Cervix

• Often vaginal bleeding or pelvic pain
• Abnormal cytology screening seen in ~88% of cases, either as glandular or squamous cell abnormalities (Cytojournal 2016;13:28)
• Often spreads to pelvic structures and regional lymph nodes
• Metastases most often to ovaries and fallopian tubes, less frequently to distant organs
• Stage is the most important prognostic factor; 5 year overall survival rates vary depending on stage: FIGO stage I - 79%, II - 37%, III / IV - less than 9% (see Staging)

• 34 year old woman with atypical glandular cells on Pap smear (Case #495)
• 50 year old woman with adenocarcinoma of the cervix involving the fallopian tube mucosa (Diagn Pathol 2016;11:77)
• 72 year old woman with intracranial metastases (Int J Gynecol Cancer 2005;15:561)
• Woman with ovarian recurrence after radical trachelectomy (Am J Obstet Gynecol 2005;193:1382)
• Woman with vaginal metastasis associated with traumatic vaginal tear (Gynecol Oncol 2005;96:857)

• See Grossing
• When grossly visible (by definition, FIGO stage IB or greater), lesion can be exophytic, ulcerated or flat (Int J Gynaecol Obstet 2019;145:129, Int J Gynaecol Obstet 2019;147:279)
• On cut sectioning, there is variable growth into cervical wall
• Barrel shaped cervix with diffuse enlargement, if lesion is widely invasive

• Diagnosis of invasion by endocervical adenocarcinoma is based on the following features:
  • Stromal infiltration in the form of:
    • Marked glandular confluence with cribriform or microacinar architecture
    • Irregularly shaped, angulated or fragmented glands with an adjacent desmoplastic stromal reaction
    • Tumor cell clusters or individual cells
    • Lymphovascular space invasion
  • Increased number of glands with loss of a lobular arrangement and glandular density exceeding that of the normal cervix
  • Glands are often close to thick walled vessels (Int J Gynecol Pathol 2005;24:125)
• Superficially invasive carcinoma (FIGO stage IA1) is defined as a microscopic tumor with depth of 3 mm or less and negative resection margins (in partial samples)

Histologic types of HPV related endocervical adenocarcinoma

• Usual adenocarcinoma represents 70 - 90% of all endocervical adenocarcinomas and is characterized by:
  • Mucin depleted epithelium, meaning mucinous cells comprise < 50% of the tumor volume; in turn, most of the population has columnar, nonmucinous indistinct cytoplasm
  • Cells have columnar shape; nuclei are elongated, enlarged and hyperchromatic with coarse chromatin
  • Loss of polarity and nuclear overlapping
  • Brisk mitotic activity; mitotic figures are usually apical
• Mucinous adenocarcinoma is characterized by:
  • Mucinous epithelium representing 50% or more of the tumor volume (usually represents the majority of the lesion)
  • Mucinous epithelium can be of endocervical type, intestinal type or (rarely) with signet ring cells
  • Intestinal adenocarcinomas show intestinal differentiation, goblet cells and (occasionally) Paneth cells (Arch Pathol Lab Med 1990;114:731)
  • A novel variant, described as invasive stratified mucin producing carcinoma, is included in this subset; it is commonly associated with stratified mucin producing intraepithelial lesion (SMILE) and thought to represent an invasive manifestation of this type of growth (Am J Surg Pathol 2016;40:262, Am J Surg Pathol 2020;44:1374, Am J Surg Pathol 2020;44:873)

Pattern based classification (Silva system)

• Silva system classifies HPV associated adenocarcinomas based on growth pattern, rather than the size or grade of the invasive component (Int J Gynecol Pathol 2013;32:592, Am J Surg Pathol 2015;39:667)
  • Tumors with a nondestructive pattern of invasion (pattern A) are associated with a 0% rate of lymph node metastases, whereas focally (B) and diffusely (C) destructive patterns have 4% and 23% rates of nodal involvement, respectively
  • Similarly, pattern A tumors had 0% recurrence and 0% fatality rates, compared with pattern B tumors (1.2% and 0%, respectively) and pattern C tumors (22.1% and 8.8%, respectively)
  • Multiple independent retrospective studies have validated the association between pattern of invasion and lymph node metastases, recurrence rates as well as survival
  • However, there are reports of early, well differentiated, adenocarcinoma in situ (AIS)-like adenocarcinomas with ovarian metastases (Am J Surg Pathol 2008;32:1835)

