Krukenberg tumor complicating pregnancy

Krukenberg tumor complicating pregnancy Report of a case with androgenic activity

LEON PARRISH FOX, M.D. WERNER].

STAMM, M.D.*

San Jose, California

T H E K R U K E N B E R G T U M 0 R IS a very rare and interesting ovarian lesion which has occasionally been found associated with pregnancy. In this extremely unusual case the gestate manifested massive virilization during the development and growth of the tumor. This special, solid type of malignant neoplasm is usually secondary from a gastrointestinal tract or other mucinous gland lesion; but occasionally it is a true primary tumor of the ovary. The gross appearance, growth pattern, and the microscopic characteristics, including the identifying signet-ring ce!ls and alteration of the ovarian stroma, arc well-known features. This tumor is generally regarded as hormonally inactive. However, observations in recent years have pointed to functional hormonal properties in several cases. 31 • 35 This is not surprising in the presence of the marked stromal activity noted in these lesions. The incidence of malignant ovarian neoplasms found during gestation has been reported to be .5.5 per cent. 10 Thirty cases of Krukenberg tumor associated with preg-

nancy have been documented, with pertinent data, and of these, 2 have been determined to be of primary origin (Table I). In 2 other previously reported cases there has been associated extensive masculinization, such as found here. 13 • 34 Case report

A 27-year-old gravida iv, para iii was rcff't-red by her family physician during the thirty-second werk of gestation complaining of obstipation, generalized abdominal pain, and extreme pdvic pressure. Antenatal care had been initiated at the 11fteenth week and recorded as uneventful until the twenty-third wePk when intermittent uterine cramps and constipation started a prog-ressive course without apparent cause. One month latrr. rapid virilization and wasting- began, and a mass was palpated in tht· pelvis adjoining the uterus and fixed at the rectal shelf. Proctological biopsy showed inflammatory reaction only. The past and family histori<'S were irrelt·vant. The menarche occurred at age 1:1 and menses had been regular and normal. Thn·e uncomplicated pregnancies, 6, 4, and 2 )'f'ars prrviously had resulted in living normal children. Examination showrd a small. thin 27-ycar-old gravid patient who had apparently lost considerable' weight recently and aged beyond her years. The facies were masculine, gaunt. and anxious with striking- acne and hirsutism extending over the body and exhibiting- a male escutcheon. The breasts were of medium size, flat, and colostrum was present. The abdomen was tPrrn pregnancy size, and then· was edema of the wall. A large, firm, tender mass was palpable in the right flank area contiguous with the uterus and extending into the pelvis. Free fluid signs were inconclusive. Vulvar and vaginal

From the Departments of Obstetrics and Gynecology and Pathology, O'Connor Hospital. *Present address: Dominican Santa Cruz HosPital, Santa Cruz, California. Presented as a part of a Symposium of Interesting and Unusual Cases, at the Thirty-first Annual Meeting of the Pacific Coast Obstetrical and Gynecological Society, Santa Barbara, California, Nov. 4-7, 1964.

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Volume 92 ~umber 5

edema were present but the clitoris was not enlarged. Bimanually, the mass was palpable in the posterior cul-de-sac area and involved the rectum at 7 em., fixed in the sacral curve. Vaginal cytology showed no abnormal cells and exhibited a normal pregnancy pattern. Advised hospitalization for proper evaluation and treatment was refused by the patient until 2 and one-half weeks later when vomiting and discomfort caused admission. She arrived in active labor and promptly was delivered of a 3yt pounds female infant who died in a few hours with respiratory difficulty. There was noticeable enlargement of the clitoris but no other fetal abnormalities were noted. Postdelivery examination showed a seriously ill patient with dehydration and exhaustion. The temperature was 99.6° F., pulse 128, respiration 24, and blood pressure 132/90. Virilization had increased and the abdomen was distended with fluid. The uterus was firm and deflected to the left by a 25 em. hard mass. Above the uterus there was another hard mass about 10 em. in diameter. Laboratory studies were not remarkable. The blood picture and urine were consistent with dehydration. The chest and bone survey x-rays showed no metastatic lesions. Fluid balance was stabilized and laparotomy was done on the fourth postpartum day. The 3,000 c.c. of blood-tinged ascitic fluid was aspirated. The right ovary was completely involved in a hard tumor mass with the tube adherent and was easily delivered and removed. The uterus. left ovary, and tube appeared to be normal. Th<" greater omentum was thick, indurated, and enlarged into a 12 em. mass fixed ben('ath the transverse colon on the left side. The thickened pelvic peritoneum was studded with tumor, while the posterior cul-de-sac and sigmoid were densely infiltrated. The stomach, gallbladder, and small bowel were matted together by soft, irregular adhesions, but no specific neoplasm could be identified. The liver, spleen, and kidneys were not at this time grossly involved. A wedge of the omentum was removed for study and the abdomen was closed. A catheter conduit was fixed in the left lower quadrant for chemotherapy administration. Cytological study of the peritoneal fluid showed malignant cells. A 17-ketosteroid determination shortly after operation was reported as 1.3 mg. per kilogram. The course was stormy but stabilized with

