Peutz-Jeghers syndrome with “adenoma malignum” of the cervix

GYNECOLOGIC

ONCOLOGY

lo,

12% 133 (1980)

Peutz-Jeghers Syndrome with “Adenoma Malignum” of the Cervix A Report of Two Cases

LARRY MCGOWAN, M.D.,*2 ROBERTH. YOUNG, M.D.,1-,l AND ROBERTE. SCULLY, M.D.* *Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, George Washington University Medical Center, Washington D.C. 20037, and tDepartment OfPathology, Harvard Medical School, and James Homer Wright Laboratories of the Massachusetts General Hospital, Boston, Massachusetts 02114 Received January 25, 1980 Two cases of the Peutz-Jeghers syndrome associated with cervical adenocarcinoma of the “adenoma malignurn” type are reported with a review of four similar cases, three of which have been reported elsewhere. One of our two patients also had bilateral ovarian sex cord tumors with annular tubules and the other had bilateral ovarian mutinous cystadenomas of borderline malignancy. The relatively frequent occurrence of “adenoma malignum” of the cervix, an otherwise rare form of cervical cancer, in women with the Peutz-Jeghers syndrome, warrants close supervision of these patients by a gynecologist to assure early detection and treatment of this highly malignant tumor.

INTRODUCTION

The Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disorder characterized by gastrointestinal polyps and mucocutaneous melanin pigmentation. The pigmentation is spotty, appearing on the buccal mucosa and skin, most often that of the fingers and toes. The gastrointestinal manifestations are mainly bleeding with secondary anemia and recurrent intussusception. The polyps are hamartomatous, being composed of several types of epithelial cell and bundles of smooth muscle. A distinctive ovarian tumor characterized by the formation of ring-shaped tubules and designated “sex cord tumor with annular tubules” (SCTAT) is also very common in association with the PJS [l]. Within the last decade, three cases of a rare well-differentiated but often fatal cervical adenocarcinema termed “adenoma malignurn” have been reported in women with this disorder [2-41. The present article describes two cases of fatal “adenoma malig* Dr. Young is a recipient of a Junior Faculty Clinical Fellowship from the American Cancer Society. * Address reprint requests to Larry McGowan, M.D., 2150 Pennsylvania Avenue, N.W., Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, George Washington University Medical Center, Washington, D.C. 20037. 125 0090-8258/80/050125-09$01.00/O Copyright @ 1980 by Academic Press. Inc. All rights of reproduction in any form reserved.

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num” of the cervix, one associated with bilateral SCTAT, and the other with bilateral ovarian mutinous cystadenomas of borderline malignancy. CASE REPORTS

Case 1: C.M. had bleeding per rectum and abdominal pain at the age of 11 years. A hamartomatous polyp of the colon was removed, and the diagnosis pf PJS was made because of associated circumoral melanin pigmentation. At the age of 26 years, intestinal obstruction due to jejunal intussusception was relieved surgically. Four months’later 14 small intestinal polyps were removed. Between the ages of 17 and 22 years, the patient had six curettages of the uterus for irregular bleeding. Histologic examination of all the specimens showed proliferative endometrium. At the age of 23 years, pelvic examination revealed a left adnexal mass; at laparotomy, a 3-cm-diameter left ovarian tumor was found and a left salpingo-oophorectomy was performed. On gross examination the tumor had a smooth external surface and firm, gray-yellow cut surfaces. Microscopic examination showed a SCTAT, characterized by rounded epithelial nests within which annular tubules surrounded hyaline bodies (Fig. 1); focal calcification was present. At the age of 29 years, the patient had another episode of irregular uterine bleeding. Fractional curettage revealed adenocarcinoma of the endocervix, and she was referred to the senior author for treatment. Physical examination, including a pelvic examination, was normal except for the presence of circumoral melanin pigmentation. A complete blood count, urinalysis, and a biochemical

FIG. 1. Sex cord tumor with annular tubules, Case 1. Rounded epithelial nests contain annular tubules enclosing hyaline material. x 160.

