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Table of Contents
Year : 2020  |  Volume : 3  |  Issue : 3  |  Page : 590-593

Cervical adenocarcinoma- a paradigm shift

Department of Pathology, Polo Labs, Associated with Ivy Hospital, Ajitgarh, Punjab, India

Date of Submission16-May-2020
Date of Decision22-Jun-2020
Date of Acceptance15-Jul-2020
Date of Web Publication19-Sep-2020

Correspondence Address:
Kriti Chauhan
Department of Pathology, Polo Labs, Associated with Ivy Hospital, F-317, Industrial Area, Sector 74, Sahibzada Ajit Singh Nagar, Ajitgarh - 160 071, Punjab
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/CRST.CRST_201_20

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How to cite this article:
Chauhan K, Kathuria K. Cervical adenocarcinoma- a paradigm shift. Cancer Res Stat Treat 2020;3:590-3

How to cite this URL:
Chauhan K, Kathuria K. Cervical adenocarcinoma- a paradigm shift. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Oct 25];3:590-3. Available from: https://www.crstonline.com/text.asp?2020/3/3/590/295539

  Case Presentation Top

A 54-year-old postmenopausal woman presented to our hospital with the complaints of abdominal pain and bleeding per vaginum. On local examination, an endocervical polyp was identified which bled on touch. An ultrasound imaging of the abdomen revealed an endometrial polyp in addition to the endocervical polyp. There was no suspicion of malignancy. The patient refused to get any diagnostic curettage done and preferred a total hysterectomy to prevent the occurrence of a similar disease in future. A total abdominal hysterectomy with bilateral salpingo-oopherectomy was thus performed, and the specimen was sent for a histopathological examination.

On gross examination, the endometrial polyp measured 2.7 cm in length and had a firm, smooth, homogenous, gray-white cut surface. The endocervical polyp measured 2.5 cm in length and had a cystic cut surface along with hemorrhagic areas. On light microscopic examination of the hematoxylin and eosin (H & E) stained slides, the endometrial polyp revealed features of simple hyperplasia without atypia. The cervical polyp, on the other hand, showed features of malignancy [Figure 1], [Figure 2], [Figure 3], [Figure 4].
Figure 1: (a) Low-power view of the endocervical polyp showing the stratified mucin-producing intraepithelial lesion at the surface of the polyp (black arrow) along with the adjacent benign endocervix and ectocervix (yellow arrow) (H and E, ×100). (b) High-power view of SMILE (H and E, ×400)

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Figure 2: Low power view of invasive stratified mucin-producing carcinoma (black star) (H and E, ×100). High-power view of the invasive nests of stratified mucin-producing intra-epithelial lesion showing numerous mitotic figures (red arrow) and peripheral palisading of cells (black star)(H and E, ×400)

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Figure 3: (a) Low-power view of the stratified mucin-producing intraepithelial lesion (black solid star) and the invasive nests below it (H and E, ×100). (b) Low-power view of adenocarcinoma in situ (red solid star). (c) High-power view of adenocarcinoma in situ showing mitotic figures (red solid arrow) and mucin (yellow star) (H and E, ×400)

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Figure 4: (a) Another low-power view of the stratified mucin-producing intraepithelial lesion showing vesicular nuclei (white solid arrow) (H and E, ×100). (b) High-power view of the usual endocervical adenocarcinoma with a black arrow pointing at a mitotic figure present adjacent to the mucinous subtype (green solid star) (H and E, ×400). (c) Low-power view of the mucinous human papillomavirus-associated carcinoma showing intracellular mucin (green star) and apoptotic bodies admixed with neutrophils (black circle) (H and E, ×100)

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What is the diagnosis? Once you have finalized your answer, please turn to page 591 to read on.

  Diagnosis Top

Based on the international endocervical adenocarcinoma criteria and classification (IECC) the case was diagnosed as a human-papilloma-virus-associated (HPVA) carcinoma, showing features of usual endocervical adenocarcinoma (ECA), invasive stratified mucin-producing carcinoma (iSMILE), and intestinal-type mucinous ECA. There were co-existing foci of precursor lesions such as the stratified mucin-producing intra-epithelial lesion (SMILE), adenocarcinoma in situ (AIS), and cervical intraepithelial neoplasia (CIN-3). The tumor was seen originating from the endocervical polyp and invading the cervical stroma up to a depth of 9 mm. All margins were free. The ovaries, fallopian tubes, and uterine corpus were free of tumor. The lymph nodes were not excised since there was no suspicion of a malignancy clinically and no significant lymphadenopathy in the pelvic region was noted intra-operatively. Hence, the tumor was staged as pT1b1 (as per the TNM classification, 8th edition).

