Management of a Hypercalcemic Small Cell Tumor of the Ovary - A rare, rare disease on the basis of cases reported in the literature Andres Poveda, MD
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Case Discussion 3:
Management of a Hypercalcemic Small Cell
Tumor of the Ovary
A rare, rare disease on the basis of cases
reported in the literature
Andres Poveda, MD
Initia Oncology, Hospital Quironsalud
Valencia, Spain
www.initiaoncologia.com
Clinical Case Presentation • 19-years-old female, G1P1A0 • Medical history: • Beta-thallasemia minor; congenital “single-kidney” • No family history of cancer • November 2014: Presented with 8-month history of increasing abdominal distension, weight-loss, lack of appetite, and constipation • Clinical exam: Physical exam revealed a large, firm, immobile mass extending from the pubic symphysis to the umbilicus
Clinical Case Presentation November 2015: • Blood test: Hemoglobin 9.8 g/dL; LDH 650 U/L; CA125 87 U/mL; inhibins A and B, AFP, CEA, testosterone, and HCG were normal; calcium level was normal, as well • Ultrasound: Right ovarian mass 9.8 x 8.4 cm • CT imaging: Revealed a 15 x 9 x 12 cm complex right pelvic mass; peritoneal carcinomatosis (omental nodes up to 3.6 cm); moderate amount of ascites AFP, alpha fetoprotein; CEA, carcinoembryonic antigen; HCG, human chorionic gonadotropin LDH, lactate dehydrogenase
Clinical Case Presentation
December 2015:
• Exploratory laparotomy:
– The right ovarian mass was removed and frozen section
was reported as malignant neoplasm, possible granulosa
cell tumor, favor small-cell carcinoma
– R0 feasible
Question: What would be your preferred option? 1. Fertility-sparing surgery + chemotherapy 2. Radical surgery 3. Radical surgery + chemotherapy 4. Radical surgery + chemotherapy + radiotherapy 5. Radical surgery + chemotherapy + immunotherapy
Surgical Approach
December 2015:
• Exploratory laparotomy:
– The right ovarian mass was removed and frozen section
was reported as malignant neoplasm, posible granulosa
cell tumor, favor small-cell carcinoma
• She underwent optimal debulking surgery
(salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy, omentectomy and peritoneal biopsies
from the bladder peritoneum, posterior cul-de-sac, right round ligament and fallopian tube, right paracolic
gutter, anterior abdominal wall, and bowel mesentery).
No evidence of residual diseasePathology • Final pathology revealed poorly differentiated small- cell carcinoma of the ovary, hypercalcemic-type (SCCOHT), with metastases to the omentum; lymph nodes were (18/18) positive for malignancy • She was diagnosed with stage 3C high-grade, small- cell carcinoma
Immunohistochemistry • Positive: EMA (+), CK (+), CD56 (+), C-erbB-2 (1+), CA125 (focal +), vimentin, desmin, p63 and CD99 focal +; Ki67 ~60%, • Negative: Estrogen (ER), progesterone (PR), inhibin, CD99, alpha fetoprotein (AFP), CD30, CD20, CD34, S100, melan-A, CK7, CK20, CK5/6, chromogranin, synaptophosyn, CD52, p53, H caldesmon, calcitonin, muscle actin, CD117, BCL2
Molecular Characterization
• Recently, SMARCA4 mutations and SMARCA4 protein loss
were identified in SCCOHT:
– SCCOHT is a monogenic disease associated to germline or somatic
mutation in SMARCA4 gene
• SMARCA4 (BRG1) loss of expression was thought to be a
useful diagnostic marker of SCCOHT in ovarian tumors
• Related data suggested a tumor suppressor role of
SMARCA4 and that it might constitute a key therapeutic
vulnerability in SMARCA4-deficient cells
Stephens B, et al. J Cancer. 2012;3(1):58-66. Karanian-Philippe M, et al. Am J Surg Path. 2015;39(9):1197-1205. Jelinic P, et al. Nat Genet. 2014;46(5):424-
426. Ramos P, et al. Nat Genet. 2014;46(5):427-429. Karnezis AN, et al. J Pathol. 2016;238(3):389-400.Molecular Characterization
