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Background
Cervical adenocarcinomas are much rarer than their squamous cell counterparts. Nontheless, they are important diagnostic problems, distinguishing these tumors from uterine corpus adenocarcinomas. These tumors comprise 10%-15% of all cervical cancers and arise from the mucus-producing gland cells of the endocervix.
OUTLINE
PATHOGENESIS CHARACTERIZATION GENERAL Endocervical glandular atypia: does a preneoplastic lesion of adenocarcinoma in situ exist?
Goldstein NS, Ahmad E, Hussain M, Hankin RC, Perez-Reyes N.
Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, Michigan 48073, USA.
Am J Clin Pathol 1998 Aug;110(2):200-9 Abstract quote
Some believe endocervical glandular atypia (EGA), purportedly composed of cells that are less atypical than cells of adenocarcinoma in situ (AIS), is a preneoplastic precursor of AIS.
We examined 246 neoplastic and nonneoplastic cervical cone biopsy and hysterectomy specimens from 221 patients for lesions composed of glandular cells with less atypia than AIS to define and characterize their association with other glandular processes.
To avoid the circular argument of high-grade EGA (dysplasia) vs AIS, we set the minimum degree of AIS cells as the degree of atypia of the cells constituting a moderately differentiated invasive adenocarcinoma. Only 4 endocervical glandular lesions with mild atypia were found, 3 in patients with AIS or invasive endocervical-primary adenocarcinoma and 1 in a patient with invasive endometrial-primary, adenocarcinoma with endocervical extension. There were no lesions with high-grade atypia, nor was there a morphologic spectrum of cells with less atypia than AIS. Of the specimens, 14% had benign endocervical cell changes. The percentage of specimens in each group with benign endocervical cell changes was approximately equal.
Although our study is small and retrospective, it suggests that no morphologic evidence exists to support the existence of a spectrum of endocervical glandular changes that culminates in AIS.
Cdc6
Immunohistochemical localization of cdc6 in squamous and glandular neoplasia of the uterine cervix.Bonds L, Baker P, Gup C, Shroyer KR.
Department of Pathology, School of Medicine, University of Colorado Health Sciences Center, Denver.
Arch Pathol Lab Med 2002 Oct;126(10):1164-8 Abstract quote Context.-Cdc6 has been extensively studied as a marker for cellular proliferation that is expressed during the normal cell cycle. Recent studies indicate that Cdc6 may be a marker for cervical intraepithelial neoplasia (CIN) and carcinoma; however, the histologic distribution of Cdc6 has not been explicitly defined. Expression of Cdc6 in the endocervical mucosa also remains unexplored.
Objective.-The goal of the current study was to evaluate the distribution of Cdc6 protein, MIB-1 protein, and human papillomavirus (HPV) DNA in a broad range of cervical tissues, including normal, potentially premalignant, and malignant lesions of the ectocervical and endocervical mucosa.
Methods.-We used an indirect immunoperoxidase method to stain formalin-fixed, paraffin-embedded tissues and frozen tissues, including biopsy and hysterectomy specimens, for Cdc6 and MIB-1 proteins, and we used in situ hybridization to detect HPV DNA in a subset of cases.
Results.-Cdc6 staining was exclusively nuclear and was present in both squamous and glandular epithelial cells of histologic sections. Cdc6 staining was rarely present in specimens of normal cervical squamous mucosa (2/84, 2.4%) or in specimens with squamous metaplasia (3/59, 5.1%) and was not detected in normal endocervical glands (0/84). Staining was present in most cases of CIN I (31/48, 65%). Staining was present in the majority of cases of CIN II (25/28, 89%) and in all cases of CIN III (36/36) and squamous cell carcinomas (34/34). The proportion of cells staining for Cdc6 increased with the grade of dysplasia, and the proportion of stained cells in squamous cell carcinomas was similar to that in lesions of high-grade dysplasia. Cdc6 staining was present in the majority of cases in glandular lesions including adenocarcinoma in situ (11/14, 79%) and adenocarcinoma (8/10, 80%). The histologic distribution of Cdc6-immunoreactive cells was similar to that of cells with a strong signal for HPV DNA, but Cdc6 protein and HPV DNA did not colocalize at the level of individual cells.
Conclusion.-Cdc6 expression is a marker for high-grade cervical squamous and glandular dysplasia and carcinoma and is associated with HPV infection. The mechanistic basis of the association between HPV infection and Cdc6 immunopositivity remains to be determined but may represent either up-regulation of Cdc6 expression or stabilization of the Cdc6 protein.
HUMAN PAPILLOMA VIRUS
- Prevalence of human papillomavirus DNA in various histological subtypes of cervical adenocarcinoma: a population-based study.
An HJ, Kim KR, Kim IS, Kim DW, Park MH, Park IA, Suh KS, Seo EJ, Sung SH, Sohn JH, Yoon HK, Chang ED, Cho HI, Han JY, Hong SR, Ahn GH.
1Department of Pathology, Pochon CHA University, Sungnam, South Korea.
Mod Pathol. 2005 Apr;18(4):528-34. Abstract quote
The role of human papilloma virus (HPV) infection in the development of cervical carcinoma is well established, however, the prevalence of HPV DNA in cervical adenocarcinoma varies from study to study. It appears to be caused by a number of factors, one of which is that cervical adenocarcinomas comprise a heterogeneous group of multiple subtypes.
To clarify the impact of HPV infection on the development of cervical adenocarcinoma with diverse histological subtypes, we performed a population-based study in Korean women from 15 different institutes for the status of HPV infection in adenocarcinoma of uterine cervix. A total of 432 cervical adenocarcinomas from 1997 to 2001 were reviewed and classified according to the modified WHO classification. For 135 cases, HPV typing was performed with HPV DNA chip (82 cases) and PCR HPV typing (53 cases), using formalin-fixed, paraffin-embedded archival tissue. The overall prevalence of HPV infection in cervical adenocarcinoma was 90%. The infection of HPV 16 and/or HPV 18 accounted for 78% of HPV-positive adenocarcinomas. Multiple HPV types were found in 13% of the cases. The HPV DNA was rarely detected in minimal deviation adenocarcinoma.
Interestingly, HPV 16 was a predominant type in endometrioid and villoglandular types, whereas HPV 16 and HPV 18 were detected with equal prevalence in other subtypes.
In conclusion, HPV infection, mostly HPV 16 and HPV 18, is highly associated with most of the cervical adenocarcinomas, whereas endometrioid and villoglandular type have a different pattern of HPV infection status. Minimal deviation adenocarcinoma does not seem to be related with HPV infection.
Human papillomaviruses, expression of p16, and early endocervical glandular neoplasia.Riethdorf L, Riethdorf S, Lee KR, Cviko A, Loning T, Crum CP.
Division of Women's and Perinatal Pathology, Department of Pathology, Brigham and Women's Hospital, Boston, MA; and the Department of Gynecopathology, University of Hamburg, Germany.
Hum Pathol 2002 Sep;33(9):899-904 Abstract quote Adenocarcinoma in situ (ACIS) is the precursor of cervical adenocarcinoma (ACs), and its distinction from benign but morphologically atypical glandular epithelium may be difficult. The cyclin-dependent kinase inhibitor p16(ink4) is expressed in cervical squamous cell carcinomas, their precursors, and cervical ACs, and there is a strong relationship between p16 expression and the presence of human papillomavirus (HPV)-encoded E6/E7 transcription.
This study analyzed 95 cases of benign and premalignant cervical glandular ACIS lesions for p16 antigen and the proliferative marker Ki-67; HPV E6/E7 transcripts were detected by RNA/RNA in situ hybridization. HPV 16 or 18 E6/E7 transcription and strong, diffuse p16 positivity were detected only in ACIS lesions. A high and moderate Ki-67 index was observed in 76% and 22% of ACIS, respectively.
Thirty-three of 36 microglandular change, tubal, atypical tubal, and endometrial-type epithelia scored negative or weakly positive for p16. Distribution of staining in 3 strongly positive cases was heterogeneous. The diffuse distribution of p16 immunostaining in HPV16/18-positive glandular neoplasms supports a strong association with HPV infection and indicates that this biomarker may discriminate ACIS from its benign mimics. However, this distinction requires attention to staining distribution because p16 is focally expressed in tubal-endometrial epithelia and diffusely expressed in endometrium, indicating that in some cases the use of other biomarkers, such as Ki-67, may be necessary.
Because endometrial glandular epithelia may also express p16, the diagnostic application of p16 immunohistochemistry to cytological samples is uncertain.
HISTOLOGICAL TYPES CHARACTERIZATION General PRECURSOR LESIONS
Endocervical intraepithelial glandular atypia (dysplasia): a histopathologic, human papillomavirus, and MIB-1 analysis of 25 cases.Lee KR, Sun D, Crum CP.
