Ovarian extraembryonal teratoma

Ovarian extraembryonal teratoma I. Endodermal

GORDON

K.

Oklahoma J.

JIMERSON,

M.D.

City, Oklahoma

DONALD

Baltimore,

sinus tumor

WOODRUFF,

M.D.

Maryland

Forty-one cases of pure endodermal sinus ovarian tumors are reported. The extraembryonal nature of this tumor is supported with comparative studies utilizing early human implantations. The clinical picture is one of a virulent malignancy occurring in young women, and although the tumor is commonly unilateral and encapsulated at the time of initial diagnosis, the outcome is almost alujays fatal. Experience with dz;fferent therapeutic moa!alities is limited, but there is significant evidence that vigorous combination chemotherapy will improve the therapeutic outcome. (AM. J. OBSTET. GYNECOL. 127: 73, 1977.)

I N 193 9, Schiller’ described a group of ovarian tumors for which he proposed a mesonephric origin and the name mesonephroma ovarii. Jones and Jones’ suggested Schiller’s original series contained two separate tumor types, a fact that Schiller acknowledged in a later article.2 In 1946, Teilum3, 4 published the first of a series of reports devoted to the “embryonal type” Schiller mesonephroma ovarii in which he refuted the mesonephric origin and suggested the now commonly accepted theory of germ cell origin. Teilum meticulously described histologic evidence supporting the extraembryonal nature of the tumor with emphasis on the histologic similarity to the developmemal pattern associated with extraembryonal mesoblast. He5 originally suggested the name extraembryonal mesoblastoma but later replaced this name with endodermal sinus tumor, a name derived from analogies drawn between peculiar vascular bodies found in the tumor and in the developing placenta of the rat. The tumor has since been described under a variety of names including embryonal carcinoma, teratocarcinoma, embryonal

From the Departments University of Oklahoma Johns Hopkins Hospital. Received

for publication

Accepted July

teratoma, and yolk sac tumor. Adding to the confusion is the fact that many of the above names have been applied to tumors other than the endodermal sinus type as well as those tumors containing combinations of histologic patterns. In the present series, the discussion will be limited to cases containing only the endodermal sinus pattern. In a later presentation, tumors with endodermal sinus pattern mixed with other germ cell elements will be discussed. The authors recommend the adoption of the term endodermal sinus tumor under the general classification of extraembryonal teratomas (Table I), and coincidentally recommend the abandonment of the terms embryonal carcinoma, teratocarcinoma, and malignant teratomas since they have become nonspecific as well as nondescriptive.

Material The present series include 41 cases from the Emil Novak Ovarian Tumor Registry of the American Gynecologic Society. Adequate histologic sections of all cases were reviewed, and only those felt to clearly represent the endodermal sinus type of extraembryonal teratoma were included. Eighteen cases of endodermal sinus tumor combined with other germ cell tumors were excluded and are the subject of a separate report. Patient profile and clinical data were available for all cases and adequate follow-up in 34. Patient profile. The ages of the patients ranged from l’/, to 40 years with an average of 18 years. Twenty

of Gynecology Health

and Obstetrics, Sciences Center, and The

March

25, 1976.

14, 1976.

Reprint requests: Dr. G. K. Jimerson, Department of Gynecology, P. 0. Box 26901, Oklahoma City, Oklahoma 73190.

73

74

Jimerson

and Woodruff .\m.

Table

I. Germ cell tumors

Januarr, J. Obstct.

I. lY77 G\nac,t.

of the ovary

I. Undifferentiated germ cell tumors A. Germinoma II. Extraembryonal teratomas A. Choriocarcinoma B. Endodermal sinus tumot C. Polyvesicular vitelline turn01 III. Teratomas A. Immature B. Mature 1. Benign 2. With malignant element 3. Carcinoid 4. Strumma ovarii .5. Others IV. Gonadoblastoma V. Mixed germ cell tumors (tumors containing elements of two or more of the above histologic types)

Table

II. Treatment

and survival:

Stage IA

Fig. 1. Human

blastocyst at four days’ development. The cells are primitive without recognizable differentiation toward embryonal or extraembryonal elements. (From Hertig, A. T., Rock, J,, and Adams, E. C.: Am. J. Anat. 98: 435, 1956. Courtesy of Carnegie Institution of Washington, Department of Embryology, Davis Division.)

