10 months after initial diagnosis and post-mortem examination was not performed.

Materials and methods

A 78-year-old woman presented with vaginal discharge. The tumour was fixed in 10%buffered formalin and A total abdominal hysterectomy had been performed 4 sections were stained with haematoxylii and eosin and years earlier for prolapse and fibroids. Examination Grimelius stains. For electronmicroscopy, tissue which revealed three polypoid nodules in the lower third of the had been fixed in formalin was post-fixed in 2.5% right lateral vaginal wall ranging from 12 x 10 x 10mm glutaraldehyde and embedded in Spurr’s resin. Thin to 40 x 25 x 10 mm. There was no evidence of local or sections were stained with uranyl acetate and lead distant spread of tumour. Computer tomography (CT) citrate. Immunohistochemistry was performed on paraffin-embedded sections using a streptavidin-biotin Address for correspondence:Dr J.R.Miliauskas.Gribbles Pathology, complex method15 with antibodies to the following: 1 Goodwood Road, Wayville SA 5034. South Australia, Australia. 371

372 J.R.Miliauskas and A.S-Y.Leong

Figure 1. Sheet of tumour cells with uniform nuclear chromatin and scanty cytoplasm. H & E.

Figure 2. The tumour cells show distinct cytoplasmic staining for synaptophysin.

neuron specific enolase (NSE), leucocyte common antigen (LCA), 5-100protein, bovine keratin, vimentin, synaptophysin,chromogranin, serotonin, gastrin, insulin (all from Dakopatts,California, USA), CAM 5.2, Leu7 (from Becton & Dickinson, California, USA), AE1/3 (Hybritech, California, USA) and PGP 9.5.(Ultraclone,

nantly arranged in sheets with no apparent architectural pattern. In a few areas they formed trabeculae or cords. There was no signillcant stromal reaction apart from very occasional small fibro-vascular bands and no squamous or glandular differentiation was present. In two small foci, a few scattered neoplastic cells contained argyrophilic granules as demonstrated by the Grimelius stain.

Results

IMMUNOHISTOCHEMISTRY

The tumour was highly cellular, composed of small, fairly uniform cells containing round to oval to spindle shaped nuclei. The nuclei were hyperchromaticand the chromatin was fmely dispersed. The nucleoli were inconspicuous and the cytoplasm was scant (Figure 1). Numerous mitoses and apoptotic bodies were present. Necrosis was minimal and there was no significant inflammatory reaction. The tumour cells were predomi-

The tumour cells stained strongly and diffusely for NSE, chromogranin, synaptophysin (Figure 2), PGP 9.5 and focally for Leu 7 (CD 57). In addition, there was staining for cytokeratins with antibovine keratin, CAM 5.2 and AE1/3. The staining was diffuse and there was no specific localization within the cell. There was no immunoreactivity for LCA, S-100 protein, serotonin, gastrin or insulin.

w.

Vaginal small cell carcinoma 3 73

Figure 3. The turnour nuclei contained heterochromatin and distinct nucleoli. Scattered dense core granules are visible. These are better seen in the inset as 120-180 nm granules. as are poorly formed desmosomes. x 17 500. x 26 500.

ELECTRON MICROSCOPY

The tumour cells showed pleomorphic nuclei with heterochromatin and small nucleoli. Occasional poorly formed desmosomes were present and there were interdigitations of cell membranes with scattered dense core granules present, measuring between 120 to 180 nm diameter (Figure 3). Scattered intermediate filaments were present in the cytoplasm but true tonofilaments were not seen.

Discussion Small cell carcinoma of the vagina is rare. It has been suggested that these tumours can arise from multipotential epithelial stem cells. This would help to explain the presence of squamous and glandular elements in pulmonary and extrapulmonary small cell cancers8*16. The presence of extremely low numbers of a r g e n t a n or

argyrophil cells in the normal human female genital tract has also been observed17. In assessing the present case and the 1 3 previously reported cases a number of clinicopathological features can be found8-14.Usually, small cell carcinoma of the vagina presented with post-menopausal bleeding and commonly present were metastases (local and distant) and/or local direct tumour spread. One case only displayed bidirectional differentiation, i.e. combined small cell and adenocarcinomalO. Patients survival ranged from 5 to 38 months with 85% dying within 1 year. The immunohistochemistry of primary small cell carcinoma of the vagina has not been reported in detail. In one case report, immunohistochemical staining for gastrin, secretin, ACTH and glucagon were negative and only serotonin showed positivity1". A second case demonstrated positivity for NSE and cytokeratin12. In our case, positivity for cytokeratins and neuroendocrine

3 74

1.R. Miliauskas and A.S-Y.Leong

Table 1. Immunohistochemical reactions for small cell carcinomas (SCC) CAM 5.2 Keratin

AE1/3

NSE

Chromogranin

Synaptophysin

Leu 7

Serotonin

PGP 9.5

-/+

+/-

+/-

+/-

+/-

+/-

-/+ -*

+

cervical SCC”J4 Vaginal SCC (present case)

* Positive in one case report. NSE =neuron specitic enolase:

-k

+

+

+

+

+

?

