Dr. Lisa Allen, Section Head Pediatric Gynecology, SickKids; Associate Professor, University of Toronto

Transcription

1 The Ovarian Mass: the What, Why and How about Management NASPAG 2016 Workshop Dr. Lisa Allen, Section Head Pediatric Gynecology, SickKids; Associate Professor, University of Toronto Dr. Furqan Shaikh, Pediatric Hematology/Oncology, SickKids; Assistant Professor, University of Toronto Dr. J. Ted Gerstle, Director, Surgical Oncology Program, SickKids; Associate Professor, University of Toronto Objectives At the conclusion of the presentation, ti attendees will be better able to: Discuss the appropriate investigations for an ovarian mass in children and adolescents Incorporate into their practice an appropriately conservative approach to benign adnexal masses Identify features that suggest a malignancy in an ovarian mass in children and adolescents Discuss the surgical and oncologic management of malignant germ cell tumors Increase ovarian conservation in their institution by involving a multidisciplinary team of health care providers 1

2 Approach With 3 illustrative cases: Build an algorithm for the approach to the mass 2

3 Why does it matter? The goal of the prediction rule is to ensure that: Benign tumors can receive appropriately conservative management (observation, laparoscopy, cystectomy). Malignant tumors can receive appropriately aggressive management (complete resection, avoidance of spillage, delivery of intact capsule, full staging, correct assignment of adjuvant therapy). 41.2% expectant management 58.8% operative procedure Kirkham Y, Lacy L, Kives S, Allen L JOGC;2011;33(9):

4 Authors Brown (91, Philadelphia, 1993) Cass (106, Texas, 2001) Rogers (126, Toronto, 2014) Kirkham (67, Toronto, 2011)* Non neoplastic (%) Neoplastic benign (%) De Silva (134, Melbourne, 2004) Cribb (219, New Zealand, 2014) Michelotti (231, Pittsburg, 2010) Neoplastic malignant (%) * 7% Malignancy Rate Overall 4

5 Case 1 11 year old girl referred to gynecology Thelarche 1 year ago No menarche to date Left sided pelvic pain, intermittent, lasts for a few hours, sufficiently severe to present to the emergency department on 1 occasion No nausea, no vomiting Otherwise healthy, overweight (BMI 29) Pelvic ultrasound simple cyst 4.9 cm in size, right ovarian Case 1 5

6 Pediatric RMI Characteristic Odds Ratio (CI) Age 1 8 yrs 3.02 ( ) Symptom Mass 4.84 ( ) Symptom Prec Pub 5.67 ( ) Size > 8 cm 19.0 ( ) Solid 39.0 N= yr retrospective review 1 d to 19 yrs (mean 12.5) Tumor markers, while stat associated with malignancy (hcg, AFP, CA125), positive or negative not conclusive Oltmann SC et al J Pediatr Surg 2010;45:

7 Pathology # Pts Percent of Total Non-neoplastic Simple or follicular Paratubal Hemorrhagic Corpus luteum Retrospective review masses managed surgically PAG & Ped Surg (22 Sx Ped Surg primary surgical service) Neoplastic-Benign Mature teratoma Cystadenoma Endometrioid Struma ovarii Neoplastic-Malignant Borderline tumor Immature teratoma Mixed germ cell tumor Juvenile granulose cell Dysgerminoma Yolk sac tumor Embryonal Rogers E, Casadiego G, Lacy J, Gerstle T, Kives S, Allen L. JPAG (3); Benign Malignant p-value PPV NPV Pain 83/113 (73.5%) 12/16 (75%) % 72.15% <=8 years old 17/113 (15%) 5/16 (31.2%) % 95.21% Abnormal Markers 9/49 (18.4%) 9/16 (56.2%) % 94.39% LDH 7/9 (77.7%) 4/9 (44.4%) % 56.23% βhcg 0/9 (0%) 2/9 (22.2%) % 79.74% AFPNo simple 2/9 (22.2%) cysts of any 6/9 (66.7%) size were malignant % 87.8% CA 125No Malignancies 1/9 (11.1%) were 2/9 (22.2%) less than 8 cm 1.00in size 41.76% 77.98% Complex Cyst 76/113 (67.3%) 16/16 (100%) % 100% 8 cm 60/113 (53.1%) 16/16 (100%) % 100% 10 cm 34/113 (30.1%) 9/16 (56.2%) % 89.78% 8 cm + Complex Cyst 41/113 (36.3%) 16/16 (100%) % 100% Table 2: Comparison of benign vs malignant adnexal masses Pediatric patients adnexal mass cases were stratified based on their pre-operative mass characteristics as identified by either ultrasound imaging, history, or biochemical markers. A Fisher s exact test comparing the two cohorts identifies the significant differences between benign and malignant masses (p 0.05). Using the sensitivity and specificity of these pre-operative characteristics, the positive predictive value (PPV) and negative predictive value (NPV) of these criteria were also calculated. Note: 7/16 malignant cases were 8 10 cm in size Rogers E, Casadiego G, Lacy J, Gerstle T, Kives S, Allen L. JPAG (3);