Department of Pathology, Brigham & Women's Hospital, Boston, MA 02115, USA.
Hum Pathol 2000 Jun;31(6):656-64 Abstract quote The purpose of this study was to determine the likelihood that intraepithelial endocervical glandular atypias that are less severe than adenocarcinoma in situ (AIS) are precursors to AIS and, if so, whether they can be recognized by morphological or other means.
We first assessed the frequency of atypias found in association with either AIS or invasive adenocarcinoma (ACA) and then tested these cases and additional randomly encountered cases for the presence of human papillomavirus (HPV) and for their proliferative (Ki-67) index.
Lesions not fulfilling the classic criteria for AIS were subdivided into high-grade (HGGA) and low-grade glandular atypias (LGGA). Atypias and controls were microdissected and tested for HPV by the polymerase chain reaction. Serial sections were labeled for Ki-67 by immunohistochemistry with the MIB-1 antibody. Eight cases (6.8%) containing glandular atypia were found in a search of 117 consecutive cone biopsy or hysterectomy specimens that also had either AIS, ACA, or both. An additional 17 cases were either randomly encountered or were received in consultation. In 3 cases, both HGGA and LGGA were present, yielding a total of 28 lesions for study. Of the 9 HGGA cases that were associated with either AIS, ACA, or CIN II/III, 6 were positive for HPV; MIB-1 reactivity in all 6 was present in greater than 25% of the nuclei. Of the 3 HPV-negative HGGA cases in this group, the 2 that were tested showed low MIB-1 reactivity. All 3 cases of HGGA that were not associated with a diagnostic lesion were HPV-negative and had low MIB-1 reactivity. Of the 6 LGGAs associated with either AIS, ACA, or CIN II/III, 1 was positive for HPV; MIB-1 was nonreactive in this case and was low in all of the HPV-negative cases in this group that were tested. Of 10 LGGAs not associated with a diagnostic lesion, or with a low-grade squamous lesion as the only other abnormality, 2 were positive for HPV. Of these 2, one had an MIB-1 reactivity of greater than 25% and also had intestinal differentiation. MIB-1 reactivity was elevated in 2 of the 8 HPV-negative LGGAs from this group. All 10 ciliated atypias (3 HGGA, 7 LGGA) were HPV-negative and had low MIB-1 reactivity. One HPV-positive AIS control case was focally ciliated. Six of 7 foci with apoptotic bodies (5 HGGA, 2 LGGA) were HPV-positive.
The infrequent occurrence of glandular atypias with AIS and ACA and the low rate of HPV DNA positivity when they are found in isolation are evidence that most AIS lesions do not evolve through morphologically identifiable antecedents and that most isolated atypias are not AIS precursors. HGGAs associated with AIS or CIN II/III maybe either precursors to or subtle variants of AIS. However, LGGAs similarly encountered are unlikely to be either. Elevated MIB-1 reactivity may be helpful diagnostically in selected cases, but it is not reliable as an independent criterion. The presence of cilia in isolated glandular atypias favors a nonneoplastic process, whereas intestinal differentiation and apoptotic bodies each suggest neoplasia.
PAP SMEAR
Detection of adenocarcinoma in situ of the cervix in Papanicolaou tests: comparison of diagnostic accuracy with other high-grade lesions.
Renshaw AA, Mody DR, Lozano RL, Volk EE, Walsh MK, Davey DD, Birdsong GG.
Department of Pathology, Baptist Hospital, Miami, Fla, USA.
Arch Pathol Lab Med. 2004 Feb;128(2):153-7. Abstract quote
CONTEXT: Adenocarcinoma in situ of the cervix is a recently recognized interpretation in the Bethesda 2001 system. Although specific morphologic criteria have been published, recognizing this entity is still difficult.
OBJECTIVE: To compare pathologists' ability to correctly identify and categorize adenocarcinoma in situ with their ability to identify and categorize adenocarcinoma, high-grade squamous intraepithelial lesion, and squamous cell carcinoma.
DESIGN: Pathologists' reviews in the 2001 and 2002 College of American Pathologists Interlaboratory Comparison Program in Cervicovaginal Cytology Program, an interlaboratory comparison program for gynecologic cytology, were examined. Cases were usually reviewed by multiple pathologists. False-negative rates, the percentage of reviews with exact agreement with reference interpretations, and the percentage of cases in which all reviews were in exact agreement with the reference interpretation for adenocarcinoma in situ, adenocarcinoma, high-grade squamous intraepithelial lesion, and squamous cell carcinoma were compared.
RESULTS: A total of 213 reviews of cases categorized as adenocarcinoma in situ were compared with 2821 reviews of adenocarcinoma, 7535 reviews of high-grade squamous intraepithelial lesion, and 1886 reviews of squamous cell carcinoma. The false-negative rate for adenocarcinoma in situ (11.7%) was significantly higher than that for high-grade squamous intraepithelial lesion (4.6%, P <.001) and squamous cell carcinoma (3.3%, P <.001) but not for adenocarcinoma (8.9%, P =.16). Of all the reviews of adenocarcinoma in situ cases, 46.5% were interpreted specifically as adenocarcinoma in situ, compared to 72.2% of reviews of adenocarcinoma, 73.2% of high-grade squamous intraepithelial lesion, and 75.1% of squamous cell carcinoma. No individual case of adenocarcinoma in situ was always specifically recognized as adenocarcinoma in situ; 26.5% of cases of adenocarcinoma were specifically recognized as such in all reviews. Findings were similar with and without the inclusion of high-grade squamous intraepithelial lesion/carcinoma, not otherwise specified, as an acceptable review interpretation for cases of adenocarcinoma, squamous cell carcinoma, and high-grade squamous intraepithelial lesion.
CONCLUSION: These data from expert-referenced and biopsy-proven cases suggest that adenocarcinoma in situ is not as easily recognized or categorized as other serious diagnoses.
Adenocarcinoma in situ of the cervix.Schoolland M, Segal A, Allpress S, Miranda A, Frost FA, Sterrett GF.
Departments of Cytopathology and Histopathology, Western Diagnostic Pathology, Myaree, Western Australia, Australia.
Cancer 2002 Dec 25;96(6):330-7 Abstract quote BACKGROUND: The current study examines 1) the sensitivity of detection and 2) sampling and screening/diagnostic error in the cytologic diagnosis of adenocarcinoma in situ (AIS) of the cervix. The data were taken from public and private sector screening laboratories reporting 25,000 and 80,000 smears, respectively, each year.
METHODS: The study group was comprised of women with a biopsy diagnosis of AIS or AIS combined with a high-grade squamous intraepithelial lesion (HSIL) who were accessioned by the Western Australian Cervical Cytology Registry (WACCR) between 1993-1998. Cervical smears reported by the Western Australia Centre for Pathology and Medical Research (PathCentre) or Western Diagnostic Pathology (WDP) in the 36 months before the index biopsy was obtained were retrieved. A true measure of the sensitivity of detection could not be determined because to the authors' knowledge the exact prevalence of disease is unknown at present. For the current study, sensitivity was defined as the percentage of smears reported as demonstrating a possible or definite high-grade epithelial abnormality (HGEA), either glandular or squamous. Sampling error was defined as the percentage of smears found to have no HGEA on review. Screening/diagnostic error was defined as the percentage of smears in which HGEA was not diagnosed initially but review demonstrated possible or definite HGEA. Sensitivity also was calculated for a randomly selected control group of biopsy proven cases of Grade 3 cervical intraepithelial neoplasia (CIN 3) accessioned at the WACCR in 1999.
RESULTS: For biopsy findings of AIS alone, the diagnostic "sensitivity" of a single smear was 47.6% for the PathCentre and 54.3% for WDP. Nearly all the abnormalities were reported as glandular. The sampling and screening/diagnostic errors were 47.6% and 4.8%, respectively, for the PathCentre and 33.3% and 12.3%, respectively, for WDP. The results from the PathCentre were better for AIS plus HSIL than for AIS alone, but the results from WDP were similar for both groups. For the CIN 3 control cases, the "sensitivity" of a single smear was 42.5%.
CONCLUSIONS: To the authors' knowledge epidemiologic studies published to date have not demonstrated a benefit from screening for precursors of cervical adenocarcinoma. However, in the study laboratories as in many others, reasonable expertise in diagnosing AIS has been acquired only within the last 10-15 years, which may be too short a period in which to demonstrate a significant effect. The results of the current study provide some encouraging baseline data regarding the sensitivity of the Papanicolaou smear in detecting AIS. Further improvements in sampling and cytodiagnosis may be possible.
Atypical glandular cells of undetermined significance (AGUS): cytopathologic features, histopathologic results, and human papillomavirus DNA detection.
Ronnett BM, Manos MM, Ransley JE, Fetterman BJ, Kinney WK, Hurley LB, Ngai JS, Kurman RJ, Sherman ME.
Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Hum Pathol 1999 Jul;30(7):816-25 Abstract quote
We intensively reviewed 137 smears initially classified as atypical glandular cells of undetermined significance (AGUS) to refine cytological criteria for evaluating these cases, evaluate histological outcomes, and assess the value of human papillomavirus (HPV) DNA testing in management.
Consenting, nonpregnant study participants were identified from a cohort of 46,009 women receiving routine Pap smear screening in a managed care setting. Colposcopy was performed on all women, and at least one histological sample was obtained from each. Review diagnoses were assigned to smears and biopsy specimens by two separate panels of pathologists. DNA testing for cancer-associated HPV types was performed on rinses of cytological samplers after a smear and thin-layer slide had been made.
On review, 47 (34%) smears were reclassified as negative, 44 (32%) as AGUS, 30 (22%) as atypical squamous cells of undetermined significance (ASCUS), and 16 (12%) as squamous intraepithelial lesions (SIL). The 19 smears interpreted as high-grade intraepithelial lesions on review included 13 high-grade SIL (HSIL), two HSIL with AGUS, favor neoplastic (endocervical adenocarcinoma in situ [AIS]), and four AGUS, favor neoplastic (AIS).
Review histological diagnoses were negative in 105 (77%), squamous or glandular atypia in four (3%), low-grade SIL (LSIL) in nine (7%), HSIL in 12 (9%), AIS in five (4%, including two with concurrent HSIL), and endometrial carcinoma in one (1%). HPV testing identified 11 (92%) of 12 women with histologically confirmed HSIL and all five with AIS (100%).
A high-grade intraepithelial lesion or carcinoma is detected in approximately 14% of women with community-based diagnoses of AGUS who are referred for immediate evaluation. Use of refined cytological criteria and HPV DNA testing may permit improved management of women with AGUS.
VARIANTS LOBULAR ENDOCERVICAL GLANDULAR HYPERPLASIA
- Endocervical adenocarcinomas associated with lobular endocervical glandular hyperplasia: a report of four cases with histochemical and immunohistochemical analyses.
Kondo T, Hashi A, Murata S, Nakazawa T, Yuminamochi T, Nara M, Hoshi K, Katoh R.
1Departments of Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
Mod Pathol. 2005 Sep;18(9):1199-210. Abstract quote
We report on four cases of endocervical adenocarcinoma associated with lobular endocervical glandular hyperplasia using histochemical and immunohistochemical analyses. The patients ranged in age from 59 to 67 years (mean 62 years).
Chief complaints were watery vaginal discharge in two cases, genital bleeding in one and no subjective symptoms in one. Cytological examinations of the cervical smears revealed adenocarcinoma cells and benign-looking glandular cells with intracytoplasmic golden-yellow mucin in all cases. Radical hysterectomy was performed in three patients, and simple total hysterectomy was performed in one. From surgical specimens, three tumors were diagnosed as mucinous adenocarcinoma and one was adenocarcinoma in situ.
All adenocarcinomas were located proximally on the cervix, and did not involve the transformation zone. Adjacent to carcinoma tissues in the cervix, lobular endocervical glandular hyperplasia was detected. The cells of lobular endocervical glandular hyperplasia were dominantly positive with neutral mucin, and immunohistochemistry revealed that these cells had prominent pyloric gland mucin (HIK1083). Focal immunopositivity for pyloric mucin was also observed in three adenocarcinomas. Either CEA or p53 were immunopositive in all adenocarcinomas and negative in the tissues of lobular endocervical glandular hyperplasia.
Histopathological features of the present cases suggest that some endocervical adenocarcinomas may originate from lobular endocervical glandular hyperplasia.MESONEPHRIC Mesonephric Adenocarcinomas of the Uterine Cervix A Study of 11 Cases With Immunohistochemical Findings Am J Surg Pathol 2001;25:379-387
We describe the clinicopathologic and immunohistochemical features of 11 examples of this neoplasm, which occurred in women between the ages of 35 and 72 years (mean, 52 years). Most (64%) patients had abnormal vaginal bleeding. Eight tumors were stage IB, and one each was stage IIB and IVB; in one, the stage was unknown.
Microscopically, the carcinomas showed various morphologies, most commonly a small tubular pattern or a ductal pattern resembling endometrioid adenocarcinoma; one tumor had an associated malignant spindle cell component. Ten neoplasms were adjacent to hyperplastic mesonephric remnants.
Follow-up in 10 cases showed six patients to be alive without evidence of recurrence after a mean of 4.8 years. The patients with stage IIB and IVB disease had local recurrences after 2.2 and 0.7 years and died of progressive disease at 3.2 and 0.8 years, respectively. In a patient with stage IB disease, a mediastinal metastasis and a malignant pleural effusion developed 5.6 years after diagnosis, and the patient died of disease at 6.2 years. Another patient with stage IB disease and a positive vaginal cuff margin that recurred locally after 1.7 years received chemotherapy and was alive and clinically free of disease at 2.5 years.
Mesonephric adenocarcinomas were immunoreactive for epithelial markers (AE1/3; CK1, CAM 5.2, cytokeratin 7, and epithelial membrane antigen) (100%), calretinin (88%), vimentin (70%), androgen receptor (33%), and inhibin (30%, focal staining). No immunostaining was detected with cytokeratin 20, estrogen receptor, progesterone receptor, and monoclonal carcinoembryonic antigen.
Conclusion:
This staining profile is similar to that of mesonephric remnants and may be useful in the distinction of mesonephric carcinoma from mullerian endometrioid adenocarcinoma, with which it may be confused.MICROCYSTIC Microcystic Endocervical Adenocarcinomas A Report of Eight Cases
Rosemary Tambouret, M.D.; Debra A. Bell, M.D.; Robert H. Young, M.D.
From the James Homer Wright Pathology Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, MA, U.S.A.
Am J Surg Pathol 2000;24:369-374 Abstract quote
Eight endocervical adenocarcinomas with a prominent cystic component that resulted in a resemblance, in part, to certain benign lesions are described.
The patients ranged in age from 34 to 78 years (average age, 48.6 years), and three women were postmenopausal. Presentations included abnormal cervical cytology smears (n = 4) and vaginal bleeding (n = 3). One patient was pregnant at the time of diagnosis. Six tumors were typical endocervical-type and two tumors were intestinal-type adenocarcinomas. The cysts occupied 50% to approximately 90% of the tumor and ranged from 1 to 8 mm in diameter. They were lined by flattened to low cuboidal to pseudostratified epithelium with focal goblet cells and Paneth cells in the two intestinal-type tumors, and the epithelial lining of the cysts was denuded occasionally. Seven tumors contained luminal mucin, which was brightly eosinophilic in one patient and resembled the contents of mesonephric tubules, but was mucin positive on special stains. A desmoplastic stroma was identified in two patients; the remainder had no stromal reaction.
The features that resulted in mimicry of benign lesions were the cystic glands, their sometimes orderly distribution, and focal, deceptively bland cytology. All tumors contained, at least focally however, architecturally abnormal glands lined by cytologically malignant cells.
SUPERFICIAL (EARLY)
- Superficial (Early) Endocervical Adenocarcinoma In Situ: A Study of 12 Cases and Comparison to Conventional AIS.
Witkiewicz A, Lee KR, Brodsky G, Cviko A, Brodsky J, Crum CP.
From the Division of Women's and Perinatal Pathology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
Am J Surg Pathol. 2005 Dec;29(12):1609-1614. Abstract quote
Although established histologic criteria for the diagnosis of endocervical adenocarcinoma in situ (AIS) have been published, some lesions are not readily classified or present with more subtle degrees of epithelial atypia. Lesions confined to the surface mucosa may be particularly challenging, possibly because they represent early disease.
Twelve cases of superficial AIS (SAIS) confined to the surface mucosa or crypt openings culled from the in-house and consultation practices were examined histologically, immunostained for MIB-1 and p16, and analyzed (when possible) for HPV nucleic acids by DNA-DNA in situ hybridization (INFORM). The mean age was 26.7 years for SAIS versus 37.0 years for 42 consecutive cases of conventional AIS from the same practice (P < 0.001). Seven and five were biopsies and conization specimens, respectively.
Five coexisted with CIN, four arose in endocervical papillae, and two arose in endocervical polyps. Nuclear hyperchromasia was conspicuous in 10 and mitoses were present in all; however, apoptosis was rare or absent in four, and six exhibited only mild nuclear atypia. Mib-1 staining exceeded 40% in 5 of 7 cases tested, and all (8 of 8) were strongly positive for p16. Five of five were positive for HPV by ISH with an "integrated" dot-like pattern.