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screen were normal. The results of an intravenous pyelogram, upper and lower gastrointestinal barium studies, a chest film, bone and liver scans, and proctosigmoidoscopy were normal and a diagnosis of Stage IB adenocarcinoma of the cervix was made. A radical abdominal hysterectomy with a pelvic lymphadenectomy, including removal of the common iliac lymph nodes, was performed. On gross examination the wall of the endocervix appeared almost completely replaced by tumor, which extended into the corpus. A yellow nodule, 1 cm in diameter, was present in the right ovary. Histologic examination of the cervical tumor disclosed a generally well-differentiated adenocarcinoma composed mainly of glands lined by mutinous epithelium of endocervical type (Fig. 2). Cytologic atypia was mild to moderate, with many glands lined by benign-appearing cells and others by cells with atypical nuclei. The well-differentiated glands branched irregularly, invaded the muscularis, and evoked a mild desmoplastic stromal response. In a few areas small nests of malignant cells extended from the glands into the stroma. Mucicarmine and periodic acid-Schiff (PAS) stains before and after diastase digestion were positive for intracellular and intraluminal mucin; no glycogen was identified. Four common iliac lymph nodes contained metastatic adenocarcinoma. The nodule in the right ovary was a focally calcified SCTAT; isolated microscopic nests of similar tumor were scattered in the ovarian stroma away from the main nodule. External radiation therapy was administered, with 4940 rad delivered to the periaortic area and 6080 rad to the pelvis. Sixteen months postoperatively, intravenous pyelography revealed bilateral hydronephrosis. Cytologic examination of

FIG. 2. Invasive adenoma malignurn composed of glands lined by well-differentiated epithelium of endocervical type, Case 1. Many glands are abnormal in shape. X 100.

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urine obtained at the time of cystoscopy was positive for carcinoma cells. A biopsy of the vaginal apex revealed “adenoma malignum.” Progressive renal failure with hypertension developed and the patient died at the age of 33 years of uremia. An autopsy was not performed. Case 2. T.R. had an episode of bleeding per rectum at the age of 11 years. Sigmoidoscopic examination revealed colonic polyps, biopsies of which disclosed hamartomatous polyps. The diagnosis of PJS was made because of associated circumoral melanin pigmentation. Ten years later, the patient had episodes of nausea, vomiting, and abdominal pain. Small bowel obstruction was treated by surgical removal of hamartomatous polyps from the jejunum and ileum; additional polyps were excised from the stomach and colon. At the age of 27 years, a benign cyst was removed from the left lobe of the thyroid gland. Shortly thereafter, the patient was readmitted complaining of abdominal enlargement. Pelvic examination revealed a left adnexal mass. At operation, a lCcm-diameter, smooth-surfaced left ovarian cyst with attached fallopian tube was removed. On microscopic examination the cyst was lined by mutinous epithelium, which was focally stratified into two layers with slight loss of polarity and hyperchromatism of the nuclei, warranting a diagnosis of mutinous cystadenoma of borderline malignancy (Fig. 3). Argentaffin cells were easily identified in the neoplastic epithelium in hematoxylin and eosin sections and stained positively with the Masson-Fontana stain. Six months postoperatively, she had irregular uterine bleeding; fractional curettage of the uterus and a vaginal biopsy were performed. Microscopic examination revealed a well-differentiated adenocarcinoma of the endocervix with involvement of the vagina (Fig. 4). A complete blood count, urinalysis, and biochemical screen yielded normal results. A diagnosis of Stage IIA adenocarcinoma of the cervix was made. Laparotomy revealed a cystic right ovarian mass. A radical abdominal hysterectomy, upper vaginectomy, and right salpingo-oophorectomy with a pelvic lymphadenectomy was performed. On gross examination there was circumferential induration of the cervix and upper vagina. Microscopic examination revealed a deeply invasive, welldifferentiated mutinous adenocarcinoma composed of irregularly branching glands lined by epithelium of endocervial type. In most areas, cytologic atypia was

FIG. 3. Ovarian mutinous cystadenoma of borderline malignancy, Case 2, left ovary, showing moderate nuclear stratification and atypicality. Epithelium from two different areas is illustrated. x 400.