+ =positive: - =negative: +/ - =more often positive: -/ + =more often negative: ?= unknown.

markers, as well as negative results for S-100protein, LCA. serotonin, insulin and gastrin are similar to many of the described cases of small cell carcinoma of the cervix13*14(Table 1)and lung18. Small cell (neuroendocrine) carcinoma of the vagina may require differentiation from poorly differentiated squamous carcinoma of small cell type and non-Hodgkin’s lymphoma. The demonstration of neuroendocrine differentiation readily makes this distinction. At the light microscopic level, argyrophilia, or immunoreactivity for NSE,PGP 9.5, chromogranin, synaptophysin, Leu 7 or the detection of m in e s (e.g. serotonin) and polypeptides, demonstrate neuroendocrine differentiation.The finding of dense-core secretory granules ultrastructurally also helps in identifying the neuroendocrine nature of the tumour. In tumours with the appropriate light microscopic features, these adjunctive methods help in separating the small cell tumours with neuroendocrine differentiation from squamous carcinoma of small cell type.Leucocyte common antigen negativity also readily excludes the possibility of a lymphoma. It must be remembered that small cell carcinoma may display more than one direction of Werentiatlon, i.e. admixed with squamous and/or adenocarcinoma featureslg. The behaviour of primary small cell carcinoma of the vagina parallels that of small cell carcinoma of the lung. It is felt by a number of authors that local therapy is likely to fail since the disease is most likely disseminated at the time of presentation2*‘. Surgical resection and radiotherapy can be used to obtain local control and chemotherapy would need consideration even when no grossly metastatic disease is evident.

Acknowledgement We would like to thank Mrs Y.Kempster for typing the manuscript.

References 1. Walker AN, Mills SE4. Taylor PT. Cervical neuroendocrine carcinoma: a clinical and Ught microscopic study of 14 cases. Int. 1. Gynewl. Pathol. 1988;1; 64-74. 2. CUby W,Solsson AP. Bershuck A, Clarke-Pearson DI. Stage I small

cell carcinoma of the vulva treated with vulvectomy, lymphadenopathy and adjuvant chemotherapy. Cancer 1991: 67;2415241 7. 3. Kumar NB.Smallcell carcinoma of the endometriumin a 23-yearold woman: light microscopic and ultrastructure study. Am. 1. CUn. Pathol. 1984 81;98-101. 4. Olson N. Twiggs L, Sibley R. Small cell carchoma of the endometrium. Light microscopic and ultrastructural study of a case. Cancer 1982:50; 760-765. 5. Paz RA, Frigerio B, Sundblad AS et al. Small cell (oat cell) carcinoma of the endometrium. Arch. Pathol. Lab. Med. 1985: 109;270-272. 6. Copeland LJ, Cleary K,SneigeN et al. Neuroendocrine (Merkelcell) Carcinoma of the vulva. Gynecol. Oncol. 1985:22;367-378. 7. Bottles K,Lacey CG, Goldberg J et al. Merkel cell carcinoma of the vulva. (Suppl) Obstet. Qnecol. 1984:63;61-65. 8. Hopkins MP,Kumar NB. Lichter AS et al. Small cell carcinoma of the vagina with neuroendocrine features. A report of three cases. 1. Reprod. Med. 1989:34;486491. 9. Peters WA, Kumar NB, Morley GW. Carcinoma of the vagina. Cancer 1985: 55; 892-897. 10. Fukushima M. Twiggs LB, Okagaki T. Mixed intestinal adenocarcinoma-argentafh carcinoma of the vagina. Gunecol. Oncol. 1986:23;387-394. 11. Chafe W. Neuroepithelial small cell carcinoma of the vagina. Cancer 1989;64: 1948-1951. 12. Rusthoven JJ, Daya D. Small-cell carcinoma of the vagina. A cllnicopathologic study. Arch. Pathol. Lab. Med. 1990 114; 728-731. 13. Ulich TR, Liao S-Y. Layfield L et al. Endocrine and tumour differentiation markers in poorly diffemntiated small-cell carcinoids of the cervix and vagina. Arch. Pathol. Lab. Med. 1986;110; 1054-1057. 14. Gersell D.Mazoujian G, Mutch D. RudloKM. Small-cell undifferentiated carcinoma of the cervix. Am. 1. Surg. Pathol. 1988;12; 684-698. 15. Leong S-Y. G u a m P, MUos J. Cytokeratin and vimentin Intermediate filament proteins in benign and neoplastic prostatic epithelium. Histopthology 1988:13;435442. 16. Richardson Rc.Wlland LH.Undifferentiated small cell carcinoma in extra pulmonary sites. Semin. Oncol. 1982:9; 484-496. 17. Fox H.Kazzaz B. Langley FA. Argyrophil and argentafb cells in the female genital tract and in ovarian mucinous cysts.1. Pathol. Bacterlol. 1964;88;479488. 18. Blobel GA,Gould VE.Moll R et al. Co-expressionofneuroendocrine markers and epithelial cytoskeletal proteins in bronchopulmonary neuroendocrine neoplasms. Lab. Invest. 1985: 52;39-51. 19. Leong AS-Y. Canny R. Smallcell anaplastic carcinoma of the lung with glandular and squamous differentiation. Am. 1. Surg. Pathol. 1981:5; 307-309.

Small cell (neuroendocrine) carcinoma of the vagina.

We report a case of vaginal small cell (neuroendocrine) carcinoma. Immunostaining for neuron-specific enolase, PGP 9.5, chromogranin, synaptophysin, L...
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