Krukenberg tumor and pregnancy

703

electrolyte balance. During the next 10 days she was given 2 peritoneal infusions of nitrogen mustard 0.2 mg. per kilogram without event ( 200 c.c. of fluid being removed each time). At her insistence, she was dismissed on the nineteenth postoperative day only to be readmitted 4 weeks later after steady deterioration, vomiting, pain, and abdominal distention with fluid. Chest x-ray now showed metastatic pulmonary lesions and she died 2 weeks later on the sixty-seventh day following operation. Surgical pathology. The specimens consisted of a single spherical mass weighing 2,400 grams, measuring 24.0 x 16.0 x 12.0 em. in greatest dimensions, and a piece of indurated omental fat. The tumor surface was smooth and covered by an intact, mottled, grayish red glistening membrane with an attached grossly unremarkable Fallopian tube. The cut surface was tan and roughly lobulated by ill-defined septa, and there were scattered peripheral hemorrhages and cyst formation. Histologically, there were two types of cells supported by edematous connective tissue. One of these represented undifferentiated malignant cells, loosely scattered throughout the stroma and in some areas arranged in small clusters with a pseudogland formation. The cells were charac· terized by a large amount of vacuolated cytoplasm and a small irregularly shaped hyperchromatic nucleus. In some areas the nuclei were compressed and peripherally located, giving· the cells a distinct signet-ring appearance (Fig. 1). Special stains revealed an abundant amount of mucicarmine-positive material within the cytoplasm of these tumor cells (Fig. 2). The second type appeared in groups and clusters of fairly uniform-appearing polyhedral cellular elements. The nucleus was centrally placed, rounded, contained a simple nucleolus, and was surrounded by eosinophilic finely granular cytoplasm. Stains with Sudan IV showed a large amount of sudanophilic material within the cytoplasm (Fig. 3). These cells represent theca I stromal cells having undergone luteinization (Fig. 4). Hemorrhagic necrosis has occurred in several areas. Sections through the Fallopian tube showed clusters of tumor cells within dilated lymphatics. The fatty omental tissue also contained anaplastic tumor cells, many of which had the signet-ring appearance, but in one area the stroma had undergone decidual changes (Fig. 5). Autopsy findings. The postmortem examination

704

Fox and Stamm

July I l!lh'l

Table I. Summary of reported cases of Krukenberg tumor associated with pregnancy·N---------

Author and year

Age

When noted

·-~--

·-

--------

rr _' __ .,. _·

ruutzrn?,

Presenting symptoms

Jlgn.>

1

l.· nilaieral or bilateral

26

5 Months

Pain and abdominal enlargement

l\loJif'

l.lnilateral

Gobiet 17 i909

37

5 Months

Abdominal tumor

:\ow·

Bilateral

Cohn 8

25

3 Months

Vomiting, diarrhea, and abdominal cnlargcmen t

?\iow·

l!nilateral

Hyperemesis

.:\'om·

Bilateral

Burdsinsky"

