ClinicalRadiology(1991)43, 402 408
Retroconversion of Immature Teratoma of the Ovary: CT Appearances E. MOSKOVIC*, T. JOBLING'~, C. FISHER;~, E. WILTSHAW§ and C. PARSONS*
Departments of* Radiology, "~Gynaecology, ~ Histopathology and § Medicine, The Royal Marsden Hospital London We have studied seven patients presenting to the Royal Marsden Hospital between 1983 and 1989 with metastatic immature teratoma of the ovary. All patients underwent initial surgery followed by combination chemotherapy and a second laparotomy. Serial CT scans were performed at 2-3 monthly intervals from diagnosis until the second laparotomy, and the results of this were correlated with the CT appearances. In six of the seven patients CT scanning demonstrated 'retroconversion' of immature malignant tumour masses to benign mature disease during treatment. CT features of maturation included increased density of mass lesions, whose margins became better circumscribed in relation to adjacent tissues, and the onset of internal calcification, with fatty areas and cystic change. These changes on CT correlated exactly with normalization of an initially raised serum tumour marker, alpha feto-protein (AFP) in all six patients. The second laparotomy revealed only mature teratoma in all patients following chemotherapy. In three patients slow continued growth of these mature deposits necessitated further surgery for local pressure symptoms, but overall, none has shown malignant relapse, and all are currently well between 1 and 6 years after diagnosis. This is the first report of the CT appearances of retroconversion of immature ovarian teratoma in a series of patients, which is an important radiological diagnosis to make in order to avoid confusion with advancing malignancy. A review of the literature is presented. Moskovic, E., Jobling, T., Fisher, C., Wiltshaw, E. & Parsons, C. (1991). Clinical Radiology 43, 402 408. Retroconversion o f Immature Teratoma o f the Ovary: CT Appearances
Over the last 20 years the successful introduction of effective chemotherapeutic agents and regimens has dramatically improved the outlook for patients with a variety of malignant diseases. This is particularly true of testicular tumours and the lymphoproliferative diseases, where patients are often young and benefits from cure are therefore greatest. When approaching the management of rarer tumours, however, clinicians in all disciplines involved may be hampered by a lack of accurate data regarding the disease due to insufficient numbers of patients available for enrolment in trials, even in large centres. Immature ovarian teratoma is one such example, representing only 0.6% of all ovarian cancers, and occurring primarily in children and young women (Piver, 1987). Previously thought to carry a poor prognosis in common with the other ovarian germ cell tumours, improved histological classification and recent chemotherapeutic advances have led to high cure rates in patients with this tumour (Piver and Patton, 1986). The use of CT scanning to monitor response to therapy in these unusual patients provides great interest ~to the radiologist involved, since the onset of tumour 'maturation' can be accurately characterized using CT, and should not be misinterpreted. We present seven such patients. METHODS Seven patients who presented to the Royal Marsden Hospital between 1983 and 1989 with metastatic pure immature teratoma of the ovary were studied. Their average age at presentation was 29 years (range 12-35 years), and they all underwent an initial laparotomy for Correspondenceto: Dr E. Moskovic,Department of Radiology,The Royal Marsden Hospital, Fulham Road, London SW3 6JJ.
r-
diagnostic and therapeutic purposes. Depending on the extent of disease, primary surgery included some or all of the following procedures: unilateral or bilateral salpingooophorectomy, hysterectomy, general tumour debulking, omentectomy and multiple peritoneal and nodal biopsies. All the patients were subsequently treated with between four and 10 courses of combination chemotherapy, using the agents and regimen commonly employed at this institution for this disease. The drugs used in various combinations included: cisplatin, etoposide, bleomycin, cyclophosphamide, actinomycin-D, carboplatin, methotrexate, and Adriamycin. None received radiotherapy. Serum levels of the tumour marker alpha feto-protein (AFP) were monitored throughout treatment if found to be raised initially. All patients had serial abdominopelvic CT scans at approximately 2-monthly intervals from diagnosis and commencement of chemotherapy until a second laparotomy was performed, this occurring at between 6 months and 3 years after initial presentation. The purpose of the second laparotomy was both diagnostic and in some patients therapeutic; it was used to confirm 'clinical, biochemical and radiological response to chemotherapy, and also to debulk residual tumour masses when present. One patient underwent CT guided fine needle biopsy of three separate abdominal and pelvic masses prior to the second laparotomy. Following the second operation, patients continued to be monitored (although at longer intervals) with CT examinations, but none received further chemotherapy. The pathological findings at the second laparotomy for all the patients were correlated with the CT findings, and a review of all the preceding and subsequent CT examinations was performed.
RETROCONVERSION OF IMMATURE TERATOMA OF THE OVARY
RESULTS Prior to commencing chemotherapy, the CT appearances of immature ovarian teratoma in six of the seven patients comprised mainly low-attenuation, inhomogeneous soft-tissue pelvic masses, without internal calcification. These masses were evident as part of the residual primary ovarian tumour, and similar deposits were also noted both inside and around the uterus, within the parametrium, and in relation to the bladder and rectum (Figs 1, 10 and 11). In addition, more distant but again morphologically similar metastatic deposits were seen in five patients; within the abdomen, adjacent and adherent to bowel loops, in the mesentery, omentum, and retroperitoneally, causing compression of the inferior vena cava in one patient (Figs 7 and 9). Within 3 months of the onset of chemotherapy, there were obvious changes in the CT appearances of the tumour masses. They included increasing density with better circumscription of the masses in relation to surrounding tissues, and the onset of radiologically visible internal curvilinear and punctate calcification. Despite an overall increase in attenuation, areas of fatty density developed in association with the calcification, and cystic changes were also noted, and sometimes predominated (Figs 2-8, 12 and 13). In one patient the masses did not show calcification, but they became denser and better circumscribed. No regression in size of any mass lesion with treatment was observed on CT in any patient. Indeed, six of the seven patients demonstrated a measurable increase in size of the tumour masses and deposits, and four of these patients showed evidence of new abdominopelvic masses arising during or following treatment. These new mass lesions appeared radiologically differentiated, with calcification, areas of fat and cystic change, and they often continued to grow slowly following cessation of chemotherapy. The histological findings following the second laparotomy showed elements of mature benign teratoma in all the masses biopsied in all patients. Sections revealed the pattern of well-differentiated adult teratoma tissue showing various components, including squamous, columnar and glandular epithelium, cartilage, adipose tissue, cysts, neural elements, and focal areas of ossification. In some cases, mature glial tissue predominated. Three patients subsequently required further surgery for debulking of slowly enlarging mature tumour masses (perisplenic, omental, precaval, pelvic), which were causing local pressure symptoms but not invading adjacent tissues (Fig. 8). In all these patients, mature ovarian teratoma was the only finding, and, to date, no patient has shown any evidence of recurrent immature (i.e. malignant) teratoma. The patients have been followed for between 1 and 6 years, and all are well. Six of the seven patients studied showed raised serum AFP levels at diagnosis, which became normal within 3 to 4 months of starting chemotherapy, and remained normal thereafter, The CT changes described above became evident concurrently with the drop in serum AFP. , Comparing the CT findings prior to the second laparotomy with those found at operation, good overall correlation was obtained in evaluating the extent of disease, but in both the pelvis and particularly in the abdomen, some masses smaller than 1-2 cm were not visualized, especially when intimately related to bowel wall and within the
403
omentum and mesentery. In one patient, in whom CT was entirely normal throughout the period of treatment, the pelvic organs and abdominopetvic peritoneum were studded with tiny whitish nodules of mature teratoma, measuring only millimetres in diameter at laparotomy. No intrahepatic disease was identified, but one patient displayed enlarging, mainly cystic mature deposits around the surface of both the liver and spleen, the latter of which required removal f0r progressive abdominal discomfort 5 years after initial presentation (Fig. 14). In one patient, whose~,CT~, prior :to t h e onset of chemotherapy demonstrated low-attenuation material within the uterine c a v i t y , subsequent hysterectomy revealed mature teratoma within the endometrium. There was no evidence of significant ascites clinically or radiologically in any patient before or after treatment.