Adnexal removal Hysterectomy and adnexal removal Surgery and radiation therapy Surgery and chemotherapy *Mean

patients were 20 years of age or older and of these, 11 were parous. The diagnosis was made during pregnancy in one and in the immediate postpartum period in three patients. Symptoms and physical and laboratory findings. Abdominal pain was the dominant symptom in 21 of the 33 patients in whom the presenting complaint was listed. In four patients the pain was associated with torsion of the tumor, while necrosis and hemorrhage probably accounted for the discomfort in the remainder. A noticeable abdominal mass induced six patients to seek medical consultation; pelvic pressure was the presenting complaint for three patients and generalized abdominal swelling secondary to ascites was the primary symptom in two instances. Amenorrhea and hoarseness were the presenting symptoms in one patient who also had clitoromegaly. Hormonal

assays

were

not

recorded

in this

patient

and

death occurred shortly after surgery. A positive pregnancy test w-as obtained from another patient both initially and at the time of diagnosis of recurrent tumor. As reported by Wilkinson and associates” and Tsuchida and colleagues7 alpha-fetoprotein has been discovered in the serum of several patients with endodermal sinus tumors, and may be useful in following such patients regarding possible recurrence and/or response to therapy. Alpha-fetoprotein was found in the

Table

survival

for

III. Treatment

patients

who

19 3

2 0

7 IO

4 2

0 1

11 30

died of disease.

and survival:

Stages III and IV

Trcatmmt Hysterectomy, adnexai removal. and excision of implants Surgery and radiation therapy *Mean

survival

for patients

who

?

0

2

1

0

4

died

of disease.

serum of one patient in the present series. Serial studies were not available in this patient. Operative findings, treatment, and survival. A narrative description of operative findings was available in 39 patients. At the time of initial diagnosis, 29 tumors were unilateral without evidence of extension or metastasis (FIG0 Stage Ia). In almost all cases the surgeon and/or pathologist described the tumor as encapsulated without evidence of tumor excrescences. The tumors were usually very large with weights commonly exceeding I kg. and ranging up to 5 kg. The tumors ranged in size from 7 to 30 cm. with only seven being less than 15 cm. in the greatest diameter. Despite the fact that all of the latter tumors were described as unilateral, encapsulated, and without evidence of metastasis, six of the seven patients were dead within nine

Volume Number

Ovarian

127 1

extraembryonal

teratoma.

I

75

2. Fourteen-day implantation. Left, Embryonic disc with yolk sac, amnion, and developing villi. (Original magnification x40.) Right, Early villus with cytotrophoblasts, syncytiotrophoblasts. and extraembryonal mesoblast. (Original magnification x400.)

Fig.

Germ Cell

Preimplantation

PLACENTA, CORD, MtMBRANES AND YOLK SAC trophoblasts, mesoblasts, sac and amnion epithelium

Stage

yo lk Fig. 3. , Normal

months while one was living without evidence of tumor nine years after therapy. In eight patients, intraabdominal extension or metastasis was observed at the time of initial diagnosis (FIG0 Stage III) and two patients presented with extra-abdominal metastasis (FIG0 Stage IV). There were no bilateral tumors in these 39 patients. Of 34 patients in whom follow-up was available for two years or until death, 31 are dead of disease and three are living at 21/, 9, and 12 years after treatment. The tumor in each of the three survivors was Stage Ia at the time of initial diagnosis and therapy. Details regarding the mode of therapy were available in 3 1 of the 34 patients. These patients are analyzed in Tables II and III. Seventeen of 19 patients treated only by unilateral adnexal removal are dead and two are living without evidence of disease at 9 and 12 years, respectively. Hysterectomy with adnexal excision was the

of Development

EMBRYO a > ectoderm. mesoderm endoderm-in various of maturation

ADULT and stages

de\ relopment.

only therapy utilized in five patients, all of whom are dead of disease. Thus, a total of 24 patients were treated with surgery as the only mode of therapy with two survivors and 22 dead. The mean survival time for patients treated by surgery alone, and who died of disease, was seven months with a range of 1 to 17 months. Of five patients treated with surgical excision followed by radiation therapy, all are dead with the mean survival time of 10 months and range from 4 to 18 months. One patient treated with surgery followed by triethylenemelamine and whole pelvic radiation died of disease 30 months after initial diagnosis and therapy. This survival of 30 months is 12 months longer than any patient with known metastasis or recurrence treated by surgery alone or surgery and radiation therapy. Another patient was treated initially with surgical excision followed by excision of recurrent tumor combined with radiation and multiple-agent che-

76 Jimerson and Woodruff

.%m.,I.

Cell

- ----+

January Ohstet.

1. 1977 Gynecol.