1908

1910 Schmid 30

t

2-t

1922 Turolt~ 6

1923 Guiroy and Jacobl8

1928 Gauthier-Villarst6

*

8 Months

Abdominal enlargement

*

4y,

Abdominal pain

None

Unilateral

Epigastric pain

None

Bilateral

Months

t

29

1928 Bell and Datnor 4

Bilateral

32

4 Months

Pain, vomiting, and diarrhea

None

C nil a tt·ral

26

712 Months

Chest pain

Yes

Bilateral

t

6Y2 Months

t

None

29

4Y2 Months

t

None

Bilateral

35

6 Months

Pain and vomiting

None

Bilateral

Diarrhea

None

Bilateral

Hyperemesis, abdominal tumor

None

Bilatt'ral

1932 Esau 13

1933 Frankl 14

1933 Frankl14

1933 Puppel2fl

t

1933

37

Wendt"'

16 Weeks

1935 18

von Bud 5

4 Months

1935 Hagstrom~ 0

1938

W atrin, Vermelin, and Chalnot 39

33

23 Weeks

Vomiting

None

Bilateral

28

17 Weeks

Abdominal enlargement

:-.Tone

Bilateral

32

23 Weeks

Abdominal pain

Non<"

Unilateral

32

At term

Tumor found on examination

l\iom·

Bilateral

26

First trimester

Diarrh~a

None

lTnilateral

39

At term

Abdominal pain and tumor

None

Bilateral

1939 Horta Barbosa, Salles, and Pinheiro2 1

1940 de Oliveira

Sarmento~ 8

1942 Garcia Orcoyen 15

and

aseite~

1945 Ameline and co-workers"

1952

*Cases reported by Barata-Ribeiro,a Enzer, 12 Jarcho,2 2 Shaw, 3!! and Vigne-sa 1 and cite-d previously as being ay;;sociated with pre~nancy tinfonnation not given in :report.

Krukenberg tumor and pregnancy

Volume 92 Numbei5

Tumor origin

Obstetric outcome

Treatment of tumor

705

Results Died 3 ~/::! months post partum; metastases

Stomach

Live birth at term

Oophorectomy

Stomach

Intrauterine death

Radical operation and x-ray

Colon

Aborted at 3 months

Oophorectomy

Stomach

Removed

Stomach

Premature live birth

Oophorectomy

Died 3 days after operation; circulatory collapse

Stomach

Delivered at 6Y2 months

None

Died 6 days post partum; perforated stomach

Stomach

Live birth at term

Stomach (pyloris)

Removed

Stomach

Live birth 32 weeks

m

m

utero

utero

Bilateral salpingo-oophorectomy, hysterectomy

t

t Died 3 weeks after operation; torsion and peritonitis

t

t

Bilateral salpingo-oophorectomy, hysterectomy

Died 4Y2 months post partum; carcinomatosis

Bilateral oophorectomy

Died 27 months post partum; intestinal obstruction

t

t

t

Delivered at 6)12 months

Stomach

Delivered at 4Y2 months

Bilateral oophorectomy

Stomach

Cesarean hysterectomy at 6 months

Bilateral salpingo-oophorectomy

Died few days postoperative; ileus

Rectum

Aborted 2 weeks postoperative

Exploratory laparotomy

Died 24 hours postabortal; marasmus

Cesarean section at term live birth

Bilateral oophorectomy

t

Undelivered

Attempted induction of labor

Died during induction; metastases

Hysterectomy at 17 weeks

Hysterectomy, bilateral salpingo-oophorectomy

Died 36 hours after operation

Stomach

Delivered at 26 weeks

None

Died 7 days post partum; torsion and peritonitis

Stomach

Live birth at term

Supravaginal hysterectomy, bilateral salpingooophorectomy

Alive one month after operation

Stomach

Cesarean section, live birth

None

Died aftt'r operation

Stomach

Live birth; pseudohermaphrodite

Hysterectomy, bilateral salpingo-oophorectomy, and gastrectomy

Alive at 4 months

t Stomach

t

could not be verified in the references. 11

t

July I 1%.-,

706 Fox and Stamm

Table

Am.

J.

