Management of immature teratoma of the ovary in children by conservative resection and chemotherapy

Management of Immature Teratoma of the Ovary in Children by Conservative Resection and Chemotherapy By Ann M. Kosloske,

Blaise E. Favara,

Taru

Hays, Francis J. Major,

and Wm. Carl Bailey

0

VARIAN TUMORS are rare in children, accounting for only 10; of and information about their biologic behavior pediatric malignancies,‘-3 and management is accumulating slowly. Terminology remains a stumbling block in comparison of series. However, of the tumors formerly known as malignant teratomas4 a specific group has been designated immature teratoma5 or solid teratoma.6 This tumor occurs most commonly in the first two decades of life: it is aggressive but not truly malignant, and it may have a good prognosis. Our experience in treating six patients with immature teratoma of the ovary by conservative surgical resection and combined chemotherapy forms the basis of this report. CLINICAL Six patients with immature

teratoma

MATERIAL

of the ovary

were followed

at our institution

from

1968

through 1975 (Table I). All were white. Ages ranged from 4 to 17 yr. The presenting symptom was pain in three, a mass in two, and acute torsion of the ovarian mass in one. Unilateral oophorectomy or salpingo-oophorectomy was done initially in ail patients. Five patients required a second operation for removal of recurrent abdominal tumor. Immature teratoma comprised 135; (7 of 54) of all ovarian neoplasms seen at our institution over a 32-yr period. Chemotherapy with vincristine, actinomycin D. and cyclophosphamide was administered (Table 2) for I yr. A clinical stage was assigned to each case, according to the criteria of the International Federation of Gynecology and Obstetrics (FIGA).2 An outline of our management of suspected immature ovarian teratoma is as follows: I Exploration is performed through a generous incision. with inspection of all peritoneal

sur-

faces. including the infradiaphragmatic area. The tumor is gently mobilized. to avoid rupture of any cystic elements. and unilateral salpingo-oophorectomy is performed. Wedge biopsy of the contralateral ovary is carried out. If peritoneal implants are present, biopsies are taken, and the abdomen is closed. 2. The diagnosis of immature teratoma is established after thorough sectioning of the tumor. The Thurlbeck-Scully grading system6 is applied. 3. Triple-agent chemotherapy is administered to patients with grade 2 or 3 tumor. No chemotherapy is given to patients with grade 0 or grade I tumors. Chemotherapy is given to patients with implants or recurrences ofgrade I, 2, or 3 tumors. 4. Follow-up of these children includes abdominal and pelvic examinations at l-3-mo intervals. Chest and abdominal roentgenograms are obtained every 2 3 mo. in search of nodules or neocalcifications suggesting recurrent (secondary) teratomas. Culdocentesis, with cytologic examination of peritoneal fluid. and ultrasonic echogram are helpful in dehnition of suspected masses. Radioisotope scans have not been useful. a-Fetoprotein assays and carcinoembryonic antigen

From rhe Departments Dcspartment Presented Raton.

of’Obstetrics before

the 7th Annual

Fla.. April29-Mar

Addrex~for Me.rico

School

reprint of’

of Surgery.

Pathology.

and Gwecology.

and

University

Meeting

Oncology.

The Children’s

of ColoradoMedical

of the .4trreri<,an

Pediatric

Cenrer, Surgical

Hospital,

and rhe

Denver, Colo. Association.

Bora

1. 1976. requests:

Medicine.221

ci 1976 hv Grime & Stratron,

Ann

M. Kosloske.

I Lomas

M.D..

Departmenr

Blvd. NE. .4Ihuquerque.

of Surgery.

Universily

of Nex,

N. M. 87131.

Inc.

Journal of Pediatric Surgery, Vol. 11, No. 5 (October),

1976

839

KOSLOSKE

840

ET AL.