SAIS is an early variant of AIS that 1) occurs at a younger mean age, 2) exhibits variable atypia, and 3) arises adjacent to morphologically normal columnar epithelium. Diffuse p16 expression and integrated HPV pattern are identical to that seen in more extensive forms of the disease. Superficial AIS should be suspected in endocervical columnar epithelium with segmental nuclear hyperchromasia with mitotic activity, and confirmed by biomarker staining (p16 and Mib-1) if the pathologist is uncertain of the diagnosis.VILLOGLANDULAR Villoglandular papillary adenocarcinoma of the uterine cervix with bulky lymph node metastases.
Utsugi K, Shimizu Y, Akiyama F, Hasumi K.
Department of Gynecology, Cancer Institute Hospital, 1-37-1 Kami-lkebukuro, Toshima-ku, Tokyo 170-8455, Japan.
Eur J Obstet Gynecol Reprod Biol 2002 Nov 15;105(2):186-8 Abstract quote A patient with stage IIb cervical adenocarcinoma underwent Wertheim hysterectomy with pelvic lymphadenectomy and bilateral adenexectomy followed by radiotherapy.
Review of histologic sections diagnosed villoglandular papillary adenocarcinoma (VGPA) with metastatic lymph nodes. The patient has been disease-free for 17 years.
This patient is the third case of VGPA with lymph node metastasis ever reported.
SPECIAL STAINS/
IMMUNOPEROXIDASECHARACTERIZATION Special stains Reappraisal of Orthodox Histochemistry for the Diagnosis of Minimal Deviation Adenocarcinoma of the Cervix
Isamu Hayashi, M.T.; Hitoshi Tsuda, M.D.; Tadakazu Shimoda, M.D.
From the Department of Clinical Laboratory (I.H., T.S.), and Pathology Division (H.T.), National Cancer Center Hospital and Research Institute, Tokyo, Japan.
Am J Surg Pathol 2000;24:559-562 Abstract quote
Minimal deviation adenocarcinoma (MDA), or adenoma malignum, of the uterine cervix is a diagnostically problematic disease because of the difficulty in differentiating it histologically from normal cervical glands.
To evaluate the use of mucin phenotyping for differentiating MDA from other conditions, we performed alcian blue pH 2.5/periodic acid-Schiff (AB-PAS) staining and high iron diamine (HID)-AB staining on routinely processed sections of 11 MDAs, 20 unremarkable cervical glands, 9 cervical glandular hyperplasias occurring in association with mucinous ovarian tumors, and 41 conventional cervical adenocarcinomas.
In all 11 MDAs and 11 conventional cervical adenocarcinomas, the tumor cell cytoplasm was stained diffusely red by PAS, indicating that MDA cells produce neutral mucin almost exclusively. The amount of acid mucins, both sulfomucin and sialomucin, was decreased markedly by HID-AB. For four MDAs, preoperative biopsy specimens also showed diffuse cytoplasmic neutral mucin. In contrast, the cytoplasm of constituent cells was stained purple to violet by AB-PAS in all unremarkable cervical glands and glandular hyperplasias, indicating that both acid and neutral mucins were produced in equal amounts, sulfomucin being stained predominantly by HID-AB. Of the 30 conventional cervical adenocarcinomas, 28 showed both acid and neutral mucins and two showed acid mucin only in goblet cells, or in part of the cytoplasm or cell surface of constituent cells, where acid mucin consisted predominantly of sulfomucin in 14 and sialomucin in 16.
AB-PAS and HID-AB are simple and orthodox histochemical methods which are effective for differential diagnosis of MDA and can contribute to its early detection and treatment.
IMMUNOPEROXIDASE
A panel of immunohistochemical stains, including carcinoembryonic antigen, vimentin, and estrogen receptor, aids the distinction between primary endometrial and endocervical adenocarcinomas.McCluggage WG, Sumathi VP, McBride HA, Patterson A.
Department of Pathology, Royal Group of Hospitals Trust, Belfast, Northern Ireland.
Int J Gynecol Pathol 2002 Jan;21(1):11-5 Abstract quote The histological distinction between a primary endometrial and a primary endocervical adenocarcinoma is often difficult, especially in small biopsy specimens. A preoperative distinction is important because primary surgical management differs between the two tumors. Cases of primary endometrioid endometrial (n=30) and primary endocervical (n=26) adenocarcinoma of endocervical type were stained immunohistochemically with the monoclonal antibodies against carcinoembryonic antigen (CEA), vimentin, estrogen receptor (ER), and 34 beta E12. In all cases the origin of the adenocarcinoma was confirmed by examination of the definitive pathology specimen.
There was diffuse positive nuclear staining for ER in 28 of 30 (93%) endometrial adenocarcinomas. ER was negative in 16 of 26 endocervical adenocarcinomas, and there was focal weak nuclear staining in the other cases. Vimentin was positive in 29 of 30 (97%) endometrial adenocarcinomas but in only 2 of 26 (8%) endocervical adenocarcinomas. CEA was positive in 25 of 26 (96%) endocervical adenocarcinomas, mostly with diffuse membranous and cytoplasmic staining. Positivity with CEA was present in 21 of 30 (70%) endometrial adenocarcinomas but was largely confined to squamoid areas with only 12 tumors exhibiting focal membranous staining of the glandular component. 34 beta E12 was diffusely positive in all except one cervical adenocarcinoma.
In endometrial carcinomas, positivity was strongest in squamoid areas but there was positive staining, either focally or diffusely, of the glandular component in 27 cases. In summary, primary endometrioid endometrial adenocarcinomas are characterized by diffuse, strong, positive staining for vimentin and ER and negative or very focal, positive staining of the glandular component for CEA. In contrast, primary endocervical adenocarcinomas are characterized by CEA positivity, which is usually but not always diffuse, negativity for vimentin, and negativity or focal weak positivity for ER. 34 beta E12 is of no value in the distinction between endometrial and endocervical adenocarcinomas.
A panel of immunohistochemical stains, comprising CEA, vimentin, and ER, generally allows confident preoperative distinction between a primary endometrial and endocervical adenocarcinoma.
Immunohistochemical Staining in the Distinction Between Primary Endometrial and Endocervical Adenocarcinomas: Another Viewpoint Seiryu Kamoi, M.D.; Muna I. AlJuboury, M.D.; Marie-Rose Akin, M.D.; Steven G. Silverberg, M.D.
From the Departments of Pathology, University of Maryland School of Medicine and Medical Center, Baltimore, Maryland (S.K., M.I.A, S.G.S.), Loma Linda University School of Medicine, California (M.R.A.), Riyadh Armed Forces Hospital, Saudi Arabia (M.I.A.), and the Department of Obstetrics and Gynecology, Nippon Medical School Chiba Hokusoh Hospital, Japan (S.K.).
Int J Gynecol Pathol 2002 Jul;21(3):217-23 Abstract quote Several studies have reported on the use of antibodies to monoclonal carcinoembryonic antigen (CEA) and vimentin (VIM) to distinguish between adenocarcinomas of endometrial (EM) and endocervical (EC) origin, with variably enthusiastic results. It is still unclear whether site of origin or pathway of differentiation (endometrioid [em] versus mucinous [m]) is more important in predicting immunohistochemical differences.
In the present study, paraffin blocks from adenocarcinomas of known origin were retrieved and immunostained with monoclonal antibodies to VIM and CEA, as well as cytokeratins (CK) 4, 18, and 20, estrogen receptor (ER), and progesterone receptor (PR). Positivity was scored on a scale from 0 to 12, with emphasis on the pattern of differentiation (tumors with mixed patterns received separate scores for the em and m foci). Mean CEA scores for emEM (n = 27), mEM (17), mEC (10), and emEC (6) were 0.4, 0.9, 5.1, and 1.2, respectively. VIM scores were 6.9, 1.3, 0, 4.4; ER, 5.7, 4.2, 0, 1.6; PR, 7.6, 2.8, 0.1, 6.0; CK4, 9.2, 4.4, 8.5, 10.6; CK18, 6.4, 3.4, 5.5, 8.4; CK20, 0.7, 0, 0.5, 0.4. Both site and differentiation influenced these results, with the latter more important for VIM and PR, the former for ER, both for CEA (only mEC was frequently strongly positive), and neither for the CKs studied. No one stain or combination reliably distinguished endometrial from endocervical origin.
The only immunostaining pattern that might identify a site of origin with more accuracy than hematoxylin & eosin evaluation alone is the combination of high VIM and ER scores in an endometrioid carcinoma, suggesting with about 95% accuracy in this series an endometrial origin of the tumor.
Cdx-2
Primary cervical adenocarcinoma with intestinal differentiation and colonic carcinoma metastatic to cervix: an investigation using Cdx-2 and a limited immunohistochemical panel.
Raspollini MR, Baroni G, Taddei A, Taddei GL.
Department of Human Pathology and Oncology, University of Florence, Florence, Italy.
