LETTER
TO THE
EDITOR
A Case of HPV-negative Intestinal-type Endocervical Adenocarcinoma In Situ With Coexisting Multifocal Intestinal and Gastric Metaplasia To the Editor: We read with interest the recent article by Howitt et al1 describing an immunophenotypically distinct subset of intestinal-type endocervical adenocarcinoma in situ (iAIS), which appears unassociated with human papillomavirus (HPV) infection and occurs in older women. We present another case of HPV-negative iAIS occurring in an older woman, which is made even more noteworthy by the extremely unusual coexistence of multifocal intestinal and gastric metaplasia involving the endocervix, lower uterine segment, and endometrium. A 73-year-old woman with no prior history of cervical dysplasia FIGURE 1. iAIS exhibiting focal nuclear stratification, increased mitoses, and apopunderwent elective simple vaginal toses (hematoxylin and eosin). hysterectomy for uterine prolapse. Histology revealed features of pro- field, and, although the abnormal related subset of iAIS as described by lapse with hyperkeratosis of the ec- endometrial glands exhibited a degree Howitt et al.1 High-risk HPV intocervical squamous epithelium, with of architectural complexity in the fection is implicated in the pathono evidence of koilocytosis or squ- form of mild glandular crowding, genesis of most “usual” types of amous dysplasia. Many of the endo- there was no evidence of an invasive premalignant and malignant cervical cervical glands in 2 sections (the entire process. The intestinal/gastric-type glandular lesions.2 Indeed most cases cervix was examined histologically) glands were positive with CDX2 and of iAIS are positive for high-risk HPV showed intestinal metaplasia with MUC6 and focally with CK20. There and show diffuse p16 staining.3 By goblet cells exhibiting focal nuclear was diffuse CK7 positivity. Occa- demonstrating that a small subset of stratification and increased mitotic sional chromogranin-positive cells iAIS shows variable staining with p16 and apoptotic activity, consistent with were present basally. An increased and MIB-1 (Ki67) and are negative iAIS (Fig. 1). The goblet cells were MIB-1 proliferation index was pres- for HPV by type-specific DNA analintermixed with normal endocervical ent within the atypical glands ranging ysis, Howitt and colleagues suggested cells and cells with more abundant from 30% to 40%. P16 was negative an alternative non–HPV-driven pathopale cytoplasm resembling gastric and p53 exhibited “wild-type” stain- genesis, with a tendency to occur in a surface foveolar and pyloric glandular ing with occasional positive nuclei. distinctly older age group. Houghton epithelium. Similar mixed intestinal/ Linear array HPV genotyping (Roche et al4 have previously reported 3 HPVgastric-type glands were also seen Molecular Diagnostics, Pleasanton, negative intestinal-type cervical adwithin the lower uterine segment and CA) performed twice on a repre- enocarcinomas, which may represent the within the endometrium, where they sentative paraffin block, including the invasive counterpart of HPV-negative were admixed with atrophic endo- iAIS, was negative. iAIS. metrial glands (Fig. 2). The abnormal A proportion of non–HPVWe believe that the endocervical glands within the cervix were confined lesion in this case represents a further related adenocarcinomas of the cervix to the normal endocervical glandular example of the unusual non–HPV- are part of the important emerging Am J Surg Pathol
Volume 38, Number 2, February 2014
www.ajsp.com |
289
Letter to the Editor
Am J Surg Pathol
FIGURE 2. Intestinal and gastric metaplasia within the endometrium (hematoxylin and eosin).
spectrum of benign, premalignant, and malignant endocervical glandular lesions exhibiting gastric differentiation, documented primarily by Japanese investigators over the past decade.5 These include lobular endocervical glandular hyperplasia (complex gastric metaplasia), simple gastric metaplasia, minimal-deviation adenocarcinoma, and the recently described gastric-type adenocarcinoma (GAS).6,7 Both minimaldeviation adenocarcinoma and GAS are thought to arise through an HPVindependent mechanism and exhibit aggressive clinical behavior. Although uncommon, they are not rare, and they may be more prevalent in Japan where GAS is estimated to account for 10% to 30% of all cervical adenocarcinomas.6,7 In the era of HPVtargeted screening and vaccination, the relative importance of this growing subset of HPV-negative cervical neoplasms is likely to increase.