Germi noma

‘*

choriocarci polyvesicular tumor

Teratomas imature mature struma ovarii

noma vitelline Fig. 4.

Germ cell tumors. primitive mesoblast, further differentiation occurs with formation of placental connective tissue and the epithelial lining of the yolk sac. Hertig’ refers to the most undifferentiated extraembryonal cell as primitive trophoblast and describes the mesoblastic developmental pathway as follows: Thus, trophoblast is a multipotential tissue. It gives rise, by in situ delamination from primitive cytotrophoblast, to placental connective tissue (mesoblast), blood vessels and amniotic epithelium. The primitive mesoblastic or fibroblastic tissue in turn forms the primary and definitive yolk sacs, exclusive of the endodermal portion of the germ disc. It also contributes largely, if not wholly, to the mesenthyme or connective tissue of the body stalk or umbilical cord.

Fig. 5. Endodermal sinus tumor. An area with sheets of amphophilic undifferentiated cells similar to the preimplantation stage of development. (Original magnification x 160.) (Typical endodermal sinus patterns were seen elsewhere in this tumor.)

motherapy utilizing vincristine, actinomycin-D, cytoxan. This patient is living and well 25 months initial diagnosis and therapy.

and after

Comment The extraembryonal nature of the endodermal sinus pattern is most convincingly seen in comparative studies with normal extraembryonal development. Normal preimplantation development is seen in Fig. 1. During this stage of development, the cells are primitive without recognizable differentiation. Soon after implantation, embryonal and extraembryonal differentiation occurs with the embryonic portion consisting of the germ disc. During early stages of development, extraembryonal tissues predominate and include the amnion, mesoblastic connective tissue, yolk sac, cytotrophoblast, and syncytiotrophoblast (Fig. 2). From the undifferentiated preimplantation cells, extraembryonal differentiation may occur into either mature trophoblast or extraembryonal mesoblast. From the

The normal extraembryonal pathway from which mesoblasts are derived is indicated by the continuous line in Fig. 3. The histologic similarities between normal extraembryonal development and endodermal sinus tumors, as previously described by Teilum. were apparent in all tumors studied. The developmental pathway for extraembryonal teratomas is illustrated in Fig. 4. The most primitive cells, analogous to preimplantation development. are seen in Fig. 5. These are found as aggregates of amphophilic cells with large nuclei. abundant cytoplasm, and no recognizable attempts at organogenesis. Other areas reveal a loose meshwork of spindle cells with a stellate arrangement of cytoplasmic extensions. As seen in Fig. 6, these cells cannot be differentiated from the extraembryonal connective tissue found in the normal pregnancy. Coursing through the mesoblastic connective tissue are channels lined by eptthelium that varies from low columnar to flat. This epithelium seems identical to the normal yolk sac (Fig. 7). Associated with these basic histologic patterns are found many variations, several of which are striking. The primitive mesoblast tends to be prominent around vessels forming a perivascular mantle that varies in

Volume Number

Ovarian extraembryonal teratoma. I 77

127 1

Fig. 6. Lef, x450.) Right,

Extraembryonal Extraembryonal

mesoblast mesoblast

in 14 day in enhdermal

human implantation. (Original magnification sinus tumor. (Original magnification X330.)

Fig. 7. Left, Epithelial lined channel in endodermal sinus tumor. (Original magnification x410.) Right, Yolk sac epithelium from a 14 day human implantation. (Original magnification x440.)

Fig. 8. Endodermal sinus tumor. Left, Large vessel with thick perivascular mantle of tumor cells. (Original magnification x60.) Right, Longitudinal section of a small vessel with mantle. (Original magnification X300.)

78

Jimerson

and Woodruff

January

I. 1977

Am. J. Ohstet.

Fig. 9. Endodermal (Original magnification

sinus

pattern

in center

of photograph.

Fig. 11. Ovarian germ cell tumor with benign merits mixed with endodermal sinrls pattern. nification X5.5.)

X360.)

the

fact

that

tumors It

with

of germ

mixed The

patterns young

fact that

thickness with

with

their

the

mantles

epithelial-lined

dermal

sinus

pattern

tracytoplasmic are commonly sive

the

(Fig.

8).

of tumor

cells,

often

channel,

thus

described

positive

These

bodies,

and

diastase

munohistochemical tionship

size

to Reichert’s

studies membrane

Smaller protrude

into

forming

the (Fig.

eosinophilic the subject

illustrated

in

resistant.” have

vessels,

by Teilums

and extracellular seen and have been

studies.