Arch Pathol Lab Med. 2003 Dec;127(12):1586-90. Abstract quote
CONTEXT: Cdx-2 is expressed in normal colonic epithelia and in most colorectal adenocarcinomas. No data exist on Cdx-2 expression in primary cervical adenocarcinoma with colonic differentiation.
OBJECTIVE: To ascertain the utility of Cdx-2 and a limited immunohistochemical panel in differentiating between primary cervical adenocarcinoma with intestinal differentiation and secondary (colonic) cervical adenocarcinoma, which call for different surgical and chemotherapeutic treatment protocols.
DESIGN: We examined cervical tract adenocarcinomas in women with previously negative medical histories for neoplastic disease and in women with colonic carcinoma. An immunohistochemical panel consisting of cytokeratin 7, cytokeratin 20, carcinoembryonic antigen, and a new marker, Cdx-2, was evaluated in all cases. The clinical data, the morphologic features, and the immunohistochemical staining patterns were compared.
RESULTS: Of the tumors diagnosed as metastatic intestinal adenocarcinoma of the cervix, based on clinical data and hematoxylin-eosin-stained sections, all were Cdx-2 positive, whereas Cdx-2 was not expressed in any of our cases of primary cervical adenocarcinoma with colonic differentiation. Carcinoembryonic antigen was expressed both in primary cervical tumor and in secondary (intestinal) cervical adenocarcinoma. Cytokeratin 20 was not expressed in our cases of cervical adenocarcinoma, and it was not expressed in 7.15% of cervical metastases from intestinal carcinoma. Immunostaining with cytokeratin 7 was positive in cervical adenocarcinoma, but was negative in secondary (intestinal) cervical adenocarcinoma.
CONCLUSIONS: Our immunohistochemical analysis shows that Cdx-2 has good specificity and would be a good marker to use in a limited panel of immunohistochemical markers, such as cytokeratin 7, cytokeratin 20, and carcinoembryonic antigen, to distinguish primary cervical adenocarcinoma from intestinal metastases to the cervix.IMP3
Adenocarcinoma in situ of the uterine cervix remains a diagnostic challenge in a small proportion of cases. This suggests a need for biomarker that may be of help in establishing the diagnosis.
The aim of this study was to evaluate the potential of insulin-like growth factor-II mRNA-binding protein 3 and cyclin-dependent kinase inhibitor p16(INK4a) as biomarkers for adenocarcinoma in situ. Forty-four samples of adenocarcinoma in situ from 40 patients and 23 control cases of benign uterine cervix were included in this study. In addition to benign endocervical epithelium, 19 of these 23 control cases also showed focal tubal metaplasia.
Cytoplasmic immunoreactivity for insulin-like growth factor-II mRNA-binding protein 3 was identified in 41 (93%) adenocarcinoma in situ samples, among which, 29 (71%), 10 (24%), and 2 (5%) samples showed insulin-like growth factor-II mRNA-binding protein 3 positive staining in 50% or more, >5 to <50 and <5% of adenocarcinoma in situ lesional cells, respectively. Immunohistochemical reaction intensity for insulin-like growth factor-II mRNA-binding protein 3 was found to be strong in 34 adenocarcinoma in situ samples, intermediate in five, and weak in two.
All 23 control cases were negative for insulin-like growth factor-II mRNA-binding protein 3. p16(INK4a) expression was identified in all of the adenocarcinoma in situ samples with intermediate staining intensity seen in seven samples and strong in the remainder. Fourteen of 19 (74%) tubal metaplasia cases showed p16(INK4a) immunoreactivity in >50% of the tubal metaplastic epithelium with staining intensity ranging from weak to strong.
Our findings demonstrate significant expression of insulin-like growth factor-II mRNA-binding protein 3 and p16(INK4a) in adenocarcinoma in situ as compared to benign endocervical glands, suggesting that expression of these biomarkers may be helpful in the distinction of adenocarcinoma in situ from benign endocervical glands, particularly in difficult borderline cases.p16 Evaluation of p16 and pRb expression in cervical squamous and glandular neoplasia.
Tringler B, Gup CJ, Singh M, Groshong S, Shroyer AL, Heinz DE, Shroyer KR
Hum Pathol. 2004 Jun;35(6):689-96. Abstract quote
p16(INK4a) is known to play a critical role as a negative regulator of cell cycle progression and differentiation by controlling the activity of the tumor-suppressor protein pRb. The present study evaluated the expression of p16(INK4a) and pRb in cervical squamous and glandular neoplasia.
Immunohistochemical staining was performed for p16(INK4a) and pRb in formalin-fixed, paraffin-embedded tissue sections of the uterine cervix using an indirect immunoperoxidase method. p16(INK4a) staining was detected in 7 of 108 sections (6.5%) of normal squamous mucosa, in scattered ciliated columnar cells in 33 of 88 sections (37.5%) of normal endocervical glands, in 9 of 30 sections (30%) with Nabothian cysts, and in 4 of 4 areas (100%) of tubal metaplasia.
In contrast, strong p16(INK4a) staining was found in 13 of 18 cases (72.2%) of cervical intraepithelial neoplasia (CIN) I and in all cases of CIN II/III (n = 46), squamous cell carcinoma (n = 18), endocervical glandular dysplasia (n = 10), adenocarcinoma in situ (n = 23), and invasive adenocarcinoma (n = 12). pRb expression was detected in each diagnostic category; however, the proportion of pRb-positive cells was relatively decreased in high-grade premalignant and malignant lesions of the squamous and endocervical mucosa and showed a generally inverse correlation with the expression of p16(INK4a) at the tissue level.
These findings confirm a correlation between the expression of p16(INK4a) and pRb in cervical neoplasias and indicate that p16(INK4a) is a specific marker for premalignant and malignant lesions of the squamous and endocervical mucosa.
p16INK4a Is a Useful Marker for the Diagnosis of Adenocarcinoma of the Cervix Uteri and Its Precursors: An Immunohistochemical Study With Immunocytochemical Correlations.Negri G, Egarter-Vigl E, Kasal A, Romano F, Haitel A, Mian C.
Am J Surg Pathol 2003 Feb;27(2):187-93 Abstract quote p16 is a tumor suppressor gene that plays a central role in the regulation of the cell cycle. In squamous cervical cancers, overexpression of p16 is induced by HPV and associated with the carcinogenesis of cervical epithelia.
The aim of this study was to determine whether immunostaining of p16 is useful in detecting adenocarcinomas of the cervix uteri in histologic and cytologic routine specimens. A total of 45 surgical specimens, including 18 cases of invasive carcinoma, 8 cases of adenocarcinoma in situ, 4 cases of endocervical glandular atypia (cervical glandular intraepithelial neoplasia), and 15 reactive lesions of the endocervical glands were immunostained using a specific anti-human p16 monoclonal antibody (clone E6H4, mtm laboratories AG, Heidelberg, Germany). Furthermore, immunocytochemical analysis was performed on 10 preoperative ThinPrep cytologic samples with abnormal glandular cells and compared with the human papillomavirus status as assessed with the Hybrid Capture II test. p16 was detected immunohistochemically in all 26 cases of adenocarcinoma of the cervix uteri, including 18 invasive and 8 in situ carcinomas. Only a focal expression was evidenced in the four specimens with endocervical glandular atypia, and no reaction was found in reactive lesions. Also, the immunocytochemical analysis on the 10 ThinPrep specimens evidenced a strong expression of p16 in neoplastic endocervical cells. In all cases this was associated with a high-risk HPV-positive typing.
p16 is a useful marker for the detection of the adenocarcinoma of the cervix uteri and its precursors. The immunocytochemical detection on ThinPrep specimens may contribute to an early detection of endocervical lesions.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES ARIAS-STELLA REACTION
Arias-Stella Reaction of the Endocervix: A Report of 18 Cases With Emphasis on Its Varied Histology and Differential Diagnosis.
Nucci MR, Young RH.
*Division of Women's and Perinatal Pathology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School; and daggerJames Homer Wright Pathology Laboratories, Massachusetts General Hospital and Department of Pathology, Harvard Medical School, Boston, MA.
Am J Surg Pathol. 2004 May;28(5):608-612. Abstract quote
We report 18 cases of Arias-Stella reaction involving the endocervix with an emphasis on histologic features that can be encountered and result in the misdiagnosis of carcinoma. The patients ranged in age from 19 to 44 years. Two patients had a history of oral contraceptive use and 15 were pregnant; clinical information was not available in one case. Ten lesions presented as cervical polyps, and six were incidental findings in specimens obtained because of cervical dysplasia, dysfunctional uterine bleeding, fibroids, and a missed abortion. One patient was found to have a cervical "lesion" on a routine gynecologic examination. In the remaining patient, a cervical biopsy was obtained, for unknown reasons, at the time of termination of pregnancy.