()b..;t. 8.:

l~vlH'f

I~~Cont'd

Author and year

Age

When noted

Presenting symPtoms

Virilizing signs

Unilnteral or bilateral

Pelvic pressure, vaginal bleeding

None

Bila tr ral

35-36 Weeks

Weight loss, hematemesis

None

Bilateral

32 Weeks

Vomiting

None

Bilateral

Presence of tumor

None

l.' llilatr·ral

Abdominal enlargement; hematemesis

None

Bilateral

Ovarian enlargement

0/une

lJ nilateral

Alter 1 1952

35

3 Months

Alter I 1952

33

Burke 7 1953

22

Moore 26 1954

22

Gustafson, Gardiner, and Stout19 1954

30

t

6 Months

t

13 Weeks

Lawrence, Larson, and Hauge23 1957

20

9 Weeks

Abdominal pain

None

l ' nilateral

Day and Murray 1 0 1958

41

4-5 Months

Abdominal enlargement

:\one

Bilateral

Spadoni 34

20

6

~[onths

En1esis, abdotnina.l pain,

Yes

Unilateral

Yes

Unilateral

Ward 38 1954

and enlargement

1964 Fox and Stamm 1964

27

23 Weeks

Vomiting, constipation, and pain

·---- - --- - ---·--~·----~··-·-- - -.-

Fig. 1. Metastatic tumor cells m ovary. (x430. )

Fig. 2. Mucicarmine positive tumor cells in ovary. (x430.)

was permissively restricted to the abdom en. The extremely emaciated and dehydrated body showed a diffuse growth of black hair over the entire surface. An acneiform rash was present over the face and chest. The entire abdominal and pelvic contents were

fused into a single firm mass by dense fibrous and tumorous adhesions. The stomach measured 12.0 x 6.0 x 6.0 em. in external dimensions and 1 em. in thickness and was lined by a relatively smooth serosal surface. The mucosal surface had a rough, corrugated, and cobblestone appearance

Volume 92 Number 5

Krukenberg tumor and pregnancy

Tumor origin

Obstetric outcome

t

t

Treatment of tumor

707

Results

Removal of tumor after pregnancy

Died 10 months after operation

Stomach

Live birth at 36 weeks

None

Died one week post partum; carcinomatosis

Stomach

Stillborn at 32 weeks

None

Died 2 days post partum; peri toni tis

Apparently aborted

Oophorectomy

Living with possible metastatic symptoms 11 years postoperative; had 2 succeeding pregnancies terminating with live births

Stomach

Cesarean section at 6 months; baby died

Bilateral sal pingo-oophorectomy

Died 6 months after operation; carcinomatosis

Stomach

Live birth at term

Oophorectomy, gastroenterostomy

Died 4 months post partum: carcinomatosis

Primary

Live birth at term

Oophorectomy

Died 3 Y2 months post partum; metastases

Primary

Hysterotomy, 5 months

Hysterectomy, bilateral salpingo-oophorectomy

Died 5 months after operation; carcinomatosis

Breast

Live premature birth at 7 Y2 months

Postpartum hysterectomy, bilateral salpingooophorectomy

Died 6 months after operation; carcinomatosis

Stomach

Live premature birth at 34 weeks; neonatal death

Oophorectomy

Died 7 months post partum: carcinomatosis

t

Fig. 3. Sudan (x430.)

IV~positive

luteinized stromal cells.

(Fig. 6) . The small and large bowel were firmly adherent by hard tumorous and fibrous adhesions, but the mucosal lining appeared uninvolved. The tumor extended retroperitoneally in a haphazard fashion and there was a right hydronephrosis and hydroureter resulting from compression of the

Fig. 4. (x430.)

Luteinization of thecal stromal cells.

lower ureter by tumor. The left ovary could not be identified within the tumor masses. The adrenal glands were not enlarged and grossly not involved by tumor. Microscopic examination revealed a complete replacement and generalized thickening of the

708

Fox and Stamm

Fig. 5. Anaplastic tumor rells and dec idual changes in omentum . ( · 43 0.)