8 NPV 100% PPV 37.1% Case 1 What is likelihood of resolution with serial follow up? Would you prescribe her an oral contraceptive pill to aid resolution? Would you order any additional testing? A th f t hi t t Are there any features on history or assessment that could help you decide if mass more likely to be managed expectantly successfully? 8

9 Functional cysts (Hemorrhagic Cysts Follicular Cysts) Pathologic Cysts (Cystadenomas, Paratubal/Paraovarian Cysts, Dermoids < 8 cm, Endometriomas < 8 cm) Kirkham Y, Lacy L, Kives S, Allen L JOGC;2011;33(9): % expectant management 58.8% operative procedure Retrospective review 114 pts presenting to PAG (ER or ambulatory clinic) with an adnexal mass Mean age 12.7+/-3.9 years (neonate to 18) Jan 2003-Jan 2006 Expectant management n=47 Prescribed CHC 12 (25.5%) No CHC 35 (74.5%) Kirkham Y, Lacy L, Kives S, Allen L JOGC;2011;33(9):

10 Desogestrel and 30 ug EE 84% (31/37) resolution by weeks on U/S Expectant 77% (30/39) Levonorgestrel and EE 64% (37/58) resolution by 2 to 3 mo on U/S 2/3 to ¾ resolve by 3 months Not affected by OCP Expectant 61% (33/54) Cochrane Review Oral Contraceptives for Functional Ovarian Cysts (2014) Do symptoms guide us? *all patients with these symptoms went to surgery Only symptom that differed inc abdl girth Pain 73% Incidental Increased 8.8% girth 7.9% Precious puberty 1.8%* Nausea and vomiting 3.5%* Kirkham Y, Lacy L, Kives S, Allen L JOGC;2011;33(9):

11 *All patients with nausea/vomiting and precocious puberty underwent surgical therapy Kirkham Y, Lacy L, Kives S, Allen L JOGC;2011;33(9): Size Range: Surgical group 4.0 to 35 cm Conservative group 2.5 to 9.8 cm Size matters Largest cyst managed without surgery 10 cm Kirkham Y, Lacy L, Kives S, Allen L JOGC;2011;33(9):

12 Age matters 67% no surgery 18.2% no surgery 47.6% no surgery Kirkham Y, Lacy L, Kives S, Allen L JOGC;2011;33(9): Features associated with expectant management: Neonate/Postmenarcheal Size of mass (< 9.8cm) No: Increased girth Precocious puberty Nausea and vomiting 12

13 3 months later: Are you going to offer surgery? If so what surgical approach? Cystadenomas Paratubal/Paraovari an Cysts Dermoids < 8 cm Endometrioma Kirkham Y, Lacy L, Kives S, Allen L JOGC;2011;33(9):

14 Case 1 Laparoscopy Paratubal Cystectomy Kirkham Y, Lacy L, Kives S, Allen L JOGC;2011;33(9): Benign Masses: 50/59 preservation ovary (84%) Malignancies: 3/8 cystectomy Kirkham Y, Lacy L, Kives S, Allen L JOGC;2011;33(9):

