Endocrinological Markers in Gynaecological Tumours - an overview. Tumour markers are biochemical indicators selectively produced by the neoplastic tissue or by other cells in the body in response to neoplasm and released into the blood and detectable in blood or other tissue fluids. Various molecules that can act as Tumour Markers: Enzymes and Isoenzymes (ALP, LDH) Hormones (Beta-HCG, HPL, Inhibin, AMH) Oncofoetal Proteins (CEA, AFP) Carbohydrate epitopes( CA125, CA 15-3, CA 19-9) Receptors( oestrogen, progesterone and testosterone) Serum and tissue protein( TAG 72, HE 4)

1. ENDOCRINOLOGICAL
MARKERS IN
GYNAECOLOGICAL
TUMOURS

2. Professor and Unit Chief, L.T.M.M.C & L.T.M.G.H, Sion Hospital
Joint Treasurer, FOGSI (2021-2024)
President, MOGS (2022-2023)
Member Oncology Committee, SAFOG (2021-2023)
Joint Secretary, AFG(2022-2023)
Dean AGOG & Chief Content Director, HIGHGRAD & FEMAS Courses
Editor-in-Chief, FEMAS, JGOG & TOA Journal
60 publications in International and National Journals with 109 Citations
National Coordinator, FOGSI Medical Disorders in Pregnancy Committee (2019-2022)
Chair & Convener, FOGSI Cell Violence Against Doctors (2015-16)
Member, Oncology Committee AOFOG (2013-2015)
Coordinator of 11 batches of MUHS recognized Certificate Course of B.I.M.I.E at L.T.M.G.H (2010-16)
Member, Managing Committee IAGE (2013-17), (2018-20), (2022-2023)
Editorial Board, European Journal of Gynaec. Oncology (Italy)
Course Coordinator of 3 batches of Advanced Minimal Access Gynaec Surgery (AMAS) at LTMGH
(2018-19)
DR. NIRANJAN CHAVAN
MD, FCPS, DGO, MICOG, DICOG, FICOG, DFP,
DIPLOMA IN ENDOSCOPY (USA)

3. • The history of currently used tumour markers began in the 1940s, the first
discovered being alpha-fetoprotein in 1956, followed by that of
carcinoembryonic antigen in 1965.
• Since then the range of tumor markers has widened continuously.
• Their chemical structure and genetics are now well known.

4. TUMOUR MARKERS
Tumour markers are biochemical indicators selectively
produced by the neoplastic tissue or by other cells in the
body in response to neoplasm and released into the
blood and detectable in blood or other tissue fluids.

5. CLINICAL APPLICATION
Tumour markers can be used to
• Confirm presence of tumour
• Monitor progress of a disease
• Monitor response to treatment
• Can not be used as primary
modality for diagnosis of tumour
• No marker is completely specific;
therefore, diagnostic
immunohistochemistry testing
must be used in conjunction with
morphologic and clinical findings.

6. CHARACTERISTICS OF AN IDEAL
TUMOUR MARKER
• It should have high sensitivity and specificity for cancer cells.
• Correlate marker level with size or extent of actual tumour.
• Measurement in blood or urine should be able to detect subclinical disease.
• Inexpensive and acceptable.

7. VARIOUS MOLECULES THAT CAN
ACT AS TUMOUR MARKERS
• Enzymes and Isoenzymes (ALP
, LDH)
• Hormones (Beta-HCG, HPL, Inhibin, AMH)
• Oncofoetal Proteins (CEA, AFP)
• Carbohydrate epitopes( CA125, CA 15-3, CA 19-9)
• Receptors( oestrogen, progesterone and testosterone)
• Serum and tissue protein( TAG 72, HE 4)

9. ENDOCRINOLOGICAL
MARKERS IN
GYNAECOLOGICAL
TUMOURS

10. BETA HUMAN CHORIONIC
GONADOTROPIN (BETA HCG)
• Both beta-hCG and human
placental lactogen (hPL) are
the most useful markers for
trophoblastic disease and
can be localized in
syncytiotrophoblasts of
partial and complete
hydatidiform moles

11. • Increased levels of beta-HCG occur in patients with
1. Choriocarcinoma of the uterus
2. Embryonal carcinomas
3. Polyembryomas
4. Mixed cell tumours
5. Dysgerminomas

12. HCG
• Selectively produced by the syncytiotrophoblast
• Normal titre 20 to 30 mIU/ml
• Glycoprotein having molecular weight 36,000 to 40,000
• Half life 32 to 37 hours
• Has two fractions alpha and beta.
• There is an immunological and biological similarity
between alpha fraction and pituitary gonadotropins.
• Beta fraction of HCG is specific which is measured by
immunological & biological methods, RIA and enzyme
immunoassay.