Fig. 6. Postmortem photograph of stomach lesion. Linitis plastica. gastric mucosa by poorly differentiatPd adenocarcinoma. The tumor ct'lls had infiltrated, singly and in small clusters, the underlying submucosa and muscularis layers, producing a fibrous reaction which resulted in marked thickening of the gastric wall, typifying a linitis plastica lesion. Signet-ring cells were scattered throughout the tumor. Retroperitoneal lymph nodes, liver, endometrium, and myometrium, as well as small foci within the submucosa of duodenum and small bowel were seconda rily involved. Comment

The diagnosis of Krukenberg tumor of the ovary before surgical exploration is highly improbable. This is especially true during pregnancy, as shown in this case. Rapidly progressive abdominal pain, tumor enlargement, and encroachment upon the lower bowel associated with sudden dramatic virilization were impressive but gave no clue to the true diagnosis.

july I , 1%5 \m.

J,

Oh:.;t. & Gyncc

More thorough laboratory investigation regarding the extreme masculine chanr.;es would have afforded interesting data. if conditions had been more favorable for the-ir performance. Other cases have documented the presence of high levels of ketosteroid> in these tumors when the luteiniz<·d stroma cells are apparently influenced by such specific types of metastatic neoplasms. Turunen'15 was the first to suggest that the metastatic tumors may be endocrinologically active. He described menstrual irregularities and endometrial hyperplasia in a number of patients , as well as return to normal levels of abnormally elevated estrogen and 17 -ketosteroid \·alues after removal of the involwd ovaries. Scully and Richardson"' also found indirect evidence of hormonal imbala nce in several patients. Most of the hormonally aniw cases previously reported have pointed to the elaboration of estrogenic compounds. Howevt·r , a number of cases with virilization have suggested androgenic activity of the tumor. Histochemical demonstration of steroids in luteinized cells has been tried by a number of methods. These include the Sudan IV stain, phenylhydrazine, and sulfuric acid reactions, as well as evaluation for autofluorescence and birefringence."'· c:. Although a number of functioning tumor~ follow a characteristic staining reaction, the evidence of hormone production by this means is, at best, circumstantial. In some cases of hormonally active tumors, the ex pected histochemical pattern has not been followed." With the recent progress in stProid chemistry, more direct methods of determina tion of abnormal hormonal activity of the diseased ovary have become availabh~. Spadoni, Lindberg, and Herrrnann 3 " were able to isolate a number of hormonal fractions directly from a vi rilizing Krukenberg tumor in a young pregnant woman. They were successful by histochemical techniques in demonstrating probable hormone production by the luteinized stromal cells. In the present case, histochemical studies showed the presence of Sudan IV- positive droplets in the cytoplasm of the luteinized

Volume 92 Number 5

stromal cells. However, application of other known methods for the histologic demonstration of steroids failed to give conclusive results. The marked degree of external virilization of the patient strongly suggests production of androgens by the Krukenberg tumor in the absence of adrenal abnormalities. The low normal postoperative urinary 17 -ketosteroid level is in keeping with normal or low values observed after removal of such tumors. a:>, ":; It is of interest to note that the infant at birth showed a moderate degree of clitoral hypertrophy, indicating excessive androgen production by the mother. The presence of the marked decidual reaction of the omentum also involved by metastatic tumor is somewhat difficult to evaluate. Under circumstances of normal pregnancy, such a reaction would not be surprising. However, Ober and associates~ 7 reported a well-marked decidual reaction of the endometrium in the case of a 46-year-old patient with signs of virilization from a Krukenberg tumor. It appears that the hormone

Krukenberg tumor and pregnancy

709

production by the luteinized stromal cells may be of a rather mixed nature due to elaboration of substances at various levels in the chain of synthesis of steroid hormones." 1 • 3 " Summary

The problem of the Krukenberg tumor complicating pregnancy has been reviewed, and all such case reports have been studied and tabulated with pertinent data abstracted from the 30 known cases. This third known case in which the tumor was involved in extreme androgenic activity and clinical masculinization has been presented with detailed observations and discussion of the clinical and pathological implications.

Grateful appreCiatiOn is expressed to Drs. Arthur T. Hertig, Boston, John I. Brewer, Chicago, and Leslie B. Grams, San Jo>e, for their counsel in reviewing the micropathology in the case presented. Dr. Jorge Franco was very helpful in translating many of the references. The rPferring physician, Dr. Robert J. O'Neill, was most cooperative.

