Epithelial Ovarian Cancer and Pseudomyxoma Peritonei

◈ Epithelial Ovarian Cancer
1. Pathology : Ovarian cancer의 90%는 epithelium or mesothelium orign
① Invasive Cancer
: Serous type (75%), mucinous (20%), endometrioid (2%),
: Clear cell, Brenner, and undifferentiated carcinoma (<1%)
② Borderline Tumors
- Tumor of low malignant potential
- Confined to the ovary for long periods,
- Predominantly in premenopausal women
: 30~50대에 흔함 invasive carcinoma는 50-70대에 흔함
- Good prognosis
- Metastatic implants
: noninvasive vs invasive form
: invasive form이 peritoneal cavity에 progressive, proliferative disease를 발생시켜 intestinal obstruction, death에 이를 가능성이 더 높다
- 20~25% : spread beyond the ovary

2. Etiology
① Associated with low parity, infertility, early menarche and late menopause
=> Suppression of ovulation과 관련성 있다는 가설을 뒷받침
=> Repetitive disruption and repair of surface epithelium -> higher probability of spontaneous mutations
3. Prevention
① Having at least one child (risk reduction of 0.3 to 0.4)
② Oral contraceptive (>5 year) : only documented method of chemoprevention
③ Fenretinide(4-hydroxyretinoic acid) -> 현재 trial 중
④ Prophylactic oophorectomy : reduce risk of ovarian cancer, but not eliminate peritoneal carcinoma
4. Screening
① TV-USG : >95% sensitivity for the detection of early-stage
② CA-125 : sensitivity - 50% of stage I
- 60% of stage II
=> 두가지 모두 false positive 때문에 cost effective 하지 않고 routine으로 이용되지 않는다.
5. Symptoms and Signs
- Most of pts has no symptoms
`① In early-stage disease
- Irregular menses, urinary frequency or constipation, lower abdominal distension, pressure, pain(such as dyspareunia)
- Acute Sx : pain secondary to rupture or torsion
② In advanced-stage disease
- Related Sx with ascites, omental metastases, and bowel metastases
; abdominal distention, bloating, constipation, nausea, anorexia, or early satiety
- Premenopausal women : Irregular or heavy mense
- Postmenopausal women : vaginal bleeding
③ Sign
- Pelvic mass on P/E ; solid irregular, fixed mass
- Upper abdominal mass or ascites

6. Diagnosis
- DDx with benign neoplasm, functional cysts of the ovaries, pelvic inflammatory disease, endometriosis, pedunculated uterine leiomyomas, diverticulitis, colonic mass, pelvic kidney
- CA125 : distinguishing malignant from venign pelvic mass
: postmenopausal pts에서 >95 U/ml 이면 96% positive predictive value for malignancy
- Cystic mass > 8cm : tumor 가능성 높음
- Preoperative evaluation
: Chest radiography, IVP,
: CT, MRI - pelvic mass가 definite하면 필요치 않지만, ascites가 있거나 pelvic mass가 없어 liver or pancreatic tumor를 찾아볼 때 시행 가능
: ovarian metastasis의 primary origin을 찾기 위해
- 45세 이상의 환자는 colonoscopy시행하고, gastric symptom이 있는 경우에는 E.G.D 시행한다. breast mass가 만져지는 경우 mammography 시행하고 PAP smear와 함께 irregular mense 또는 postmenopausal vaginal bleeding이 있을 경우 EM Ca를 확인하기 위해 endocervical curettage & EM Bx 시행

7. Patterns of Spread
① Transcoelomic : Exfoliation of cells that implant along the surfaces of the peritoneal cavity
② Lymphatic : pelvic and paraaortic LN
-> lymphatic channels of the diaphragm and retroperitoneal LN
-> supraclavicular LN

③ Hematogenous : lung and liver (only 2-3%)
: diaphragm 위쪽으로 침범이 진단된 환자의 대부분은 right pleural effusion 있음

8. Prognostic Factors
① Pathologic Factors
1) Hystologic type : Clear cell carcinoma - poor prognosis
2) Hystologic grade : Grade가 높을수록 예후가 나쁨
② Biologic Factors
1. Ploidy : low-stage cancer -> tend to be diploid
: high-stage cancer -> tend to be aneuploid
2. Protooncogenes : HER-2/neu oncogene -> poor prognosis
: p53 mutation
③ Clinical Factors
: Stage
: Extent of residual disease after primary surgery
: Volume of ascites
: Patient age
: Performance status



9. Treatment of Early stage disease
① Surgical staging(Exploratory laparotomy)
: FIGO staging based on findings at surgical exploration
- FIGO stage




② Stage I
1. Borderline Tumors
- Surgical resection of the primary tumor
- No subsequent chemotherapy or radiation therapy
- For preservation of ovarian function
-> 환자 원하면 unilateral oophorectomy 시행 가능
-> 2-18년 사이에 8%정도 재발
2. Stage Ia and Ib, grade 1
- TAH + BSO
- 환자 원하면 unilateral oophorectomy 가능
3. Stage Ia and Ib, grade 2 or 3 & Stage III
- Adjuvant chemotherapy
; carboplatin and paclitaxel for 3-6 cycles
; older women - short course of a single agent(carboplatin or paclitaxel)

