International Journal of Gynecological Pathology 34:228–231, 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, finding 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 situ—Endometrial polyp—High-risk HPV—Skip 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 lesion—adenocarcinoma 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 Vincent’s 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 Women’s Hospital; Murdoch Children’s 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 conflicts of interest. Address correspondence and reprint requests to Peter Russell, MD, Douglass Hanly Moir Pathology, 14 Giffnock 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 journal’s 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 findings 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 diffusely 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 (5–10). 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 identified in 4 of a series of 55 invasive cervical adenocarcinomas by E7 type-specific 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 finding 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 finding 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 differentiation 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 immunoprofile 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 finding 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 definite complete excision of her lesion (hysterectomy), as she is desirous of continued fertility. Effective 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 effective 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;16:272–8. 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;29:88–92. 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 confirm the cervical origin of the corpus tumor. Amer J Surg Pathol 2009;33:914–24. 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;133:2253–8. Andersson S, Rylander E, Larsson B, et al. The role of human papillomavirus in cervical adenocarcinoma carcinogenesis. Eur J Cancer 2001;37:246–50. 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;98:303–15. 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;73:1005–8. Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189:12–9. Clifford GM, Smith JS, Plummer M, et al. Human papillomavirus types in invasive cervical cancer worldwide: a metaanalysis. Brit J Cancer 2003;88:63–73. Dahlstrom LA, Ylitalo N, Sundstrom K, et al. Prospective study of human papillomavirus and risk of cervical adenocarcinoma. Int J Cancer 2010;127:1923–30. Bertrand M, Lickrish GM, Colgan TJ. The anatomic distribution of cervical adenocarcinoma in situ: implications for treatment. Am J Obstet Gynecol 1987;157:21–5. Colgan TJ, Lickrish GM. The topography and invasive potential of cervical adenocarcinoma in situ, with and without associated squamous dysplasia. Gynecol Oncol 1990;36:246–9. Ostor AG, Duncan A, Quinn M, et al. Adenocarcinoma in situ of the uterine cervix: an experience with 100 cases. Gynecol Oncol 2000;79:207–10. Ostor AG, Pagano R, Davoren RA, et al. Adenocarcinoma in situ of the cervix. Int J Gynecol Pathol 1984;3:179–90. Nicolae A, Preda O, Nogales FF. Endometrial metaplasias and reactive changes: a spectrum of altered differentiation. J Clin Pathol 2011;64:97–106. 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;30:492–6. Wells M, Tiltman A. Intestinal metaplasia of the endometrium. Histopathology 1989;15:431–3. Zheng W, Yang GC, Godwin TA, et al. Mucinous adenocarcinoma of the endometrium with intestinal differentiation: a case report. Hum Pathol 1995;26:1385–8. 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;23:380–4. Karadayi N, Gecer M, Kayahan S, et al. Association between human papillomavirus and endometrial adenocarcinoma. Med Oncol 2013;30:597–601.
Int J Gynecol Pathol Vol. 34, No. 3, May 2015
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, finding 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 situ—Endometrial polyp—High-risk HPV—Skip 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 lesion—adenocarcinoma 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 Vincent’s 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 Women’s Hospital; Murdoch Children’s 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 conflicts of interest. Address correspondence and reprint requests to Peter Russell, MD, Douglass Hanly Moir Pathology, 14 Giffnock 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 journal’s 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 findings 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 diffusely 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 (5–10). 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 identified in 4 of a series of 55 invasive cervical adenocarcinomas by E7 type-specific 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 finding 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 finding 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 differentiation 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 immunoprofile 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 finding 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 definite complete excision of her lesion (hysterectomy), as she is desirous of continued fertility. Effective 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 effective 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;16:272–8. 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;29:88–92. 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 confirm the cervical origin of the corpus tumor. Amer J Surg Pathol 2009;33:914–24. 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;133:2253–8. Andersson S, Rylander E, Larsson B, et al. The role of human papillomavirus in cervical adenocarcinoma carcinogenesis. Eur J Cancer 2001;37:246–50. 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;98:303–15. 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;73:1005–8. Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189:12–9. Clifford GM, Smith JS, Plummer M, et al. Human papillomavirus types in invasive cervical cancer worldwide: a metaanalysis. Brit J Cancer 2003;88:63–73. Dahlstrom LA, Ylitalo N, Sundstrom K, et al. Prospective study of human papillomavirus and risk of cervical adenocarcinoma. Int J Cancer 2010;127:1923–30. Bertrand M, Lickrish GM, Colgan TJ. The anatomic distribution of cervical adenocarcinoma in situ: implications for treatment. Am J Obstet Gynecol 1987;157:21–5. Colgan TJ, Lickrish GM. The topography and invasive potential of cervical adenocarcinoma in situ, with and without associated squamous dysplasia. Gynecol Oncol 1990;36:246–9. Ostor AG, Duncan A, Quinn M, et al. Adenocarcinoma in situ of the uterine cervix: an experience with 100 cases. Gynecol Oncol 2000;79:207–10. Ostor AG, Pagano R, Davoren RA, et al. Adenocarcinoma in situ of the cervix. Int J Gynecol Pathol 1984;3:179–90. Nicolae A, Preda O, Nogales FF. Endometrial metaplasias and reactive changes: a spectrum of altered differentiation. J Clin Pathol 2011;64:97–106. 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;30:492–6. Wells M, Tiltman A. Intestinal metaplasia of the endometrium. Histopathology 1989;15:431–3. Zheng W, Yang GC, Godwin TA, et al. Mucinous adenocarcinoma of the endometrium with intestinal differentiation: a case report. Hum Pathol 1995;26:1385–8. 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;23:380–4. Karadayi N, Gecer M, Kayahan S, et al. Association between human papillomavirus and endometrial adenocarcinoma. Med Oncol 2013;30:597–601.
Int J Gynecol Pathol Vol. 34, No. 3, May 2015