Tumor classification based on pattern of stromal invasion (pattern based classification, Silva system)

• Classifies tumors into 3 categories as follows:

Pattern A	Well demarcated glands with rounded contours, frequently forming groups No destructive stromal invasion No single cells or cell detachment No lymphovascular invasion Complex intraglandular growth acceptable (i.e. cribriform, papillae) Lack of solid growth (i.e. architecturally well to moderately differentiated) Depth of tumor or relationship to large cervical vessels not relevant
Pattern B	Localized (limited, early) destructive stromal invasion arising from pattern A glands (well demarcated glands) Individual or small groups of tumor cells, separated from the rounded gland, often in a focally desmoplastic or inflamed stroma Foci may be single, multiple or linear at base of tumor With or without lymphovascular invasion Lack of solid growth (i.e. architecturally well to moderately differentiated)
Pattern C	Diffuse destructive invasion, characterized by diffusely infiltrative glands with associated extensive desmoplastic response Glands often angulated or with canalicular pattern, with interspersed open glands Confluent growth filling a 4x field (5 mm): glands, papillae (stroma only within papillae) or mucin lakes Solid (architecturally poorly differentiated); nuclear grade is disregarded With or without lymphovascular invasion

Tumor grade of adenocarcinoma

• For usual type adenocarcinoma, not variants; not universally accepted, not proven to be prognostically significant (Int J Gynecol Pathol 2021;40:S66)
  • Grade 1:
    • Well differentiated (10% or less solid growth)
    • Tumor contains well formed regular glands with papillae
    • Cells are elongated and columnar with uniform oval nuclei
    • Minimal stratification (fewer than 3 cell layers in thickness)
    • Infrequent mitotic figures
  • Grade 2:
    • Moderately differentiated (11 - 50% solid growth)
    • Tumor contains complex glands with frequent bridging and cribriform formation
    • Solid areas up to 50% of tumor
    • Nuclei more rounded and irregular
    • Small nucleoli present
    • Mitoses more frequent
  • Grade 3:
    • Poorly differentiated (over 50% solid growth)
    • Sheets of malignant cells
    • Few glands are discernible
    • Cells are large and irregular with pleomorphic nuclei
    • Occasional signet cells are present
    • Mitoses are abundant with abnormal forms
    • Marked desmoplasia
    • Necrosis is common

Contributed by Carlos Parra-Herran, M.D.



Contributed by Tanner Storozuk, M.D. and Jennifer Bennett, M.D. (Case #495)

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Under the current WHO classification, which is considered a variant of HPV associated endocervical adenocarcinoma?

1. Gastric type
2. Endometrioid
3. Usual
4. Clear cell

C. Usual adenocarcinoma, the most common form adenocarcinoma of the cervix, is associated with HPV. Gastric type and clear cell carcinomas are known to be HPV independent. Endometrioid carcinoma is no longer a recognized subtype of HPV associated adenocarcinoma, as it leads to confusion with the usual type. True endometrioid carcinoma of the cervix is exceedingly rare and likely arises from cervical endometriosis. The term should be reserved to cases with definitive endometrioid morphology, negative p16 / HPV testing and absence of an endometrial primary.

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Reference: HPV related adenocarcinoma (usual type and variants)

Which of the following is a known adverse prognostic factor in patients with HPV associated endocervical adenocarcinoma?

1. Pattern A invasion
2. Lymphovascular space invasion
3. Early stage
4. Negative margin status

B. Lymphovascular space invasion

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Reference: HPV related adenocarcinoma (usual type and variants)