International Journal of Gynecological Pathology

34:228231, Lippincott Williams & Wilkins, Baltimore

r 2015 International Society of Gynecological Pathologists

Case Report

Endocervical Adenocarcinoma In Situ Presenting in Fundal

Endometrial Polyp: The Mother of All Skip Lesions
Jennifer M. Roberts, M.B.B.S. (Hons), Alyssa M. Cornall, Ph.D., Vincent Lamaro,
Sepehr N. Tabrizi, Ph.D., and Peter Russell, M.D.

B.Med.,

Summary: A 38-yr-old woman, with a previous history of low grade squamous intraepithelial
lesion in the cervix, presented with heavy menstrual bleeding. At hysteroscopy, a fundal polyp
was removed from the right cornu which displayed many glands lined by atypical, mitotically
active epithelium with features characteristic of endocervical adenocarcinoma in situ (AIS) of
intestinal subtype. Subsequent cervical liquid-based cytology and colposcopically directed
biopsies revealed no causative lesion, but residual PreservCyt from the ThinPrep vial tested
positive for high risk HPV type other than HPV 16 and 18. Further biopsies from the
endocervical canal and base of the resected polyp showed intestinal type AIS, while all those
from the intervening anterior and posterior endometrial lining exhibited normal endometrium
only. Genomic DNA extracted from the endometrial polyp and second set of endocervical
biopsies tested positive for HPV 31, an uncommon cause of endocervical glandular neoplasia.
Endocervical AIS typically arises in the transformation zone but may be found exclusively in
the endocervical canal and rarely as high as 30mm from the ectocervix. Contiguous spread
into the lower uterine segment is known to occur, as are proximate so-called skip lesions.
However, nding a skip lesion 80mm from the transformation zone poses an interesting
pathogenetic conundrum as well as a therapeutic dilemma in a young patient desirous of
retaining fertility. Issues relating to pathogenesis include necessary metaplasia of the
endometrial glandular epithelium to susceptible endocervical type epithelium within the
polyp or metastatic implantation of transformed endocervical glandular cells onto the polyp.
The current management plan involves regular hysteroscopic surveillance of the uterine
cavity. Key Words: Endocervical adenocarcinoma in situEndometrial polypHigh-risk
HPVSkip lesion.

Contiguous or noncontiguous spread of human

papillomavirus (HPV)-associated high-grade squamous
intraepithelial lesion from the cervix to the endometrium
of the corpus and even the fallopian tubes and ovaries is
rare but well documented (1). With the corresponding
glandular lesionadenocarcinoma in situ (AIS)cephalad contiguous extension has been described (2,3) but
the presence of a skip lesion in a fundal polyp is
unique and, in a young woman, raises issues of
pathogenesis as well as of clinical management.

From the Douglass Hanly Moir Pathology (J.M.R., P.R.),

Macquarie Park; St Vincents Clinic (V.L.); Department of
Obstetrics Gynaecology and Neonatology (P.R.), University of
Sydney, Sydney, NSW; Regional HPV Labnet Reference Laboratory (A.M.C., S.N.T.), Department of Microbiology and
Infectious Diseases, The Royal Womens Hospital; Murdoch
Childrens Research Institute (A.M.C., S.N.T.); and Department
of Obstetrics and Gynaecology (S.N.T.), University of Melbourne,
Parkville, Vic., Australia.
The authors declare no conicts of interest.
Address correspondence and reprint requests to Peter Russell,
MD, Douglass Hanly Moir Pathology, 14 Ginock Avenue,
Macquarie Park, NSW 2113, Australia. E-mail: prussell@dhm.
com.au.
Supplemental Digital Content is available for this article. Direct
URL citations appear in the printed text and are provided in the
HTML and PDF versions of this article on the journals Website,
www.intjgynpathology.com.

DOI: 10.1097/PGP.0000000000000166

CLINICAL HISTORY
A 38-yr-old woman with a history of cervical lowgrade squamous intraepithelial lesion 16 yr previously,
228

ENDOCERVICAL AIS IN ENDOMETRIAL POLYP

229

FIG. 1. Endometrial polyp showing both benign endometrial

glands (lower and right margins) and glands lined by endocervical
AIS (upper left)..

