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. Author manuscript; available in PMC: 2020 May 1.
Published in final edited form as: Int J Gynecol Pathol. 2019 May;38(3):263–275. doi: 10.1097/PGP.0000000000000519

Morphologic features of gastric-type cervical adenocarcinoma in small surgical and cytology specimens

Gulisa Turashvili 1, Elizabeth G Morency 2, Mihaela Kracun 1, Deborah F DeLair 1, Sarah Chiang 1, Robert A Soslow 1, Kay J Park 1, Rajmohan Murali 1
PMCID: PMC6230321  NIHMSID: NIHMS955016  PMID: 29750702

Introduction

In 2018, ~13,240 women will be newly diagnosed with cervical carcinoma in the United States.1 Endocervical adenocarcinoma accounts for approximately 25% of all primary cervical carcinomas.2–4 High-risk human papillomavirus (HPV) infection has been shown to be important in the pathogenesis of the vast majority of cervical adenocarcinomas, most of which are endocervical adenocarcinomas of usual type.5–10 Only approximately 5–10% of cervical adenocarcinomas are unrelated to HPV, although this figure may be higher in Japanese populations.11–13 HPV-negative cervical adenocarcinomas include gastric-type, clear cell, mesonephric, and endometrioid adenocarcinomas.12, 14, 15 Gastric-type cervical adenocarcinoma (GCA) is the most common subtype not driven by HPV, defined as a subtype of mucinous adenocarcinoma with gastric differentiation in the 2014 World Health Organization classification of cervical tumors.6 These tumors span the morphologic spectrum with the well-differentiated forms being termed ““minimal-deviation adenocarcinoma.16–18 Common histologic features of GCA include: 1) voluminous clear, foamy or pale eosinophilic cytoplasm; 2) distinct cell borders; and 3) immunohistochemical evidence of gastric differentiation (expression of HIK1083).11, 18–21

Most cases of GCA are sporadic, although associations with mutations in the STK11 tumor suppressor gene (Peutz-Jeghers syndrome) have been described.22–24 GCA can arise in a background of a non-obligate precursor lesion, lobular endocervical glandular hyperplasia (LEGH),19, 25–28 which has been shown to share molecular alterations, such as 3q gain and 1p loss, with minimal deviation adenocarcinomas.25, 27, 29 Evidence of gastric differentiation in the form of pyloric metaplasia is present in both LEGH and minimal deviation adenocarcinoma.19, 30 GCA has also been thought to represent a component of so-called "synchronous mucinous metaplasia and neoplasia of the female genital tract".18

In contrast to HPV-driven endocervical adenocarcinomas of usual type, GCA is an aggressive, chemo-refractory tumor with a propensity for peritoneal and abdominal spread.11, 12, 31–33 Most patients present at advanced stage, and reported 5-year disease-free survival rates range between 30–42% compared to 77–91% for patients with endocervical adenocarcinomas of usual type.11, 33, 34 Therefore, accurate diagnosis is important to ensure the institution of appropriate management as early as possible. Clinical recognition and histopathologic diagnosis of GCA can be challenging. Patients can present with vaginal bleeding, mucoid discharge or abdominal discomfort. However, some patients may be asymptomatic, or may present with abnormal cytologic findings in cervicovaginal specimens or metastases to the ovaries, mimicking primary ovarian neoplasms. Furthermore, well-differentiated forms of GCA (also known as minimal deviation adenocarcinomas) exhibit deceptively bland morphologic appearances.35 This could potentially lead to under-recognition or misdiagnosis, particularly in limited material such as small biopsies and cytologic preparations. In this study, we sought to document the morphologic features of GCA in surgical biopsy and cytology specimens.

Materials and Methods

The study was performed in accordance with institutional research guidelines (protocol no. 16-1684). Women with a histologic diagnosis of GCA or minimal-deviation adenocarcinoma between 2004 and 2017 were identified from the laboratory information system of the Department of Pathology, Memorial Sloan Kettering Cancer Center. Other histologic subtypes of HPV-unassociated endocervical adenocarcinoma such as clear cell, mesonephric and serous carcinomas were excluded. Patients with abnormal findings in exfoliative and non-exfoliative (including fine-needle aspiration, FNA) cytologic specimens and small surgical specimens (biopsies and curettings) were selected. Pathology reports and all available cytologic and hematoxylin-eosin (H&E) stained histologic slides from the selected cases were retrieved for pathologic review.