  Differential Diagnosis Top

SMILE is a rare cytological entity often confused with CIN, AIS, adenosquamous carcinoma, and glandular metaplasias.[1],[2] It is an in situ variant of cervical adenocarcinoma characterized by stratified, immature epithelial cells with peripheral palisading and varying quantities of intracytoplasmic mucin throughout the lesional epithelium. There is unequivocal evidence of the presence of human-papilloma-virus (HPV) infection-related features such as-mitotic figures and apoptotic bodies.[3] When invasive nests of tumor cells exhibit similar features, it is called iSMILE. CIN bears a very similar morphology to SMILE, but unlike SMILE, the mucin is confined to the cells on the surface, and there is an absence of clear, distinct intracytoplasmic vacuoles. AIS shows a classical glandular formation with luminal spaces. In contrast, SMILE, despite being mucin-rich, does not show glandular formation. SMILE shows hyperchromatic nuclei with a high MIB-1 proliferation) index, while glandular metaplasias have a finely dispersed nuclear chromatin with prominent nucleoli and a low MIB-1 proliferation index. Considering the co-existence of SMILE with a spectrum of intraepithelial and invasive cell phenotypes, it is suggested that SMILE represents some kind of phenotypic instability. Some authors use the term “adenosquamous carcinoma in situ” interchangeably with SMILE.[4] However, there are others who argue that the diagnosis of adenosquamous carcinomas should be considered only in the presence of both unequivocal definite malignant glandular and squamous components.[5] HPVA with benign squamous differentiation, HPVA with iSMILE components, and pure iSMILE should not be considered as adenosquamous carcinomas, because the squamous component in them is not malignant.[5] Most iSMILEs and adenosquamous carcinomas are positive for p16 and HPV, but strong diffuse expression of MUC-6 along with the scant expression of p63 and p40 in the palisade around the invasive nests and the relative lack of PAX8 suggest that iSMILE may be of reserve cell origin as compared to the pure adenosquamous carcinomas.[5]

  Discussion Top

SMILE is distinct from the two most common precancerous cervical lesions, AIS and squamous intraepithelial lesion, and is considered a third category of in situ cervical lesions. However, these three lesions can co-exist.[2] The World Health Organization (WHO) 2014 classification has placed SMILE along with AIS under the category of cervical adenocarcinoma (ECA) precursors.[6] The WHO classifies ECA solely based on cytoplasmic features and descriptive morphological characteristics of the tumor cells. It provides no understanding of the etiology and behavior of endocervical glandular dysplasia.[7] To overcome this limitation, a different classification system was proposed in 2018, called IECC that provides a better insight into the etiology and behavior of ECA. This system broadly divides the ECAs into HPVA and not HPVA (NHPVA) or those with limited HPV association.[7],[8] [Table 1] highlights the various subtypes of HPVA and NHPVA with a brief description of their cytological features. In addition to these specific morphological features, to qualify as an HPVA adenocarcinoma, the lesion must show appreciable/identifiable apical mitoses and apoptotic bodies throughout. The IECC system was devised based on a study comprising 409 patients. The diagnoses established by the histological examination as per IECC were further confirmed by ancillary techniques like immunohistochemistry for p16, p53, vimentin, and progesterone receptor and chromogenic in situ hybridization using RNA probes that could recognize 18 strains of high-risk HPV. It was found that 76% of the carcinomas classified as usual-type, a subtype of HPVA ECAs, by IECC were p16-and HPV-positive, 16.2% were either p16-or HPV-positive, and 74% were negative for both. The usual-type ECA was also found to be the most common subtype, followed by the gastric-type ECA.[8] The gastric-type ECA is considered a more aggressive subtype of the NHPVA ECAs and is notorious for metastasizing to distant organs and the peritoneum. A comparison of the clinical outcomes between HPVA and gastric-type ECA has indicated that NHPVA gastric-type ECA is significantly more aggressive and has a worse clinical outcome than the usual type ECA. Such relevant information regarding the behavior and prognosis of the tumor type is lacking in the WHO classification. Gastric-type ECA is considered a subtype of the “mucinous ECA” in the WHO classification and is treated similarly to all other variants of mucinous adenocarcinoma. This limitation can be overcome by adopting a classification scheme like IECC, which links the cytological features seen under a light microscope with the HPV status of the patient. This can provide better therapeutic, predictive, and prognostic information to the treating physicians, similar to the classification systems adopted for the vulva and oropharynx based on the pathogenesis, and have been found to be more informative and reproducible than the current WHO scheme. [Table 2] shows a few cases reported in the literature that bore a similar diagnosis.
Table 1: Microscopic features of various subtypes of HPVA and NHPVA