Microscopic examination showed a varied histologic appearance including vacuolated clear cytoplasm (18 cases), intraglandular tufts (16 cases), hobnail cells (14 cases), oxyphilic cytoplasm (13 cases), delicate filiform papillae (12 cases), intranuclear pseudoinclusions (10 cases), cribriform intraglandular growth (3 cases), and a single mitotic figure in 1 case. The histologic changes involved the superficial glands (6 cases), deep glands (4 cases), or both (8 cases); confluent or extensive gland involvement was seen in 8 cases. Follow-up information, available in four cases (4, 2, 1, 1 years), was unremarkable.
The principal consideration in the differential diagnosis was clear cell carcinoma. The features most helpful in this distinction were the usual lack of a mass suspicious for cancer, absence of a desmoplastic response, lack of an infiltrative pattern, spectrum of cytologic atypia, low nuclear-cytoplasmic ratio, and usual lack of mitotic activity.ECTOPIC PROSTATE TISSUE Ectopic Prostatic Tissue in the Uterine Cervix A Report of Four Cases and Review of Ectopic Prostatic Tissue
Marisa R. Nucci, M.D.; Judith A. Ferry, M.D.; Robert H. Young, M.D. Clement PB, Young RH, eds.
From the Department of Pathology, Division of Women's and Perinatal Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, U.S.A. (M.R.N.); and James Homer Wright Pathology Laboratories, Massachusetts General Hospital and the Department of Pathology, Harvard Medical School, Boston, Massachusetts, U.S.A. (J.A.F., R.H.Y.).
Am J Surg Pathol 2000;24:1224-1230 Abstract quote
We report four examples of prostatic tissue occurring in the uterine cervix of patients aged 22, 25, 31, and 77 years.
Three were incidental findings in loop excisions (two patients) and cone biopsy (one patient) of the cervix for high-grade squamous dysplasia. One presented as a cervical mass, clinically suspected to represent a fibroid. The prostatic tissue consisted of ducts and acini, some of which had papillary or cribriform patterns. Squamous metaplasia was prominent in all cases. No Wolffian duct tissue was present. The glandular epithelium in all cases was positive for prostatic acid phosphatase and prostate-specific antigen. High molecular weight keratin, performed in two cases, highlighted basal cells in a manner similar to the normal prostate.
These unusual cases, only one of which is documented previously, further complicate the often-challenging area of interpretation of benign glandular lesions of the cervix. The unusual phenomenon of ectopic prostate tissue in general is reviewed.
ENDOCERVICOSIS
Endocervicosis involving the uterine cervix: a report of four cases of a benign process that may be confused with deeply invasive endocervical adenocarcinoma.Young RH, Clement PB.
James Homer Wright Pathology Laboratories, Massachusetts General Hospital 02114, USA.
Int J Gynecol Pathol 2000 Oct;19(4):322-8 Abstract quote Four cases of endocervicosis that involved the outer cervical wall and paracervical connective tissue are reported; in one case there was also transmural involvement of the urinary bladder. A diagnosis of cervical adenocarcinoma was an initial concern of the referring pathologist in three cases.
The patients were from 29 to 45 years of age; there was a history of cesarean section in two cases. Two patients presented with pelvic pain, one with dysmenorrhea, and one with symptoms related to an ovarian tumor. In three cases, a gross abnormality of the outer aspect of the cervix was noted at the time of hysterectomy and in the fourth at the time of macroscopic pathologic examination. The anterior wall of the cervix in each case was involved by a firm rubbery mass, 1 to 2.5 cm in maximal dimension, with cysts seen on sectioning in two.
Microscopic examination disclosed a dominant population of glands of variable size and shape, including cystically dilated glands, lined by mucinous endocervical-type epithelium that ranged from columnar to flattened. All the glands had lining cells with bland cytologic features with absent to rare mitotic figures. A periglandular stromal reaction, present in two cases, was related to mucin extravasation. A cuff of endometriotic stroma was present around rare glands in one case. The appearance of the lesion was similar to that of endocervicosis of the urinary bladder, and as in that site, raised concern for adenocarcinoma, specifically for the minimal deviation (adenoma malignum) type of cervical adenocarcinoma.
Awareness of the distinctive features of endocervicosis in this site, including its dominant location in the outer portion of the cervix and paracervical connective tissue and the typical presence of an uninvolved zone of cervical wall between the endocervicosis and the eutopic endocervical glands, facilitate the correct diagnosis.
ENDOMETRIAL ADENOCARCINOMA Distinction of Endocervical and Endometrial Adenocarcinomas: Immunohistochemical p16 Expression Correlated With Human Papillomavirus (HPV) DNA Detection
Ansari-Lari, M Ali MD*; Staebler, Annette MD*; Zaino, Richard J MD‡; Shah, Keerti V MD, DRPH§; Ronnett, Brigitte M MD*†
From the Departments of *Pathology and †Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD; ‡Department of Pathology, Pennsylvania State University College of Medicine, Hershey, PA; and §Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD. The current affiliation of Dr. Staebler is Institute of Pathology, University of Muenster, Muenster, Germany.
The American Journal of Surgical Pathology : Volume 28(2) February 2004 pp 160-167 Abstract quote Determining the origin of uterine adenocarcinomas can be difficult in biopsy and curettage specimens because the morphologic spectrum of endocervical and endometrial adenocarcinomas overlaps. In hysterectomy specimens, the primary site is often equivocal for tumors that involve the lower uterine segment and endocervix and lack identifiable precursor lesions. Most endocervical adenocarcinomas (ECAs) contain high-risk human papillomavirus (HPV) DNA, whereas endometrial adenocarcinomas (EMAs) rarely do. p16 is an inhibitor of cyclin-dependent kinases, and overexpression of p16 has been observed in cervical intraepithelial lesions and invasive carcinomas associated with high-risk HPV types.
We evaluated the utility of immunohistochemistry for p16 in the distinction of ECAs and EMAs. p16 expression was assessed in 24 unequivocal EMAs and 19 unequivocal ECAs and correlated with HPV DNA detection by in situ hybridization and polymerase chain reaction. These assays were then used to assist in the classification of four lower uterine segment/upper endocervical adenocarcinomas (LUS/EC-A) of equivocal origin. p16 expression was moderate-strong and diffuse in 18 ECAs (median 90% of tumor cells positive, range 90%-100%), and weak and diffuse in one. Fourteen of these were positive for HPV DNA, whereas 5 lacked detectable HPV DNA by in situ hybridization; one of these 5 was positive by polymerase chain reaction. In contrast, EMAs displayed weaker staining with patchy distribution (median 30% of tumor cells positive, range 5%-70%) and none contained HPV DNA by in situ hybridization. Two LUS/EC-As, which were positive for HPV, exhibited strong, diffuse p16 expression, consistent with endocervical origin of the tumors. The remaining 2 LUS/EC-As showed patchy p16 staining and did not contain detectable HPV DNA, consistent with the endometrial origin of the tumors.
The p16 expression pattern can distinguish ECAs from EMAs. Compared with HPV DNA detection by in situ hybridization, p16 immunohistochemistry appears to be a more sensitive and easier to perform method for distinguishing ECAs from EMAs, can be used to assist in the classification of LUS/EC-As of equivocal origin, and should be evaluated for its utility in the prospective classification of uterine adenocarcinomas in curettage specimens prior to hysterectomy.
Endometrial endometrioid adenocarcinoma with a deceptive pattern of spread to the uterine cervix: a manifestation of stage IIb endometrial carcinoma liable to be misinterpreted as an independent carcinoma or a benign lesion.Tambouret R, Clement PB, Young RH.
Am J Surg Pathol. 2003 Aug;27(8):1080-8. Abstract quote The prognosis of endometrial endometrioid adenocarcinoma is determined in part by stage; endocervical stromal involvement (stage IIB) imparts a worsened prognosis.
We describe a deceptive pattern of stage IIB disease that mimics a primary endocervical glandular proliferation and may lead to understaging of endometrial endometrioid adenocarcinoma. Fifteen cases of endometrial endometrioid adenocarcinoma with a peculiar pattern of cervical involvement were identified from our consultation files. All cases were referred in consultation because of doubt about the nature of the cervical process and its relation to the corpus tumor; in a few instances, the cervical proliferation was considered possibly benign and in one case was misinterpreted as mesonephric hyperplasia. The patients ranged from 49 to 84 years in age (mean age 64.9 years). There was usually a grossly evident endometrial tumor. The cervix was unremarkable grossly in at least 11 patients. The cervical tumors were composed of variably shaped, often tubular glands with little or no stromal response and mainly invaded as widely spaced glands that often appeared deceptively benign. In 14 cases luminal secretions, mainly eosinophilic, were identified, often leading to consideration of a mesonephric lesion. Ten of the endometrial tumors were grade 1, four grade 2, and one grade 3. One was noninvasive, nine superficially invasive, and five deeply invasive. In four cases myoinvasion had, at least in part, a diffusely infiltrative pattern. The tumors in the cervix showed no in situ component and no definite surface involvement. Continuity with the corpus tumor could be demonstrated in 12 cases. Ten of the cervical tumors invaded more deeply than the endometrial tumor, four invaded to a similar depth, and only one was more superficial than its endometrial counterpart. The cervical and corpus tumors had a similar immunoprofile in nine cases: all were vimentin positive, eight estrogen positive and one negative, four carcinoembryonic antigen negative, and five with focal apical or rare cytoplasmic staining.