Cytologic slides were reviewed with particular attention to the following features: the presence of single cells and cell groups (and the architecture of the cell groups); cell shape; cell borders; cytoplasm (volume and character); nuclear features (shape, pleomorphism, outline, chromatin, and number and size of nucleoli); and any other notable features such as type of background cells and tumor grade. For cases with available histologic slides, the cytologic findings were correlated with the histologic appearances.

Results

A total of 59 specimens were reviewed from 23 patients, including histology specimens alone from 6 patients, cytology specimens alone from 4 patients, and both types of specimen from 13 patients (Table 1). The median patient age was 52 (range 29–83) years.

Table 1.

Summary of 59 specimens from 23 patients

Patient Age Specimen Diagnosis Type Submitted
diagnosis		 IHC
Cytology Histology
1 47 CC Adenocarcinoma Primary N/A
CB GCA Primary N/A Positive CK7, mCEA; negative p16, ER, PR, vimentin
2 36 CC AGC, NOS Recurrent N/A
CC AGC, NOS Recurrent N/A
CC AGC, NOS Recurrent N/A
CC AGC, favor adenocarcinoma Recurrent N/A
CC Adenocarcinoma Recurrent N/A
3 46 CC AGC, favor adenocarcinoma Primary N/A
CB Favor GCA Primary N/A Positive CK7; negative CK20, ER, PR, p16, PAX8
ECC Favor GCA Primary N/A
4 63 PF Adenocarcinoma Primary N/A
5 65 CC AGC, NOS Recurrent N/A
6 65 PF Positive (adenocarcinoma) Primary Suspicious for adenocarcinoma Positive p53 (diffuse); negative p16, ER
EMB Consistent with GCA Primary N/A
7 83 CC Suspicious for adenocarcinoma Primary Atypical glandular cells, favor neoplastic Positive PAX8, mCEA; patchy p16; negative ER, vimentin, p53 (null)
EMB High grade adenocarcinoma Primary N/A
8 47 VB GCA Primary Features of GCA and MDA Positive CK7, mCEA; negative CK20, ER, PR, p16
CB GCA Primary N/A
PB GCA Primary N/A
Pelvic lymph node biopsy IS Adenocarcinoma Recurrent N/A
9 47 VC Adenocarcinoma Recurrent N/A
VB Consistent with GCA Recurrent N/A No, known GCA
10 41 Neck lymph node FNA Adenocarcinoma Metastatic N/A
11 44 VC Adenocarcinoma Primary Suspicious for adenocarcinoma Positive CK7, CK20, PAX8; negative ER, PR, p16, CDX2, TTF1, HNF1-beta
VB Mucinous adenocarcinoma Primary N/A
12 48 CC Adenocarcinoma Primary N/A
ECC Atypical pyloric metaplasia, suspicious for adenocarcinoma Primary Low grade mucinous adenocarcinoma No, known GCA
EMB Atypical pyloric metaplasia, suspicious for adenocarcinoma Primary Atypical pyloric metaplasia, suspicious for adenocarcinoma
13 52 EMC Suggestive of GCA Primary Mucin-producing adenocarcinoma Positive CK7, CK20, CDX2, CEA, HNF1-beta, PAX8, p53 (diffuse); negative GATA3, napsin-A, p16, mammaglobin
ECC GCA Primary Mucin-producing adenocarcinoma
CB (multiple) GCA Primary Mucin-producing adenocarcinoma
CC Adenocarcinoma Primary N/A
14 64 CC Adenocarcinoma Primary Adenocarcinoma, favor endometrial origin
ECC Consistent with GCA Primary Endometrioid adenocarcinoma with mucinous differentiation Positive CEA, HNF1-beta, CA-IX; negative ER, PR, p16, vim
EMC Consistent with GCA Primary N/A
PF Positive (adenocarcinoma) Metastatic N/A
15 69 EMB Consistent with GCA Primary Adenocarcinoma with clear cell features Patchy p16; negative ER, PR
CB Consistent with GCA Primary Adenocarcinoma with clear cell features
Pelvic mass FNA Consistent with GCA Metastatic N/A
16 44 EMB Endocervical adenocarcinoma with intestinal differentiation Primary N/A Negative p16
PF Positive (adenocarcinoma) Metastatic N/A
17 68 ECC GCA Primary Adenocarcinoma, moderately to poorly differentiated Positive CK7, CA-IX, napsin-A, p53 (diffuse), PAX8 (focal); negative p16, WT1, ER
EMC GCA Primary N/A
PF Positive (adenocarcinoma) Primary Negative for malignant cells
18 52 UB GCA Metastatic N/A No, known GCA
19 64 ECC Favor GCA Primary GCA with areas of MDA No
EMB Favor GCA Primary N/A No
CB (multiple) Favor GCA Primary N/A No
20 29 ECC Consistent with GCA Primary Mucinous adenocarcinoma, moderately differentiated Negative p16
EMC Atypical mucinous epithelium Primary N/A
CB (multiple) Consistent with GCA Primary N/A
BB Consistent with GCA Recurrent N/A
21 54 EMC GCA Primary Mucinous adenocarcinoma, well differentiated Negative p16
22 58 ECC GCA Primary Suspicious for GCA No
EMC GCA Primary N/A No
CB GCA Primary N/A No
ECC GCA Primary N/A No
23 56 CB (multiple) GCA Primary GCA with usual type areas Negative p16, vimentin, wild type p53, HPV ISH
ECC GCA Primary N/A
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Abbreviations: AGC, atypical glandular cells; BB, bladder biopsy; CB, cervical biopsy; CK, cytokeratin, CC, cervical cytology; ECC, endocervical curettage; EMB, endometrial biopsy; EMC, endometrial curettage; ER, estrogen receptor; FNA, fine needle aspiration; GCA, gastric type adenocarcinoma; HNF, hepatocyte nuclear factor; HPV, human papillomavirus; IS, imprint smear; ISH, in situ hybridization; mCEA, monoclonal carcinoembryonic antigen; MDA, minimal deviation adenocarcinoma; N/A, not applicable; NOS, not otherwise specified; PB, pelvic biopsy; PF, pelvic fluid; PR, progesterone receptor; UB, umbilical biopsy; VB, vaginal biopsy; VC, vaginal cytology.