290 | www.ajsp.com
The second noteworthy feature of our case is the extremely rare coexistence of intestinal and gastric metaplasia simultaneously within the uterine cervix, lower uterine segment, and endometrium. It is unclear whether these represent multifocal synchronous independent lesions or upward spread from the lesion within the endocervix, although we favor the former. An intestinal or enteric phenotype is supported by immunohistochemical analysis with positivity for CK20 and CDX2 and basal chromogranin-positive neuroendocrine cells. The gastric phenotype is supported by positivity for MUC6, a marker of gastric pyloric gland mucin. Endometrial intestinal metaplasia is extremely rare, with only 3 cases previously reported.8,9 Only 5 cases of concomitant intestinal and gastrictype metaplasia have been reported in the endocervix,1,8,10 and 1 of these represents the only other report of
Volume 38, Number 2, February 2014
coexisting endometrial intestinal and gastric metaplasia.8 To the best of our knowledge, our case represents the first report of coexisting multifocal intestinal/gastric metaplasia and cervical iAIS. Intestinal metaplasia with goblet cells in the cervix almost always indicates a premalignant or malignant endocervical glandular lesion.11 Given the paucity of reported cases of intestinal metaplasia within the endometrium, the implications of this finding are not well defined. Two of the 3 previously reported cases of endometrial intestinal metaplasia had coexisting intestinal metaplasia within the cervix (in the third case the cervix was not investigated). As such, Nicolae et al8 suggested that the finding of intestinal metaplasia in the endometrium warrants evaluation of the cervix to exclude a coexistent cervical glandular lesion. We now add a fourth case of concomitant endometrial and cervical intestinal metaplasia and, in addition, demonstrate the coexistence of iAIS, thus providing further evidence in support of this. The significance of the admixed gastric metaplasia within the endometrium is unknown. In summary, we report a further example of HPV-negative iAIS occurring in an older woman. We stress the increasing importance of recognizing non–HPV-related premalignant and malignant cervical glandular lesions. We demonstrate the exceedingly rare coexistence of intestinal and gastric metaplasia within the endocervix and endometrium.
Karen L. Talia, MBBS, FRCPA* Andrea Cretney, FRCPA* W. Glenn McCluggage, FRCPathw *Department of Pathology Box Hill Hospital, Eastern Health Melbourne, Vic., Australia wDepartment of Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. r
2013 Lippincott Williams & Wilkins
Am J Surg Pathol
Volume 38, Number 2, February 2014
ACKNOWLEDGMENTS The authors thank Dr Jackie Jamison (Antrim Area Hospital) for performing the HPV studies.
4.
REFERENCES 1. Howitt B, Herfs M, Brister K, et al. Intestinal-type endocervical adenocarcinoma in situ. An immunophenotypically distinct subset of AIS affecting older women. Am J Surg Path. 2013;37: 625–633. 2. Du J, Nasman A, Carlson JW, et al. Prevalence of human papillomavirus (HPV) types in cervical cancer 2003-2008 in Stockholm, Sweden, before public HPV vaccination. Acta Oncol. 2011;50: 1215–1219. 3. McCluggage WG, Shah R, Connolly LE, et al. Intestinal-type cervical adenocarcino-
r
2013 Lippincott Williams & Wilkins
5.
6.
7.
ma in situ and adenocarcinoma exhibit a partial enteric immunophenotype with consistent expression of CDX2. Int J Gynecol Pathol. 2008;27:92–100. Houghton O, Jamison J, Wilson R, et al. p16 immunoreactivity in unusual types of cervical adenocarcinoma does not reflect human papillomavirus infection. Histopathology. 2010;57:342–350. Mikami Y, McCluggage WG. Endocervical glandular lesions exhibiting gastric differentiation: an emerging spectrum of benign, premalignant, and malignant lesions. Adv Anat Pathol. 2013;20:227–237. Kojima A, Mikami Y, Sudo T, et al. Gastric morphology and immunophenotype predict poor outcome in mucinous adenocarcinoma of the uterine cervix. Am J Surg Pathol. 2007;31:664–672. Kusanagi Y, Kojima A, Mikami Y, et al. Absence of high-risk human papillomavirus (HPV) detection in endocervical adeno-
Letter to the Editor
8.
9. 10.