REFERENCE;S

1. Alter, N. M.: Cited by Ovarian Tumor Registry. Personal communication. 2. Ameline, A., LePage, F., Hugier, J., Seneze, J., and Schramm, B.: Arch. mal. app. digest. 41: 565, 1952. 3. Barata Ribeiro, P.: Rev. brasil. cir. 17: 327, 1948. 4. Bell, W. B., and Datnor, M. M.: Am. J. Cancer 16: 439, 1932. 5. von Bud, G.: Orvosi hetil. 79: 146, 1935. 6. Burdsinsky, T. A.: Zentralbl. Gynak. 32: 410, 1908. 7. Burke, S.: J. Obst. & Gynaec. Brit. Emp. 60: 915, 1953. 8. Cohn, F.: Monatsschr. Geburtsh. u. Gynak. 31: 333, 1910. 9. Case Records, Massachusetts General Hospital: New England J. Med. 253: 926, 1955. 10. Day, A., and Murray, D. J.: Canad. M. A. J. 78: 9-4-1, 1958. 11. Diddle, A. W.: Cancer 8: 1026, 1955. 12. Enzer, N.: Ann. Surg. 92: 148, 1930. 13. Esau, P.: Zentralbl. Gynak. 57: 1167, 1933. 14. Frankl, 0.: Zentralbl. Gynak. 57: 788, 1933. 15. Garcia Orcoyen, J.: Rev. espan. cir. 1: 395, 1945. 16. Gauthier-Villars, P.: Ann. d'anat. path. 5: I, 1928.

17. Gobiet, J.: Wien klin. Wcbnschr. 22: 121, 1909. 18. Guiroy, A. J., and Jacob, A.: Bull. Soc. obst. et gynk 17: 535, 1928. 19. Gustafson, G. W., Gardiner, S. H., and Stout, F. E.: AM. J. 0BST. & GYNEC. 67: 1210, 1954. 20. Hagstrom, H. T.: AM. J. 0BST. & GYNEC. 36: 498, 1938. 21. Horta Barbosa, L. A., Salles, N., and Pinheiro, J.: Rev. gynec. et d'obst. 2: 281, 1940. 22. Jarcho, J.: Am. J. Surg. 41: 537, 1938. 23. Lawrence, W. D., Larson, P. N., and Hauge, E. T.: Obst. & Gynec. 10: 84, 1957. 24. McKay, D. J., and Robinson, D.: J. Endocrinol. 41: 378, 1947. 25. McKay, D. J., Robinson, D., and Hertig, A. T.: AM. J. 0BST. & GYNEC. 58: 625, 1949. 26. Moore, J. M.: Cited by Ovarian Tumor Registry. Personal communication. 27. Ober, W. B., Pollak, Ann, Gerstmann, K., and Kupperman, H.: AM. J. 0BsT. & GYNEC. 84: 739, 1962. 28. de Oliveira Sarmento, A.: An. brasil. ginec. 14: 81, 1942. 29. Puppel, E.: Zentralbl. Gynak. 57: 49, 1933. 30. Schmid, H. H.: Arch. Gynak. 117: 418, 1922.

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71 0 Fox and Stamm

31. Scully, R. E., and Richardson, G. S.: Cancer 14: 827, 1961. 32. Shaw, W.: ]. Obst. & Gynaec. Brit. Emp. 33: 256, 1926. 33. Spadoni, L., Lindberg, M., and Herrmann, W. L.: Obst. & Gynec. 23: 630, 1964. 34. Spadoni, L.: Personal communication. 35. Turunen, A.: Acta. endocrinol. 20: 50, 1955. 36. Turolt, Max: Zentralbl. Gynak. 47: 1836, 1923.

Am.

J.

Ob~t.

& Gyncc

37. Vignes, H.: Paris med. 1: 249, 1934. 38. Ward, S. V.: AM. ]. 0BST. & Gv~Ec. 67: 1210, 1954. :l9. Watrin, ].. Vermelin, H .. and Ch:dnot. 1'. · Bull. Soc. gynec. et obst. 28: 37, 1939. +0. Wendt. F.: Svenska lak-tidning 32: 51, J9:Fi. 303 North 15th Street San jose 12, California