Table 1. Clinicopothologic Data on Six Patients with Immakwe Teratoma of the Ovary

Patient I

Race 4/W

Side R

Treatment

Pathologic Grade

Clinical

Age/

Presentation

Primary

Moss. ascites

2

Surgical

lmpant 0

Chemotherapy VAC*

Right

x 7 mo

FOllOW.Up Alive, well, free of clinical disease 14 mo off

oophorectomy

chemotherapy ReUJrrerKe:

0

0

Local resection

under right diaphragm calcifications 7mo 2

16/W

Pain, ascites

I

Not

2

Cul-de-sac mew (8 cm) dis-

Left

biop-

appeared within 2 mo

oophorectomy

of chemotherapy; olive,

sied ReClJrrenCEZ:

0

0

Local resection

VAC x 1 yr

well, normal menser,

broad ligo-

free of clinical disease

ment 3 mo 3

16/W

IO mo off chemotherapy

Pain

L

N0tle

2

Left

Cul-de-sac mass

ReCllrrtYlCe:

3

o-2

Local resection

(1cm)

disappeared within 6

oophorectomy VAC x 1 yr

wk of chemotherapy;

brood ligo-

alive, well, normal

ment 4 mo

menses, free of clinical disease 2 yr off chemotherapy

4

8/W

Torwon of cyst

R

NotIe

2

Right solpingo-

None

Alive, well, normal menres, free of clinical disease

oophorectomy RKUrreKe:

0

0

Local resection

2

NOIVZ

Right salpingo-

8 yr postoperatively

uterosocrol ligament 8mo 5

17/W

Pain

R

Alive, well, normal menses, free of clinical

oophorectomy RKUrtetlCe:

3

Local resection

VAC x 1 yr

disease 2 yr off chemo-

loparotomy

therapy; pregnant, not

SCOT6 mo 6

9/W

R

yet delivered

Mass

NOW2

1

Right ralpingo-

None

Alive, well, free of clinical

oophorectomy

disease 1 yr after diagnosis

*VAC

= vincristine,

octinomycin

D, cyclophosphomide.

titers (CEA) have shown no abnormalities in any of the four patients operation; thus neither has been of diagnostic or prognostic value. 5. Reoperation is indicated for recurrences (secondary tumors). Local the procedure of choice. Radical or castrating surgery is avoided.

tested,

before

resection

and

after

of the mass

is

PATHOLOGY Specimens were fixed in IO”,, formalin and routinely processed. Special strains were made when necessary. The number of blocks examined in the six cases of immature teratoma ranged from 4 to 37 in primary tumors, with an average of 15 blocks per case. For recurrent tumors the average number of blocks studied was 9 per case. Peritoneal fluid from two cases was studied after cytocentrifuge preparation. tumors in all six cases Pathologic features of these cases have been reported.7m9 The primary contained tissues originating from all three embryonic germ layers, and in all cases the element Table 2. Chemotherapy Regimen for Immature Teratoma of Ovary Vincristine

1.5 mg/m2*

Actinomycin

D 0.4

Cyclophosphamide *All

drugs

were

given

intravenously.

mg/m2 300

mg/m2

Once,

alternate

Once,

weekly

Once,

alternate

weeks x 6, off 7 weeks

TERATOMA

Fig. 1. (A) Case 1. Gross specimen shows cut surface on the left and intact surface on the right. Note multiple small cystic areas, but the overall pattern is one of a solid tumor. (B) H&Estained section at x 154 magnification showing foci of immature neuroectodermal tissues forming rosettes and pseudoresettes in a Bbrillary glial matrix. Such areas of incomplete differentiation influence the grading of the ThurlbeckScully classification.

lacking

full differentiation

The primary Peritoneal

tumor

implants

was neuroectodermal.

was graded were graded

htstologically

Grade

0: All cells well differentiated.

Grade

I: Cells well differentiated

Grade

2: Moderate

quantities

according

by the same crtterta.

to the criteria

The criteria

of Thurlbeck

except in rare small foci of embryonal of embryonal

tissue

present:

and Sc~lly.~

are:

cells show

tissues. atypicality

and

mitotic

activity. Grade

3: Large

quantities

of embryonal

tissue present:

cells show atypicality

and mitotic

activity.