Submitted diagnosis – diagnosis made by submitting pathologists in cases submitted for consultation to our institution by external laboratories.

There were 37 histology specimens including endocervical curettings (n=10), cervical biopsies (n=9), endometrial biopsies (n=6), endometrial curettings (n=6), vaginal biopsies (n=3), pelvic biopsy (n=1), bladder biopsy (n=1), and umbilical biopsy (n=1). The 22 cytology specimens included: cervical specimens (n=12), pleural fluid (n=5), vaginal specimens (n=2), touch preparation of pelvic lymph node core biopsy (n=1), and neck lymph node FNA (n=1), and pelvic mass FNA (n=1). Overall, more than one specimen was available in 18 patients. Details of the histologic and cytologic specimens are presented in Table 1.

Of 59 specimens, the diagnosis of GCA was rendered in 72% (31/43) of specimens diagnosed between 2013 and 2017 in contrast to only 19% (3/16) of specimens diagnosed between 2004 and 2013.

Histologic findings

Histologic specimens showed well or moderately differentiated adenocarcinomas exhibiting a predominantly glandular architecture with variable architectural complexity (Figures 1A–C). Neoplastic glands were composed of intermediate to large polygonal or columnar cells with moderate to large amounts of pale or foamy cytoplasm. Cytoplasmic borders were well defined in many areas of the tumors (Figures 2A–D). Nuclei exhibited mild to moderate pleomorphism and nucleoli were readily identified in many tumor cells (Figures 1C, 2B). Metastatic GCAs exhibited similar histology and awareness of these diagnostic features and/or clinical history was essential for diagnosis (Figure 3A–D).

Figure 1.

Figure 1

Figure 1

Figure 1

Figure 1

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Histology of primary gastric-type adenocarcinoma. The neoplastic glands are simple to angulated (A) or architecturally complex (B, C). Atypical glands admixed with fragments of normal endocervical glands, originally reported as “atypical pyloric metaplasia, highly suspicious for adenocarcinoma” (D). [A – endocervical curettage from patient 22; B – endocervical curettage from patient 14; C – endometrial biopsy from patient 12; D – endometrial biopsy from patient 7. Hematoxylin-eosin stain, ×200 (a, b, d), ×400 (c)]

Figure 2.

Figure 2

Figure 2

Figure 2

Figure 2

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Histology of primary gastric-type adenocarcinoma. The neoplastic glands are composed of columnar cells with foamy and/or vacuolated cytoplasm with well-defined cytoplasmic borders, and moderately pleomorphic nuclei with vesicular nuclear chromatin and one or more conspicuous nucleoli (A–D). [A – vaginal biopsy from patient 8, ×400; B – vaginal biopsy from patient 11; C – cervical biopsy from patient 8; D – cervical biopsy from patient 13. Hematoxylin-eosin stain, ×200 (A, C, D), ×400 (B)]

Figure 3.