11.
carcinoma with gastric morphology and phenotype. Am J Surg Pathol. 2010;177: 2169–2175. 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; 30:492–496. Wells M, Tiltman A. Intestinal metaplasia of the endometrium. Histopathology. 1989; 15:431–433. Mikami Y, Hata S, Fujiwara K, et al. Florid endocervical glandular hyperplasia with intestinal and pyloric gland metaplasia: a worrisome benign mimic of “adenoma malignum”. Gynecol Oncol. 1999;74:504–511. McCluggage WG. Premalignant lesions of the lower female genital tract. Pathology. 2013;45:214–228.
www.ajsp.com |
291
TO THE
EDITOR
A Case of HPV-negative Intestinal-type Endocervical Adenocarcinoma In Situ With Coexisting Multifocal Intestinal and Gastric Metaplasia To the Editor: We read with interest the recent article by Howitt et al1 describing an immunophenotypically distinct subset of intestinal-type endocervical adenocarcinoma in situ (iAIS), which appears unassociated with human papillomavirus (HPV) infection and occurs in older women. We present another case of HPV-negative iAIS occurring in an older woman, which is made even more noteworthy by the extremely unusual coexistence of multifocal intestinal and gastric metaplasia involving the endocervix, lower uterine segment, and endometrium. A 73-year-old woman with no prior history of cervical dysplasia FIGURE 1. iAIS exhibiting focal nuclear stratification, increased mitoses, and apopunderwent elective simple vaginal toses (hematoxylin and eosin). hysterectomy for uterine prolapse. Histology revealed features of pro- field, and, although the abnormal related subset of iAIS as described by lapse with hyperkeratosis of the ec- endometrial glands exhibited a degree Howitt et al.1 High-risk HPV intocervical squamous epithelium, with of architectural complexity in the fection is implicated in the pathono evidence of koilocytosis or squ- form of mild glandular crowding, genesis of most “usual” types of amous dysplasia. Many of the endo- there was no evidence of an invasive premalignant and malignant cervical cervical glands in 2 sections (the entire process. The intestinal/gastric-type glandular lesions.2 Indeed most cases cervix was examined histologically) glands were positive with CDX2 and of iAIS are positive for high-risk HPV showed intestinal metaplasia with MUC6 and focally with CK20. There and show diffuse p16 staining.3 By goblet cells exhibiting focal nuclear was diffuse CK7 positivity. Occa- demonstrating that a small subset of stratification and increased mitotic sional chromogranin-positive cells iAIS shows variable staining with p16 and apoptotic activity, consistent with were present basally. An increased and MIB-1 (Ki67) and are negative iAIS (Fig. 1). The goblet cells were MIB-1 proliferation index was pres- for HPV by type-specific DNA analintermixed with normal endocervical ent within the atypical glands ranging ysis, Howitt and colleagues suggested cells and cells with more abundant from 30% to 40%. P16 was negative an alternative non–HPV-driven pathopale cytoplasm resembling gastric and p53 exhibited “wild-type” stain- genesis, with a tendency to occur in a surface foveolar and pyloric glandular ing with occasional positive nuclei. distinctly older age group. Houghton epithelium. Similar mixed intestinal/ Linear array HPV genotyping (Roche et al4 have previously reported 3 HPVgastric-type glands were also seen Molecular Diagnostics, Pleasanton, negative intestinal-type cervical adwithin the lower uterine segment and CA) performed twice on a repre- enocarcinomas, which may represent the within the endometrium, where they sentative paraffin block, including the invasive counterpart of HPV-negative were admixed with atrophic endo- iAIS, was negative. iAIS. metrial glands (Fig. 2). The abnormal A proportion of non–HPVWe believe that the endocervical glands within the cervix were confined lesion in this case represents a further related adenocarcinomas of the cervix to the normal endocervical glandular example of the unusual non–HPV- are part of the important emerging Am J Surg Pathol
Volume 38, Number 2, February 2014
www.ajsp.com |
289
Letter to the Editor
Am J Surg Pathol
FIGURE 2. Intestinal and gastric metaplasia within the endometrium (hematoxylin and eosin).
spectrum of benign, premalignant, and malignant endocervical glandular lesions exhibiting gastric differentiation, documented primarily by Japanese investigators over the past decade.5 These include lobular endocervical glandular hyperplasia (complex gastric metaplasia), simple gastric metaplasia, minimal-deviation adenocarcinoma, and the recently described gastric-type adenocarcinoma (GAS).6,7 Both minimaldeviation adenocarcinoma and GAS are thought to arise through an HPVindependent mechanism and exhibit aggressive clinical behavior. Although uncommon, they are not rare, and they may be more prevalent in Japan where GAS is estimated to account for 10% to 30% of all cervical adenocarcinomas.6,7 In the era of HPVtargeted screening and vaccination, the relative importance of this growing subset of HPV-negative cervical neoplasms is likely to increase.