This immunoprofile in conjunction with routine morphologic similarity between the two tumors and the usual documented continuity between them indicate that the cervical process represents spread from the endometrial endometrioid adenocarcinoma.
It is important for both therapeutic and prognostic reasons that the cervical abnormality is not misinterpreted as a benign or malignant primary endocervical glandular process.
Hormone Receptor Immunohistochemistry and Human Papillomavirus In Situ Hybridization Are Useful for Distinguishing Endocervical and Endometrial Adenocarcinomas
Annette Staebler, M.D.; Mark E. Sherman, M.D.; Richard J. Zaino, M.D.; Brigitte M. Ronnett, M.D.
Am J Surg Pathol 2002; 26(8):998-1006 Abstract quote
Determining the origin of uterine adenocarcinomas can be difficult in biopsy and curettage specimens because the morphologic spectrum of endocervical and endometrial adenocarcinomas overlaps. In addition, in hysterectomy specimens the primary site is often equivocal for tumors that involve predominantly the lower uterine segment and endocervix and lack identifiable precursor lesions.
We assessed the value of immunohistochemistry for estrogen and progesterone receptors and in situ hybridization for human papillomavirus DNA detection in making this clinically relevant distinction. We evaluated a set of 48 adenocarcinomas of unequivocal origin (24 endocervical carcinomas and 24 endometrial endometrioid carcinomas without cervical extension) and then tested seven lower uterine segment/endocervical carcinomas of equivocal origin to determine whether patterns established in the initial set would permit definitive assignment of primary site for the equivocal set. Only one (4.2%) of 24 endocervical carcinomas was positive for both estrogen receptor and progesterone receptor, whereas 18 (75%) of 24 endometrial carcinomas were positive for estrogen receptor and 23 (95.8%) of 24 endometrial carcinomas were positive for progesterone receptor (p <0.001, ?2 test). Human papillomavirus DNA was detected in 16 (66.7%) of 24 endocervical carcinomas and in none of 24 endometrial carcinomas (p <0.001, ?2 test). Of the seven tumors of equivocal origin, five could be definitively classified as either endocervical or endometrial in origin based on their demonstration of a characteristic profile with these assays (either estrogen receptor/progesterone receptor-negative/human papillomavirus-positive, consistent with endocervical origin or estrogen receptor/progesterone receptor-positive/human papillomavirus-negative, consistent with endometrial origin).
We conclude that hormone receptor immunohistochemistry and human papillomavirus in situ hybridization are useful for distinguishing endocervical and endometrial adenocarcinomas. The clinical utility of these techniques should be evaluated in studies that include curettage and biopsy specimens.MINIMAL DEVIATION ADENOCARCINOMA Mitotic Activity and Apoptosis in Endocervical Glandular Lesions Suzuko Moritani, M.D.; Olga B. Ioffe, M.D.; Satoru Sagae, M.D.; Laila Dahmoush, M.D.; Steven G. Silverberg, M.D.; Takanori Hattori, M.D., Ph.D.
From the Department of Pathology (S.M., T.H.), Shiga University of Medical Science, Ohtsu, Shiga, Japan; Department of Pathology (O.B.I., S.G.S.), University of Maryland Medical System, Baltimore, Maryland; Department of Obstetrics and Gynecology (S.S.), Sapporo Medical University, Sapporo, Hokkaido, Japan; and Cytology Section (L.D.), National Institute of Health/National Cancer Institute, Bethesda, Maryland.
Int J Gyn Pathol 2002;21:125-133 Abstract quote To evaluate the significance of mitotic activity and apoptosis in the differential diagnosis of endocervical glandular lesions, we examined the frequency of mitoses and apoptosis in 89 endocervical glandular lesions from 78 patients, which consisted of benign reactive changes (7 cases), lobular or diffuse laminar endocervical glandular hyperplasia (4), microglandular hyperplasia (3), tunnel clusters (7), nabothian cysts (2), mesonephric remnants (3), tubal metaplasia (3), endocervical glandular dysplasias (including atypical tubal metaplasia) (EGD) (7), adenocarcinoma in situ (AIS) (31), microinvasive adenocarcinoma (7), frankly invasive adenocarcinoma (12), and minimal deviation adenocarcinoma (3).
Mitotic index (MI; mitotic figures per 1000 cells) was significantly higher in AIS, microinvasive adenocarcinoma, and frankly invasive adenocarcinoma than any other lesions examined. Microinvasive adenocarcinoma showed the highest MI. Apoptosis was detected consistently and frequently in AIS, microinvasive adenocarcinoma, and frankly invasive adenocarcinoma. AIS showed the highest apoptotic index (AI; apoptoses per 1000 cells). Frequent apoptotic bodies and mitotic figures are a common feature of endocervical glandular malignancies (except for minimal deviation adenocarcinoma) and are an important feature that can facilitate their differentiation from benign and borderline lesions. High MI in microinvasive adenocarcinoma might aid the distinction of microinvasive adenocarcinoma from AIS. Although both MI and AI of EGD were between those of benign reactive changes and of AIS, MI and AI alone are not sufficient to differentiate EGD from benign reactive changes.
MI and AI are not helpful in the differential diagnosis between minimal deviation adenocarcinoma and its benign mimics.
STRATIFIED MUCIN-PRODUCING INTRAEPITHELIAL LESION Stratified Mucin-Producing Intraepithelial Lesions of the Cervix Adenosquamous or Columnar Cell Neoplasia?
Jeong-Ja Park, M.D.; Deqin Sun, M.S.; Bradley J. Quade, M.D., Ph.D.; Cythia Flynn, M.D.; Ellen E. Sheets, M.D.; Annie Yang, B.S.; Frank McKeon, Ph.D.; Christopher P. Crum, M.D.
From the Division of Women's and Perinatal Pathology, Department of Pathology, Brigham and Women's Hospital (J.-J.P., D.S., B.J.Q., C.P.C.), Department of Pathology, Massachusetts General Hospital (C.F.), Department of Obstetrics and Gynecology (E.E.S.), Brigham and Women's Hospital, and the Department of Cell Biology (A.Y., F.M.), Harvard Medical School, Boston, Massachusetts, U.S.A.
Am J Surg Pathol 2000;24:1414-1419 Abstract quote
BACKGROUND: Squamous (CIN) and glandular (ACIS) intraepithelial lesions often coexist in the same cervical specimen. However, a less common and little studied variant consists of a stratified epithelium resembling CIN in which conspicuous mucin production is present (Stratified Mucin-producing Intraepithelial LEsions (SMILE). This report describes the phenotypic characteristics of the SMILE, its associated lesions, and its immunophenotype.
METHODS: Eighteen SMILEs were identified by the presence of conspicuous cytoplasmic clearing or vacuoles in lesions otherwise resembling CIN. The morphologic spectrum of SMILEs was detailed; including associated intraepithelial and invasive cervical neoplasms. In addition, selected cases were stained for muci-carmine, markers of squamous cell/reserve cell differentiation (keratin-14 and p63), and proliferative activity (Mib-1).
RESULTS: Stratified neoplastic epithelial cells with a high Mib-1 index and a rounded or lobular contour at the epithelial-stromal interface characterized SMILEs. In contrast to CIN, in which mucin droplets are confined to surface cells, mucin was present throughout the epithelium, varying from indistinct cytoplasmic clearing to discrete vacuoles. SMILEs were distinguished from benign metaplasia by nuclear hyperchromasia and a high Mib-1 index. All but three coexisted with either a squamous (CIN) or glandular (ACIS) precursor lesion. Nine of nine coexisting invasive carcinomas contained glandular, adenosquamous differentiation, or both. SMILEs stained negative for keratin-14 and variably for p63. When present, staining with p63 was confined to basal areas of SMILEs and was absent in areas of columnar differentiation.
CONCLUSIONS: SMILEs are unusual cervical intraepithelial lesions best classified as variants of endocervical columnar cell neoplasia based on immunophenotype. The distribution and immunophenotype of SMILEs are consistent with a neoplasm arising in reserve cells in the transformation zone. The coexistence of a wide spectrum of intraepithelial and invasive cell phenotypes suggests that SMILEs are a marker for phenotypic instability, emphasizing the importance of identifying SMILEs and ensuring a complete examination of specimens containing this unusual precursor lesion.