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Table 2: A list of similar reported cases from literature

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  Conclusion Top

To conclude, it can be said that the classification systems based on the etiology and likely behavior of the tumor are more informative. In the current era of HPV vaccination for cervical cancers, immunity is conferred to HPVA ECAs only. The risk of occurrence of NHPVA ECAs persists, because of which their relative incidence is likely to increase. Routine cervical cancer screening programs like HPV DNA polymerase chain reaction cannot detect the NHPVA ECAs. In such scenarios, a careful simple cytological and histological examination of the H and E stained sections under a light microscope could be more beneficial and cost-effective. Moreover, by adopting an etiology based classification like IECC for the routine reporting of cervical specimens, the pathologists can contribute significantly towards providing pertinent information to the treating clinicians.


The authors are extremely thankful to the head of the department, the technical staff, especially Mr. Kamal and Miss Priyanka, for their timely help and support in the making of this article.

Declaration of patient consent:

The authors certify that they have obtained the patient consent form. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understood that her name and initial would not be published and due efforts would be made to conceal her identity.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.[9]

  References Top

Park JJ, Sun D, Quade BJ, Flynn C, Sheets EE, Yang A, et al. Stratified mucin-producing intraepithelial lesions of the cervix: Adenosquamous or columnar cell neoplasia? Am J Surg Pathol 2000;24:1414-9.  Back to cited text no. 1
Fukui S, Nagasaka K, Iimura N, Kanda R, Ichinose T, Sugihara T, et al. Detection of HPV RNA molecules in stratified mucin-producing intraepithelial lesion (SMILE) with concurrent cervical intraepithelial lesion: A case report. Virol J 2019;16:76.  Back to cited text no. 2
Lei R. Invasive stratified mucin-producing carcinoma: A clinicopathological analysis of three cases. Cancer Biol Ther 2019;20:1403-7.  Back to cited text no. 3
Onishi J, Sato Y, Sawaguchi A, Yamashita A, Maekawa K, Sameshima H, et al. Stratified mucin-producing intraepithelial lesion with invasive carcinoma: 12 cases with immunohistochemical and ultrastructural findings. Hum Pathol 2016;55:174-81.  Back to cited text no. 4
Stolnicu S, Hoang L, Hanko-Bauer O, Barsan L, Terinte C, Pesci A, et al. Cervical adenosquamous carcinoma: Detailed analysis of morphology, immunohistochemical profile, and clinical outcomes in 59 cases. Mod Pathol 2019;32:269-79.  Back to cited text no. 5
Lax SF, Horn LC, Löning T. Categorization of uterine cervix tumors: What's new in the 2014 WHO classification. Pathologe 2016;37:573-84.  Back to cited text no. 6
Hodgson A, Park KJ. Cervical Adenocarcinomas: A heterogeneous group of tumors with variable etiologies and clinical outcomes. Arch Pathol Lab Med 2019;143:34-46.  Back to cited text no. 7
Stolnicu S, Barsan I, Hoang L, Patel P, Terinte C, Pesci A, et al. International endocervical adenocarcinoma criteria and classification (IECC): A new pathogenetic classification for invasive adenocarcinomas of the endocervix. Am J Surg Pathol 2018;42:214-26.  Back to cited text no. 8
Schwock J, Rouzbahman M, Geddie WR. Stratified mucin-producing intraepithelial lesion of the cervix: A diagnostic challenge. Cytojournal 2014;11:22.  Back to cited text no. 9
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