Hyperchromatic-crowded groups (HCG) in pap smears

Question 2: What is your final interpretation?

1. AIS

2. Invasive endocervical adenocarcinoma (ADC)

3. Invasive endometrioid ADC

4. Metastatic ADC

5. MGH

Answer to Question 2: Option B, invasive endocervical ADC.

Brief review of the topic

The frequency of endocervical ADC among all cervical neoplasias has increased in the last decades, from <10% to up to 27%, not only due to a real increase in annual incidence but also due to a decrease in frequency of invasive squamous cell carcinoma.^[3] There are several subtypes, and these include (a) usual endocervical ADC, including well-differentiated villoglandular papillary ADC, (b) endometrioid, including minimal deviation endometrioid ADC, (c) mucinous, including gastric, minimal deviation mucinous, intestinal, and signet ring cell ADC, (d) clear cell, (e) serous, and (f) mesonephric ADC.^[3]

Of the various histological subtypes of endocervical ADC, usual endocervical type is the most common, accounting for about 75% of all cervical ADCs.^[8] Among usual endocervical type tumors, HPV DNA is identified in 80%–100% of cases, with HPV 16 and 18 accounting for about 95%.^[8,9] HPV 18 alone actually accounts for about 50% of endocervical ADC.^[10] Patient ages range from 22 to 80 years, with an average of 45.^[8,9] Similar to squamous cell carcinoma, early cervical ADC is usually asymptomatic and most commonly detected through cervical cytology cancer screening, which is primarily the screening method for cervical squamous cell lesions. However, symptomatic cases may present with dyspareunia, postcoital bleeding, abnormal vaginal bleeding including menorrhagia and metrorrhagia, postmenopausal bleeding, and abnormal vaginal discharge. In addition, a cervical mass may be detected on pelvic examination performed for another indication.^[11]

Cervical cytology preparations may show HCG with atypical features suggestive of malignancy including sheets and strips with nuclear crowding, overlap and/or pseudostratification, rare cell groups with rosettes (gland formations) or feathering, enlarged and elongated nuclei with hyperchromasia, coarse chromatin with heterogeneity, occasional mitoses and/or apoptotic debris, cells with increased nuclear-to-cytoplasmic ratios, and ill-defined cell borders.^[12] The tumor cells usually show abundant intracytoplasmic mucin which may be scant and focal in some cases.^[13]

HCG were first described by DeMay in 1995 and are a frequent occurrence in Pap tests.^[2] Benign glandular cell HCG are seen far more frequently than either abnormal glandular cell HCG or squamous cell HCG in routine Pap tests.^[2] Benign endometrial cells may also present as HCG in Pap tests, as small, crowded cells, with degenerate and hyperchromatic nuclei.^[2] Mitotic figures are typically not seen in exfoliated cells but may be seen in directly sampled cells. One of the most important abnormal glandular causes of HCG is endocervical neoplasia, including both AIS and invasive ADC.^[2] In addition, endometrial ADC may also present as HCG. The other most clinically significant differential diagnosis with HCG is that of a high-grade squamous intraepithelial lesion (CIN2/3), with or without involvement of endocervical glands.^[2] Therefore, a careful scrutiny of HCGs on Pap tests is mandatory to prevent a false-positive diagnosis.^[2]

Endocervical-type ADC in cervical biopsy exhibits a variety of architectural patterns ranging from well differentiated to poorly differentiated.^[13] The well-differentiated tumors may show exophytic papillary growth, infiltrative growth, or both. The invasive tumor may be composed of irregular cystic and tubular glands, glands with intraluminal papillary infoldings, or cribriform glands.^[13] In moderately differentiated tumors, the growth is more confluent with sheets of small cribriform glands, and poorly differentiated ADCs show solid areas of undifferentiated cells that may be undistinguishable from poorly differentiated squamous cell carcinoma.^[13]

On IHC, endocervical-type ADC demonstrates strong and diffuse nuclear (and cytoplasmic) immunoreactivity for p16, cytoplasmic and membranous immunoreactivity for mCEA, and strong-to-weak nuclear immunoreactivity for PAX8.^[13]

The tumor cells are nonimmunoreactive for PR and vimentin, with negative to weak positivity for ER.^[13] Finally, the Ki-67 index usually exceeds 25%, with an average of 53%, indicating high proliferation activity in the tumor cells.^[14] Invasive endocervical-type ADC is treated with a combination of surgery, radiation therapy, and/or chemotherapy depending on the stage. Prognosis depends on a variety of factors including stage, nodal status, tumor volume, depth of cervical stromal invasion, lymphovascular invasion, and grade. However, in general, cervical ADC tends to carry a worse prognosis than squamous cell carcinoma.^[11] Important treatment considerations include the preservation of fertility when possible, especially among younger patients. Unfortunately, because cervical ADCs tend to be multifocal, there is a greater concern for residual disease than with squamous cell carcinoma.^[11] Consequently, in making management decisions, the clinical team must decide whether preservation of fertility is the safest and best option for the patient.

Q3. Which of the following HPV genotypes account for about 50% of cervical ADC cases?

1. HPV 16

2. HPV 18

3. HPV 31

4. HPV 33.

HPV 18 infection accounts for approximately 50% of cervical ADC cases.^[10]

Q4. Which of the following is not a risk factor for cervical ADC?

1. HPV 16 infection

2. HPV 18 infection

3. Cigarette smoking

4. Oral contraception use

5. Overweight/obesity.

While cigarette smoking is a risk factor for squamous cell carcinoma, it does not appear to increase the risk of cervical ADC.^[15] All other risk factors listed have positive associations with cervical ADC, although there is some discussion on whether lower rates of screening contribute to increased risk of cervical ADC among overweight/obese women.^[16,17]

Q5. Which of the following patterns of invasion are associated with the greatest risk of lymph node metastases?

1. Pattern A (Well-demarcated glands without destructive stromal invasion)

2. Pattern B (Early destructive stromal invasion arising from well-demarcated glands)

3. Pattern C (Diffuse destructive invasion with solid or confluent architecture).

Pattern C is described as a diffuse, destructive invasion. Tumors of this pattern carry a 23.8% risk of lymph node metastases. Pattern B consists of early destructive stromal invasion by well-demarcated glands and has a 4.4% risk of lymph node metastasis. Finally, pattern A involves well to moderately differentiated ADC containing well-demarcated glands with intraglandular growth, but no desmoplastic stromal reaction, and is not associated with lymph node metastases.^[18]

Correct answers to additional questions:

Q2-b, Q3-b, Q4-c, Q5-c.