FIG. 3. Endocervical adenocarcinoma in situ showing strong

diffuse p16 immunopositivity in contrast with nearby negative
endometrial glands (top right).

presented to her gynecologist with heavy menstrual

bleeding. Hysteroscopy and dilatation and curettage
revealed a tan fundal endometrial polyp 17  10  5
mm, in the region of the right cornu, which was
removed. The ndings in the endometrial polyp
prompted colposcopy and a liquid-based cervical
Papanicolaou (Pap) test. Colposcopy showed no
visible lesions, and biopsies of the transformation
zone were negative for squamous and glandular
neoplasia. The Pap test was also negative, however,
residual PreservCyt from the ThinPrep (Hologic Inc.,
Marlborough, MA) vial tested positive for a high-risk
HPV (HR-HPV) type other than HPV 16 and HPV 18
on the COBAS 4800 HPV Test (Roche Molecular
Systems, Pleasanton, CA).

In an attempt to link the changes in the fundal

polyp to the HPV results on the liquid-based cervical
sample, a later hysteroscopy targeted endometrial
tissue from the base of the resected polyp, multiple
biopsies from the anterior and posterior uterine
cavity and biopsies from the upper endocervical
canal.

The fundal lesion was a simple endometrial polyp

with scattered cystically dilated endometrial-type
glands, displaying no proliferative activity. In addition, there were many glands lined by intestinal-type

FIG. 2. Endocervical adenocarcinoma in situ in endometrial polyp.

Glands are lined by crowded atypical goblet cells with mitoses and
apoptosis.

FIG. 4. Endometrial polyp showing estrogen receptor immunopositivity in small endometrial glands and stroma in contrast with
negative endocervical adenocarcinoma in situ.

PATHOLOGIC FINDINGS

Int J Gynecol Pathol Vol. 34, No. 3, May 2015

230

J. M. ROBERTS ET AL.
DISCUSSION

FIG. 5. Endocervical canal biopsy showing adenocarcinoma

in situ.

epithelium (Fig. 1, see Supplemental Fig. 1, Supplemental Digital Content 1, http://links.lww.com/

IJGP/A27) associated with nuclear atypia, mitotic
activity, and apoptotic bodies (Fig. 2); all features
typical of endocervical AIS of intestinal subtype. No
stromal reaction was seen around these atypical
glands, nor was there any suggestion of invasive
adenocarcinoma in the polyp.
All glandular elements, both normal and atypical,
stained strongly for cytokeratin-7. The atypical
glands stained diusely and strongly for p16, whereas
the normal endometrial glands showed only focal
nuclear staining typical of normal endometrium
(Fig. 3). Conversely, the normal endometrial glands
showed reactivity for vimentin and estrogen receptor
(Fig. 4), whereas the atypical glands did not.
The further biopsies taken in the endocervical
canal showed intestinal-type AIS (Fig. 5). Biopsies
from the site of the base of the uterine polyp showed
focal atypical glands consistent with endocervicaltype AIS in 1 fragment only, admixed with multiple
fragments of cycling endometrium. Biopsies from the
anterior and posterior uterine walls showed only
normal endometrium.

MOLECULAR ANALYSIS
Genomic DNA extracted from 3-mm sections of the
fundal endometrial polyp and the endocervical
biopsy both tested positive for HPV 31 using the
RHA kit HPV SPF10-LiPA25, version 1 (Labo Biomedical Products BV, Rijswijk, The Netherlands) as
previously described (4).

