Ectopic Prolactin-Producing Pituitary Adenoma in a BenignOvarian Cystic Teratoma

Saba Al-Bazzaz & Jason Karamchandani &Eva Mocarski & Eva Horvath & Fabio Rotondo &

Kalman Kovacs

# Springer Science+Business Media New York 2014

Abstract We report the presence of pituitary tissue in abenign ovarian cystic teratoma removed surgically from a43-year-old woman. The pituitary consisted of non-tumorous neurohypophysis and adenohypophysis containingmainly prolactin (PRL)-immunopositive cells (80 % of cells)and a small PRL-producing adenoma. The ultrastructure of thetumor cells differed significantly from PRL cells in the non-tumorous and adenomatous intrasellar pituitary. It appears thatcells differing in ultrastructure from intrasellar pituitary PRLcells can also produce PRL.

Keywords Pituitary . Ovarian teratoma . PRL .

Immunohistochemistry

Introduction

Mature cystic teratomas are the most frequent ovarian germcell tumors in young women [1]. These tumors may contain avariety of different tissues derived from all three germinallayers. Willis described 28 different types of mature tissuethat may be found in a teratoma including skin, bone, connec-tive tissue, and cartilage, but pituitary was not mentioned [2].

Russell and Painter [1] were the first to recognize thepresence of pituitary tissue in a mature ovarian teratoma.Axiotis et al. [3] reported a corticotroph pituitary adenomawithin an ovarian teratoma causing Cushing’s syndrome.

Subsequently, Palmer et al. [4] published a case of PRLomain the wall of an ovarian dermoid cyst causinghyperprolactinemia.

We report here the histologic, immunohistochemical, andelectron microscopic findings in a benign ovarian cystic tera-toma containing PRL-producing endocrine cells removed bysurgery from a 43-year-old woman.

Clinical Findings

A 43-year-old G3P3 presented requesting a pelvic ultrasoundbecause of vaginal blood staining after bowel movement. Theultrasound showed a uterus normal in size with a normalendometrial stripe. There were two cysts in the left adnexumeach measuring 9 mm. A 3.2-cm complex mass was seen inthe right adnexum. Portions of the cyst appeared to be filledwith viscous fluid, other areas were echogenic. The differen-tial diagnosis included hemorrhagic cyst and dermoid cyst.Her periods occurred every 2 months with secondary dysmen-orrhea of 2 years duration described as being sharp to dull.There was no dyspareunia. On pelvic examination, the uteruswas mobile. There was fullness in the right adnexum whichwas mobile. No nodularity was noted.

The ultrasound was repeated after 3 months. The left ovaryhad a physiological follicle. The right ovary measured 4.5×4.1×2.9 cm and was occupied by a hypoechoic lesion withechogenic clumps measuring 4.5×3.7×2.8 cm, most consis-tent with an endometrioma. The differential diagnosis includ-ed dermoid cyst but was felt less likely. Blood hormone levelswere not measured. At the patient’s request, she was taken tothe operating room for a bilateral salpingo-oophorectomy.Intraoperatively, the patient was found to have a cyst in theright ovary measuring 4 cm and a normal-appearing leftfallopian tube and ovary.

S. Al-Bazzaz (*) : J. Karamchandani : E. Horvath : F. Rotondo :K. KovacsDepartment of Laboratory Medicine, Division of Pathology, St.Michael’s Hospital, 30 Bond Street, Toronto, ON, CanadaM5B 1W8e-mail: albazzazs@smh.ca

E. MocarskiDepartment of Obstetrics and Gynecology, St. Michael’s Hospital,Toronto, ON, Canada

Endocr PatholDOI 10.1007/s12022-014-9299-6

Morphologic Findings

On gross examination, the right ovary, received in pieces,consisted predominantly of cyst wall, measuring 4×4×1.5 cm in aggregate. The contents included a tooth andRokitansky nodule mixed with thick creamy material. Theleft ovary measured 2×1.5×1.5 cm and contained a cyst filledwith a blood clot. The fallopian tubes were unremarkable.

