◙ Are BOTs considered malignant ??

◙ What is the mean age for BOTs ??

◙ Can BOTs be associated with ascites ??

◙ Can BOTs cause lymphadenopathy or peritoneal deposits ??

◙ Do we have a staging system for BOTs ??

◙ Can we use chemo-Rx for BOTs ??

◙ Tumours of borderline malignancy,

◙ Tumours of low malignant potential,

◙ Atypical proliferative tumours.

◙ In 1929, Howard C. Taylor, was the 1st to use of the term“(semi-malignant tumours)” for

a subset of large ovarian tumours that had an indolent clinical course with relatively

favourable outcome despite the presence of peritoneal disease.

◙ However, BOTs were not considered a distinct entity until 1971, when the FIGO& WHO

established a separate borderline category of tumours.

◙ Since then, a considerable controversy has surrounded the definition & management of

BOTs, because of their enigmatic pathogenesis & confusing biologic behaviour.

◙ BOTs are relatively un-common, (incidence = 1.5-–2.5 / 100,000 people / year).

◙ BOTs = 15-–20% of ovarian epithelial neoplasms.

◙ Most commonly they affect white women of reproductive age typically during the 4th

decade. Up to 27% of patients with BOTs are < 40 years.

◙ The mean age of presentation is ≈ 10-20 years earlier than that of invasive ovarian

carcinomas.

◙ BOTs are histologically characterized as epithelial tumours with a stratified

growth pattern but without destructive stromal invasion.

◙ According to the 2003 WHO classification, BOTs are classified into serous,

mucinous, endometrioid, clear cell, & transitional (Brenner) subtypes.

◙ Serous & mucinous neoplasms constitute the majority of BOTs (65% & 32%

respectively).

◙ Unclear because of the small number of cases & the lack of RCSs.

◙ Risk factors linked with BOTs are as invasive ovarian cancer.

◙ As epithelial ovarian tumours, BOTs, originate from tubal or ovarian surface

epithelium or epithelial inclusion cysts

◙ Rarely seen in women with BRCA mutations.

◙ It was postulated that specific genetic changes contribute to the pathogenesis &

stepwise progression of BOTs to low-grade invasive ovarian carcinomas.

◙ Unlike high-grade serous carcinomas (ch.ch. by p53 mutations in > 50%),

◙ serous BOTs are ch.ch. by KRAS & BRAF mutations in 2/3 of cases,

◙ mucinous BOTs are characterized by KRAS mutations, &

◙ β-catenin & PTEN mutations are commonly seen with endometrioid BOTs.

◙ In addition, endometriosis is an important precursor of endometrioid & clear cell BOTs.

◙ Ch.Ch. of BOTs:

◙ Stratification of papillae

◙ Microscopic papillary projections or tufts (arising from the epith. lining of the

papillae.

◙ Epith. pleomorphism

◙ Atypicality

◙ Mitotic activity

◙ NO stromal invasion

◙ Compared to benign serous tumours, BOTs have more abundant papillary

projection, & shows more inc. of bilaterality..

◙ Divided into 2 types:

◙ Typical serous borderline tumours (90%), &

◙ Borderline tumours with micropapillary patterns (5-–10%)

◙ Unlike high-grade serous carcinomas, they are resistant to platinum-based

chemotherapy. However, prognosis is generally excellent.

invasive25%

non-invasive

75%

Peritoneal Implants ◙ Because women with extra-ovarian spread

of disease have a very good prognosis, the

peritoneal lesions are classified as implants

instead of metastases, & LN involvement is

not named metastases, they may be:

1. non-invasive = just stuck on the peritoneal

surfaces, or

2. Invasive = invaded the underlying tissue such as

omentum & bowel wall.

L.N.s27%

Regional L.N.s◙ LN involvement has no prognostic value,

they may serve as sites of recurrence &

progression to carcinoma.

◙ Commonly involved lymph nodes are:

** Pelvic,

** Omental & mesenteric,

** Para-aortic, &

** Supra-diaphragmatic regions.

◙ Do not have a clearly defined origin, consist of two histologic subtypes:

- The intestinal (85%), & - The mullerian or endo-cervical-like (15%).