Figure 3

Figure 3

Figure 3

Figure 3

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Histology of metastatic gastric-type adenocarcinoma. Typical morphologic features with variable degree of atypia ranging from well differentiated (A), moderately differentiated (B, C) to poorly differentiated (D). [C – pelvic sidewall biopsy from patient 8; B – umbilical biopsy from patient 18; C–D – bladder biopsy from patient 20. Hematoxylin-eosin stain, ×200 (A, B, D), ×100 (C)].

The diagnosis of GCA was usually readily apparent, and was challenging only in a minority (3/37, 8%;) of cases in which the neoplastic glandular epithelium was scant, fragmented and/or well-differentiated (Figure 1D). However, the specific diagnosis varied depending on knowledge of prior history of GCA and/or the availability of concurrent specimens exhibiting typical features described above (Table 1). Confirmatory ancillary studies (immunohistochemistry for p16 and in situ hybridization for high-risk HPV subtypes) were performed in 14 of 19 patients (74%) with available histologic specimens (Table 1). In three of these patients, a prior diagnosis of GCA was already established. Of 20 histology specimens submitted to our center for consultation, GCA was suspected by the outside pathologist in only 5 (25%) cases. Of the remaining 15 cases, the spectrum of diagnoses rendered by the outside pathologists ranged from “suspicious for adenocarcinoma” (n=3, 20%) to “adenocarcinoma” (n=12, 80%), including description of mucinous differentiation (n=6) and cytoplasmic clearing (n=3).

Cytologic findings

In 22 cytology specimens from 17 patients, the diagnostic categories included “atypical glandular cells, not otherwise specified” (n=4), “atypical glandular cells, favor adenocarcinoma” (n=2), “suspicious for adenocarcinoma” (n=1), and “adenocarcinoma” (n=15). The cytologic features are summarized in Table 2. The slides showed cohesive, crowded, three-dimensional clusters and variably disorganized monolayer sheets of tumor cells were seen in all cases, as well as single tumor cells in 11/17 (65%) cases (Figures 4A–D). The cells were columnar or polygonal in shape, and exhibited moderate to abundant amounts of pale, foamy and/or vacuolated cytoplasm with well-defined cytoplasmic borders (Figures 5A–D, 6A–B).

Table 2.

Summary of cytological features

Case Single
cells		 Cell
shape		 Well-
defined cell
borders		 Cyto quality Nuclear
outlines		 Nuclear
membrane		 Chromatin Nucleoli
number		 Background
1 (CC) Yes C and P In some groups Occasionally foamy Irregular Thin Fine 1
2 (CC ×5) No C and P In some groups Occasionally foamy, with rare vacuoles Irregular Thin Fine to coarse; hyperchromatic 1 Acute inflammatory cells**
3 (CC) No P In some groups Occasionally foamy Smooth Thin Fine 1+
4 (PF) Yes P Yes Occasionally foamy, with rare vacuoles Mostly smooth; some irregularity Thin Fine 1+
5 (CC) Yes P Yes Occasionally foamy Smooth Thick Fine 1+
6 (PF) Yes P In some groups Occasionally foamy Irregular Thin Coarse, hyperchromatic 1+ **
7 (CC) Yes P In some groups Pale, foamy Irregular Thin Fine to coarse; hyperchromatic 1+ Diathesis and acute inflammatory cells**
8 (IS) Yes P Yes Pale, foamy Smooth Thin Fine 1+ Mucin
9 (VC) Yes C and P Yes Pale, foamy Smooth Thin Fine 1 Diathesis and acute inflammatory cells**
10 (FNA) Yes* C and P Yes Pale, foamy Irregular Thick Fine 1+ Diathesis and acute inflammatory cells**
11 (VC) No P Yes Occasionally foamy Irregular Thick Coarse, hyperchromatic 1+ Diathesis and acute inflammatory cells**
12 (CC) Yes* C and P In some groups Occasionally foamy Irregular Thick Fine 1 Acute inflammatory cells**
13 (CC) No C and P In some groups Occasionally foamy, with rare vacuoles Irregular Thick Fine 1+ **
14 (CC, PF) Yes C and P In some groups Occasionally foamy, with rare vacuoles Irregular Thin Fine 1+
15 (FNA) Yes* P In some groups Occasionally foamy Mostly smooth; some irregularity Thin Fine 1+
16 (PF) No C and P In some groups Occasionally foamy Irregular Thick Fine 1+
17 (PF) No C and P In some groups Occasionally foamy Irregular Thick Fine 1+ Mesothelial cells
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Abbreviations: C = columnar; CC, cervical cytology; FNA, fine needle aspiration; IS, imprint smear; P = polygonal; PF, pelvic fluid; VC, vaginal cytology;

*

Stripped nuclei also present;

**

Neutrophils admixed with some cell groups; 1+ = more than 1.