S A M P L E CASE R E P O R T S Case 1. Aged 33 years. Underwent total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO) in October 1987 for metastatic immature teratoma of the right ovary, Stage III. C T at the start of chemotherapy showed a large low-attenuation pelvic mass which gradually increased in size over 6 months, became more dense, and developed internal calcification (Figs 1-6). A further new calcified mass was seen later in the ileum. A second laparotomy (June 1988) confirmed a large multilocutated pelvic mass, which was removed, and three further masses were found in the serosa o f the ileum and in the midileal mesentery. Pathologically, all sections revealed mature teratoma only. A raised A F P returned to normal 3 m o n t h s after the onset of chemotherapy. The patient remains well. Case 2. Aged 34 years. Underwent LSO for Stage I immature ovarian teratoma in November 1987. CT initially was normal, but a towattenuation mass was noted lying in front of the IVC in March 1988 (Fig. 7) which gradually developed internal calcification and areas of fat density. Over the next year, this mass continued to increase in size and began to compress the IVC (Fig. 8). At second laparotomy in March 1989, the 5 cm precaval mass was removed which on histological examination revealed mature teratoma only. The serum A F P was initially raised but became normal by the time the precaval mass was demonstrated. The patient remains well. Case 3. Aged 12 years. Underwent RSO in January 1989 for immature ovarian teratoma Stage I. Initial C T scans were normal but by April 1989, low-attenuation masses were identified in both adnexae, and a further nodule was seen lying anterior to the bladder (Figs 10 and 1 I). Chemotherapy was then initiated, and over the next 6 months the pelvic masses enlarged and showed increasing density with areas of internal calcification and fat (Figs 12 and 13). CT-guided needle biopsies of the pelvic and abdominal masses in July 1989 revealed mature tissue only. This was confirmed at a subsequent laparotomy in November 1989 when the pelvic masses were debulked, and again in February 1990 when further surgery was required for debulking o f more mature disease. Serum A F P was raised prior to the onset of chem0therapy but became normal within 3 m o n t h s of starting treatment. Case 4. Aged 23 years. U n d e r w e n t !apar0t0my~in~ May 1983 for inoperable extensive pelvic immature ovarian teratoma Stage III. Chemotherapy wgts c o m m e n c e d post,operatively. By July 1983 CT scans showed the mass to occupy the entire pelvic cavity extending up into the abdomen, and a second paracolic mass was evident in relation to the caecum. The masses were of mixed attenuation with areas of fat, calcification and cystic change. At second laparotomy in October 1983 a pelvic mass weighing 2 kg was removed together with the adherent uterus and ovaries.:Fiirther masses involving the appendix, o m e n t u m and peritoneum were also excised. Multiple pelvic, peritoneal, serosal and omental seedlings were noted, extending up to both diaphragmatic domes, pathologically, all tissue removed revealed mature teratoma. Chemotherapy was stopped, and from 1984 to 1988 the patient remained Welt and was monitored with CT, This showed the multiple mature, mainly cystic deposits to increase gradually in size. They were located mainly over the surface of the liver (Fig. 14), and around the spleen and right kidney. Because of increasing abdominal discomfort, the patient underwent a third laparotomy in M a r c h 1988, and numerous cystic masses were removed from around the right kidney, paracolic gutters and sigmoid mesentery. A n 8 cm mass was also removed from the splenic hilum. Agair~, all masses revealed mature disease only. Serum
404
CLINICAL RADIOLOGY
Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.
Fig. 5.
Fig. 6.
Fig. 1 - Untreated immature ovarian teratoma. Multiple low-attenuation pelvic masses (arrowheads). Figs 2, 3 and 4 - Same patient as in Fig. 1. Twomonthly scans following start of chemotherapy showing turnout maturation with increased density o f pelvic masses and onset of internal calcification. Figs 5 and 6 Same patient as in Fig. 1. Abdominal scans showing increasing density and calcification within maturing abdominopelvic turnout deposits over 2 m o n t h s whilst on chemotherapy.
RETROCONVERSION OF IMMATURE TERATOMA OF THE OVARY
Fig. 7.
405
Fig. 8.
Fig. 7 Immature teratoma deposit: untreated. A mass is seen compressing the IVC (arrow). Fig. 8 - Same patient as in Fig. 7. Following chemotherapy, t u m o u r maturation is evident with internal calcification, and areas of fatty change (arrow). The mass has also increased in size.
Fig. 9 - I m m a t u r e ovarian teratoma: untreated. A soft tissue mass is seen in association with bowel wall (arrowhead).
A F P was raised at diagnosis in June 1983, but had become normal by the second laparotomy in October 1983. The patient remains well 6 years from initial diagnosis.