◙ Like serous BOTs, they may be associated with abdominal or pelvic implants,

which may be invasive.

◙ It is important to exclude metastatic adenocarcinoma, most commonly from

the GIT (appendicular or colonic primary).

◙ Immunohistochemistry using a cytokeratin panel is useful in differentiating

metastatic versus primary ovarian tumours.

◙ Mucinous BOTs are most often stage I at time of diagnosis, & it is unusual

to find extra-ovarian disease.

◙ There is strong evidence that the mucinous BOTs associated with

pseudomyxoma peritonei (ascites with abundant mucoid or gelatinous

material) are actually metastatic rather than an ovarian primary.

Subtypes Include

1. Endometrioid BOTs:

◙ Resemble endometrioid endometrial adenocarcinoma.

◙ They arise either from the surface ovarian epithelium, or from endometriosis.

2. Clear cell BOTs:

◙ ch.ch. by the presence of clear or hobnail cells.

3. Brenner (transitional) BOTs:

◙ Transitional cell tumours with atypical or malignant features of the epithelium.

All has NO stromal invasion

Hobnail cells lining the glands. They have bulbous hyperchromatic nuclei that protrude into the gland lumen.

Clear cell BOT

◙ Approximately 15-23% of patients with BOTs are asymptomatic.

◙ As with other ovarian tumours, BOTs are difficult to detect clinically until

they are advanced in size or stage.

◙ The most common presenting symptoms were:

o abdominal pain,

o increasing girth or abdominal distention, &

o abdominal mass.

◙ There is no characteristics imaging to distinguish BOTs from other ovarian

tumours using U/S, CT, MRI, or PET scans.

◙ Intra-tumoural blood flow is seen in (90%) of BOTs, as in malignant

neoplasms (92%).

◙ The RI & PI are significantly reduced in carcinoma & BOTs (compared with

benign tumours).

◙ Pre-operative CT scanning should be considered to identify foci of

metastasis. & is also useful for follow-up.

Serous BOT (transvaginal scan): Multilocular-solid tumour with papillae, rather smooth inner cyst wall, & regular septa & anechoic intra-cystic fluid.

Exophytic implants on the surface of contralateral ovary (TAS):Hyperechogenic implants surround the contralateral ovary without involvement of ovarian stroma.

Mucinous BOT of intestinal type (TAS):Large, multilocular tumour with “honeycomb” nodule on the posterior inner wall & intra-cystic fluid of low-level echogenicity.

Mucinous BOT of endocervical type (TVS):Multilocular-solid tumour with larger number of endophytic & exophytic papillae, high intra-papillary flow density, & intra-cystic fluid with low-level echogenicity.

◙ CA125 levels are do not aid in diagnosis or follow up care in BOTs.

◙ Calculation of RMI or ROMA is not useful in predicting BOTs.

◙ Static DNA cytometry can be performed on biopsy specimens. (95% of BOTs have

diploid DNA excellent prognosis).

◙ Microarray technology, (for the characterization of the tumour genome) is not

widely studied in BOTs, because of low incidence & good prognosis.

◙ For unilateral stage I disease, unilat. SO , or careful cystectomy may be

done , with proper examination of the contralateral ovary.

◙ Better to remove the opposite ov. = due to the frequent bilateral

synchronous tumours & the possibility of occult metastases (6-43%).

◙ Hysterectomy is indicated = because of the high prevalence of synchronous

endom carc. + ut serosa & endom are common sites for occult

metastases.

◙ For more advanced disease, more radical surgery is performed.

◙ As 3-17% of patients are < 40 years, fertility sparing surgery may

be considered.

◙ Comprehensive staging of BOTs is of significant prognostic value & is

performed surgically.

◙ Another common component of staging is the descri ption of the type

of implants, as these have significant prognostic value.

◙ Frozen section may be used, BOTs are diagnosed by frozen section in

58 - 86% of cases.