Int J Gynecol Pathol Vol. 34, No. 3, May 2015

We describe what appears to be a unique example

of multicentric endocervical-type AIS. Endocervical
AIS is the precursor lesion of endocervical adenocarcinoma and like its squamous counterpart highgrade squamous intraepithelial lesion is causally
related to HR-HPV types. The most common
genotypes found in endocervical AIS and adenocarcinoma are HPV 18 and HPV 16 (510). In this
instance, HR-HPV Type 31 was detected in the tissue
sections at the 2 sites of AIS. HPV 31 has also been
previously identied in 4 of a series of 55 invasive
cervical adenocarcinomas by E7 type-specic
PCR (8), but is generally regarded as a rare cause
of cervical adenocarcinoma (6).
AIS typically arises in the transformation zone,
however, may be found exclusively within the endocervical canal (11,12). The highest reported focus of
AIS in the endocervix (measured from the ectocervix)
was 30 mm in 2 series (11,12). In addition, skip
lesions or multicentricity is uncommon but well
described (13,14). Endocervical AIS has been described
spreading contiguously into the endometrium (2,3).
However, the nding of a skip lesion high in the
uterine fundus, potentially 80 mm from the transformation zone, has not previously been described. It is
possible that in our case there is contiguity between the
endocervical and the uterine fundal lesion, but nding
this would require thorough sectioning of a hysterectomy specimen, a procedure not as yet agreed to by
surgeon or patient. Nevertheless, biopsies from the
polyp base showing very focal disease and negative
biopsies from anterior and posterior uterine walls
suggest that such contiguity does not exist.
Mullerian epithelia have great potential for metaplasia and endometrial mucinous metaplasia is well
described (15). In its architecturally simple form, it
recapitulates the histochemical and immunophenotypic
properties of endocervical epithelium (15). We postulate that in our case, metaplastic endocervical-type
mucinous glands in an endometrial polyp were infected
with HPV contemporaneously with the endocervical
epithelium, with development of intestinal-type AIS.
Three cases of intestinal metaplasia involving glands in
the endometrium or in endometrial polyps have been
described (16,17). In 2 of these, similar glands were
seen in the cervix. HPV-associated neoplasia was not
considered in the oldest case (17) and excluded in the 2
recent cases (16) by means of negative p16 immunostaining in both and negative HPV detection (GenoFlow HPV Array Test Kit and PCR) in 1. Our case

ENDOCERVICAL AIS IN ENDOMETRIAL POLYP

seems unique, in that there is evidence that the
endometrial lesion is HPV-related and associated with
a typical, morphologically indistinguishable HPVrelated lesion in the cervix.
A second potential explanation is that the fundal
lesion represents metastatic disease by way of
neoplastic cells shed from the in situ cervical lesion.
Transuterine and even transtubal spread of endocervical AIS has been documented with development of
morphologically identical ovarian lesions (2), so this
is plausible if highly unlikely.
The probability that the neoplastic glands are of
endometrial nature is low but should also be
considered. Intestinal dierentiation has been described in a mucinous endometrial adenocarcinoma (18) but HPV is thought not to be causally
associated with endometrial neoplasia (3,19,20). The
morphology and immunoprole of the intestinal
glands in our case are identical to those of the
endocervical AIS, and HPV 31 was detected in both
the polyp and the endocervical biopsy material.
Regardless of pathogenesis, this nding presents a
clinical management dilemma. Most young women
with endocervical AIS have a very good chance of
preserving fertility with standard excisional treatment.
This woman, however, is unable to undergo denite
complete excision of her lesion (hysterectomy), as she is
desirous of continued fertility. Eective follow-up is
constrained by the potentially large surface area of the
endometrium which may be involved. Further, continued sampling of the endometrium could negatively
impact on her fertility (through development of
Asherman syndrome) or lead to emergency hysterectomy because of the inherent vascular nature of
cornual surgery. Currently, the patient is having
regular hysteroscopic surveillance. Screening cytology
of the endometrium has never been proven to be
eective and there are no published data regarding
diagnostic HPV testing of an endometrial sample.

3.

4.

5.
6.

7.

8.
9.
10.
11.
12.
13.
14.
15.
16.

17.
18.

REFERENCES
1. Pins MR, Young RH, Crum CP, et al. Cervical squamous cell
carcinoma in situ with intraepithelial extension to the upper
genital tract and invasion of tubes and ovaries: report of a case
with human papilloma virus analysis. Int J Gynecol Pathol
1997;16:2728.
2. Chang MC, Nevadunsky NS, Viswanathan AN, et al.
Endocervical adenocarcinoma in situ with ovarian metastases:

19.

