Peutz-Jeghers syndrome

The patient was a 48-year-old nulligravid woman who was diagnosed with Peutz-Jeghers syndrome at least 10 years prior to presentation. In the intervening period, she underwent several polypectomies for hamartomatous lesions of the stomach, duodenum, and colon. Her past medical history was also significant for a radical mastectomy performed to excise an invasive carcinoma of the right breast that was discovered following a routine mammogram. That tumor measured 3 cm in maximal dimension, was of infiltrating ductal type, extended to the deep chest wall margins of resection, and had metastasized to 1 of 20 axillary lymph nodes. As a component of her postoperative evaluation for metastatic disease, a computed tomographic scan of the pelvis revealed a 6-cm, heterogenous, solid to cystic, left adnexal mass. One month subsequent to this discovery, she underwent a total hysterectomy and bilateral salpingo-oophorectomy. The surgical specimen was submitted to our laboratory and was processed routinely.

Grossly, the left and right ovaries each measured 4 × 3 cm. There were significant tuboovarian adhesions on the left side, and the cut surface of the left ovary was soft and hemorrhagic, but solid. The right fallopian tube, right ovary, uterine corpus, and uterine cervix were all grossly unremarkable. Microscopically, distinctive tubular structures, dispersed singly (Figure 1) but occasionally in aggregates (Figure 2), were present in the cortical and medullary stroma of both ovaries. Each structure consisted of cells with basally situated rows of bland nuclei and abundant supranuclear, clear to vacuolated cytoplasm that were concentrically arranged around hyaline or eosinophilic basement membrane-like material. In many tubules, nuclei were arranged immediately subjacent to the basement membrane-like material. Simple ringlike tubular forms, as well as complex cribriform-type structures, were present. Immunohistochemically (Dako Autostainer, DakoCytomation, Carpinteria, Calif), the constituent cells of the tubular structures were positive for calretinin (clone 6021, dilution 1:50; Cell Marque Corporation, Hot Springs, Ark), inhibin (clone R1, dilution 1:100; Serotec, NC), and epithelial membrane antigen (clone E29, dilution 1:1280, DakoCytomation). Other findings of note in the left ovary were extensive endometriosis, a small endometrioid adenofibroma, and a small Brenner tumor. The right ovary also showed endometriosis.

What is your diagnosis?

Pathologic Diagnosis: Ovarian Sex Cord Tumor With Annular Tubules

In 1970, Robert E. Scully1 described 10 examples of a distinctive ovarian tumor that were characterized by multicentricity, simple and complex annular tubules, and calcification, which he designated sex cord tumors with annular tubules (SCTAT). One of the 10 cases had been described previously under the category "sex cord-mesenchyme tumors of indeterminate type" in a book coauthored by Scully and published 12 years earlier.2 In addition to its distinctive morphologic appearance, this tumor was segregated because of its apparent high incidence among ovarian tumors associated with the Peutz-Jeghers syndrome (PJS). Peutz-Jeghers syndrome is an autosomal dominant disorder that is characterized by mucocutaneous pigmentation, intestinal hematomatous polyps,3 and a significantly increased risk of developing various tumors of the uterine cervix (the so-called minimum-deviation adenocarcinoma), breast, ovary, gastrointestinal tract, and testes.4 In Scully's seminal series, 3 of 10 cases of SCTAT, as well as 3 additional cases from the literature that he reviewed, occurred in patients with PJS.1 In a comprehensive synopsis of reported and new cases up to that point, Young et al5 reported 74 cases in 1982, 27 (36%) of which were in PJS patients. In spite of the extensive similarities in their morphologic appearance, the clinicopathologic features of those SCTAT cases occurring in patients with PJS and in those without PJS appear to be distinct. In the PJS patients in the Young et al series,3 the tumors were generally small, multifocal (82%), bilateral (62%), calcified (62.5%), and not grossly appreciable in more than 70% of cases. In contrast, tumors occurring in patients without PJS were all unilateral, rarely multifocal or calcified, usually grossly visible (79%), and were large enough for preoperative palpation in more than half of the cases.5

The histogenesis and/or direction of differentiation of SCTAT has been a source of some disagreement in the literature. As noted previously, Scully considered SCTAT to have morphologic features intermediate between granulosa cell and Sertoli cell tumors. Other authors, primarily based on ultrastrucrural findings, have favored either a granulosa cell6 or a Sertoli cell origin.7