DISCUSSION Immature teratoma of the ovary represents one of the malignant tumours of germ cell origin. As a group, these tumours constitute less than 3% of all ovarian cancers, and occur predominantly in children and women under 30 years of age. In embryonic life, primordial germ cells arise in the yolk sac and migrate along the dorsal mesentery into the developing gonads to be incorporated into the sex cords. It is from these undifferentiated germ cells within the gonads that the majority of germ cell tumours are thought to arise (Kurman and Norris, 1978; Slayton, 1984; Piver, 1987). The immature ovarian teratoma is the third commonest of the germ cell tumours (after dysgerminoma and
endodermal sinus tumour), accounting for 20% of these primitive malignancies. It must be distinguished from the far commoner mature ovarian teratoma (the so-called 'dermoid cyst'), which although almost always benign, undergoes malignant transformation in 1-2% of cases, usually to a squamous cell carcinoma. Microscopically, the immature teratoma contains elements representing all three embryonic layers: endoderm, mesoderm and ectoderm, and its diagnostic hallmark is the presence of immature components, most prominently neuroectodermal, such as neural and glial cells. The degree of immaturity and amount of immature tissue present have been incorporated into a grading system from 1 to 3, which reflects increasing metastatic capability and has both prognostic and therapeutic significance. A grade of 0 is given to mature tissue; this is benign and does not progress (Norris et al., 1976; Piver, 1987). With rare exception, immature teratoma of the ovary is a unilateral tumour, the presence of contralateral ovarian involvement implying metastatic disease. Up to 5% o f patients are reported to have a contralateral mature tumour ('dermoid cyst') at presentation (Norris et al., 1976). Malignant extra-ovarian spread occurs in a similar fashion to the epithelial ovarian tumours, with direct extension to adjacent pelvic structures and by implantation of metastatic growths on pelvic and abdominal peritoneal surfaces. Unlike the epithelial tumours, significant ascites is not a prominent feature. Extra-abdominal metastasis is a late and uncommon event. The outlook for patients with metastatic immature teratoma prior to the introduction of comNnation chemotherapy was poor (Norris e t al., 1976; Sculty, t977; Gatlion et al., 1983; Stayton, 1984). In a review of 58 patients in 1976, Norris et al. found that survival related directly to the stage and grading of the tumour and its metastases. Patients with Stage I Grade I disease showed 100% survival following unilateral salpingo-oophorectomy alone, but those with metastatic disease fared badly, with 25% of those with Grade II disease alive at 7 years and none of those with Grade III disease. Because of the rarity of these tumours, few surveys
406
CLINICAL RADIOLOGY
Fig. 10.
Fig. 11.
Fig. 12.
Fig. 13.
Figs 10 and 11 - Immature ovarian teratoma: untreated. Low-attenuation masses are seen within the pelvis bilaterally and lying anteriorly to the bladder (arrows). Figs 12 and 1 3 - Same patient as Figs 10 and 11. Retroconversion of the t u m o u r deposits is evident following 3 m o n t h s of chemotherapy. T u m o u r deposits are better demarcated, denser, and show areas of calcification and fat (arrows).
Fig. 14 Mature teratomatous deposits following chemotherapy 5 years previously. Multiple cystic lesions are shown over the surface of the liver (arrow).
have been undertaken. This, combined with a lack of histological consensus over their classification and confusion with other germ cell tumours, led to a generalized paucity of information in the literature regarding their behaviour and management. However, over the last 15 years, the combination of accurate staging techniques, improved histological terminology and grading, and in particular chemotherapy, has radically altered the prognosis for these patients. The outlook now for patients with immature ovarian teratoma is greatly improved (Gershenson et al., 1986; Piver, 1987), and initial surgery followed by combination chemotherapy (involving agents such as cisplatin, vincristine, bleomycin, etoposide, cyclophosphamide, and actinomycin D) has yielded sustained remission rates of around 80% even in cases with advanced disease with high histological grades. Our series reflects this trend. The presence of serum tumour markers in this group of patients is variable. Some reports have documented raised AFP levels in up to 65% of cases (Gallion et al., 1983; Slayton, 1984), and if present, this is useful in monitoring response to therapy. Interestingly, six of the seven cases we studied displayed elevated A F P levels on
R E T R O C O N V E R S I O N OF I M M A T U R E T E R A T O M A OF THE O V A R Y
presentation, and all returned to normal following treatment. Disaia and his co-workers first reported three cases of maturation of immature ovarian teratoma following combination chemotherapy in 1977 and two further cases were described in 1983 by Aronowitz et al. (Disaia et al., 1977; Aronowitz "et al., 1983). In both groups the patients responded well and had sustained remissions at between 2 and 6 years after diagnosis. Since then, this phenomenon has been referred to sporadically in the literature and has been called 'retroconversion', 'transformation', 'in-vivo maturation' or 'in-situ destruction'. ~Phe mechanism for the chang e is unclear. Proposed theories include suggestions that chemotherapy induces maturation of immature tissue ('in-vivo maturation'), that it preferentially destroys the immature elements thereby allowing mature components to flourish ('in-situ destruction'), or that retroconversion occurs spontaneously, and is unrelated to the administration of chemotherapy (Disaia et al., 1977; Aronowitz et al., 1983; Lentini et al., 1986). Although there have been isolated reports of spontaneous conversion of immature to mature tissue in ovarian teratoma, the aggressive behaviour of the tumours in our series prior to the onset of chemotherapy, a n d their subsequent rapid sterilization on clinical, radiological and biochemical grounds suggests chemotherapy as the causal factor, and makes this latter theory less tenable. The true incidence of retroconversion is also unknown. It was previously thought to occur infrequently (Disaia et al., 1977; Aronowitz et al., 1983; Lentini et al., 1986), but our experience suggests otherwise, since all the cases in our study showed tumour maturation on second-look laparotomy. This m a y well reflect the use of more effective chemotherapeutic agents and regimens causing improved patient survival. Testicular germ cell tumours are known to exhibit this phenomenon, albeit rarely, following both chemotherapy and radiotherapy, and this has also been associated with a good prognosis (Hong et al., 1977). Information in the radiological literature regarding the appearances and behaviour of ovarian germ cell tumours is sparse. The CT findings in a single case following retroconversion of hepatic metastases from ovarian terat o m a was reported by Lentini et al. in 1986; they described improved definition of the deposits with the onset of internal calcification and fatty spaces 14 months after the commencement of chemotherapy (Lentini et al., 1986). We can confirm the usefulness of CT in documenting response to chemotherapy since six of the seven cases in our series.showed analogous changes visible on CT within 3 to 4 months of starting treatment, and corresponding with a return to normal of previously raised serum A F P levels. The CT findings that suggest maturation are increasing density of tumour masses, with internal changes within these masses including some cystic components, fatty areas and curvilinear and punctate calcification. These masses do not invade surrounding soft tissues or bone but may gradually compress them. The appearances after maturation are thus similar to the CT appearances of a primary mature ovarian teratoma or 'dermoid cyst' which have been well described (Friedman et al., 1982). In view of the close correlation of the CT changes with normalization of the serum tumour marker AFP, we suggest it is possible to predict retroconversion to mature teratoma on radiological grounds alone. This provides a