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FIG. 4.

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Vaginal specimen, Case 2, showing well-differentiated glands of endocervical type. x 160.

minimal, but in a few foci, less well-differentiated glandular epithelium was seen and focally there was single cell invasion of the stroma. Masson-Fontana stains for argentaffin granules and Grimelius stains for argyrophil granules were negative. Mucicarmine stains were positive for intracellular and intraluminal mucin. The right ovary was replaced by a multiloculated cystic tumor measuring 14 x 12 x 5 cm. Microscopic examination revealed cysts as well as small glands lined by mutinous epithelium containing scattered argentafhn cells. Moderate atypicality of the lining epithelium was present focally and a few small cysts contained cellular papillae (Fig. 5). A diagnosis of mutinous cystadenoma of borderline

FIG. 5. Ovarian mutinous cystadenoma of borderline malignancy, Case 2, right ovary, showing nuclear stratification, atypicality, and cellular papillae. x 400.

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malignancy was made. Two pelvic lymph nodes contained metastatic adenocarcinema, in which argentafhn cells were absent. One year postoperatively she was referred to LMCG with several episodes of small and large bowel obstruction. A peritoneal biopsy confirmed the presence of metastatic adenocarcinoma, which contained no argentafEn cells. A sigmoid colostomy was performed. The disease progressed relentlessly despite three courses of adriamycin and vincristine, and the patient died of diffuse intraabdominal tumor at the age of 29 years. An autopsy was not performed. DISCUSSION The two patients with the Peutz-Jeghers syndrome described in this report had rare gynecologic neoplasms. Both of them had “adenoma malignum” of the cervix and one had bilateral ovarian sex cord tumors with annular tubules. Adenoma malignum of the cervix is a rare neoplasm composed predominantly of histologically well-differentiated glands lined by mucin-filled cells of endocervical type (Fig. 2). In 1963, McKelvey and Goodlin [5] reported five cases of this type of tumor, four of which were fatal within four years of presentation. These authors pointed out its deceptively benign appearance, with the neoplastic glands resembling normal endocervical glands and making diagnosis on biopsy specimens difficult. They emphasized the irregular size and shape of the glands as important clues to their malignant nature. Twelve years later, Silverberg and Hurt [6] reported five additional cases, introducing the designation “minimal deviation adenocarcinoma.” Their cases resembled those reported by McKelvey and Goodlin on microscopic examination but were associated with a better prognosis. Probably other examples of this rare tumor have been included in various series of cervical adenocarcinonia cases within the category of well-differentiated adenocarcinoma. Although the tumors in our two patients contained foci of dedifferentiation and stromal invasion by single cells and small clumps of cells, the predominant appearance of marked differentiation justifies our diagnosis of adenoma malignum. We have reviewed slides from three of the four other cases of adenocarcinoma of the cervix associated with the PJS [2,3,6,7]. We feel that the designation of adenoma malignum is also warranted for all of these three cases because of the presence of large areas composed of very well-differentiated mutinous glands and it seems highly probable that it is for the fourth case on the basis of the microscopic description. The occurrence of these six unusual cervical cancers in patients with the PJS (Table 1) appears highly significant in view of the great rarity of this tumor in general. Also, the fact that four of the six patients died within 5 years of presentation emphasizes the importance of awareness of cervical adenoma malignum as a complication of this disorder. Although several types of ovarian tumor have been reported in women with the PJS, a clear-cut association has been established only with the distinctive sex cord tumor with annular tubules (Fig. 1) which was present bilaterally in Case 1 and in three of the other five cases listed in Table 1. It was not encountered in the case of Kese [4] and in Case 2, but the former was reported before the initial description of this neoplasm, which may be of microscopic size and relatively inconspicuous. A SCTAT may also have been obscured in Case 2 because of the extensive