20.

231

a unique variant with potential for long-term survival. Int J

Gynecol Pathol 2010;29:8892.
Yemelyanova A, Vang R, Seidman JD, et al. Endocervical
adenocarcinomas with prominent endometrial or endomyometrial involvement simulating primary endometrial carcinomas:
utility of HPV DNA detection and immunohistochemical
expression of p16 and hormone receptors to conrm the
cervical origin of the corpus tumor. Amer J Surg Pathol
2009;33:91424.
Cornall AM, Roberts JM, Garland SM, et al. Anal and
perianal squamous carcinomas and high-grade intraepithelial
lesions exclusively associated with low-risk HPV genotypes 6
and 11. Int J Cancer 2013;133:22538.
Andersson S, Rylander E, Larsson B, et al. The role of human
papillomavirus in cervical adenocarcinoma carcinogenesis. Eur
J Cancer 2001;37:24650.
Castellsague X, Diaz M, de Sanjose S, et al. Worldwide human
papillomavirus etiology of cervical adenocarcinoma and its
cofactors: implications for screening and prevention. J Nat
Cancer Inst 2006;98:30315.
Tase T, Okagaki T, Clark BA, et al. Human papillomavirus
DNA in glandular dysplasia and microglandular hyperplasia:
presumed precursors of adenocarcinoma of the uterine cervix.
Obstet Gynecol 1989;73:10058.
Walboomers JM, Jacobs MV, Manos MM, et al. Human
papillomavirus is a necessary cause of invasive cervical cancer
worldwide. J Pathol 1999;189:129.
Cliord GM, Smith JS, Plummer M, et al. Human papillomavirus types in invasive cervical cancer worldwide: a metaanalysis. Brit J Cancer 2003;88:6373.
Dahlstrom LA, Ylitalo N, Sundstrom K, et al. Prospective
study of human papillomavirus and risk of cervical adenocarcinoma. Int J Cancer 2010;127:192330.
Bertrand M, Lickrish GM, Colgan TJ. The anatomic
distribution of cervical adenocarcinoma in situ: implications
for treatment. Am J Obstet Gynecol 1987;157:215.
Colgan TJ, Lickrish GM. The topography and invasive
potential of cervical adenocarcinoma in situ, with and without
associated squamous dysplasia. Gynecol Oncol 1990;36:2469.
Ostor AG, Duncan A, Quinn M, et al. Adenocarcinoma in situ
of the uterine cervix: an experience with 100 cases. Gynecol
Oncol 2000;79:20710.
Ostor AG, Pagano R, Davoren RA, et al. Adenocarcinoma
in situ of the cervix. Int J Gynecol Pathol 1984;3:17990.
Nicolae A, Preda O, Nogales FF. Endometrial metaplasias and
reactive changes: a spectrum of altered dierentiation. J Clin
Pathol 2011;64:97106.
Nicolae A, Goyenaga P, McCluggage WG, et al. Endometrial
intestinal metaplasia: a report of two cases, including one
associated with cervical intestinal and pyloric metaplasia. Int J
Gynecol Pathol 2011;30:4926.
Wells M, Tiltman A. Intestinal metaplasia of the endometrium.
Histopathology 1989;15:4313.
Zheng W, Yang GC, Godwin TA, et al. Mucinous adenocarcinoma of the endometrium with intestinal dierentiation: a
case report. Hum Pathol 1995;26:13858.
Jones MW, Onisko A, Dabbs DJ, et al. Immunohistochemistry
and HPV in situ hybridization in pathologic distinction
between endocervical and endometrial adenocarcinoma: a
comparative tissue microarray study of 76 tumors. Int J
Gynecol Cancer 2013;23:3804.
Karadayi N, Gecer M, Kayahan S, et al. Association between
human papillomavirus and endometrial adenocarcinoma. Med
Oncol 2013;30:597601.

Int J Gynecol Pathol Vol. 34, No. 3, May 2015