407
useful adjunct in confirming response to treatment both in patients initially positive for AFP, and also in those whose serum turnout markers were never raised. The continuing presence of tumour masses radiologically characteristic of mature teratoma whilst on treatment, and also the development of similar new masses following treatment should not be mistaken for advancing malignancy. Following adequate treatment, once maturation is established radiologically and if possible biochemically, what then is the role of a second laparotomy in these patients? It has been suggested that a 'second-took' operation is required to diagnose foci of residual immature disease (Gershenson et al., 1986; Piver, 1987). However, with the advent of more effective chemotherapeutic regimens, this situation appears less likely to arise; all seven patients in our series showed mature teratoma only at second operation. It would seem reasonable therefore to forego a second operation in patients with normalized tumour markers and radiologically retroconverted tumour masses. I f there is doubt about the radiological appearances after adequate chemotherapy, or in the absence of measurable tumour markers, CT guided percutaneous needle biopsy of tumour masses may also provide a useful alternative to further surgery. This proved diagnostic in one of our patients in whom CT guided biopsies of three pelvic masses revealed mature tissue only, thereby sparing the patient further surgical intervention at this stage. What about patients with small volume abdominopelvic disease not detected by CT? It is well documented that CT underestimates tumour masses smaller than 1-2 cm particularly within the mesentery and omentum, when closely related to small bowel loops, and in the absence of ascites (Silverman et al., 1988; Buy et al., 1988; Megibow et al., 1988; Reuter et al., 1988; Stehman et al., 1988). This is particularly relevant in germ cell ovarian malignancies which, like the much c o m m o n e r epithelial tumours, have a propensity to metastasize transperitoneally. Our experience confirms this problem: in one patient in whom serial CT was consistently normal throughout treatment, second-look laparotomy revealed multiple minute mature serosal and peritoneal deposits (so-called 'gliomatosis peritoneil'), and in other patients, CT failed to detect the full extent of mature deposits within the abdominopelvic cavity, particularly relating to the bowel and mesentery. This feature should be borne in mind when assessing serial CT scans in these patients, the occurrence of apparently new slowly growing mature deposits in areas previously thought free o f tumour should not be surprising. Finally, the frequency of abdominopelvic CT scanning, both before and after t u m o u r maturation is established, needs careful review. The long-term outlook for patients with immature ovarian teratoma is n o w good, and the viability of their remaining ovaries,should be preserved if at all possible (Gershenson et al., I986; Piver, t987). Clearly, the presence of measurable serum A F P as a reliable tumour marker is invaluable in tailoring a CT imaging policy. After a baseline scan at diagnosis, and again following completion of chemotherapy and normalization of the A F P level, CT could perhaps be limited in this group of patients to situations where the onset of new symptoms or signs suggest pressure effects from mature disease, or if the serum A F P starts to rise again. In our experience, the latter situation has not occurred. If no
408
CLINICAL RADIOLOGY
tumour marker is available, the case for serial CT evidence of increasing tumour maturation would appear stronger, with CT-guided biopsy of doubtful lesions as an adjunct. It must be emphasized that only by the enrolment of substantial numbers of patients into clinical and radiological trials within specialist centres, can firm policies regarding the investigation and management of these rare tumours be developed. REFERENCES
Aronowitz, J, Estrada, R, Lynch; R & Kaplan, AL (1983). Retroconversion of malignant immature teratomas of the ovary after chemotherapy. Gynaecologic Oncology, 16, 414-421. Buy, J-N, Moss, AA, Ghossain, MA, Sciot, C, Malbec, L, Vadrot, D, Paniel, BJ & Decroix, Y (1988). Peritoneal implants from ovarian tumours: CT findings. Radiology, 169, 691-694. Disaia, PJ, Saltz, A, Kagan, AR & Morrow, PM (1977). Chemotherapeutic retroconversion of immature teratoma of the ovary. Obstetrics and Gynaeeology, 49, 346 350. Friedman, AC, Pyatt, RS, Hartman, DS, Downey EF Jr & Olsen, WB (1982) CT of benign cystic teratomas. American Journal of Roentgenology, 138, 659-665. Gallion, H, van Nagell, JR, Donaldson, ES, Hanson, MB & Powell, DF (1983). Immature teratoma of the ovary. American Journal of Obstetrics and Gynaecology, 146, 361-365. Gershenson, DM, Kavanagh, J J, Copeland, LJ, Del Junco, G, Cangir, A, Saul, PB, Stringer, CA et al. (1986). Treatment of nondysgerminomatous germ cell tumors of the ovary with vinblastine, bleomycin and cisplatin. Cancer, 57, 1731 1737. Gershenson, DM, Copeland, L J, Del Junco, G, Edwards, CL, Wharton, JT & Rutledge, FN (1986). Second-look laparotomy in the management of malignant germ cell tumours of the ovary. Obstetrics and Gynaecology, 67, 789-793.
Hong, WK, Wittes, RE, Hadju, ST, Cvitkovic, E, Whitmore, WF & Golbey, RB (1977). The evolution of mature teratoma from malignant testicular teratomas. Cancer, 40, 2987-2992. Kurman, RJ & Norris, HJ (1978). Germ cell tumours of the ovary. Pathology Annual, 13, 291-325. Lentini, JF, Love, MB, Ritchie, WGM & Sedlacek, TV (1986). Computed tomography in retroconversion of hepatic metastases from immature ovarian teratoma. Journal of Computer Assisted Tomography, 10, 106~1062. Megibow, AJ, Bosniak, MA, Ho, Ag, Beller, U, Hulnick, DH & Beckman, EM (1988). Accuracy of CT in detection of persistent or recurrent ovarian carcinoma: correlation with second-look laparotomy. Radiology, 166, 341 345. Norris, HJ, Zirkin, HJ & Benson, WL (1976). Immature (malignant) teratoma of the ovary. Cancer, 37, 2359-2372. Piver, MS & Patton, T (1986). Ovarian cancer in children. Seminars in Surgical Oneology, 2, 163-169. Piver, SM (Ed) (1987). Ovarian Malignancies: Diagnostic and Therapeutic Advances. (Clinical Obstetrics and Gynaecology). Churchill Livingstone, Edinburgh. Reuter, KL, Griffin, T & Hunter, RE (1989). Comparison of abdominopelvic computed tomography results and findings at second-look laparotomy in ovarian carcinoma patients. Cancer, 63, 1123 1128. Scully, RE (1977). Ovarian tumours: a review. American Journal of Pathology, 87, 68. Silverman, PM, Osborne, M, Dunnick, NR & Bandy, LC (1988). CT prior to second-look operation in ovarian cancer. American Journal o f Roentgenology, 150, 829 832. Slayton, RE (1984). Management of germ cell tumours of the ovary. Seminars in Oncology, 11, 299-313. Stehman, FB, Calkins, AR, Wass, JL, Smirz, LR, Sutton, GP & Ehrlich, CE (1988). A comparison of findings at second-look laparotomy with preoperative computed tomography in patients with ovarian cancer. Gynaecologic Ontology, 29, 37-42.