Since SCTAT occurring in patients with PJS are typically microscopic, often incidental findings, the question arises as to the true nature of these lesions, that is, whether they are truly neoplasms or whether they merely represent hyperplastic nodules of granulosa cells or hamartomas. Delides et al8 carefully sectioned 588 ovaries reported to be of normal size and identified characteristic SCTAT in 7 cases, with an average diameter of 0.17 mm. The authors suggested that the word tumor in these small SCTAT be replaced with nest, to more accurately reflect their nature. In his seminal report, Scully rationalized use of the word tumor by referring to the spectrum of sizes in these lesions: "the fact that lesions of all sizes up to large tumor masses have been observed supports the concept that all of them are neoplastic, varying only in size."1

With respect to biologic behavior and malignant potential, cases of SCTAT occurring in PJS patients also appear to be different from their non-PJS counterparts. In the former group, all the reported cases with one exception9 have behaved in a benign fashion. In the sole malignant case, a bilateral SCTAT occurring in a 47-year-old woman with PJS was found to have metastasized to the right and left pelvic lymph nodes. Among the cohort of patients with PJS, clinically malignant behavior in SCTAT occurs with a much higher frequency; metastases developed in 7 (15%) of 47 patients in the Young et al series.5 In either case, however, SCTAT may be associated with significant morbidity, such as precocious puberty, bleeding anomalies, or premature ovarian failure. In further support of the dichotomy between the PJS-associated SCTAT and the non-PJS-associated cases are the molecular findings recently reported by Connolly et al.10 Mutations in the PJS-associated gene STK11, which maps to 19p13.3, were recently found in 2 PJS-associated SCTAT cases and in none of 5 non-PJS-associated SCTAT cases.10

References

1. Scully RE. Sex cord tumor with annular tubules: a distinctive ovarian tumor of the Peutz-Jeghers syndrome. Cancer. 1970;25:1107-1121.

2. Morris JM, Scully RE. Endocrine Pathology of the Ovary. St Louis, Mo: CV Mosby; 1958.

3. Jeghers H, McKusick VA, Katz KH. Generalized intestinal polyposis and melanin spots of the oral mucosa, lips and digits: a syndrome of diagnostic significance. N Engl J Med. 1949;241:994-1006.

4. Giardiello FM, Welsh SB, Hamilton SR, et al. Increased risk of cancer in the Peutz-leghers syndrome. N Engl J Med. 1987;316:1511-1514.

5. Young RH, Welch WR, Dickersin CR, Scully RE. Ovarian sex cord tumor with annular tubules: review of 74 cases including 27 with Peutz-Jeghers syndrome and four with adenoma malignum of the cervix. Cancer. 1982;50:1384-1402.

6. Crissman JD, Hart WR. Ovarian sex cord tumors with annular tubules: an ultrastructural study of three cases. Am J Clin Pathol. 1981;75:11-17.

7. Tavassoli FA, Norris HJ. Sertoli cell tumors of the ovary: a clinicopathologic study of 28 cases with ultrastructural observations. Cancer. 1980;46:2281-2297.

8. Delides CS, Elemenoglou J, Caras G. Sex cord nests with annular tubules: the incidence of identifying them in normal ovaries. Acta Morphol Hung. 1988;36:3-6.

9. Lele SM, Sawh RN, Zaharopoulos P, et al. Malignant ovarian sex cord tumor with annular tubules in a patient with Peutz-Jeghers syndrome: a case report. Mod Pathol. 2000;13:466-470.

10. Connolly DC, Katabuchi H, Cliby WA, Cho KR. Somatic mutations in the STK11/LKB1 gene are uncommon in rare gynecological tumor types associated with Peutz-Jegher's syndrome. Am J Pathol. 2000;156:339-345.

Oluwole Fadare, MD

Accepted for publication September 19, 2003.

From the Department of Pathology, Yale University School of Medicine and Yale-New Haven Hospital, New Haven, Conn.

The author has no relevant financial interest in the products or companies described in this article.

Corresponding author: Oluwole Fadare, MD, Department of Laboratory Medicine, CB407, Yale University School of Medicine, 20 York Street, New Haven, CT 06504 (email: oluvvole.fadare@yale.edu).

Reprints not available from the author.

Copyright College of American Pathologists Mar 2004
Provided by ProQuest Information and Learning Company. All rights Reserved