15 Benign Cyst Cystectomy Rate n= 2126 pts yrs OR 1.36 ( ) Surgeons OR 0.51 ( ) Overall Laparoscopy rate 62% Benign Laparoscopy rate 69% Rogers E, Casadiego G, Lacy J, Gerstle T, Kives S, Allen L. JPAG (3);

16 Advantages Laparoscopy Visibility of abdominal cavity Shorter length of stay/shorter recovery Rogers E, Casadiego G, Lacy J, Gerstle T, Kives S, Allen L. JPAG (3); Less postoperative pain Cosmesis Safe: 2/158 cases, minor complications (1.2%) Rieger et al JPAG2015; benign laparotomies Reduced to: only 21 (40% reduction) Rogers E, Casadiego G, Lacy J, Gerstle T, Kives S, Allen L. JPAG (3);

17 Laparoscopy Laparotomy P Malignancy 2 (3%) 14 (29 %) <.001 Borderline tumor 0 (0%) 5 (36%) 1 Immature teratoma 1 (50%) 3 (21%).45 Mixed germ cell tumor 0 (0%) 2 (14%) 1 Juvenile granulosa cell 1 (50%) 1 (7%).24 Dysgerminoma 0 (0%) 1 (7%) 1 Yolk sac tumor 0 (0%) 1 (7%) 1 Embryonal 0 (0%) 1 (7%) 1 Benign 78 (97%) 35 (71%) <.001 Simple cyst 42 (54%) 10 (29%).02 Mature teratoma 26 (33%) 15 (43%).4 Cystadenoma 9 (12%) 10 (29%).03 Endometrioma 1 (1%) 0 (0%) 1 Rogers E, Casadiego G, Lacy J, Gerstle T, Kives S, Allen L. JPAG (3); Case 1 if this was imaging? Does this change your thoughts on how to manage this patient? 17

18 Mature Cystic Teratoma Risk of spillage Cyst Rupture Chemical Peritonitis Templeman 2000 (n=14 l/s) 92.8% 0% Savasi 2009 (n=23 l/s) 100% 0% Nezhat 1999 (n-470 adults) 66% 0.2% Savasi, Lacy, Gerstle, Stephens, Kives, Allen JPAG 2009;22(6):360-4 Templeman CL et al Hum Reprod 2000;15: Nezhat CR eta al JSLS 1999; Mature Cystic Teratoma Recurrence rate Overall recurrence rate Laparoscopy Open Requring surgery Laberge 2006 (n=245) 0% 7.6%* 4.2 vs 0%* Rogers 2014 (n=66) 10.6% 15% 3.8% 3% Harada 2013 (n=382) 4.2% 2.9% *stat significant All new dermoids were identified on first postsurgical u/s ( / days) Recommend single ultrasound at 6-12 mo post-op Rogers EM, Allen LM, Kives S JPAG 2014;JPAG:24(4)

19 Predictive factors for dermoid recurrence n=382 23% bilateral 28% multiple Intraop spill 47% 88% l/s Factor HR 95% CI P value Age < Large (>8 cm) Bilateral Multiplicity Intraop spill L/s Overall recurrence rate 4.2% (16/382) 21.0% recurrence if young, large and bilateral 3.4% if none Harada M Eur J Obstet Gynecol Reprod Biol 2013;171: Improved decision making with consensus Kirkham Y, Lacy L, Kives S, Allen L JOGC;2011;33(9):

20 Marro A, Allen L, Kives S, Moineddin R, Chavhan G Accepted/In Press, Pediatr Radiol Simulated Impact of Pelvic MRI in Treatment Planning for Paediatric Adnexal Masses 21/32 cases after MRI: discordance in at least 1 aspect of management 11 in oophorectomy vs cystectomy category Consensus reading Discrepancy less in suspicion for malignancy vs choices of surgical approach in the benign mass Is cystectomy viable in the very large ovarian mass? Surgeon A Surgeon B Consensus Oophorectomies 13 Oophorectomies 4 Oophorectomies 4 Marro A, Allen L, Kives S, Moineddin R, Chavhan G Accepted/In Press, Pediatr Radiol 20