36

47

37

4. Costa 1911

5. Gloor 1978

6. Young Cl al.

1

Mucoid tumor, wall of endocervix, Stage HA

Infiltrating tumor, Stage HA

Ulcerated, friable 2-3-cm lesion, Stage IB

Polypoid mass

Infiltrating endocervital tumor with vaginal extension, Stage HA

Infiltrating endocervical tumor, Stage IB

Cervix

H,BSO, radiotherapy

H,BSO

H,BSO, radiotherapy, 5-fluorouracil

H,BSO, cobalt 60

RH+PLD, RSO, adriamycin, vincristine

RH+PLD, RSO, radiotherapy

Treatment

SCTAT,B, micro

SCTAT,B, micro implants of adenoma malignurn

SCTAT,B, micro

N.A.R.

Cystadenoma, borderIine,B

SCTAT,B

Ovaries

Polyps, stomach, SI

Polyps SI,LI. Breast Ca,B, with LNM,R. (Mother died of uterine tumor)

Polyps,SI,LI Mutinous metaplasia, tube. LNM

Polyps, SI

Polyps, stomach, jejunum, ileum, and LI. LNM

Polyps,SI,LI; LNM

Other findings

OF THE CERVIX

Vaginal smear positive for Ca, I year

Dead, I year, 4 months Osteolytic bone mets. ? origin, “0 autopsy

Dead, 5 years, “0 autopsy

Well, 6 months

Dead, 17 months, no autopsy

Dead, 3 years, no autopsy

Follow-up

description, is consistent with “adenoma malignum.”

intestine; LNM, lymph node metastases; micro, microscopic. a Slides have not been reviewed. Patient presented with gelatinous vaginal discharge and had well-differentiated

adenocarcinoma

which, from the

Note. RH+PLD, Radicle abdominal hysterectomy with pelvic lymphadenectomy; H, hysterectomy; SCTAT, sex cord tumor with annular tubules; SO, salpingo-oophorectomy; N.A.R., no abnormality reported; L, left; Ca, carcinoma; R, right; LI, large intestine; B, bilateral; SI, small

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28

2. G.W. 5787

3. KeseD I%9

29

I. G.W. 2922

Case no.

Age at diagnosis (cervix)