PAS

vessel

Fig.

chemotherapy.

are

Although

suggested of the

mouse

im-

their

rela-

embryo,

REFERENCES

1. Schiller, 1939.

W.: Mesonephroma

ovarii,

Am. J. Cancer

35: 1.

two were Although more

extensive

to add

to the

however.

did

patients

treated

gical

of aggressive

three

survivors

than

therapy

and and

vigorous

or wirh

these

30

patient

is

recur-

metastatic and

encouragis similar

and

two

surgery The

use of such for

Of

despite

chemotherapy

of choice

not

survived

a second

18 months.

associates”

did

rime. one

or

this

Chemotherapy.

recurrent

alone,

radia-

adnexal reare relatively

survival

diagnosis

The

in

radiation

time.

initial

to combination early

and/or

and

longer

by Forney

by unilateral of patients

with

number

15 or more

lack

of disease

surgery

the

treated

chemotherapy,

patient by

lived

the

the with

removal.

Of

survival

after

No

treated

ing response ports

pattern

tumors

the

to influence

dying

tumor.

were

surgery

with

25 months

adjunctive

The

explains

patients

mean

seem

before

reports

other

supporting

adnexal

treated only the numbers

seem

radiation,

11).

probably

explains

small,

tumor

10,

of these

further

rent

in

sinus

types

(Fig.

elrmag-

of origin.”

endodermal

by unilateral

ago

endo-

bodies of exten-

occur

treated

and

9). In-

found

theory

cell tumor

origin

years

living

are

squamous (Original

are the subject of another report. age of the patients in whom extraem-

most

months

find

cell

tion series, moval.

bodies this

germ

teratomas

of patients

and extracellular eosinophilic bodies corner. (Original magnification

to

other

theory

bryonal

lower

similar weakens

is common

mixed

Fig. 10. Intracytoplasmic best seen in right x480.)

very

seriously

Gynwol.

to

certainly

sup-

agents

as the

lesions

after

sur-

removal.

2. Jones, H. W., and Jones, G. E. S.: Mesonephroma of the ovary: Further studies, Arch. Pathol. 33: 18, 1942. 3. Teilum. G.: Gonocytoma: Homologous ovarian and tes-

Volume

12i

Number

1

4.

5.

6.

7.

titular tumors. I. With discussion of “Mesonephroma ovarii” (Schiller: Am. J. Cancer, 1939), Acta Pathol. Microbiol. &and. 23: 242, 1946. Teilum. G.: Classification of endodermal sinus tumors (mesoblastoma vitellinum) and so-called “embryonal carcinomas” of the ovary, Acta Pathol. Microbial. Stand. 64: 407, 1965. Teilum, G.: Endodermal sinus tumors of the ovary and testis. Comparative morphogenesis of the so-called mesonephroma ovarii @chiller) and extraembryonic (yolk sac-allantoic) structures of the rat’s placenta, Cancer 12: 1092, 1959. Wilkinson, E. J., Friedrich, E. G., and Hosty, T. A.: Alpha-fetoprotein and endodermal sinus tumor of the ovary, AM. J. OBSTET. GYNECOL. 116: 711, 1973. Tsuchida, Y., Sarto, S., Ischida, M., Ohmi, K., Urano, Y., Endo, Y., and Oda, T.: Yolk sac tumor (endodermal sinus tumor) and alpha-fetoprotein. A report of three cases, Cancer 32: 917, 1973.

Ovarian

extraembryonal

teratoma.

I

79

8. Hertig, A. T.: Human trophoblast, Springfield, Ill., 1968, Charles C Thomas, Publisher, p. 16. 9. Teilum, G.: “Mesonephroma ovarii (Schiller): Extraembryonic mesoblastoma of germ cell origin in ovary and testis. Acta Pathol. Microbial. Stand. 27: 249. 1950. 10. Pierce, G. B.. Midgley, A. R., SirRam. J., and Feldman, J. D.: Perietal yolk sac carcinoma: Clue to histogenesis of Reichart’s membrane of the mouse embryo, Am. J. Pathol. 41: 549, 1962. 11. Pierce. G. B., Stevens, L. C., and Nakane, P. K.: Ultrastructural analysis of the early development of teratocarcinoma, J. Nat]. Cancer Inst. 39: 755, 1967. 12. Forney. J. P., Disaia, P. J., and Morrow, C. P.: Endoderma1 sinus tumor. A report of two sustained remissions treated with a combination of actinomycin D, 5fluorouracil, and cyclophosphamide, Obstet. Gynecol. 45: 186, 1975.