Retroconversion of Immature Teratoma of the Ovary: CT Appearances E. MOSKOVIC*, T. JOBLING'~, C. FISHER;~, E. WILTSHAW§ and C. PARSONS*
Departments of* Radiology, "~Gynaecology, ~ Histopathology and § Medicine, The Royal Marsden Hospital London We have studied seven patients presenting to the Royal Marsden Hospital between 1983 and 1989 with metastatic immature teratoma of the ovary. All patients underwent initial surgery followed by combination chemotherapy and a second laparotomy. Serial CT scans were performed at 2-3 monthly intervals from diagnosis until the second laparotomy, and the results of this were correlated with the CT appearances. In six of the seven patients CT scanning demonstrated 'retroconversion' of immature malignant tumour masses to benign mature disease during treatment. CT features of maturation included increased density of mass lesions, whose margins became better circumscribed in relation to adjacent tissues, and the onset of internal calcification, with fatty areas and cystic change. These changes on CT correlated exactly with normalization of an initially raised serum tumour marker, alpha feto-protein (AFP) in all six patients. The second laparotomy revealed only mature teratoma in all patients following chemotherapy. In three patients slow continued growth of these mature deposits necessitated further surgery for local pressure symptoms, but overall, none has shown malignant relapse, and all are currently well between 1 and 6 years after diagnosis. This is the first report of the CT appearances of retroconversion of immature ovarian teratoma in a series of patients, which is an important radiological diagnosis to make in order to avoid confusion with advancing malignancy. A review of the literature is presented. Moskovic, E., Jobling, T., Fisher, C., Wiltshaw, E. & Parsons, C. (1991). Clinical Radiology 43, 402 408. Retroconversion o f Immature Teratoma o f the Ovary: CT Appearances
Over the last 20 years the successful introduction of effective chemotherapeutic agents and regimens has dramatically improved the outlook for patients with a variety of malignant diseases. This is particularly true of testicular tumours and the lymphoproliferative diseases, where patients are often young and benefits from cure are therefore greatest. When approaching the management of rarer tumours, however, clinicians in all disciplines involved may be hampered by a lack of accurate data regarding the disease due to insufficient numbers of patients available for enrolment in trials, even in large centres. Immature ovarian teratoma is one such example, representing only 0.6% of all ovarian cancers, and occurring primarily in children and young women (Piver, 1987). Previously thought to carry a poor prognosis in common with the other ovarian germ cell tumours, improved histological classification and recent chemotherapeutic advances have led to high cure rates in patients with this tumour (Piver and Patton, 1986). The use of CT scanning to monitor response to therapy in these unusual patients provides great interest ~to the radiologist involved, since the onset of tumour 'maturation' can be accurately characterized using CT, and should not be misinterpreted. We present seven such patients. METHODS Seven patients who presented to the Royal Marsden Hospital between 1983 and 1989 with metastatic pure immature teratoma of the ovary were studied. Their average age at presentation was 29 years (range 12-35 years), and they all underwent an initial laparotomy for Correspondenceto: Dr E. Moskovic,Department of Radiology,The Royal Marsden Hospital, Fulham Road, London SW3 6JJ.
r-
diagnostic and therapeutic purposes. Depending on the extent of disease, primary surgery included some or all of the following procedures: unilateral or bilateral salpingooophorectomy, hysterectomy, general tumour debulking, omentectomy and multiple peritoneal and nodal biopsies. All the patients were subsequently treated with between four and 10 courses of combination chemotherapy, using the agents and regimen commonly employed at this institution for this disease. The drugs used in various combinations included: cisplatin, etoposide, bleomycin, cyclophosphamide, actinomycin-D, carboplatin, methotrexate, and Adriamycin. None received radiotherapy. Serum levels of the tumour marker alpha feto-protein (AFP) were monitored throughout treatment if found to be raised initially. All patients had serial abdominopelvic CT scans at approximately 2-monthly intervals from diagnosis and commencement of chemotherapy until a second laparotomy was performed, this occurring at between 6 months and 3 years after initial presentation. The purpose of the second laparotomy was both diagnostic and in some patients therapeutic; it was used to confirm 'clinical, biochemical and radiological response to chemotherapy, and also to debulk residual tumour masses when present. One patient underwent CT guided fine needle biopsy of three separate abdominal and pelvic masses prior to the second laparotomy. Following the second operation, patients continued to be monitored (although at longer intervals) with CT examinations, but none received further chemotherapy. The pathological findings at the second laparotomy for all the patients were correlated with the CT findings, and a review of all the preceding and subsequent CT examinations was performed.
RETROCONVERSION OF IMMATURE TERATOMA OF THE OVARY
RESULTS Prior to commencing chemotherapy, the CT appearances of immature ovarian teratoma in six of the seven patients comprised mainly low-attenuation, inhomogeneous soft-tissue pelvic masses, without internal calcification. These masses were evident as part of the residual primary ovarian tumour, and similar deposits were also noted both inside and around the uterus, within the parametrium, and in relation to the bladder and rectum (Figs 1, 10 and 11). In addition, more distant but again morphologically similar metastatic deposits were seen in five patients; within the abdomen, adjacent and adherent to bowel loops, in the mesentery, omentum, and retroperitoneally, causing compression of the inferior vena cava in one patient (Figs 7 and 9). Within 3 months of the onset of chemotherapy, there were obvious changes in the CT appearances of the tumour masses. They included increasing density with better circumscription of the masses in relation to surrounding tissues, and the onset of radiologically visible internal curvilinear and punctate calcification. Despite an overall increase in attenuation, areas of fatty density developed in association with the calcification, and cystic changes were also noted, and sometimes predominated (Figs 2-8, 12 and 13). In one patient the masses did not show calcification, but they became denser and better circumscribed. No regression in size of any mass lesion with treatment was observed on CT in any patient. Indeed, six of the seven patients demonstrated a measurable increase in size of the tumour masses and deposits, and four of these patients showed evidence of new abdominopelvic masses arising during or following treatment. These new mass lesions appeared radiologically differentiated, with calcification, areas of fat and cystic change, and they often continued to grow slowly following cessation of chemotherapy. The histological findings following the second laparotomy showed elements of mature benign teratoma in all the masses biopsied in all patients. Sections revealed the pattern of well-differentiated adult teratoma tissue showing various components, including squamous, columnar and glandular epithelium, cartilage, adipose tissue, cysts, neural elements, and focal areas of ossification. In some cases, mature glial tissue predominated. Three patients subsequently required further surgery for debulking of slowly enlarging mature tumour masses (perisplenic, omental, precaval, pelvic), which were causing local pressure symptoms but not invading adjacent tissues (Fig. 8). In all these patients, mature ovarian teratoma was the only finding, and, to date, no patient has shown any evidence of recurrent immature (i.e. malignant) teratoma. The patients have been followed for between 1 and 6 years, and all are well. Six of the seven patients studied showed raised serum AFP levels at diagnosis, which became normal within 3 to 4 months of starting chemotherapy, and remained normal thereafter, The CT changes described above became evident concurrently with the drop in serum AFP. , Comparing the CT findings prior to the second laparotomy with those found at operation, good overall correlation was obtained in evaluating the extent of disease, but in both the pelvis and particularly in the abdomen, some masses smaller than 1-2 cm were not visualized, especially when intimately related to bowel wall and within the
403
omentum and mesentery. In one patient, in whom CT was entirely normal throughout the period of treatment, the pelvic organs and abdominopetvic peritoneum were studded with tiny whitish nodules of mature teratoma, measuring only millimetres in diameter at laparotomy. No intrahepatic disease was identified, but one patient displayed enlarging, mainly cystic mature deposits around the surface of both the liver and spleen, the latter of which required removal f0r progressive abdominal discomfort 5 years after initial presentation (Fig. 14). In one patient, whose~,CT~, prior :to t h e onset of chemotherapy demonstrated low-attenuation material within the uterine c a v i t y , subsequent hysterectomy revealed mature teratoma within the endometrium. There was no evidence of significant ascites clinically or radiologically in any patient before or after treatment.