290 | www.ajsp.com
The second noteworthy feature of our case is the extremely rare coexistence of intestinal and gastric metaplasia simultaneously within the uterine cervix, lower uterine segment, and endometrium. It is unclear whether these represent multifocal synchronous independent lesions or upward spread from the lesion within the endocervix, although we favor the former. An intestinal or enteric phenotype is supported by immunohistochemical analysis with positivity for CK20 and CDX2 and basal chromogranin-positive neuroendocrine cells. The gastric phenotype is supported by positivity for MUC6, a marker of gastric pyloric gland mucin. Endometrial intestinal metaplasia is extremely rare, with only 3 cases previously reported.8,9 Only 5 cases of concomitant intestinal and gastrictype metaplasia have been reported in the endocervix,1,8,10 and 1 of these represents the only other report of
Volume 38, Number 2, February 2014
coexisting endometrial intestinal and gastric metaplasia.8 To the best of our knowledge, our case represents the first report of coexisting multifocal intestinal/gastric metaplasia and cervical iAIS. Intestinal metaplasia with goblet cells in the cervix almost always indicates a premalignant or malignant endocervical glandular lesion.11 Given the paucity of reported cases of intestinal metaplasia within the endometrium, the implications of this finding are not well defined. Two of the 3 previously reported cases of endometrial intestinal metaplasia had coexisting intestinal metaplasia within the cervix (in the third case the cervix was not investigated). As such, Nicolae et al8 suggested that the finding of intestinal metaplasia in the endometrium warrants evaluation of the cervix to exclude a coexistent cervical glandular lesion. We now add a fourth case of concomitant endometrial and cervical intestinal metaplasia and, in addition, demonstrate the coexistence of iAIS, thus providing further evidence in support of this. The significance of the admixed gastric metaplasia within the endometrium is unknown. In summary, we report a further example of HPV-negative iAIS occurring in an older woman. We stress the increasing importance of recognizing non–HPV-related premalignant and malignant cervical glandular lesions. We demonstrate the exceedingly rare coexistence of intestinal and gastric metaplasia within the endocervix and endometrium.
Karen L. Talia, MBBS, FRCPA* Andrea Cretney, FRCPA* W. Glenn McCluggage, FRCPathw *Department of Pathology Box Hill Hospital, Eastern Health Melbourne, Vic., Australia wDepartment of Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. r
2013 Lippincott Williams & Wilkins
Am J Surg Pathol
Volume 38, Number 2, February 2014
ACKNOWLEDGMENTS The authors thank Dr Jackie Jamison (Antrim Area Hospital) for performing the HPV studies.
4.
REFERENCES 1. Howitt B, Herfs M, Brister K, et al. Intestinal-type endocervical adenocarcinoma in situ. An immunophenotypically distinct subset of AIS affecting older women. Am J Surg Path. 2013;37: 625–633. 2. Du J, Nasman A, Carlson JW, et al. Prevalence of human papillomavirus (HPV) types in cervical cancer 2003-2008 in Stockholm, Sweden, before public HPV vaccination. Acta Oncol. 2011;50: 1215–1219. 3. McCluggage WG, Shah R, Connolly LE, et al. Intestinal-type cervical adenocarcino-
r
2013 Lippincott Williams & Wilkins
5.
6.
7.
ma in situ and adenocarcinoma exhibit a partial enteric immunophenotype with consistent expression of CDX2. Int J Gynecol Pathol. 2008;27:92–100. Houghton O, Jamison J, Wilson R, et al. p16 immunoreactivity in unusual types of cervical adenocarcinoma does not reflect human papillomavirus infection. Histopathology. 2010;57:342–350. Mikami Y, McCluggage WG. Endocervical glandular lesions exhibiting gastric differentiation: an emerging spectrum of benign, premalignant, and malignant lesions. Adv Anat Pathol. 2013;20:227–237. Kojima A, Mikami Y, Sudo T, et al. Gastric morphology and immunophenotype predict poor outcome in mucinous adenocarcinoma of the uterine cervix. Am J Surg Pathol. 2007;31:664–672. Kusanagi Y, Kojima A, Mikami Y, et al. Absence of high-risk human papillomavirus (HPV) detection in endocervical adeno-
Letter to the Editor
8.
9. 10.
11.
carcinoma with gastric morphology and phenotype. Am J Surg Pathol. 2010;177: 2169–2175. 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; 30:492–496. Wells M, Tiltman A. Intestinal metaplasia of the endometrium. Histopathology. 1989; 15:431–433. Mikami Y, Hata S, Fujiwara K, et al. Florid endocervical glandular hyperplasia with intestinal and pyloric gland metaplasia: a worrisome benign mimic of “adenoma malignum”. Gynecol Oncol. 1999;74:504–511. McCluggage WG. Premalignant lesions of the lower female genital tract. Pathology. 2013;45:214–228.
www.ajsp.com |
291