◙ Complete staging laparotomy is recommended, this include:

◙ Peritoneal wash, or ascetic fluid sampling for cytology.

◙ Biopsy specimens of the pelvic peritoneum (culdesac, pelvic wall, & bladder

peritoneum),

◙ biopsy specimens of the abdominal peritoneum (paracolic gutters & diaphragmatic

surfaces),

◙ biopsy specimens of the omentum, intestinal serosa & mesentery, and

◙ retroperitoneal lymph nodes (pelvic and para-aortic).

◙ Recurrences are mostly following inadequate staging.

◙ Laparoscopic management of BOTs is associated with a higher rate of cyst

rupture and incomplete staging.

◙ however, laparoscopy lower morbidity & fewer adhesions ( imp. for

fertility).

◙ It should be performed by oncologic surgeons trained in extensive

laparoscopic procedures (for optimal surgical staging, complete debulking, &

better results).

◙ Well differentiated.

◙ Young women of low parity.

◙ Otherwise normal pelvis.

◙ Encapsulated & free of adhesions.

◙ No invasion of capsule, lymphatics or mesovarium.

◙ Peritoneal washings negative.

◙ Adequate evaluation of the other ovary & negative omental biopsy result.

◙ Probable close follow up

◙ Excision of residual ovary after completion of childbearing (+/-)

◙ No clear evidence that chemo-Rx can decrease relapse rates or improve

survival in BOTs.

◙ BOTs treated with adjuvant chemo-Rx or radio-Rx showed high persistent or

recurrent disease (40%).

◙ Poor response rates is explained by the low proliferation rate of BOTs.

◙ > 90% of serous BOTs are oestrogen-receptor positive, but there are only case

reports of major responses to tamoxifen, leuprolide, and anastrazole.

◙ The effect of antiangiogenic or other newer targeted agents on BOTs is not

known.

Management of BOTs

Stage I

Childbearing desired

YES

Oophorectomy or

Cystectomy

NO

TAH + BSO

(staging)

Stage II-III

Optimal cyto-reduction & Post-operative observation

Minimal growth & no symptoms

Observation

Moderate growth &/or symptomatic

Repeat Cyto-reduction

Rapid growth, ascites, or worsening histology

Chemo-Rx

◙ Overall prognosis is excellent, as:

◙ 60-75 % of cases are stage I disease when diagnosed.

◙ About 95% of BOTs have di ploid DNA.

◙ The 5 year survival rate for patients with stage I = 95%, &

The 10 year survival rate is 70-95%, depending on histologic findings.

◙ Increased stage worse prognosis.

◙ Five features are related to poor prognosis (based on transformation

of BOTs to invasive disease):

a) Cell type,

b) Stage,

c) Implant type (for serous borderline tumours),

d) The presence of a micropapillary architecture (for serous borderline

tumours),&

e) Microinvasion

◙ Age at diagnosis also influence prognosis.

◙ Patients with stage I disease have a recurrence rate of about 15%,

◙ Cystectomy is associated with a higher recurrence rate (up to 31%).

◙ Recurrences were noted only in un-staged stage 1 BOTs.

◙ If the tumour is aneuploid, the recurrence rate is high.

◙ In some studies of fertility sparing surgery for BOTs, the conception rate was 50% of with no foetal

anomalies.

◙ Surgical treatment of BOTs can postoperative infertility due to adhesions & insufficient residual

ovarian tissue after resection.

◙ Some studies show that women treated with ovarian stimulation for IVF have a two-fold increased

risk of BOTs, especially of serous histo-type

◙ In addition, with a prolonged follow-up 15 or more years after the first IVF treatment, they also

observed the increased risk of primary ovarian carcinomas.

◙ Therefore, all patients with previous history of BOTs should receive detailed counselling regarding the

potential risks associated with ovarian stimulation and should undergo close follow-up during and

after IVF therapy.

◙ HRT to prevent cardiovascular disease & osteoporosis & to

improve quality of life is an important issue, as many patients

with BOTs are relatively young women. HRT should be offered to

these patients.