DISCUSSION

The term immature teratoma of the ovary comes from the recent World Health Organization classification.5 It is a neoplasm comprised of tissues derived from all three germ layers, at least one of which lacks full differentiation.

842

KOSLOSKE

ET AL.

Most often the immature component is neuroectodermal. Immature teratoma has been described in previous literature under a variety of names, including solid teratoma, malignant teratoma, teratoblastoma, teratocarcinoma, and embryonal teratoma. It has been considered inappropriately in the same category as mixed germ cell tumors or secondary malignant tumors arising in mature cystic teratomas. It is imperative that immature tissues in a teratoma not be equated with malignancy. The grading system proposed by Thurlbeck and Scully in 19606 was designed to quantitate the occurrence of such undifferentiated components, and it appears to correlate well with the clinical behavior of these tumors in our series and in othersi We and others9 have found no correlation between the FIGA clinical staging system and biologic behavior of immature teratoma. For accurate grading it is mandatory that thorough sampling of tumor be undertaken and carefully studied. One tumor in this series was initially diagnosed as benign teratoma (patient 3) without note of immature elements. The subsequent evolution of secondary tumors compelled reexamination of the original surgical specimen and subsequent identification of embryonal elements. Radical surgery, with total hysterectomy, bilateral salpingo-oophorectomy, and omentectomy, is recommended for adults with malignant ovarian tumors2*” and has been advised for children with malignant tumor that extends beyond the capsule of the ovary. ~‘~1’~ The pattern of dissemination of immature teratoma, however, differs from that of adult epithelial carcinomas. Immature teratoma appears to spread via the peritoneal fluid, rather than the regional lymphatics; thus radical resection of the pelvic organs cannot increase the chance for cure. Harris and Boles” have pointed out the rarity of specific indications for radical surgery in a child with ovarian malignancy. Unilateral salpingo-oovariectomy was curative in all four of their curable patients. Our experience suggests that radical surgery is unnecessary for immature teratoma of the ovary, even in cases with local spread beyond the capsule. The low-grade aggressiveness of the tumor was well controlled by conservative resection and triple-agent chemotherapy. Preservation of a normally functioning contralateral ovary was achieved in all four postpubertal patients, who resumed normal menses. One of these young women (patient 5) is completing pregnancy. Wedge biopsy of the contralateral ovary is important, however, because the bilaterality of immature teratoma is 13°A.‘o Combined chemotherapy became a part of our treatment protocol because of unfavorable results with surgery alone for this tumor. Five patients did not receive chemotherapy after the initial operation. Teratoma recurred in four of them 3-8 mo after operation. The secondary teratoma was more mature in two patients (patients 2 and 4) but less mature in two (patients 3 and 5), suggesting that spontaneous maturation is not a predictable occurrence. Chemotherapy with vincristine, actinomycin D, and cyclophosphamide was employed in four of our six cases. Its apparent benefit was documented in two patients by the disappearance of a pelvic mass (patients 2 and 3). Although one patient developed a secondary teratoma while on chemotherapy, the secondary was more mature than the primary had been. No patient developed subsequent teratomas after cessation of chemotherapy. Several authors’0J4,‘s have observed

