Diagnosis of Gynecological Cancers

The diagnosis of any cancer is established on biopsy material. A biopsy is obtained from the tissue or organ where cancer is suspected. The biopsy material is then processed and subjected to examination under the microscope. Biopsy not only provides the diagnosis، but also informs the physicians of several other important parameters pertinent to medical care، such as the type of cancer، its grade، the degree of differentiation، the likely biological behavior of the tumor، ie. slow growing or rapidly progressing، and prognostic factors. Prognostic factors refer to features which help predict the likely course of the disease.

Other than the diagnosis and the microscopic description of the cancer، more recently، molecular studies are also performed in the overall diagnostic process. Molecular tests are not routinely available in all laboratories، and require special expertise، equipment and resources. Patients’ tissue or the blood is used for molecular studies. Molecular tests، are seldom used to ‘establish’ the diagnosis of cancer، but help to confirm the sub-type of cancer، identify prognostic factors، and more recently identify ‘targets’ on the cancer cells، against which specific anti-cancer therapy can be used. A combination of prognostic and predictive markers is sometimes called ‘biomarkers. Not all tumors offer targets، but a significant number of patients with gynecological cancers، can benefit with the targeted therapy based on molecular features.

Below we describe the methods of obtaining biopsy، the ways of how microscope can be used to establish the diagnosis، and the molecular tests for the common gynecological cancers. 

Cervical cancer:

Women who have signs and symptoms of cervical cancer or women who have had an abnormal Pap test or HPV test may need diagnostic testing. Biopsy from the uterine cervix can be obtained in the out-patient department or in the operating room. In the out-patients، colposcopic examination is performed to examine the cervix and for taking biopsy from the abnormal looking areas. In the operating room، examination is performed under anesthesia، and the biopsy is obtained. The gynecologist may decide to obtain biopsy through one of the various techniques:

Punch biopsy: A small sample of cervical tissue is taken by a sharp tool.

Endocervical curettage: Procedure involves scraping a small sample of tissue from the cervical canal using a curette.

Loop Electrosurgical Excision Procedure (LEEP): A loop of electric wire is used to cut off a slice of thin round cervical tissue.

Cone biopsy: A small، cone-shaped portion of cervix is removed.

There are two major types of cancer of the cervix – squamous cell carcinoma (around 70%)، or adenocarcinoma (around 25%). Although they are treated in a similar way، but it’s important to identify the sub-type of cancer. The diagnosis is established on the morphological appearance of the tumor using the hematoxylin and eosin stains، and further tests are done using immunohistochemistry. These include p16 (to study the relationship of cancer with human papilloma virus (HPV))، and PD-1 and PDL-1 for evaluating combined positive score (CPS)، and see whether the patient would benefit from addition of a targeted agent to the standard cytotoxic chemotherapy. Molecular test includes studying tumor mutational burden (TMB) using a test called next generation sequencing (NGS). In cancer of the cervix relapses، NGS is used to perform comprehensive genomic profile to study possible targetable changes in the genome. 

Endometrial cancer:

Women who have signs and symptoms of endometrial cancer undergo biopsy، either in the OPD using hysteroscopy or in the operating room using dilation and curettage (D&C). D&C is done under anesthesia and also helps to remove tissue samples from the uterus. During a hysteroscopy، the doctor inserts a thin، flexible tube with a light on it through the cervix into the vagina and uterus. D&C often results in more abundant sample as compared to hysteroscopic biopsy.

There are two major types of cancer of the uterus – adenocarcinoma (more than 95%)، or uterine sarcoma (2-5% of all uterine cancers). The two cancers are treated in a different way، and hence it’s important to distinguish. Adenocarcinoma of the uterus is classified further into two major sub-types – endometrioid (also called Type I)، or the serous carcinoma or carcinosarcoma (also called the type II). The diagnosis is established on the morphological appearance of the tumor using the hematoxylin and eosin stains، and further tests are done using immunohistochemistry. These include the study of mismatch repair proteins (MMR)، expression of estrogen receptor (ER)، progesterone receptor (PgR)، and Her-2/neu. All these tests may help to decide the subsequent treatment، especially if the disease was metastatic or relapses. In addition، the laboratory reports on p53 staining as well، which has prognostic significance. A loss of MMR protein expression on immunohistochemistry should also direct the clinician to request a molecular test called microsatellite instability (MSI). Other molecular test is also done using NGS، especially looking for POLE mutation، which has prognostic significance.

Around 5-6% of patients with endometrial carcinoma have a family history of uterine، colon or breast cancer، and may require further tests on the blood to see if the mutation on their gene (germline mutation) may predispose their close family relatives to develop one of those cancers.

Ovarian cancer:

Ovarian cancer can generally be classified as follows:

1. Epithelial ovarian cancer (90% of all ovarian cancers)
2. Germ cell tumors of the ovary (usually in young individuals)
3. Sex-chord stromal (2-4% of all ovarian cancers)
4. Metastases to the ovary (also called kruknnberg tumors)

In a patient with suspected epithelial ovarian cancer، generally there are two ways of establishing the diagnosis. An ultrasound guided biopsy from the deposit in the abdomen (usually over the omentum)، under local anesthesia can yield results and the subsequent treatment can be planned accordingly. Alternatively، in patients strongly suspected to have ovarian cancer (eg patients who have a high serum CA 125 levels، or those who present with symptoms of ovarian cancer and have a strong family history of breast or ovarian cancer)، and who are operable، both ovaries and the uterus، together with any other visible tumor are removed surgically (debulking surgery) and the diagnosis can be established on the resected tumor material.

The diagnosis is established on the morphological appearance of the tumor using the hematoxylin and eosin stains، and further tests are done using immunohistochemistry. These include the study p53 protein which has prognostic significance. Around 15-20% of patients with ovarian carcinoma may have mutation in BRCA1 or the BRCA2 gene، and these are studied using the NGS. Another test performed using the NGS is called homologous recombination deficiency. Both these tests help in deciding the course of treatment and the choice of agents in addition to the routine chemotherapy.

In addition، around 5-6% of patients with ovarian carcinoma have a family history of breast or ovarian cancer، and may require further tests on the blood to see if the mutation on their gene (germline mutation) may predispose their close family relatives to develop one of those cancers.