10. Treatment of Advanced stage disease
① Cytoreductive Surgery(=Debulking surgery)
- Remove as much of the tumor and its metastases as possible
- TAH + BSO + complete omentectomy + resection of any metastatic lesions
- Effects of debulking surgery
: eliminate areas that are most likely to be relatively resistant to treament
(bulky tumor -> poorly vascularized & small growth fraction -> chemotherapy or radiation에 대한 반응 적음)
: removal of the bulky tumor -> ↓ascites
: removal of the omental cake -> ↓nausea and early satiety
: removal of the intestinal metastasis -> improvement of overall nutritional status
- Goal of debulking surgery
: removal of all of the primary cancer and metastatic disease
: all metastatic nodules < 1.5 cm in maximal diameter (=> Optimal cytoreduction)

② Chemotherapy
1) Paclitaxel+Carboplatin vs Paclitaxel+Cisplatin
- Efficacy and survivals were similar
- More acceptable toxicity in carboplatin-containing regimen
2) Intraperitoneal(IP) Chemotherapy
- Value in the primary treatment of optimally respected stage III ovarian cancer remains unclear
3) Neoadjuvant chemotherapy
- 2~3 cycles of chemotherapy prior to cytoreductive surgery may be helpful in patients with massive ascites and large pleural effusion

* Chemotherapeutic Recommendation
1) Combination chemotherapy with carboplatin and paclitaxel : the treatment of choice
- Carboplatin(starting dose AUC=5~6) + Paclitaxel(175mg/m2)
: over 3 hours every 3 weeks for six cycles
2) In patients who cannot tolerate the combination
- single-agent carboplatin(AUC = 5~6)
3) In patients who have a hypersensitivity to paclitaxel
- alternative active drug (e.g. cyclophosphamide or topotecan)
4) In patients who cannot tolerate IV CTx
- oral alkylating agent

④ Immunotherapy
1) Interferon-, interferon-, and interleukin-2
2) Monoclonal antibody
- Antibodies directed toward CA125, HMFG (Human milk fat globulin)
- Herceptin: HER-2/neu oncogene
- Antibodies against mutated p53 tumor suppressor gene

11. Treatment assessment
- Second-look operation
: tumor marker나 radiologic assessment는 sensitivity가 너무 낮아 subclinical disease를 놓칠 수 있다.
- CA125
: 치료시작 시에 증가되어 있다면 대체적으로 second-look operation과 correlation 잘 되므로 치료반응을 볼때 쉽게 이용이 가능
* Second-Look Operations
① Performed on a patient who has no clinical evidence of disease
② Determine the response to therapy.
③ Essentially identical to that for the staging laparotomy

12. Second-line Therapy
① Secondary Cytoreduction
- Candidates : persistent or recurrent pelvic and abdominal tumors after primary therapy
- Suitable patient
: Reasonable chance of either prolonging life of resulting in significant palliation of symptoms
- Goal
: Remove all residual gross tumor, reduce the metastatic tumor burden <5mm maximal dimension
② Second-Line Chemotherapy
- The response rates for second-line chemotherapies : 15~35%
- Cisplatin, carboplatin, paclitaxel, docetaxel(Taxotere), topotecan, gemcitabine, etoposide(VP-16), doxorubicin (Doxil), vinorelbine (Navelbine), ifosfamide, 5-FU with leucovorin, hexamethylmelamine
③ Platinum-sensitive Versus Platinum resistant
- Cisplatin sensitive tumor : Carboplatin (Response rates : 20-30%)
- Platinum- or paclitaxel- sensitive tumor : retreatment with a platinum or paclitaxel
(Response rate : 20-25%)
- Cisplatin-refractory tumor : response rates to second-line carboplatin : < 10%.
- Platinum-resistant tumor
: non-cross-resistant agent with different anticancer mechanism (Response rate : 8-28%)
: Topoisomerase inhibitors (topotecan, etoposide), anthracycline (doxorubicin), alkylating agents (ifosfamide), or other agents (hexamethylmelamine)
- Several new combination
: Gemcitabine and platinum
: Topotecan and platinum
④ Intraperitoneal Therapy
- Candidates : complete responses with minimal residual disease(<5mm)
; Cisplatin, 5-FU, Ara-C, etoposide, mitoxantrone (Response rates : 20-40%)
; interferon-, interferon-, TNF and IL-2 (Response rate : 30-50%)
⑤ Hormonal Therapy
- Tamoxifen
- GnRH agonist (Leuprolide acetate, Lupron)
- Aromatase inhibitors (e.g., Arimidex)
⑥ Radiation Therapy
- Whole-abdominal radiation -> relatively high morbidity (30%- intestinal obstruction)

13. Prognosis


◈ Pseudomyxoma peritonei
- Mucinous cyst
-> perforate and initiate intra-abdominal transformation of the peritoneal mesothelium to a mucin-secreting epithelium
-> gradual accumulation in the peritoneal cavity of huge amounts of gelatinous material
(pseudomyxoma peritonei)
- 13 cases of pseudomyxoma
: 10 cases - originated in benign ovarian tumors
: 2 cases - originated in malignant ovarian tumors
: 1 case - originated in appendiceal mucocele
- Treatment
: Repeatedly surgery, because of the recurrent nature of the lesion
: Intraperitoneal alkylating agents -> little success
: Radiation, mucolytic agents -> disappointing
- Prognosis
: 45 % of 5-year survival
: 40% of 10-year survival