HPV related adenocarcinoma (usual type and variants)

Cervix

Adenocarcinoma

Authors: Carlos Parra-Herran, M.D., Ashwyna Sunassee, M.D.

Topic Completed: 1 September 2016

Minor changes: 28 September 2020

Copyright: 2003-2020, PathologyOutlines.com, Inc.

PubMed Search: HPV Adenocarcinoma [title] cervix

Related topics: Endocervical (mucinous) type, Endocervical microcystic, Endometrioid, Intestinal, Signet ring

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Table of Contents

Cite this page: Parra-Herran C, Sunassee A. HPV related adenocarcinoma (usual type and variants). PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/cervixhpvadenocarcinoma.html. Accessed October 26th, 2020.

Definition / general

5 - 15% of invasive cervical carcinomas, higher percentage in Jewish women

Clinical features

Second most frequent cervical carcinoma following squamous cell carcinoma (Curr Oncol Rep 2014;16:416)
Incidence increasing in US, now up to 25% of cervical cancers, due to decreasing rates of squamous cell carcinoma and difficulty in diagnosis using current screening methods
Increased frequency in young women (Cancer 2004;100:1035)
Usually associated with in situ adenocarcinoma (mean 5 year interval, which is less than for squamous lesions)
30% - 50% false negative reports by cytology
Often vaginal bleeding, pelvic pain
Spreads first to pelvic structures, then pelvic lymph nodes; metastases to ovaries, upper abdomen, distant organs
Mixed if there is 10% or more of a second component
Survival by stage: I - 79%, II - 37%, III / IV - less than 9% (see Staging)

Prognostic factors

Poor prognostic factors: high stage (including depth > 5 mm, Int J Gynecol Cancer 2004;14:104), angiolymphatic invasion, high grade (Gynecol Oncol 2004;92:262); destructive pattern of stromal invasion (see below)

Classification

Pattern based classification (Silva system)

A novel classification system based on the pattern, rather than the size or grade of the invasive component, has been proposed (Int J Gynecol Pathol 2013;32:592, Am J Surg Pathol 2015;39:667)
- Tumors with a non destructive 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 ^2,3
- Similarly, pattern A tumors had 0% recurrence and 0% fatality rates, compared to pattern B tumors (1.2% and 0%, respectively) and pattern C tumors (22.1% and 8.8%, respectively)

Case reports

34 year old woman with atypical glandular cells of undetermined significance on Pap smear (Case #495)
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)
Adenocarcinoma of the cervix involving the fallopian tube mucosa (Diagn Pathol 2016;11:77)

Treatment

Stage I tumors are treated with surgery (simple / radical hysterectomy or radical trachelectomy plus regional lymphadenecctomy) and adjuvant radiation therapy, cisplatin or other chemotherapy if adverse features present (deep invasion, extensive lymphovascular space invasion, positive margins, lymph node metastases) (Curr Treat Options Oncol 2004;5:119)
Advanced stage tumors (II - IV) receive up front radiation therapy, cisplatin or other chemotherapy
Less responsive to chemoradiotherapy than squamous cell carcinoma (Oncol Lett 2015;9:2791)

Gross description

Superficially invasive tumors are microscopic
When visible (> stage IB by definition), lesion can be exophytic or flat / plaque, usually ulcerated
On cut sectioning, there is variable growth into cervical wall
Barrel shaped cervix with diffuse enlargement, if lesion is widely invasive

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
  - Lymphatic vascular space invasion
- Increased number of glands with loss of a lobular arrangemen and glandular density exceeding that of the normal cervix
- Often glands are close to thick walled vessels (within thickness of vessel wall, Int J Gynecol Pathol 2005;24:125)
Superficially invasive carcinoma (early invasive, microinvasive, FIGO stage IA1) is defined as less than 3 mm in depth and less than 7 mm in horizontal spread and negative resection margins (in partial samples)

Tumor grade of adenocarcinoma (for usual type adenocarcinoma, not variants; not universally accepted)

Grade 1: well differentiated (10% or less solid growth); tumor contains well formed regular glands with papillae; cells are elongate and columnar with uniform oval nuclei; minimal stratification (fewer than three cell layers in thickness); infrequent mitotic figures
Grade 2: moderately differentiated (11% to 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

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

The system classifies tumors in three 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 (ie. architecture well 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. Lymphovascular invasion +/-. Lack of solid growth (ie. architecturally well 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, poorly differentiated component (architecturally high grade); nuclear grade is disregarded. Lymphovascular invasion,+/-.

