HPV associated adenocarcinoma (usual type and variants)

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Deputy Editor-in-Chief: Jennifer A. Bennett, M.D.
Carlos Parra-Herran, M.D.

Last author update: 2 November 2021
Last staff update: 12 March 2024

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PubMed Search: HPV adenocarcinoma cervix

Carlos Parra-Herran, M.D.
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Cite this page: Parra-Herran C. HPV associated adenocarcinoma (usual type and variants). PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/cervixhpvadenocarcinoma.html. Accessed June 16th, 2024.
Definition / general
  • Malignant neoplasm of the uterine cervix with a glandular phenotype
  • 5 - 25% of invasive cervical carcinomas
Essential features
ICD coding
  • ICD-O:
    • 8140/3 - adenocarcinoma, usual type
    • 8480/3 - mucinous carcinoma
    • 8482/3 - mucinous adenocarcinoma, endocervical type
    • 8144/3 - adenocarcinoma, intestinal type
    • 8490/3 - mucinous carcinoma, signet ring cell type
    • 8263/3 - villoglandular carcinoma
    • 8574/3 - adenocarcinoma with neuroendocrine differentiation
  • ICD-11: 2C77.1 - adenocarcinoma of cervix uteri
  • Infection by high risk HPV (most commonly HPV types 18 and 16)
Clinical features
  • 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)
  • Routine screening cervicovaginal cytology identifies many but not all cervical adenocarcinomas (J Low Gen Tract Dis 2017;21:91)
  • Patients with abnormal cytology or symptoms (e.g. bleeding) are referred to examination by colposcopy (J Low Genit Tract Dis 2020;24:102)
  • Adjunct imaging can be useful (pelvic ultrasound, MRI)
  • Definitive diagnosis requires biopsy
Radiology description
  • Mass occupying the canal or replacing the wall
  • Nondiscrete thickening or distortion of the wall
Prognostic factors
Case reports
Gross description
Microscopic (histologic) description
  • 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
Microscopic (histologic) images

Contributed by Carlos Parra-Herran, M.D.
Adenocarcinoma in situ

Adenocarcinoma in situ

Invasive adenocarcinoma, pattern A

Invasive adenocarcinoma, pattern A

Missing Image Missing Image

Invasive adenocarcinoma, pattern B

Invasive adenocarcinoma, pattern C Invasive adenocarcinoma, pattern C Invasive adenocarcinoma, pattern C

Invasive adenocarcinoma, pattern C

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

Invasive stratified mucin producing carcinoma (iSMILE)

Cytology description
  • Multilayering
  • May form glandular structures with central lumina or acinar formations with peripheral nuclei
  • Cells are pleomorphic, large or small with fluffy cytoplasm, cytoplasmic vacuolization, loss of nuclear polarity, true nuclear crowding, nuclei with clumped chromatin, marked variation of nucleoli, occasional mitotic figures
  • Invasion is often characterized by heavy blood with abundant glandular epithelium, even without tumor diathesis or fully malignant nuclear criteria (Cancer 2002;96:5)
  • May see morules (also seen with mesothelial cells, benign and malignant lesions)
  • Endocervical adenocarcinoma: usually columnar with granular cytoplasm, rosettes, sheets with holes versus balls, round plump cells, molded groups
  • Conventional smears that are false negative often have fewer and smaller abnormal cells, small nuclei, less atypia and less hyperchromasia (Arch Pathol Lab Med 2006;130:23)
Cytology images

Images hosted on other servers:
Missing Image

Inflammatory exocervical smear

Positive stains
Negative stains
Molecular / cytogenetics description
Sample pathology report
  • Endocervical adenocarcinoma, HPV associated type (usual / mucinous)
  • Macroscopic tumor size: __ cm
  • Depth of invasion: __ mm (out of __ mm of cervical wall thickness)
  • Pattern of invasion: A / B / C
  • Lymphovascular space invasion: present / absent
  • Resection margins (specify which): positive / negative; if negative, distance __ mm
  • Stage: FIGO stage __, TNM stage __
Differential diagnosis
Board review style question #1

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
Board review style answer #1
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)
Board review style question #2
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
Board review style answer #2
B. Lymphovascular space invasion

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Reference: HPV related adenocarcinoma (usual type and variants)
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