21 Ovary Size: pre and postop cystectomy Residual ovarian tissue in cystectomy specimens Size (cm) Volume (cm3) Affected Ovary Contralateral Ovary 30 pts (6 16 yrs, median 9.1), 18 l/s, 12 laparotomy 86.7% no ovarian tissue in the cystectomy specimen 13.3% (2 l/s, 2 laparotomy) tissue found, < 1mm, only with endometriotic cysts Reddy J Laufer M Fertil Steril 2009;91:1941 Palmara J Pediatr Surg 2012;47:

22 Case 2 15 year old girl referred to gynecology and oncology Bloating and abdominal distention x weeks, fever x days Menses at 13y, regular q monthly. No OCP. Not sexually active. Ultrasound showed large complex, mixed solidcystic heterogenous mass, 10 x 12 x 13 cm. Case 2 AFP 700 B-HCG 2 LDH

23 23

24 TUMOUR MARKERS IN OVARIAN MALIGNANCY AFP HCG INH LDH CA125 Test/Est CEA Dysgerminoma - -/+ - -/+ -/+ - - Yolk sac tumor /+ -/+ - - Immature teratoma -/ Embryonal Ca -/+ -/ Choriocarcinoma Mixed MGCT -/+ -/+ - -/+ -/+ - - Granulosa cell Sertoli-Leydig - - -/ Epithelial /+ - -/+ From Shaikh et al. Paediatric extracranial germ-cell tumours: Review. Lancet Oncology, April

25 Benign Malignant p-value PPV NPV Pain 83/113 (73.5%) 12/16 (75%) % 72.15% <=8 years old 17/113 (15%) 5/16 (31.2%) % 95.21% Abnormal Markers 9/49 (18.4%) 9/16 (56.2%) % 94.39% LDH 7/9 (77.7%) 4/9 (44.4%) % 56.23% βhcg 0/9 (0%) 2/9 (22.2%) % 79.74% AFP 2/9 (22.2%) 6/9 (66.7%) % 87.8% CA 125 1/9 (11.1%) 2/9 (22.2%) % 77.98% Complex Cyst 76/113 (67.3%) 16/16 (100%) % 100% 8 cm 60/113 (53.1%) 16/16 (100%) % 100% 10 cm 34/113 (30.1%) 9/16 (56.2%) % 89.78% 8 cm + Complex Cyst 41/113 (36.3%) 16/16 (100%) % 100% Table 2: Comparison of benign vs malignant adnexal masses Pediatric patients adnexal mass cases were stratified based on their pre-operative mass characteristics as identified by either ultrasound imaging, history, or biochemical markers. A Fisher s exact test comparing the two cohorts identifies the significant differences between benign and malignant masses (p 0.05). Using the sensitivity and specificity of these pre-operative characteristics, the positive predictive value (PPV) and negative predictive value (NPV) of these criteria were also calculated. Rogers E, Casadiego G, Lacy J, Gerstle T, Kives S, Allen L. JPAG (3); Benign Malignant p-value PPV NPV Pain 83/113 (73.5%) 12/16 (75%) % 72.15% <=8 years old 17/113 (15%) 5/16 (31.2%) % 95.21% Abnormal Markers 9/49 (18.4%) 9/16 (56.2%) % 94.39% LDH 7/9 (77.7%) 4/9 (44.4%) % 56.23% βhcg 0/9 (0%) 2/9 (22.2%) % 79.74% AFP 2/9 (22.2%) 6/9 (66.7%) % 87.8% CA 125 1/9 (11.1%) 2/9 (22.2%) % 77.98% Complex Cyst 76/113 (67.3%) 16/16 (100%) % 100% 8 cm 60/113 (53.1%) 16/16 (100%) % 100% 10 cm 34/113 (30.1%) 9/16 (56.2%) % 89.78% 8 cm + Complex Cyst 41/113 (36.3%) 16/16 (100%) % 100% Table 2: Comparison of benign vs malignant adnexal masses Pediatric patients adnexal mass cases were stratified based on their pre-operative mass characteristics as identified by either ultrasound imaging, history, or biochemical markers. A Fisher s exact test comparing the two cohorts identifies the significant differences between benign and malignant masses (p 0.05). Using the sensitivity and specificity of these pre-operative characteristics, the positive predictive value (PPV) and negative predictive value (NPV) of these criteria were also calculated. Rogers E, Casadiego G, Lacy J, Gerstle T, Kives S, Allen L. JPAG (3);