Histologic examination demonstrated that the right ovariancyst was a mature cystic teratoma lined partly by keratinizingsquamous epithelium with skin appendages and partly byrespiratory epithelium. The cyst wall contained salivary andmucous glands, mature peripheral nerve trunks representingneurohypophysis, and a well-formed adenohypophysis. Thelatter was composed of a mixture of round to oval acidophilicand basophilic cells with a finely granular cytoplasm andround central nucleus containing abundant chromatin. Theadenohypophysial cells were arranged in small acini. Neithercellular and nuclear pleomorphism nor mitotic figures wereseen. The Gordon-Sweet silver stain demonstrated the pres-ence of an acinar pattern. The acini were surrounded by adelicate network of reticulin fibers. A solid nodule measuring0.5×0.3 cm was identified under the respiratory epitheliumcomposed of cords of granular cells. Silver stain showeddisruption of the acinar pattern and the irregular distributionof the reticulin fibers (Fig. 1). In the left ovary, anendometriotic cyst was noted.

Immunohistochemistry using the streptavidin-biotin-peroxidase complex method showed the presence of variousadenohypophysial hormones in the non-tumorous adenohy-pophysis. Cytoplasmic immunopositivity for PRL was appar-ent in approximately 80 % of the cells. The remaining cellswere immunopositive for GH and ACTH in 10 % of the cellseach. TSH, FSH, and LH immunostains were negative. GFAPand S100 protein were positive in 5 % of cells.

In the small nodule regarded as an adenoma, 95 % of thecells were immunopositive for PRL (Fig. 2). GH and ACTHwere positive in 5 % of the cells each. Immunonegativity wasapparent for the other adenohypophysial hormones (TSH,FSH, and LH). Negative staining was also noted for gastrin,glucagon, calcitonin, HCG, Ki67, thyroglobulin, and TTF1.The histologic and immunohistochemical findings providedevidence that the cystic ovarian teratoma contained a part ofnon-tumorous neuro- and adenohypophysis, and a PRL-producing adenoma. For electron microscopy, a small frag-ment was removed from the paraffin block, fixed in glutaral-dehyde, osmicated, and embedded.

Although tissue preservation was suboptimal, it waspossible to confirm that in addition to collagen fibrils anddebris, the cells were endocrine cells. Their ultrastructuresignificantly differed from intrasellar non-tumorous or ade-nomatous PRL cells [5]. In contrast, they contained moreand larger secretory granules which were not located in theGolgi area. Another difference was that the endoplasmicreticulum membranes were not so numerous, and the Golgiarea was not so prominent as in intrasellar PRL cells. InPRL cells, exocytosis is a characteristic finding. In ourcase, however, the presence or absence of exocytosis couldnot be assessed because the cell membranes were lost(Fig. 3). One has to emphasize that the ultrastructural studywas undertaken on a small portion of the formalin-fixed,paraffin-embedded tissue removed from the paraffin blockand re-embedded. Only the adenoma cells were included inthe specimen. The question of whether suboptimal tissuepreservation affected the interpretation of the results cannotbe answered. However, the large size and location of thesecretory granules and the smaller volume of the Golgi areaand endoplasmic reticulum cannot be attributed to celldamage due to formalin fixation and paraffin embedding.

Fig. 1 The acinar pattern is lost and the reticulin fibers are irregularlydistributed. Gordon-Sweet silver stain. Original magnification 100×

Fig. 2 Conclusive immunostaining is noted for PRL in the ectopicpituitary adenoma. Immunostaining for PRL. Original magnification250×

Endocr Pathol

Discussion

Pituitary tissue was reported in benign ovarian cystic terato-mas [6–9]. Both adenohypophyseal and neurohypophysealtissues were noted in these cystic tumors. Extragonadal ma-ture teratomas have been described to contain pituitary tissueby Ikeda and Sasano [10] and later by Heller et al. [11]. Usingimmunostaining, different pituitary cell types have been iden-tified in benign cystic teratomas [7, 9–11]. In our case, posi-tive immunostaining of the non-tumorous cells for PRL,ACTH, and GH confirmed that they were adenohypophysealcells. In addition, positive results of GFAP and S100 proteinstaining demonstrated the presence of neurohypophysealcells.