S A M P L E CASE R E P O R T S Case 1. Aged 33 years. Underwent total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO) in October 1987 for metastatic immature teratoma of the right ovary, Stage III. C T at the start of chemotherapy showed a large low-attenuation pelvic mass which gradually increased in size over 6 months, became more dense, and developed internal calcification (Figs 1-6). A further new calcified mass was seen later in the ileum. A second laparotomy (June 1988) confirmed a large multilocutated pelvic mass, which was removed, and three further masses were found in the serosa o f the ileum and in the midileal mesentery. Pathologically, all sections revealed mature teratoma only. A raised A F P returned to normal 3 m o n t h s after the onset of chemotherapy. The patient remains well. Case 2. Aged 34 years. Underwent LSO for Stage I immature ovarian teratoma in November 1987. CT initially was normal, but a towattenuation mass was noted lying in front of the IVC in March 1988 (Fig. 7) which gradually developed internal calcification and areas of fat density. Over the next year, this mass continued to increase in size and began to compress the IVC (Fig. 8). At second laparotomy in March 1989, the 5 cm precaval mass was removed which on histological examination revealed mature teratoma only. The serum A F P was initially raised but became normal by the time the precaval mass was demonstrated. The patient remains well. Case 3. Aged 12 years. Underwent RSO in January 1989 for immature ovarian teratoma Stage I. Initial C T scans were normal but by April 1989, low-attenuation masses were identified in both adnexae, and a further nodule was seen lying anterior to the bladder (Figs 10 and 1 I). Chemotherapy was then initiated, and over the next 6 months the pelvic masses enlarged and showed increasing density with areas of internal calcification and fat (Figs 12 and 13). CT-guided needle biopsies of the pelvic and abdominal masses in July 1989 revealed mature tissue only. This was confirmed at a subsequent laparotomy in November 1989 when the pelvic masses were debulked, and again in February 1990 when further surgery was required for debulking o f more mature disease. Serum A F P was raised prior to the onset of chem0therapy but became normal within 3 m o n t h s of starting treatment. Case 4. Aged 23 years. U n d e r w e n t !apar0t0my~in~ May 1983 for inoperable extensive pelvic immature ovarian teratoma Stage III. Chemotherapy wgts c o m m e n c e d post,operatively. By July 1983 CT scans showed the mass to occupy the entire pelvic cavity extending up into the abdomen, and a second paracolic mass was evident in relation to the caecum. The masses were of mixed attenuation with areas of fat, calcification and cystic change. At second laparotomy in October 1983 a pelvic mass weighing 2 kg was removed together with the adherent uterus and ovaries.:Fiirther masses involving the appendix, o m e n t u m and peritoneum were also excised. Multiple pelvic, peritoneal, serosal and omental seedlings were noted, extending up to both diaphragmatic domes, pathologically, all tissue removed revealed mature teratoma. Chemotherapy was stopped, and from 1984 to 1988 the patient remained Welt and was monitored with CT, This showed the multiple mature, mainly cystic deposits to increase gradually in size. They were located mainly over the surface of the liver (Fig. 14), and around the spleen and right kidney. Because of increasing abdominal discomfort, the patient underwent a third laparotomy in M a r c h 1988, and numerous cystic masses were removed from around the right kidney, paracolic gutters and sigmoid mesentery. A n 8 cm mass was also removed from the splenic hilum. Agair~, all masses revealed mature disease only. Serum
404
CLINICAL RADIOLOGY
Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.
Fig. 5.
Fig. 6.
Fig. 1 - Untreated immature ovarian teratoma. Multiple low-attenuation pelvic masses (arrowheads). Figs 2, 3 and 4 - Same patient as in Fig. 1. Twomonthly scans following start of chemotherapy showing turnout maturation with increased density o f pelvic masses and onset of internal calcification. Figs 5 and 6 Same patient as in Fig. 1. Abdominal scans showing increasing density and calcification within maturing abdominopelvic turnout deposits over 2 m o n t h s whilst on chemotherapy.
RETROCONVERSION OF IMMATURE TERATOMA OF THE OVARY
Fig. 7.
405
Fig. 8.
Fig. 7 Immature teratoma deposit: untreated. A mass is seen compressing the IVC (arrow). Fig. 8 - Same patient as in Fig. 7. Following chemotherapy, t u m o u r maturation is evident with internal calcification, and areas of fatty change (arrow). The mass has also increased in size.
Fig. 9 - I m m a t u r e ovarian teratoma: untreated. A soft tissue mass is seen in association with bowel wall (arrowhead).
A F P was raised at diagnosis in June 1983, but had become normal by the second laparotomy in October 1983. The patient remains well 6 years from initial diagnosis.