843

TERATOMA

beneficial effects of combined chemotherapy in malignant ovarian tumors, although single-agent chemotherapy is not beneficial. Merrin16 reported benign transformation of testicular carcinoma coincidental to chemotherapy in seven cases; a similar mechanism might be operative for ovarian neoplasms. X-ray therapy was not employed in this series. In a recent review of ovarian carcinoma, it was found that radiation did not improve survival beyond that achieved with operation and chemotherapy.” Radiation has been advocated in children with ovarian malignancies for control of local disease.18 We did not establish a routine second-look policy because five of our six patients developed a recurrent mass within 8 mo of initial operation, requiring reoperation. This did not seem to be recurrence of incompletely resected tumor, but rather the evolution of a second neoplasm from small numbers of pleuripotential cells. seeded either spontaneously or during the first surgical procedure. Our series contains a higher percentage of solid teratomas than other recent solid series from children’s hospitals.‘2,‘9,‘0 Only one patient with immature teratoma was seen at our institution in the 25 yr prior to 1968, but six have been treated since then. This increase in caseload coincided with the establishment of a Regional Cancer Center for children at our institution in 1969. The literature offers a grim prognosis for malignant teratoma, with a mortality estimated at 45% to 89”b.l Many series, however, include mixed germ celi tumors among the teratomas, which skews the statistics unfavorably. In two reports that specifically considered only immature solid teratomas of the ovary, the mortality from the tumor was 330i6 and 43’;.” Published reports have not yet included significant numbers of patients treated with multiple-agent chemotherapy after operation. Gliomatosis peritonei, in which a solid ovarian tumor is associated with hundreds of tiny, white neuroglial nodules throughout the peritoneal cavity, has been a fascinating rarity since the early 1900s. Proskauer2? reviewed 11 cases, Robboy and Sct~lly~~ reviewed 12, and other cases have been cited.7 ‘O.“J~ If the glial implants are uniformly mature, the prognosis is probably good,?’ although this was challenged recently.15 Three of our patients (patients 1, 2, and 4) had gliomatosis peritonei. The nodules were unchanged in the two who required subsequent laparotomy for secondary teratoma. Gliomatosis peritonei appears to represent not true tumor metastasis, a term applicable only to malignant neoplasms, but rather a seeding of tissues, as occurs in endometriosis or splenosis. Immature teratoma of the ovary can lead to a fatal outcome, however, because of mechanical and metabolic effects of large tumor, associated with massive ascites. There are no cases with documented extraabdominal metastases.h.“~23 We do not apply the term malignant to this neoplasm, for it lacks both the metastatic potential and the histologic features of true malignancy. SUMMARY

Six patients with immature teratoma of the ovary were treated with surgery and chemotherapy. Surgical management consisted of unilateral salpingooophorectomy. biopsy and conservation of the contralateral ovary, and biopsy of peritoneal implants. Triple-agent chemotherapy with vincristine, actino-

KOSLOSKE

844

ET AL.

mycin D, and cyclophosphamide was given to four patients and appeared to be beneficial. Radiation therapy was not employed. Local resection of teratomatous recurrences was frequently necessary. Thorough sampling of this tumor is mandatory for establishment of an exact pathologic diagnosis. All six patients are surviving in good health at l-8-yr follow-up. The prognosis of immature teratoma in the child or adolescent appears more favorable than previously appreciated. REFERENCES I. Welch KJ: The female genital tract, in Mustard WT. Ravitch MM, Synder WH Jr, et al (eds): Pediatric Surgery (ed 2). Chicago. Year Book. 1969, p 1380 2. Janovski NA, Paramanandhan TL: Ovarian Tumors, Vol 4 of Major Problems in Obstetrics and Gynecology. Philadelphia, WB Saunders, 1973 3. Thompson JP, Dockerty MB, Symmonds RE, et al: Ovarian and paraovarian tumors in infants and children. Am J Obstet Gynecol 97: 1059. 1967 4. Scully RE: The need for uniform terminology. Hum Pathol4:602. 1973 5. Serov SF, Scully RE: Histological Typing of Ovarian Tumors (International Histological Classification of Tumors No 9). Geneva. World Health Organization, 1973 6. Thurlbeck WM. Scully RE: Solid teratoma of the ovary. A clinicopathological analysis of 9 cases. Cancer 4:804, 1960 7. Favara BE, Franciosi RA: teratoma with neuroglial implants peritoneum. Cancer 31:678, 1973 8. Nogales FF Jr, gliomatosis produced Obstet Gynecol43:915,

Oliva HA: by ovarian 1974

Ovarian on the Peritoneal teratomas.

9. Nogales FF Jr, Favara BE. Major FJ. et al: Immature teratoma of the ovary with neural component (“solid” teratoma). A clinicopathologic study of 20 cases. Hum Pathol (in press) IO. Woodruff JD, Protos P. Peterson WF: Ovarian teratomas. Relationship of histologic and ontogenic factors to prognosis. Am J Obstet Gynecol 102:702. 1968 Il. TeLinde RW, Mattingly Gynecology (ed 4). Philadelphia, 1970, p 817 12. Harris

BH,

Boles

RF: Operative JB Lippincott,

ET: Rational

surgery

for tumors

of the ovary

in children.