By immunohistochemistry, the pituitary elements in ovar-ian teratomas were found to be predominantly PRL-producingcells [7, 9]. Our case confirms previous findings; wealso observed an increase in the proportion of PRL-immunopositive cells.

To our knowledge, four cases of functioning pituitary ad-enomas were reported so far in ovarian teratomas [3, 4, 12].Two of these were ACTH-producing adenomas resulting inCushing’s syndrome [3]. Axiotis et al. [3] reported the firstcase of hormone secretion by an ectopic pituitary tumorconfirmed by immunostaining for ACTH [3]. The other two

cases were PRLomas in ovarian teratomas [4, 12]. Palmeret al. [4] demonstrated PRL-secreting cells in the neoplasticpituitary tissue by immunohistochemistry. In our case, we had95 % PRL-immunopositive cells in the pituitary nodule; theseresults are consistent with the findings of Palmer et al. [4].

Turkington [13] demonstrated PRL immunoexpression inthe cells of a bronchogenic and in a renal carcinoma provingectopic production of PRL. Our case indicates that ectopicPRL production may occur in cells that do not show thecharacteristic morphology of intrasellar pituitary PRL cells.The interpretation of this finding needs further studies.

Acknowledgments Authors are grateful to the Jarislowsky and LloydCarr-Harris Foundations for their generous support.

References

1. Russell P, Painter DM. The pathological assessment of ovarianneoplasms V: the germ cell tumors. Pathology 1982;14:47-72

2. Willis RA. Pathology of tumors. 4th ed. London: Butterworths,1967;974-80

3. Axiotis C, Lippes H, Merino M, et al. Corticotroph cell pituitaryadenoma within an ovarian teratoma: A new cause of Cushing’ssyndrome. Am J Surg Pathol. 1987; 11: 218-24

4. Palmer P, Bogojavlensky S, Bhan A, et al. Prolactinoma in wall ofovarian dermoid cyst with hyperprolactinemia. Obstet Gynecol.1990;75;540

5. Horvath E & Kovacs K. Ultrastructural diagnosis of human pituitaryadenomas. Microsc Res Tech 20:107-135, 1992

6. AkhtarM, Young I, Brody H. Anterior pituitary component in benigncystic ovarian teratomas: report of three cases. Am J ClinPathol.1975;63:14-19

7. Mckeel D, Askin F. Ectopic hypophyseal hormonal cells in benigncystic teratoma of the ovary: Light microscopic histochemical dyestaining and immunoperoxidase cytochemistry. Arch Pathol LabMed.1978;102:122-8

8. Fenoglio C, Tlumsa G, Habif D. Pituitary-containing benign cysticteratoma of the ovary in a patient with metastatic breast cancer: a casereport. Diagn Histopathol. 1982;5:143-50

9. Mow C, Edwards A, Haymen J. Ectopic pituitary with pregnancychanges in a benign cystic teratoma of the ovary. Pathol. 1999;31:431-3

10. Ikeda H, Sasano N. Demonstration of pituitary tissue with 6 cellimmunoreactions to pituitary hormone in a sacrococcygeal teratoma.Acta Pathol Jpn. 1987;37:117-22

11. Heller DS, Keohane M, Bessim S, et al. Pituitary containing benigncystic teratoma arising from the uterosacral ligament. Arch PatholLab Med. 1989;113:802-4

12. Kallenberg GA, Pesce CM, Norman B, et al. Ectopichyperprolactinemia resulting from an ovarian teratoma. J Am MedAssoc 1990;263:2472-74

13. Turkington RW. Ectopic Production of Prolactin. The New EnglandJ of Med. 1971;285:1455-8

Fig. 3 Electron microscopic image depicting adenoma cells with nuclei,cytoplasmic secretory granules and loss of cell membrane. The endocrinecells seen here do not resemble intrapituitary non-tumorous or adenoma-tous PRL cells. Original magnification 4,000x

Endocr Pathol