Effective screening programs for cervical cancer have reduced the incidence of and mortality from this disease by more than 50% since 1975. The American Cancer Society estimated that there were 12,170 new cases of cervical cancer in the United States in 2012, a number much lower than that expected in countries that do not have a robust cervical cancer screening program.

Cervical neoplasia is most commonly associated with a subset of oncogenic (high risk) types of Human Papilloma Virus (HR-HPV), and within this subset of HPV strains, type 16 (55-60%) or 18 (10-15%) are present in the majority of cervical cancers.  Low risk HPV types (LR-HPV) have not been shown to be oncogenic, and molecular testing for these viruses is not recommended by the American College of Obstetrics and Gynecology (ACOG) or the CDC.  Needlessly testing for LR-HPV increases the cost of screening and does not provide useful information about an individual patient’s risk of developing cervical cancer.

The majority of HPV infections are transient, and young women with a healthy immune system will usually clear the virus within 8 months.  Detection of HR-HPV in women under 30 with a normal Pap smear has not been shown to be helpful. In women over 30, however, the detection of HR-HPV is more likely to represent a persistent infection. For this reason, ACOG recommends HPV co-testing in women over 30 years-old. Women over 30 with a negative Pap smear and negative HR-HPV test may be followed routinely ever 5 years. 

Women over 30 with negative cytology and a positive HR-HPV have two options:

1. Repeat Pap smear and HR-HPV testing in one year, or
2. Immediate molecular testing for HPV types 16 and 18

Women with HR-HPV detected in the follow-up Pap smear and/or women who are infected with HPV genotype 16 or 18 should receive colposcopic examination.

Based on these recommendations, Calpath offers cervical cancer screening using liquid-based ThinPrep technology in conjunction with Hologic's RNA-based HR-HPV detection.  HPV RNA is only present when oncogenic types of HPV infect the host cell and begin to replicate, making this type of RNA testing more specific than previous DNA-based technology.  This increased specificity decreases the number of positive results in women that may only be transiently carrying the virus without a true infection. 

We combine our RNA-based screening test with genotyping for HPV types 16 and 18 to give our colleagues in gynecology the ability to stratify their patients over 30 who have a negative Pap smear but positive HR-HPV into two groups; one that needs colposcopy (HPV16/18+) and one that does not (HPV16/18-).

It is well known that the histopathologic diagnosis of cervical intraepithelial neoplasia, particular low-grade lesions, is plagued by poor inter- and intraobserver variability.  This results in an inconsistent threshold for the diagnosis of dysplasia, which contributes to the over-diagnosis of benign or reactive processes and increases the number of needless invasive procedures.

Two practices have been used to improve this inconsistency in the diagnosis of dysplasia; consensus review and the use of adjunct immunohistochemical surrogate markers that detect the presence of high-risk HPV (p16).

Our routine consensus conference allows for challenging or borderline cases to be reviewed by up to 6 pathologists.  Consensus review reduces the variability in the diagnosis of dysplasia that occurs when pathologists practice in isolation, and helps us maintain a consistent threshold for identifying dysplastic lesions.

The Lower Anogenital Standardization (LAST) Project for HPV-associated lesions published recommendations for the appropriate use of surrogate immunohistochemical markers for HR-HPV in cervical biopsies in 2012.  p16 is a cell cycle protein in the retinoblastoma pathway that has been shown to be upregulated in ectocervical squamous cells following infection with HR-HPV.  This change in cell biology occurs only after HR-HPV has integrated into the host genome, and for this reason positive staining with p16 in this context is accepted as a surrogate marker for persistent HR-HPV infection.  The LAST meta-analysis identified three circumstances where the use of an immunohistochemical stain for the cell cycle protein p16 is useful in diagnosis cervical dysplasia. 

1. When the differential diagnosis includes a pre-cancerous lesion (CIN 2 or 3) and a mimic of pre-cancerous lesion (atrophy, immature squamous metaplasia, etc)
2. When the diagnosis of CIN2 is being considered (because it has been shown that  CIN2 is a heterogeneous category that includes both benign and pre-malignant lesions)
3. When consensus diagnosis cannot be reached in a case where a high-grade lesion is in the differential diagnosis (CIN 2 or 3)
4. In biopsies from patients that have a high risk of having a subtle high-grade lesion (prior HSIL, ASC-H, AGUS, or ASCUS/HPV16+).

The use of p16 as a routine screening tool, or in unequivocal cases of CIN1 or CIN3 is not recommended, due to the low but non-zero false positive rate. By following these guidelines we are able to increase our consistency in the diagnosis of pre-malignant cervical lesions, and avoid the over-diagnosis of benign processes.

With our partner laboratories we are able to provide chromosomal analysis on products of conception from women with repeated miscarriages.  See the 'Specimen Guides' section for information on how to submit tissue for chromosomal analysis.

The American College of Obstetricians and Gynecologists (ACOG) recommends a classification system for abnormal uterine bleeding that separates etiologies into two categories; structural and non-structural causes.  Structural causes are evaluated and excluded by endometrial biopsy or curettage, and the lmain entity in the differential diagnosis ‘malignancy and hyperplasia,’ is another area where there has historically been poor interobserver reproducibility amongst pathologists. 

Routine consensus review of all pre-malignant and malignant diagnoses by up to 6 pathologists allows us to maintain a consistent threshold for the diagnosis of endometrial adenocarcinoma and its precursors.  This allows us to avoid the over-diagnosis of benign changes that can lead to unneccesary follow-up and procedures.

For women who are diagnosed with endometrial adenocarcinoma, in addition to estrogen and progesterone receptor status, we are able to perform immunohistochemistry for mismatch repair (MMR) proteins to identify women who may be at greater risk of having a hereditary syndrome that predisposes them to developing cancer. 

A large study in 2013 from the Cleveland Clinic found no statistically significant differences in age, histologic tumor type, grade, stage, or BMI between syndromic and sporadic cancers. Based on this evidence, they recommend universal screening of endometrial adenocarcinomas to detect possible hereditary cancer syndromes. 

We provide processing and interpretation of cyst fluids, fine needle aspirations, core biopsies, and excisional biopsies. 

Estrogen and progesterone receptor results are available one day after the initial diagnosis of malignancy. 

We test all new invasive carcimomas for HER2 by immunohistochemistry (IHC); equivocal IHC cases are reflexively tested for HER2 amplification by fluorescence in situ hybridization (FISH).

For patients undergoing definitive therapy, we process and interpret wire-guided partial mastectomies, skin and nipple-sparing mastectomies, total mastectomies, and lymph node dissections.  Intraoperative consultation is also available at selected regional surgery centers.  We routinely examine intraoperative sentinel lymph nodes and provide gross examination of margin status in partial mastectomies.  Intraoperative assessment of margin status can reduce the need for subsequent surgical procedures in patients with invasive cancer.