DISCUSSION Immature teratoma of the ovary represents one of the malignant tumours of germ cell origin. As a group, these tumours constitute less than 3% of all ovarian cancers, and occur predominantly in children and women under 30 years of age. In embryonic life, primordial germ cells arise in the yolk sac and migrate along the dorsal mesentery into the developing gonads to be incorporated into the sex cords. It is from these undifferentiated germ cells within the gonads that the majority of germ cell tumours are thought to arise (Kurman and Norris, 1978; Slayton, 1984; Piver, 1987). The immature ovarian teratoma is the third commonest of the germ cell tumours (after dysgerminoma and
endodermal sinus tumour), accounting for 20% of these primitive malignancies. It must be distinguished from the far commoner mature ovarian teratoma (the so-called 'dermoid cyst'), which although almost always benign, undergoes malignant transformation in 1-2% of cases, usually to a squamous cell carcinoma. Microscopically, the immature teratoma contains elements representing all three embryonic layers: endoderm, mesoderm and ectoderm, and its diagnostic hallmark is the presence of immature components, most prominently neuroectodermal, such as neural and glial cells. The degree of immaturity and amount of immature tissue present have been incorporated into a grading system from 1 to 3, which reflects increasing metastatic capability and has both prognostic and therapeutic significance. A grade of 0 is given to mature tissue; this is benign and does not progress (Norris et al., 1976; Piver, 1987). With rare exception, immature teratoma of the ovary is a unilateral tumour, the presence of contralateral ovarian involvement implying metastatic disease. Up to 5% o f patients are reported to have a contralateral mature tumour ('dermoid cyst') at presentation (Norris et al., 1976). Malignant extra-ovarian spread occurs in a similar fashion to the epithelial ovarian tumours, with direct extension to adjacent pelvic structures and by implantation of metastatic growths on pelvic and abdominal peritoneal surfaces. Unlike the epithelial tumours, significant ascites is not a prominent feature. Extra-abdominal metastasis is a late and uncommon event. The outlook for patients with metastatic immature teratoma prior to the introduction of comNnation chemotherapy was poor (Norris e t al., 1976; Sculty, t977; Gatlion et al., 1983; Stayton, 1984). In a review of 58 patients in 1976, Norris et al. found that survival related directly to the stage and grading of the tumour and its metastases. Patients with Stage I Grade I disease showed 100% survival following unilateral salpingo-oophorectomy alone, but those with metastatic disease fared badly, with 25% of those with Grade II disease alive at 7 years and none of those with Grade III disease. Because of the rarity of these tumours, few surveys
406
CLINICAL RADIOLOGY
Fig. 10.
Fig. 11.
Fig. 12.
Fig. 13.
Figs 10 and 11 - Immature ovarian teratoma: untreated. Low-attenuation masses are seen within the pelvis bilaterally and lying anteriorly to the bladder (arrows). Figs 12 and 1 3 - Same patient as Figs 10 and 11. Retroconversion of the t u m o u r deposits is evident following 3 m o n t h s of chemotherapy. T u m o u r deposits are better demarcated, denser, and show areas of calcification and fat (arrows).
Fig. 14 Mature teratomatous deposits following chemotherapy 5 years previously. Multiple cystic lesions are shown over the surface of the liver (arrow).
have been undertaken. This, combined with a lack of histological consensus over their classification and confusion with other germ cell tumours, led to a generalized paucity of information in the literature regarding their behaviour and management. However, over the last 15 years, the combination of accurate staging techniques, improved histological terminology and grading, and in particular chemotherapy, has radically altered the prognosis for these patients. The outlook now for patients with immature ovarian teratoma is greatly improved (Gershenson et al., 1986; Piver, 1987), and initial surgery followed by combination chemotherapy (involving agents such as cisplatin, vincristine, bleomycin, etoposide, cyclophosphamide, and actinomycin D) has yielded sustained remission rates of around 80% even in cases with advanced disease with high histological grades. Our series reflects this trend. The presence of serum tumour markers in this group of patients is variable. Some reports have documented raised AFP levels in up to 65% of cases (Gallion et al., 1983; Slayton, 1984), and if present, this is useful in monitoring response to therapy. Interestingly, six of the seven cases we studied displayed elevated A F P levels on
R E T R O C O N V E R S I O N OF I M M A T U R E T E R A T O M A OF THE O V A R Y
presentation, and all returned to normal following treatment. Disaia and his co-workers first reported three cases of maturation of immature ovarian teratoma following combination chemotherapy in 1977 and two further cases were described in 1983 by Aronowitz et al. (Disaia et al., 1977; Aronowitz "et al., 1983). In both groups the patients responded well and had sustained remissions at between 2 and 6 years after diagnosis. Since then, this phenomenon has been referred to sporadically in the literature and has been called 'retroconversion', 'transformation', 'in-vivo maturation' or 'in-situ destruction'. ~Phe mechanism for the chang e is unclear. Proposed theories include suggestions that chemotherapy induces maturation of immature tissue ('in-vivo maturation'), that it preferentially destroys the immature elements thereby allowing mature components to flourish ('in-situ destruction'), or that retroconversion occurs spontaneously, and is unrelated to the administration of chemotherapy (Disaia et al., 1977; Aronowitz et al., 1983; Lentini et al., 1986). Although there have been isolated reports of spontaneous conversion of immature to mature tissue in ovarian teratoma, the aggressive behaviour of the tumours in our series prior to the onset of chemotherapy, a n d their subsequent rapid sterilization on clinical, radiological and biochemical grounds suggests chemotherapy as the causal factor, and makes this latter theory less tenable. The true incidence of retroconversion is also unknown. It was previously thought to occur infrequently (Disaia et al., 1977; Aronowitz et al., 1983; Lentini et al., 1986), but our experience suggests otherwise, since all the cases in our study showed tumour maturation on second-look laparotomy. This m a y well reflect the use of more effective chemotherapeutic agents and regimens causing improved patient survival. Testicular germ cell tumours are known to exhibit this phenomenon, albeit rarely, following both chemotherapy and radiotherapy, and this has also been associated with a good prognosis (Hong et al., 1977). Information in the radiological literature regarding the appearances and behaviour of ovarian germ cell tumours is sparse. The CT findings in a single case following retroconversion of hepatic metastases from ovarian terat o m a was reported by Lentini et al. in 1986; they described improved definition of the deposits with the onset of internal calcification and fatty spaces 14 months after the commencement of chemotherapy (Lentini et al., 1986). We can confirm the usefulness of CT in documenting response to chemotherapy since six of the seven cases in our series.showed analogous changes visible on CT within 3 to 4 months of starting treatment, and corresponding with a return to normal of previously raised serum A F P levels. The CT findings that suggest maturation are increasing density of tumour masses, with internal changes within these masses including some cystic components, fatty areas and curvilinear and punctate calcification. These masses do not invade surrounding soft tissues or bone but may gradually compress them. The appearances after maturation are thus similar to the CT appearances of a primary mature ovarian teratoma or 'dermoid cyst' which have been well described (Friedman et al., 1982). In view of the close correlation of the CT changes with normalization of the serum tumour marker AFP, we suggest it is possible to predict retroconversion to mature teratoma on radiological grounds alone. This provides a