13. BETA- HCG
• Can be detected in pregnancy one day after
implantation, 8 days after ovulation and 9 days
after surge.
• Concentration rises exponentially until 9 to
10weeks of gestation with a doubling time of 1.3 to
2days.
• It decreases from this peak level to a plateau value
of 10,000 to 20,000 IU/ml, which is maintained for
the remainder of the pregnancy.
• BHCG level reaches its normal, non-pregnant levels
of less than 5mU/ml, 21 to 24 days after delivery.

14. BETA HCG AS A TUMOUR MARKER
• Hydatidiform mole is very much suggestive if: - urine
in dilution of 1 in 200 to 1 in 500 is positive for HCG
beyond 100 days of gestation.
• -If Beta HCG in urine in 24 hours is around 0.3 to 3
million IU during a similar period of amenorrhoea.
• Molar pregnancy patients are more prone to develop
Choriocarcinoma:-If excreting Beta HCG > 100,000
IU/ in urine in 24hours -If serum level of HCG is >
40,000 mIU/ml.

15. Choriocarcinoma
• A single tumour cell produces beta-
HCG around 5x10-5 to 5x10-4 IU/24
hours.
• Normally a woman excretes beta-
HCG of less than 4 IU in 24 hours.
• During methotrexate, treatment – The
serum level of beta-HCG is measured
at weekly intervals and
• The beta-HCG regression curve
serves as an indicator to determine
the need for a second course of
chemotherapy.

16. Patients who have undergone molar pregnancy evacuation
should undergo weekly beta-hCG monitoring until normal
levels are achieved, then monthly monitoring until 6-12
months of normal values have been achieved.
A 10% rise in beta-hCG over 3 or more weekly titres or a
beta hCG titre of 40,000 mIU/L 4-5 months after uterine
evacuation constitutes a serological diagnosis of post
molar trophoblastic disease.

17. • Following a molar pregnancy, which is mostly
a benign disease, GTN is diagnosed as follows
according to the FIGO consensus statement
of 2000
• When the plateau ß-hCG lasts for 4
measurements over a period of 3 weeks or
longer, that is day 1, 7, 14, 21.
• When there is a rise of ß-hCG of three weekly
consecutive measurements or longer, over at
least a period of 2 weeks or more days 1, 7,
14.
• When the ß-hCG level remains elevated for 6
months or more.
• GTN is diagnosed if there is a histological
diagnosis of choriocarcinoma.
Modified WHO prognostic scoring system as
adopted by FIGO(2000)

18. HUMAN PLACENTAL LACTOGEN
• Human placental lactogen(HPL) is localized in syncytiotrophoblasts
• hPL is present only during pregnancy, with maternal serum levels rising in
relation to the growth of the fetus and placenta.
• Maximum levels are reached near term, typically to 5–7 mg/L.
• Higher levels are noted in patients with multiple gestation.
• Its biological half-life is 15 minutes.
• Markedly elevated in Placental Site Trophoblastic Tumour. (PsTT)

19. • In 1983, the World Health Organization (WHO) formally acknowledged and adopted
the terminology of PSTT.
• PSTT can occur following term labor, abortion and rarely in molar pregnancy.
• Blood β-hCG was usually normal or only slightly increased, and the levels are not
proportional to the tumour burden. This differs from many of the GTDs, which often
have a high β-hCG level. However, other types of GTDs with a low serum β-hCG
level have also been reported
• Ultrasound findings often lack of specificity. A definitive diagnosis requires histology
examination in conjunction with IHC studies.
• The IHC studies show tumor cells positive for human placental lactogen (hPL)
placental alkaline phosphatase (PLAP) and smooth muscle actin (SMA).

20. INHIBIN
• Inhibins are heterodimeric protein
hormones secreted by granulosa
cells of the ovary in the female and
Sertoli cells of the testis in the male.
• Inhibin is complementary to cancer
antigen 125 (CA 125) as an ovarian
cancer marker.
• Inhibin shows a better performance
in mucinous and granulosa ovarian
cell tumours.

21. • They selectively suppress the
secretion of pituitary follicle
stimulating hormone (FSH) and
have local paracrine actions in the
gonads. [1]
• The inhibin consists of a dimer of 2
homologous subunits, an alpha
subunit and either a beta A or beta
B subunit, to form inhibin A and
inhibin B respectively.
Granulosa cell tumour histopathology
and immunostaining

22. • Elevations of serum inhibin A and B are detected in
some patients with granulosa cell tumours.
• Inhibin A elevations have been reported in
approximately 70% of granulosa cell tumours.
• inhibin is not a very good marker in non-
mucinous epithelial tumours..
• Total inhibin is elevated in 15% to 35% of
nonmucinous epithelial ovarian cancer cases.
• Elevation of 6-fold to 7-fold over the reference
range value.
• 20% of epithelial tumours of the mucinous type
with about cases have elevated inhibin A levels.