TABLE

PATIENTS WITH PEUTZ-JEGHERS SYNDROME AND ADENOMA MALIGNUM

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replacement of both ovaries by mutinous cystadenomas of borderline malignancy. Indeed, it is possible that the ovaries of all patients with the PJS harbor microscopic foci of SCTAT; in one case outside the scope of this study, we uncovered a small lesion of this type only after examining sections cut at many levels of a block [7]. Although the ovarian SCTAT is usually asymptomatic, occasionally the patient presents with irregular uterine bleeding, possibly due to estrogen secretion by the neoplastic cells. Because of the association of this tumor with the PJS, the ovaries should be examined at any laparotomy performed on a patient with this disorder. The young age at which most of these neoplasms are detected and the benign behavior to date of all those that have been associated with the PJS justify treating them by a conservative operation such as local resection. In Case 2, both ovaries were replaced by multilocular cystic tumors composed of cysts and glands lined by mutinous epithelium (Fig. 3). The nuclei of the lining cells were focally stratified into two layers with loss of polarity, hyperchromatism, and occasional mitotic figures; small papillary fronds were also present in a few cysts (Fig. 5). Although these tumors could have been metastases from the cervical adenocarcinoma, they were almost certainly independent primary mucinous cystadenomas of borderline malignancy. Metastasis of a cervical carcinoma to one or both ovaries is very rare except in advanced stages of the disease. Also, a very important clue to the nature of the tumors was their content of large numbers of argentaffin cells coupled with absence of such cells in the cervical adenoma malignum. Two mutinous cystadenomas and a mixed mutinous and endometrioid cystadenoma of the ovary [g-lo], and mutinous metaplasia of the fallopian tube 121have been reported in patients with the PJS. Although the number of cases is small, these findings may indicate an association of the PJS with primary mucinous neoplasia as well as SCTAT of the ovary. In conclusion, the Peutz-Jeghers syndrome has expanded in the past decade to include significant and sometimes life-threatening neoplasia of the female genital tract. Women with this disorder, therefore, must be evaluated frequently by the gynecologist as well as the gastroenterologist, with special emphasis on early detection of adenoma malignum of the cervix. Inspection of the exocervix and exocervical cytologic scrapes may both be normal in the presence of this tumor, so that a cytologic specimen should be carefully obtained from the entire endocervital canal with a slightly moistened cotton tip applicator. Office endocervical curettage should be performed yearly, if possible, after the patient has reached the age of 21 years. The pathologist should be alerted that the patient has the PeutzJeghers syndrome so that he may devote special attention to the problem of the diagnosis of adenoma malignum in his examination of cytologic or histologic specimens. ACKNOWLEDGMENTS We are grateful to the following for kindly providing us with pathological material relevant to this paper: Dr. Alexander Breslow, Washington, DC.; Dr. Richard T. O’KeU and Dr. Jose Costa, Kansas City, Missouri; Dr. Etienne Gloor, Lausanne, Switzerland; Dr. Nathan S. Taylor, Rochester, New York. Drs. Joceiyn Arseneau and Thomas Aretz helped with foreign language translation.

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REFERENCES 1. Scully, R. E. Sex cord tumor with annular tubules. A distinctive ovarian tumor of the PeutzJeghers syndrome, Cancer 25, 1107-l 121 (1970). 2. Costa, J. Peutz-Jeghers syndrome: Case presentation, Obstef. Gynecol. 50 (suppl.), 15S-17s (1977). 3. Gloor, E. Un cas de syndrome de Peutz-Jeghers associe a un carcinome mammaire bilateral, a un adenocarcinome du co1uterin et a des tumeurs des cordons sexuels a tubules anneles bilaterales dans les ovaires, Schweiz. Med. Wochenschr. 108, 717-721 (1978). 4. Kese, G. Adenocarcinoma cervicis uteri bei einer 28 jahrigen frau mit Peutz-Jeger-Syndrom, Zentrabl. Gynaekol. 91, 215-218 (1969). 5. McKelvey, J. L., and Goodlin, R. R. Adenoma malignum of the cervix, Cancer 16, 549-557 (1963). 6. Silverberg, S. G., and Hurt, W. G. Minimal deviation adenocarcinoma (“adenoma malignum”) of the cervix: A reappraisal, Amer. J. Obstet. Gynecol. 121, 971-975 (1975). 7. Young, R. H., Welch, W. R., Scully, R. E., and Dickersin, G. R. Ovarian sex cord tumor with annular tubules. A review of 53 cases including 16 with Peutz-Jeghers syndrome and 4 with adenoma malignurn of the cervix. In preparation. 8. Dozois, R. R., Judd, E. S., Dahlin, D. C., and Bartholomew, L. G. The Peutz-Jeghers syndrome. Is there a predisposition to the development of intestinal malignancy? Arch. Surg. 98, 509-517 (1969). 9. Humphries, A. L., Jr., Shepherd, M. H., and Peters, H. J. Peutz-Jeghers syndrome with colonic adenocarcinoma and ovarian tumor, J. Amer. Med. Assoc. 197, 296-298 (1966). 10. Steenstrup, E. K. Ovarian tumours and Peutz-Jeghers syndrome, Actu Obstet. Gynecol. Stand. 51, 237-240 (1972).