407
useful adjunct in confirming response to treatment both in patients initially positive for AFP, and also in those whose serum turnout markers were never raised. The continuing presence of tumour masses radiologically characteristic of mature teratoma whilst on treatment, and also the development of similar new masses following treatment should not be mistaken for advancing malignancy. Following adequate treatment, once maturation is established radiologically and if possible biochemically, what then is the role of a second laparotomy in these patients? It has been suggested that a 'second-took' operation is required to diagnose foci of residual immature disease (Gershenson et al., 1986; Piver, 1987). However, with the advent of more effective chemotherapeutic regimens, this situation appears less likely to arise; all seven patients in our series showed mature teratoma only at second operation. It would seem reasonable therefore to forego a second operation in patients with normalized tumour markers and radiologically retroconverted tumour masses. I f there is doubt about the radiological appearances after adequate chemotherapy, or in the absence of measurable tumour markers, CT guided percutaneous needle biopsy of tumour masses may also provide a useful alternative to further surgery. This proved diagnostic in one of our patients in whom CT guided biopsies of three pelvic masses revealed mature tissue only, thereby sparing the patient further surgical intervention at this stage. What about patients with small volume abdominopelvic disease not detected by CT? It is well documented that CT underestimates tumour masses smaller than 1-2 cm particularly within the mesentery and omentum, when closely related to small bowel loops, and in the absence of ascites (Silverman et al., 1988; Buy et al., 1988; Megibow et al., 1988; Reuter et al., 1988; Stehman et al., 1988). This is particularly relevant in germ cell ovarian malignancies which, like the much c o m m o n e r epithelial tumours, have a propensity to metastasize transperitoneally. Our experience confirms this problem: in one patient in whom serial CT was consistently normal throughout treatment, second-look laparotomy revealed multiple minute mature serosal and peritoneal deposits (so-called 'gliomatosis peritoneil'), and in other patients, CT failed to detect the full extent of mature deposits within the abdominopelvic cavity, particularly relating to the bowel and mesentery. This feature should be borne in mind when assessing serial CT scans in these patients, the occurrence of apparently new slowly growing mature deposits in areas previously thought free o f tumour should not be surprising. Finally, the frequency of abdominopelvic CT scanning, both before and after t u m o u r maturation is established, needs careful review. The long-term outlook for patients with immature ovarian teratoma is n o w good, and the viability of their remaining ovaries,should be preserved if at all possible (Gershenson et al., I986; Piver, t987). Clearly, the presence of measurable serum A F P as a reliable tumour marker is invaluable in tailoring a CT imaging policy. After a baseline scan at diagnosis, and again following completion of chemotherapy and normalization of the A F P level, CT could perhaps be limited in this group of patients to situations where the onset of new symptoms or signs suggest pressure effects from mature disease, or if the serum A F P starts to rise again. In our experience, the latter situation has not occurred. If no
408
CLINICAL RADIOLOGY
tumour marker is available, the case for serial CT evidence of increasing tumour maturation would appear stronger, with CT-guided biopsy of doubtful lesions as an adjunct. It must be emphasized that only by the enrolment of substantial numbers of patients into clinical and radiological trials within specialist centres, can firm policies regarding the investigation and management of these rare tumours be developed. REFERENCES
Aronowitz, J, Estrada, R, Lynch; R & Kaplan, AL (1983). Retroconversion of malignant immature teratomas of the ovary after chemotherapy. Gynaecologic Oncology, 16, 414-421. Buy, J-N, Moss, AA, Ghossain, MA, Sciot, C, Malbec, L, Vadrot, D, Paniel, BJ & Decroix, Y (1988). Peritoneal implants from ovarian tumours: CT findings. Radiology, 169, 691-694. Disaia, PJ, Saltz, A, Kagan, AR & Morrow, PM (1977). Chemotherapeutic retroconversion of immature teratoma of the ovary. Obstetrics and Gynaeeology, 49, 346 350. Friedman, AC, Pyatt, RS, Hartman, DS, Downey EF Jr & Olsen, WB (1982) CT of benign cystic teratomas. American Journal of Roentgenology, 138, 659-665. Gallion, H, van Nagell, JR, Donaldson, ES, Hanson, MB & Powell, DF (1983). Immature teratoma of the ovary. American Journal of Obstetrics and Gynaecology, 146, 361-365. Gershenson, DM, Kavanagh, J J, Copeland, LJ, Del Junco, G, Cangir, A, Saul, PB, Stringer, CA et al. (1986). Treatment of nondysgerminomatous germ cell tumors of the ovary with vinblastine, bleomycin and cisplatin. Cancer, 57, 1731 1737. Gershenson, DM, Copeland, L J, Del Junco, G, Edwards, CL, Wharton, JT & Rutledge, FN (1986). Second-look laparotomy in the management of malignant germ cell tumours of the ovary. Obstetrics and Gynaecology, 67, 789-793.
Hong, WK, Wittes, RE, Hadju, ST, Cvitkovic, E, Whitmore, WF & Golbey, RB (1977). The evolution of mature teratoma from malignant testicular teratomas. Cancer, 40, 2987-2992. Kurman, RJ & Norris, HJ (1978). Germ cell tumours of the ovary. Pathology Annual, 13, 291-325. Lentini, JF, Love, MB, Ritchie, WGM & Sedlacek, TV (1986). Computed tomography in retroconversion of hepatic metastases from immature ovarian teratoma. Journal of Computer Assisted Tomography, 10, 106~1062. Megibow, AJ, Bosniak, MA, Ho, Ag, Beller, U, Hulnick, DH & Beckman, EM (1988). Accuracy of CT in detection of persistent or recurrent ovarian carcinoma: correlation with second-look laparotomy. Radiology, 166, 341 345. Norris, HJ, Zirkin, HJ & Benson, WL (1976). Immature (malignant) teratoma of the ovary. Cancer, 37, 2359-2372. Piver, MS & Patton, T (1986). Ovarian cancer in children. Seminars in Surgical Oneology, 2, 163-169. Piver, SM (Ed) (1987). Ovarian Malignancies: Diagnostic and Therapeutic Advances. (Clinical Obstetrics and Gynaecology). Churchill Livingstone, Edinburgh. Reuter, KL, Griffin, T & Hunter, RE (1989). Comparison of abdominopelvic computed tomography results and findings at second-look laparotomy in ovarian carcinoma patients. Cancer, 63, 1123 1128. Scully, RE (1977). Ovarian tumours: a review. American Journal of Pathology, 87, 68. Silverman, PM, Osborne, M, Dunnick, NR & Bandy, LC (1988). CT prior to second-look operation in ovarian cancer. American Journal o f Roentgenology, 150, 829 832. Slayton, RE (1984). Management of germ cell tumours of the ovary. Seminars in Oncology, 11, 299-313. Stehman, FB, Calkins, AR, Wass, JL, Smirz, LR, Sutton, GP & Ehrlich, CE (1988). A comparison of findings at second-look laparotomy with preoperative computed tomography in patients with ovarian cancer. Gynaecologic Ontology, 29, 37-42.