26 MRI second level exam Greater specificity to characterize the benign mass Useful to differentiate non adnexal masses Used in our institution for staging vs CT to decrease radiation ACOG Practice Bulletin

27 Complex vs Complex Lesion Hemorrhagic cyst Mucinous cystadenoma Mature Teratoma Indicators of malignancy Description Various stages of hemorrhage, acute, clot formation, retraction (fibrin strands, retracting thrombus, fluid levels Different densities of fluid (layering of mucin) Fat/Fluid levels, calcifications with posterior echogenic shadowing, fine echogenic bands hyperechoic mural module Solid components > 2cm in size, thick septations, multiple papillary projections,ascites, high doppler content 27

28 Surgical Staging in Adults Adapted d from adult experience with epithelial l ovarian cancer Adult staging generally comprehensive Peritoneal cytology and biopsies Omentectomy Retroperitoneal lymphadenectomy (bilat pelvic, para-aortic nodes) Removal of any suspicious tissue, with tumor reductive surgery to be performed in the event of disseminated i d disease Bivalve and bx of contralateral ovary Is the same comprehensive staging required in pediatric ovarian malignancies? 2 intergroup trials undertaken by POG and CCG ( ) 131 girls with primary ovarian MGCTs Staging was as per adult recommendations, but compliance, yield and utility of each step examined. Complete staging almost never performed (3/131) No bilateral node sampling (97%), no biopsy contralateral ovary (60%), no omentectomy (36%), no peritoneal cytology (21%). 6-year survival >93% for all stages 28

29 Component Tumor Capsule Ascites Peritoneal implants Omentum Lymph nodes Contralateral ovary Findings Visual assessment of capsule integrity incorrect ~20% 23/100 positive cytology 5 upstaged based solely on cytology 0/7 normal areas positive (for malignancy) 18/29 abnormal areas positive 1/23 normal areas positive 7/45 abnormal areas positive 0/18 grossly normal nodes positive 19/46 grossly abnormal nodes positive 0/21 normal-appearing ovaries positive 11/21 abnormal positive 29

30 Excerpts from COG AGCT1531 Surgical Guidelines (draft version) The approach for ovarian tumors with known malignancy preoperatively has historically i been by open technique. The current study will expand the guidelines to allow tumors less than 10 cm in diameter by imaging to be approached laparoscopically if desired. This will require the tumor to be placed into a retrieval bag without capsule violation; and if a cystic component is decompressed it must be done with the neck of the bag exteriorized through the incision to avoid any possibility of spill. All other staging criteria must still be completed. it is important to avoid capsular disruption intraoperatively and the tumor must be provided to the pathologist intact to allow thorough assessment of the tumor capsule. If removal would require en bloc removal of structures in addition to ovary and tube, only a biopsy should be done. Case 2 Surgical pathology showed teratoma with yolk sac tumor Evidence of capsule rupture, ascites cytology positive, peritoneal implant and omental biopsies negative. Staging? Further treatment? 30

31 Who needs adjuvant chemotherapy? Until recently, all patients with ovarian malignant germ cell tumors or stromal tumors received adjuvant chemotherapy (four cycles of Peb; cisplatin, etoposide, bleomycin). Recently, it has been noted that a strategy of close surveillance after initial iti surgery for stage I patients t (Figo stage Ia and Ib) can allow at least half of all patients to avoid chemotherapy. This has made strict staging maneuvers all the more important. 31

32 Half the patients eventually required chemotherapy (which means half did not). All patients who recurred on surveillance had elevated AFP, and recurred within 9 months (median 2 months). Nearly all patients could be salvaged with adjuvant chemotherapy started at recurrence. One patient died, but this patient had chemo-refractory disease, and hence final outcome may not have been different. 32