23. • According to this study, the most widely used marker for ovarian cancer, serum CA-
125, was less helpful in identifying mucinous borderline cystic tumours.[3]
• Among the women with mucinous borderline cystic tumours, (11 percent) tested had
an elevated serum CA 125 concentration, whereas (77 percent) with this tumour who
were tested had elevated serum inhibin concentrations.
• The finding of elevated serum inhibin concentrations in women with mucinous
borderline cystic tumours suggests that the capacity to secrete inhibin is increased
early in the process of malignant transformation.
• The high frequency of elevated values in women with mucinous carcinomas (82
percent) is particularly important because there is no hormonal marker for this type of
cancer.

24. ANTI-MULLERIAN HORMONE (AMH)
• The Anti-Mullerian hormone
(AMH), which is produced by fetal
Sertoli cells, is responsible for
regression of Mullerian ducts
during male sex differentiation.
• Ovarian granulosa cells also
secrete AMH from late in fetal life.

25. • The patterns of expression of AMH and its type II receptor in the post-natal ovary indicate
that AMH may play an important role in ovarian folliculogenesis.
• AMH can be used as a diagnostic marker and therapeutic agent for ovarian cancer,
specifically for granulosa cell tumours (GCT). Its diagnostic performance seems very good,
with a sensitivity between 76 and 93%.
AMH immunostaining of granulosa
cell tumours (GCT).

26. • It is largely recognized that AMH
and alpha-inhibin exhibit a higher
degree of sensitivity than estradiol
in progressive GCT.
• However, AMH is elevated only in
sex cord stromal tumours, while
inhibin may be elevated in different
types of cancer

27. • It is known that there is no clinically significant fluctuation of serum AMH levels during the menstrual
cycle in healthy premenopausal women.
• Serum AMH measurement can be reliably used in the follow-up of AGCT patients at any time of the
cycle.
• Serum AMH and inhibin B measurements perform equally in detecting AGCTs, and combining them
improves the detection of AGCT recurrence compared with inhibin B measurement alone.
• The development of novel improved detection methods and a better understanding of AMH as a
molecule will shed more light on the biological role and clinical applications of AMH in AGCTs[4]

28. REFERENCES
• 1. https://oncology.testcatalog.org/
• 2. La Marca A, Volpe A. The Anti-Mullerian hormone and ovarian cancer. Hum Reprod Update [Internet].
2007;13(3):265–73. Available from: http://dx.doi.org/10.1093/humupd/dml060
• 3. Phocas I, Sarandakou A, Sikiotis K, Rizos D, Kalambokis D, Zourlas PA. A comparative study of serum alpha-beta A
immunoreactive inhibin and tumor-associated antigens CA125 and CEA in ovarian cancer. Anticancer Res. 1996
Nov-Dec;16(6B):3827-31. PMID: 9042265.
• 4. Färkkilä A, Koskela S, Bryk S, Alfthan H, Bützow R, Leminen A, Puistola U, Tapanainen JS, Heikinheimo M, Anttonen
M, Unkila-Kallio L. The clinical utility of serum anti-Müllerian hormone in the follow-up of ovarian adult-type
granulosa cell tumors--A comparative study with inhibin B. Int J Cancer. 2015 Oct 1;137(7):1661-71. doi:
10.1002/ijc.29532. Epub 2015 Apr 11. PMID: 25808251.

29. FUTURE OF TUMOUR MARKERS
• It is proving extremely difficult to find new cancer biomarkers with adequate
sensitivity and specificity to be used in the clinic.
• Even within the same tumour, molecular heterogeneity is enormous and
differences can be seen in primary vs. metastatic sites or as tumours evolve over
time.
• These new findings support the view that it is highly unlikely to identify a single
marker which will be elevated in nearly all patients with a specific malignancy.

30. • There are currently hundreds, if not thousands, of
rare tumor markers which perform at high
specificity (> 90%), but at relatively low sensitivity (<
30%).
• Borrowing from the principles of precision
medicine, these low sensitivity markers, may be
useful to specific patients.
• We can apply screening new patients for hundreds
of cancer biomarkers to identify a few that are
informative, and then use them clinically.

31. • This is similar to what is currently done with
genomics to identify personalized therapies.
• This approach may explain why some
biomarkers are elevated in only a small
group of patients.
• It is likely that these differences in
expression are linked to specific genomic
alterations, which could then be found with
genomic sequencing.