IHC Detects Loss of SMARCA4 Protein
IHC, immunohistochemistry Courtesy of Dr A Gonzalez MartínMolecular Characterization SMARCA4 and SMARCA2 IHC Loss of SMARCA4 • Sensitivity 91% (83/91) • Specificity 99% (15/2324) – 15 cases were CCC – 4% (15/360) of CCC are SMARCA4 negative – CCC does not enter in the differential diagnosis of SCCOHT Loss of SMARCA4 and SMARCA2 is exclusive of SCCOHT Karnezis AN, et al. J Pathol. 2016;238(3):389-400. Courtesy of Dr A Gonzalez Martín
Hypercalcemic Small-Cell Ovarian Cancer
Review
Wang JJ, et al. Onco Targets Ther. 2016;9:1409-1414.Small Cell Ovarian Cancer
Background
• Small-cell carcinoma of the ovary (SCCO) is a rare, highly malignant
tumor that affects mainly young women
– The median age of diagnosis is 24 years old
• Approximately two thirds of patients with SCCO have hypercalcemia
(SCCOHT)
• SCCO is very aggressive and grows very quickly. Therefore, we believe
the importance of finding and treating this cancer early, while the tumor
is relatively small, is critical
• Keep in mind: Many doctors have never seen a patient with small-cell
ovarian cancer
Small Cell Ovarian Cancer Foundation. www.smallcellovarian.org. Accessed 24 January 2019.Small Cell Ovarian Cancer
Clinical Features
• Most patients with SCCOHT present late with advanced disease
• The prognosis is generally very poor
– 45% overall survival for stage IA
–Small Cell Ovarian Cancer
Clinical Features
• The disease’s tendency for rapid progression and high
recurrence also makes treatment a challenge
• Several therapeutic regimens have been proposed;
however, there is no consensus on the optimal strategy
Dickersin GR, et al. Cancer. 1982;49(1):188-197. Qin Q, et al. Ecancermedicalscience. 2018;12:832.SCCOHT
Largest Treatment Series Reported
• Young et al 150 Am J Surg Pathol 1994
• Callegaro-Filho et al 47 Gyn Oncol 2016
• Pautier et al (prospective) 27 Ann Oncol 2007
• Harrison et al 17 Gyn Oncol 2006
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• In total:Treatment Options for the Patient • Surgery • Radiotherapy • Chemotherapy • Immunotherapy
Treatment Options for the Patient • Surgery • Radiotherapy • Chemotherapy • Immunotherapy
Surgery
• Standard:
This will be standard staging and where appropriate
lymphadenectomy and debulking of disease to try and
achieve no residual disease should be performed1
• Controversial:
Fertility sparing surgery
– Small case series have reported good outcomes with USO and adjuvant chemotherapy2,3
– The largest report suggest a trend for better outcome after a procedure that includes
BSO, inclusive of patients with stage IA tumors:
• 8 of 14 patients (57%) with stage IA survived without recurrence in comparison with
• 5 of 21 patients (23%) who had a USO (P = .075)4
BSO, bilateral salpingo-oophorectomy; USO, unilateral salpingo-oophorectomy
1. Reed NS, et al. Int J Gynecol Cancer. 2014;24(9 Suppl 3):S30-S34. 2. Woopen H, et al. Eur J Obstet Gynecol Reprod Biol. 2012;165(2):313-317.
3. Qin Q, et al. Ecancermedicalscience. 2018;12:832. 4. Young RH, et al. Am J Surg Pathol. 1994;18(11):1102-1116.Treatment Options for the Patient • Surgery • Radiotherapy • Chemotherapy • Immunotherapy
Radiotherapy • The role of radiotherapy in the treatment of SCCOHT is largely unknown, but there is limited information to suggest a potential benefit • In the series by Young, five of the 14 patients with stage IA disease received adjuvant radiotherapy, and four (80%) were long-term survivors Young RH, et al. Am J Surg Pathol. 1994;18(11):1102-1116. Harrison ML, et al. Gynecol Oncol. 2006;100(2):233-238. Reed NS, et al. Int J Gynecol Cancer. 2014;24(9 Suppl 3):S30-S34. Callegaro-Filho D, et al. Gynecol Oncol. 2016;140(1):53-57.