J Pediatr

Surg 9:289, 1974 13. Groeker WR: Ovarian tumors during infancy and childhood. Am J Obstet Gynecol 86: 1027, 1963 14. Bronsther B, Abrams MW: Ovarian tumors in childhood. Pediatr Annals 4:565, 1975 15. Wollner N, Exelby P, Lewis J, et al: Malignant ovarian tumors in childhood. Cancer 37:1953, 1976 16. Merrin C, Baumgartner G, Wajsman Z: Benign transformation of testicular carcinoma by chemotherapy. Lancet 1:43, 1975 17. Tobias J’S, Griffiths CT: Management of ovarian carcinoma. Current concepts and future prospects. N Engl J Med 294:818,877, 1976 18. Cham WC, Wollner N, Exelby P, et al: Patterns of extension as a guide to radiation therapy in the management of ovarian neoplasms in children. Cancer 37: 1443, 1976 19. Towne BH, Mahour GH, Wooley MM, et al: Ovarian cysts and tumors in infancy and childhood. J Pediatr Surg IO:31 I, 1975 20. Ein SH: Malignant ovarian tumors in children. J Pediatr Surg 8:539, 1973 LM: Solid 21. Wisniewski M, Deppisch teratomas of the ovary. Cancer 32:440, 1973 22. Proskauer GG: Solid teratomas of the ovary with neuroglial metastases. Am J Obstet Gynecol 52:845, 1946 23. Robboy SJ, Scully RE: Ovarian teratoma with glial implants on the peritoneum. An analysis of 12 cases. Hum Path01 1:643, 1970 24. Ein SH, Darte JMM, Stephens CA: Cystic and solid ovarian tumors in childrena 44-year review. J Pediatr Surg 5: 148, 1970 25. Albites V: Solid teratoma of the ovary with malignant gliomatosis peritonei. Review of the world literature. Int J Gynecol Obstet l2:59, 1974

845

TERATOMA

Discussion S. Ein (Toronto): Since most pediatric surgical centers have seen only a few malignant or near malignant ovarian tumors, few of us are experts in the field. We have long been proponents of the conservative management of ovarian tumors. benign and malignant. Furthermore, prior to the last few years, much of what had been published about pediatric ovarian tumors was written by adult gynecologists, I am pleased to see that one of your coauthors is a gynecologist who has proposed a conservative surgical approach. We are still not doing wedge biopsies of the opposite ovary, and I can’t really see the benefit of doing it. especially when other tumor is left behind. Although this tumor does not fall into the category of a true malignancy. it certainly seems to be closer to a malignant lesion than a benign one much like histiocytosis X; hence the need for chemotherapy. Our experience gives us the impression that such tumors are cured only by early, complete surgical excision, and radiotherapy plus chemotherapy are not beneficial. Here, however. we have a maiignantlike ovarian tumor that of necessity is incompletely excised. has some local recurrences. and seems to respond to triple chemotherapy by maturing and being cured. Yet two of the six tumors matured without any chemotherapy. It sounds a bit like the neuroblastoma story. Do we excise as

much as is safely possible and do nothing further, surgical treatment? At this point it appears that

or do we add triple chemotherapy to the posttriple chemotherapy for this type of ovarian