PROGNOSIS AND TREATMENT CHARACTERIZATION DEPTH OF INVASION
Is the invasion depth in millimeters valid to determine the prognosis of early invasive cervical adenocarcinoma? A case of recurrent FIGO stage IA1 cervical adenocarcinoma.Utsugi K, Shimizu Y, Akiyama F, Hasumi K.
Department of Gynecology, Department of Pathology, Cancer Institute Hospital, Cancer Institute, 1-37-1, Kami-Ikebukuro, Toshima-ku, Tokyo, 170-8455, Japan.
Gynecol Oncol 2001 Jul;82(1):205-7 Abstract quote BACKGROUND: Recurrence of FIGO stage IA1 cervical adenocarcinoma is extremely rare. We herein report a patient with early invasive cervical adenocarcinoma who developed a recurrence in the vaginal stump.
CASE: A 52-year-old female complained of contact bleeding. Biopsy of the uterine cervix verified cervical adenocarcinoma, and the patient underwent Okabayashi hysterectomy with pelvic lymphadnectomy and bilateral adnectomy. Histopathologic examination of the uterus revealed an invasive cancer 3 mm in depth. Neither lymph node metastasis nor lymph-vascular space invasion was observed. However, the depth of her normal cervical gland area was 2 mm only, and the cancer invasion involved an area which was deeper than the normal cervical gland area. The vaginal stump recurrence developed 4 years after surgery.
CONCLUSION: The depth of invasion with reference to that of normal cervical glands may become a possible prognostic factor for early invasive cervical adenocarcinoma.
ENDOCERVICAL CURETTAGE
Endocervical curettage at conization to predict residual cervical adenocarcinoma in situ.Lea JS, Shin CH, Sheets EE, Coleman RL, Gehrig PA, Duska LR, Miller DS, Schorge JO.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9032, USA.
Gynecol Oncol 2002 Oct;87(1):129-32 Abstract quote OBJECTIVE: To determine if performing an endocervical curettage (ECC) at the time of conization is a useful diagnostic tool for predicting residual cervical adenocarcinoma in situ (AIS) among women who might wish to preserve their fertility.
METHODS: All patients diagnosed with AIS from 1995 to 2000 at four institutions were identified. Data were retrospectively extracted from clinical records. Women included in the statistical analysis were (1) younger than 40 years, (2) had an ECC performed at the time of the initial cone biopsy, (3) had a clearly demarcated surgical margin pathologically, and (4) underwent a second surgical procedure.
RESULTS: Twenty-nine (24%) of 123 AIS patients met criteria for inclusion. The median age was 33 years (range, 17 to 39) and 13 (46%) were nulliparous. Initial surgery was a cold-knife conization (n = 17) or loop electrosurgical excision procedure (n = 12). Twelve (41%) ECCs and 15 (52%) cone margins were histologically positive. Sixteen patients underwent a repeat conization; 13 underwent hysterectomy. Thirteen (45%) patients had residual AIS at the time of their second surgical procedure. ECC had a superior positive predictive value (100% vs 47%; P < 0.01) and negative predictive value (94% vs 57%; P = 0.01) compared to cone margin in predicting residual AIS. None of the women undergoing fertility-sparing surgery developed recurrent AIS or adenocarcinoma.
CONCLUSION: ECC performed at the time of conization may be a useful tool for predicting residual AIS in women considering fertility preservation.
HISTOLOGIC GRADING
Proposal of a new scoring scheme for the diagnosis of noninvasive endocervical glandular lesions.Ioffe OB, Sagae S, Moritani S, Dahmoush L, Chen TT, Silverberg SG.
Am J Surg Pathol 2003 Apr;27(4):452-60 Abstract quote The differential diagnosis of endocervical glandular lesions can be very difficult, and the interobserver agreement on borderline cases can be low.
We are proposing a new scoring system to aid in the reproducibility of the diagnosis of noninvasive endocervical glandular lesions. The total of 67 diagnostically difficult cases were independently reviewed by five pathologists. After the completion of the first round review, a consensus diagnosis was reached for each lesion by all participants.
This consensus diagnosis was used as the reference diagnosis. According to the consensus, the lesions included 21 benign/reactive conditions, 7 endocervical glandular dysplasias, and 39 adenocarcinomas in situ. During the second round review, all cases were assessed using the new scoring scheme, according to which separate scores from 0 to 3 were given to each lesion for: 1) nuclear atypia, 2) stratification, and 3) sum of mitoses/apoptoses (counted in the two most active glands, and the average number used). These three scores were then added to result in the total score (0-3 = benign; 4-5 = endocervical glandular dysplasia; 6-9 = adenocarcinoma in situ). Complete agreement between all observers in the first round review was seen in 35 of 67 cases (52.2%), kappa = 0.565. This agreement improved in the second round with the use of the scoring scheme: 52 of 67 cases (77.6%), kappa = 0.705. If the benign and endocervical glandular dysplasia diagnostic categories were combined, the overall agreement in the second round review would be 63 of 67 cases (94%), meaning that the scheme affords accurate distinction between adenocarcinoma in situ and lesser lesions.
We propose applying this new scoring scheme to the diagnosis of noninvasive endocervical glandular lesions to improve interobserver agreement. The use of this scheme will result in more consistency of data in series from different institutions and will allow uniformity on the issue of adenocarcinoma in situ precursor lesions.
MARGINS The status and distance of cone biopsy margins as a predictor of excision adequacy for endocervical adenocarcinoma in situ.
Goldstein NS, Mani A.
Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, Michigan 48073, USA.
Am J Clin Pathol 1998 Jun;109(6):727-32 Abstract quote
Cervical cone biopsy has become an important surgical procedure for endocervical adenocarcinoma in situ (AIS), especially for patients who desire to retain their fertility. Establishing the usefulness of the endocervical margin status in cone biopsy specimens as a predictor of residual AIS is paramount.
We examined the status of the endocervical margin in the cone biopsy specimen, the distance between the most proximal AIS and the endocervical margin in the cone biopsy specimen, and the endocervical curettage (ECC) specimen performed at the time of cone biopsy and residual AIS in the hysterectomy specimens of 61 patients with specimens accessioned from 1968 through 1997; 43 (30%) of patients with a negative endocervical margin had residual AIS in the hysterectomy specimen. Conversely, 10 of 18 (56%) patients with a positive endocervical margin in the cone biopsy specimen had no AIS in the hysterectomy specimen. All 6 patients with AIS in the ECC specimen had residual AIS. No patient with an endocervical margin in the cone biopsy specimen greater than 10 mm had residual AIS. Patients with distances less than 10 mm had equal percentages of residual AIS.
In general, more patients with a negative endocervical margin in the cone biopsy specimen had no residual AIS in the hysterectomy specimen than those with a positive endocervical margin in the cone biopsy specimen. However, the status of this margin is not useful for predicting the presence of residual AIS. Pathologists should report the distance between the endocervical cone biopsy margin and the closest AIS.
TREATMENT
Population-based study of microinvasive adenocarcinoma of the uterine cervix.Webb JC, Key CR, Qualls CR, Smith HO.
Department of Obstetrics and Gynecology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131, USA
Obstet Gynecol 2001 May;97(5 Pt 1):701-6 Abstract quote OBJECTIVE: To analyze lymph node status and survival rates of women with microinvasive cervical adenocarcinoma (International Federation of Gynecology and Obstetrics stages IA(1) and IA(2)).
METHODS: The Surveillance, Epidemiology, and End Results (SEER) Public-Use Database was used to identify cases of microinvasive cervical adenocarcinoma diagnosed between 1988 and 1997. Variables analyzed included stage, extent of surgery, lymph node status, radiation therapy, and age. Statistics included analysis of trends, analysis of variance, log-rank test, one-sided binomial confidence interval estimation, and power analysis.
RESULTS: Among 301 reported cases, 131 had stage IA(1) and 170 IA(2) disease. Simple hysterectomies were done in 54 women with IA(1) and 64 with IA(2) disease and radical hysterectomies were done in 50 and 83 women, respectively. Only one of 140 women who had lymphadenectomy had a single positive lymph node. There were four tumor-related deaths (one with IA(1), and three with IA(2) disease). There were no deaths among 96 women (47, IA(1); 49, IA(2)) treated by simple hysterectomy alone. The mean follow-up was 46.5 months (range 1--119). The censored survival rate was 98.7% overall (99.2% IA(1), 98.2% IA(2)). Power analysis estimated that 720 patients would be required in each group to detect a 2% difference in survival. Using one-sided 95% confidence interval estimations, the risk-adverse events rate for IA(1) was no more than 3.57%, and 4.50% for IA(2) disease.
CONCLUSION: Prognosis is excellent for microinvasive adenocarcinoma of the uterine cervix. In 96 cases (31.9%), simple hysterectomy alone proved adequate.
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Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
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Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
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Cervical Squamous Cell Carcinoma
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