Example of Diversity in Radiotherapy Treatment
Comparison of Patients With and Without Recurrent Disease
Recurrence No Recurrence
(N = 35, 74.5%) (N = 12, 25.5%) P Value
Age at diagnosis (N = 47)
Mean 30.6 27.8 .3191
Median 31.0 28.5 .2930
Stage (N = 47) .4384
I 10 (28.6%) 6 (50.0%)
II 4 (11.4%) 2 (16.7%)
III 19 (54.3%) 4 (33.3%)
IV 2 (5.7%) 0 (0.0%)
Primary adjuvant therapy (N = 42) .1006
None 2 (6.3%) 0 (0.0%)
Chemotherapy 28 (87.5%) 7 (70.0%)
Chemotherapy followed by radiotherapy 1 (3.1%) 3 (30.0%)
Primary chemoradiation 1 (3.1%) 0 (0.0%)
Callegaro-Filho D, et al. Gynecol Oncol. 2016;140(1):53-57.Treatment Options for the Patient • Surgery • Radiotherapy • Chemotherapy • Immunotherapy
Chemotherapy
• Due to the rarity of SCCO, there are no randomized, controlled trials
that identify optimal treatment
• The majority of recommended treatment plans are derived from case
reports and small case series
• The only prospective trial: 27 patients on a phase II trial consisting of
radical surgical resection followed by four to six cycles of
chemotherapy (P+A+E+C) and, in case of complete remission,
additional high-dose chemotherapy with CB+E+C)
– This intensive regimen demonstrated a 49% 3-year overall survival rate, which was
consistent with previously published reports with less intensive chemotherapy
• Various chemotherapy regimens have been proposed, including
platinum compounds
P, cisplatin; A, doxorubicin; E, etoposide; C, cyclophosphamide; CB, carboplatin
Pautier P, et al. Ann Oncol. 2007;18(12):1985-1989. Reed NS, et al. Int J Gynecol Cancer. 2014;24(9 Suppl 3):S30-S34. Stewart L, et al. Gynecol Oncol
Rep. 2016;18:45-48.Example of Diversity in Chemo Treatment
Primary Adjuvant Chemotherapy Regimens (N = 39)
Chemotherapy regimen Number of Patients (%)
Cisplatin/carboplatin and etoposide (CE) 15 38.5%)
Vinblastine, cisplatin, cyclophosphamide, bleomycin, doxorubicin, and
10 (25.6%)
etoposide (VPCBAE)
Carboplatin and paclitaxel 7 (17.9%)
Carboplatin, paclitaxel, and bevacizumab 1 (2.6%)
Bleomycin, etoposide, and cisplatin (BEP) 3 (7.7%)
Cisplatin, cyclophosphamide, doxorubicin, and etoposide (CPAE) 1 (2.6%)
Cisplatin and etoposide followed by paclitaxel and carboplatin 1 (2.6%)
High-dose chemotherapy (induction with carboplatin and paclitaxel x 3
cycles, mobilization with cyclophosphamide, etoposide, and cisplatin x 1
1 (2.6%)
cycle, followed by hyper-fractioned cyclophosphamide, doxorubicin, and
vincristine, followed by autologous stem cell transplant)
Callegaro-Filho D, et al. Gynecol Oncol. 2016;140(1):53-57.Treatment Options for the Patient • Surgery • Radiotherapy • Chemotherapy • Immunotherapy
Immunotherapy • SCCOHT is a monogenic disease and consequently displays low tumor mutational burden (TMB) • Cases of response to anti–PD-1 immunotherapy have been reported • A study of 11 SCCOHT tumors has shown PD-L1 expression, T-cell and TAM infiltration (unexpected 10/11) Jelinic P, et al. J Natl Cancer Inst. 2018;110(7):787-790.
Molecular Characterization and
Possible Targeted Therapies
• SMARCA4 alteration leads to BRG1 loss of function,
which may allow for sensitivity to tazemetostat
• Tazemetostat is an EZH2 inhibitor currently
implemented in a phase II trial that includes SCCOHT
(clinicaltrials.gov, NCT02601950)1
• PD-1 and PD-L1 inhibitors, in turn, may offset
adaptive immune evasion of the SCCOHT tumor cells2
1. Lin DI, et al. Gynecol Oncol. 2017;147(3):626-633. 2. Chan-Penebre E, et al. Mol Cancer Ther. 2017;16(5):850-860.Treatment of This Patient
Tumor Board Recommendation
• PDS
• Chemotherapy: Cisplatin (20 mg/d d1-5 , q/3 wks ) +
etoposide (100 mg/ m2 d1-5, q/3 wks), 4 cycles
(patient refused to continue until 6 due to toxicity)
• Consider radiotherapy (finally not given to avoid
adding toxicity, she has congenital single kidney)
• Current status: Free of disease 30+ monthsQuestion: What would be your preferred option? Please vote again 1. Fertility-sparing surgery + chemotherapy 2. Radical surgery 3. Radical surgery + chemotherapy 4. Radical surgery + chemotherapy + radiotherapy 5. Radical surgery + chemotherapy + immunotherapy
Small-Cell Ovarian Cancer Hypercalcemic
Summary
• Rare cancers which are often difficult to distinguish from
other epithelial ovarian cancers
• Management is multidisciplinary and should be
discussed at tumor boards
• Expert pathologic review is essential
• Prognosis in advanced stages is usually poor and, even
in stage 1 and 2, disease less than 40% will be cured
• Association with paraneoplastic phenomena such as
hypercalcemia and hyponatremiaNon-Answered Questions • Optimal choice for first-line chemotherapy – For example cisplatin or carboplatin usage – TC vs BEP vs EP vs…. • Role of adjuvant therapy in early stages • Role of radiotherapy not seem to be a common isolated event • Given the rarity of these tumors it is very difficult to conduct clinical trials
Small-Cell Ovarian Cancer Hypercalcemic
Take Home Messages
• Small-cell cancer of the ovary remains a challenging tumor
to treat
• Mutation in SMARCA4 and epigenetic silencing of SMARCA2
is pathognomonic for SCCOHT, and can be detected by IHC
• Targeted therapy as well as immunotherapy are promising
• International prospective multicenter registries are needed
with collection of data with homogenous treatment
– Clinical trials within cooperative groups are crucial
• Please refer these patients to specialized centers!!Hoping to See You Soon
Thanks!
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