33 Pooled analysis of pediatric and adult clinical trials 179 patients with pure immature teratomas Pediatric patients (N=98, COG) Surgery alone 90 5y EFS 91% OS 99% Adult patients (N=91, GOG) Surgery alone 0 5y EFS 87% OS 93% Grade 1: no relapses, regardless of age or stage Grade 2: only one adult relapse, stage IIIc Grade 3: 33

34 Case 3 14 year old girl with 4 week history of shortness of breath, transferred from northern community 2 week history of abdominal pain Recent decrease in appetite Menses at 13y, regular q monthly. No OCP. X-ray ordered by primary care provider: calcifications seen PE: large, palpable abdominal mass extending above the umbilicus 34

35 Case 3 AUS demonstrated a large abdominal-pelvic mass: 19 x 8.6 x 21cm, complex solid-cystic mass with calcification Case 3 How should this case be managed? Any additional investigations? 35

36 Case 3 AFP=1 Beta HCG<1 CA125= 97 (upper limit 35) LDH 711 (elevated) MRI 20 x 15 x 11 cm solid 5 7 x 51 with ascites MRI 20 x 15 x 11 cm, solid 5.7 x 5.1, with ascites, peritoneal seeding, second mass 11 x 8 cm *thought to be bilateral 36

37 Repeat MRI 37

38 Case 3 Surgical approach? 38

39 Case 3 Surgical approach: lower midline laparotomy Left salpingo-oopherectomy complete staging per algorithm Intra-operative findings: pre-operative rupture of the tumour capsule and multiple peritoneal implants Case 3 Pathology: mature teratoma with rupture of the capsule and gilomatosis Is adjuvant therapy required? 39

40 Ovarian Teratoma and Gliomatosis Peritonei (GP) Gliomatosis peritonei: a clinicopathologic and immunohistochemical study of 21 cases; Li Liang, Yifen Zhang, Anais Malpica, et al; MD Anderson Cancer Center, Houston, TX; Mod Pathol December; 28(12): Mature ovarian teratoma with gliomatosis peritonei A case report; Das CJ, Sharma R, Thulkar S, et al; All India Institute of Medical Sciences, New Delhi, India; Indian Journal of Cancer, July - September 2005, Volume 42, Issue 3 Ovarian Teratoma and Gliomatosis Peritonei (GP) Rare condition often associated with immature ovarian teratoma, but can be associated with mature ovarian teratoma and mixed germ cell tumours Characterized by the presence of mature glial tissue in the peritoneum Diagnosed commonly at time of initial surgery for ovarian mass (71%) but can develop secondarily (29%) Age range: 5-42 yrs (mean 19 yrs); < 18 yrs = 30% May co-exist with metastatic immature and/or mature teratoma 40

41 Ovarian Teratoma and Gliomatosis Peritonei (GP) GP is considered grade 0 teratoma and is usually associated with favorable prognosis and managed conservatively On rare occasions, malignant transformation to a glial neoplasm Can be part of growing teratoma syndrome, characterized by increasing growth of metastatic mass that is composed of mature teratoma (especially in patients who have received chemotherapy for malignant germ cell tumor) Paradoxically, patients who have immature ovarian teratomas in association with GP appear to have an improved prognosis Ovarian Teratoma and Gliomatosis Peritonei (GP) At laparotomy: all peritoneal, omental, diaphragmatic surfaces must be extensively sampled If no other teratomatous elements or malignant glial tissue is found in the implants, the mature glial implants can be ignored Therapy should be directed by the stage and grade of the primary ovarian tumor and not by the mature glial implants 41

42 Summary Many ovarian cysts will resolve without t surgical management Only a small proportion of patients with ovarian tumors are malignancies. A prediction rule can allow the best balance in conservative vs oncologic management. Tumors known or suspected to be malignant require a surgical approach that t allows complete intact t resection and full staging. Stage I ovarian tumors can be treated with surveillance alone, with chemotherapy reserved for recurrence. 42