tumor may well be beneficial. M. Kumar /Memphis]: My remarks will pertain to the difference in the nomenclature of this disease by various pathologists. Different institutions have adopted different pathologic classifications. Adoption of a common histopathologic classitication by all centers concerned with this disease will be helpful in the understanding and treatment of this neoplasm. At St. Jude. Teilum classification has been adopted by our pathologists. They would call what was presented here embryonal cell carcinoma with teratomatous elements. However. our surgical and combined therapy methods are similar to what Dr. Kosloske has recommended here. Although the literature indicates that the presence of glial elements portends a favorable prognosis, two of our patients with this element died despite therapy. I would like to know Dr. Kosloske’s experience in this regard. P. &e/b?: (New, York/c I may be a radical devil’s advocate in discussing this excellent paper. We have studied a series of 20 ovarian carcinomas in children. Histologic classification has been complicated and makes serious comparison difficult. The tumors we saw were very aggressive and showed other malignant elements such as choriocarcinoma and endodermal sinus tumor as part of the picture. We also noted a high incidence of metastatic spread to the periaortic nodes. For these reasons we have advocated more radical local surgery including retroperitoneal node dissection for these highly malignant tumors. It seems that for the grade I and II tumors conservative surgery is indicated. and perhaps no other treatment should be added. In grade III teratomas perhaps some require more radical surgery and radiation and multiple-drug chemotherapy. depending on the histologic grading and staging. We agree very positively with the idea of repeated laparotomy in these children for resection of all bulk disease. Our patients have had an average of three laparotomies. and one child had seven laparotomies. including hepatic lobectomy for ovarian carcinoma. This last child is free of disease 2 yr off treatment. Would you consider elective second looks in these patients because of the high incidence of local recurrences’? R. Soper (Iowa Ci~yi: I would like to ask Dr. Kosloske how she rationalizes her experience with the I2 patients that Dr. Scully reported.* all of whom had grade 0 glial implants in the parietal peritoneum and who survived I to 38 yr, their survival not depending on treatment, Perhaps children with ovarian teratomas with grade 0 peritoneal glial implants do not require postoperative radiotherapy or chemotherapy, r. Boles (Columbusi:

We have

had

three

similar

patients:

in one, the pathologists

called

the

tumor frankly malignant. This patient did have widespread peritoneal metastases. Following a conservative salpingo-oophorectomy she was treated with chemotherapy and is now clinically well 3 yr later. The ascites disappeared, and she has had no recurrence. It is obviously far too early to determine her ultimate prognosis. *Robboy SJ, Scully 1:643. 1970.

RE: Ovarian

teratoma

with glial implants

on the peritoneum.

Hum

Pathol

KOSLOSKE

846

ET AL.

The tumor of the second patient was classified histologically as benign, but grossly it also had peritoneal implants; it had the same sort of surgical management with a conservative resection and biopsy of the peritoneal implants. This patient, unlike the first, did not have chemotherapy, and is now 4 yr following operation and is also clinically well. The third patient had a clinically benign teratoma, histologically classified also as benign. There were no peritoneal implants, This patient, 2 yr postoperatively, developed a metastasis in the left lower lobe of the lung. This was locally resected, and the removed tologically. This was 3 yr ago. This patient has received no further therapy well. This is an important and obviously poorly understood group of tumors.

tissue was benign hisand is also clinically

A. Kosloske (closing): We advocated wedge biopsy of the opposite ovary because of a reported incidence of 13% bilaterality of the tumor. The glial elements were unchanged in the patients in our series who required repeat laparotomy. We did not see glial elements become malignant. Four of the six patients did have some suggestion of calcification on plain films of the abdomen. We advocate no chemotherapy if the primary tumor was grade 0 or grade I, and we recommend chemotherapy for grade 11 or grade III. We did not develop a second-look policy in these patients because 5 of our 6 patients developed recurrent tumor within 8 mo. requiring laparotomy; thus we did not have to set a policy; they set it for us. Dr. Soper referred to Skully’s series of 12 patients who had a very benign course with gliomatosis peritonei. Again, we added chemotherapy because 4 of the first 5 patients treated with surgery alone developed recurrent tumor, and we felt that we could not count on spontaneous maturation. Dr. Boles’ patient developed pulmonary metastasis, which must be an unusual manifestation of this disease. I would suspect that if the pathologist went back and made additional sections of the primary tumor, he would eventually find an immature focus. I want to stress the importance of the pathologist in making the exact diagnosis of this tumor. In our series our pathologist averaged 15 blocks per tumor and studied as many as 37 blocks. tumors in children be distinguished from one another exact pathologic diagnosis.

It is exceedingly important that ovarian and that the therapy be tailored to the