Histologic types of HPV related endocervical adenocarcinoma

Endocervical mucinous (usual) adenocarcinoma: Represents 70% - 90% of all adenocarcinomas. Its usual morphologic features are:
- Variable mucinous cytoplasm with staining similar to normal endocervical glands, usually cytoplasm is less mucinous compared to normal (“mucin depleted”)
- Cells have columnar shape; nuclei are elongated and enlarged, they are hyperchromatic with coarse chromatin
- Loss of polarity and nuclear overlapping
- Brisk mitotic activity; mitotic figures are usually apical
Endometrioid: Morphologically similar to endometrial endometrioid adenocarcinoma
- Glandular epithelium has columnar shape and round nuclei with open or mildly coarse chromatin
- Squamous or secretory differentiation can be seen
- Primary endocervical endometrioid carcinomas are secondary to high risk HPV infection, and overexpress p16
- Differential diagnosis includes a primary endometrial carcinoma with cervical involvement, and the exceedingly rare instance of a primary endometrioid carcinoma arising in cervical mucosal endometriosis
Intestinal (goblet cell): Mucinous carcinoma with variable amounts of intestinal differentiation, goblet cells and (occasionally) Paneth cells (Arch Pathol Lab Med 1990;114:731)
Microcystic: Very rare form composed of cysts lined by otherwise conventional (usual type) endocervical adenocarcinoma
- Can be confused with tunnel clusters or deep nabothian cysts
- Mean patient age is 49 years, range 34 to 78 years (Am J Surg Pathol 2000;24:369)
- Cysts occupy 50% - 90% of tumor, 1 - 8 mm in diameter
- Lined by flat to low cuboidal to pseudostratified epithelium
- Luminal mucin is common, resembles contents of mesonephric tubules
- Variable desmoplastic stroma

Microscopic (histologic) images

Contributed by Carlos Parra-Herran, M.D.

HPV related adenocarcinoma

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 vs. 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:

Inflammatory exocervical smear

Positive stains

p16: Overexpressed in > 95% of cases (diffuse, strong nuclear and cytoplasmic staining)
mCEA: 100% (any degree of staining)
CK7

Negative stains

ER and PR (weak staining in up to 20% of cases)
p53: Normal staining pattern (not overexpressed or absent)
CD10 (positive only in mesonephric adenocarcinomas)
p63 (Hum Pathol 2001;32:479)
Vimentin (usually)
CDX2, CK20
Usually EBV negative (Arch Pathol Lab Med 1999;123:1098)

Molecular / cytogenetics description

Associated with HPV16 and HPV18 in 85% - 95% of cases (Am J Clin Pathol 1996;106:52)

Differential diagnosis

Adenocarcinoma in situ:
- No histologic features of invasion as described above
- Reproducibility of the distinction between invasive and in situ adenocarcinoma is poor and distinction cannot be made in up to 20% of cases (Mod Pathol 2016;29:879, Int J Gynecol Pathol 2000;19:29)
Endometrial endometrioid adenocarcinoma extending to cervix:
- No in situ cervical adenocarcinoma
- Continuity between cervix and endometrial tumors
- Usually myometrial invasion
- Often bland squamous differentiation
- Stains may be helpful: negative or focal / superficial for CEA and mucin; positive for vimentin, ER and PR; p16 not overexpressed, negative for HPV by PCR (Am J Surg Pathol 2002;26:998)
Gastric type adenocarcinoma: eosiniphilic cytoplasm with distinct cellular borders, p16 not overexpressed, abnormal p53 staining
Clear cell adenocarcinoma: cuboidal cells with clear cytoplasm and marked nuclear atypia, negative mCEA
Metastatic colorectal adenocarcinoma: very rare; CDX2+, CK7-, CK20+ (Arch Pathol Lab Med 2003;127:1586, Jpn J Clin Oncol 1999;29:640)
Metastatic adenocarcinoma (not colonic): usually clinical evidence of widespread disease, angiolymphatic invasion, no surface involvement
Mesonephric remnants: deep, do not extend to surface, contain eosinophilic secretions, no mitotic activity, no atypia, CD10+
Microglandular hyperplasia:
- Does not extend below deep margin of normal endocervical glands
- Usually young women taking oral contraceptives or pregnant
- Few mitotic figures

Additional references

Mod Pathol 2000;13:261

Board review style question #1

Which morphologic feature may help distinguish stratified mucin producing lesions (SMILE) / invasive stratified mucin producing carcinomas (iSMILE) from more common HPV related cervical malignancies?

Brisk mitotic activity and apoptotic bodies
Large nuclear / cytoplasmic ratio
Mucin vacuoles throughout the full thickness of the epithelium
Quantity of cytoplasmic mucin

Board review answer #1

C. Mucin vacuoles throughout the full thickness of the epithelium

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Reference: HPV related adenocarcinoma (usual type and variants)