Note: All cases showed cohesive, crowded, three-dimensional cell groups exhibiting disorganized architecture.

Figure 4.

Figure 4

Figure 4

Figure 4

Figure 4

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Cytology of gastric-type adenocarcinoma. Tumor cell arrangements. Cohesive, crowded, three-dimensional clusters, along with singly dispersed cells (A, B) and variably disorganized monolayer sheets (C) and clusters (D). Mucin is apparent in the background in (B). [A – neck lymph node fine-needle aspiration from patient 10, DiffQuik stain, ×200; B – pelvic lymph node biopsy touch preparation from patient 8, DiffQuik stain, ×200; C – vaginal specimen from patient 9, Papanicolaou stain, ×400; D – pelvic fluid from patient 4, Papanicolaou stain, ×400].

Figure 5.

Figure 5

Figure 5

Figure 5

Figure 5

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Cytology of gastric-type adenocarcinoma. Tumor cell morphology. Columnar or polygonal tumor cells exhibiting moderate to abundant amounts of pale, foamy and/or vacuolated cytoplasm with well-defined cytoplasmic borders (A–C). Round to oval, moderately pleomorphic nuclei with finely granular/vesicular nuclear chromatin and one or more conspicuous nucleoli (C–D). [A – pelvic lymph node biopsy touch preparation from patient 8, DiffQuik stain, ×400; B, C – vaginal specimen from patient 9, Papanicolaou stain, ×600 (B), ×400 (C); D – cervical specimen from patient 2, Papanicolaou stain, ×400].

Figure 6.

Figure 6

Figure 6

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Cytology of gastric-type adenocarcinoma. A–B) Cell groups in neck lymph node fine-needle aspiration from patient 10, showing the typical nuclear features, along with neutrophils admixed with tumor cell groups and in the background. [A, B Papanicolaou stain, ×400].

All tumors contained round to oval, moderately pleomorphic nuclei. The nuclear chromatin was finely granular/vesicular (13/17, 77%) or variably coarse and hyperchromatic (4/17, 24%). Nuclear membranes ranged from smooth (7/17, 41%) to irregular (10/17, 59%), and were thick in 7/17 (41%) tumors. All tumors showed one (5/17, 29%) or more (12/17, 71%) conspicuous nucleoli (Figures 5A–D, 6A–B). Inflammatory diathesis was identified in the background in 4/17 (24%) cases and neutrophils were seen admixed with tumor cell groups in 8 (47%) cases (Figures 6A–B).

Of 5 cytology specimens submitted to our center for consultation, GCA was not suspected by the outside pathologist in any of the cases. The spectrum of outside diagnoses ranged from “negative for malignant cells” in pelvic fluid (1/5, 20%) to “atypical glandular cells, favor neoplastic” (cervical specimen; 1/5, 20%) to “suspicious for adenocarcinoma” in (pelvic fluid and vaginal specimen; 2/5, 40%) and “adenocarcinoma favor endometrial origin” (cervical specimen; 1/5, 20%).

Discussion

Our study describes histologic and cytologic features of GCA in small surgical and cytology specimens. Pathologic diagnosis of GCA requires awareness of benign and malignant mimics that also exhibit gastric differentiation.36 Well-differentiated forms of GCA such as minimal-deviation adenocarcinoma are comprised of deeply invasive and haphazardly distributed glands lined by bland cells with only focal atypia including conspicuous eosinophilic nucleoli, glandular irregularity or papillary structures and stromal desmoplasia. GCA is characterized by variably sized simple to angulated or irregular glands lined by cells with basally located nuclei, abundant clear, foamy or pale eosinophilic cytoplasm and distinct cell borders. Moderately- and poorly-differentiated forms exhibit high grade cytologic features such as enlarged, irregular, hyperchromatic or vesicular nuclei, prominent eosinophilic nucleoli and variable mitotic activity, although nuclear-cytoplasmic ratio is generally low.11, 12, 14, 18–21, 36, 37 Some glands can also show a cribriform growth pattern.11, 12 Based on these morphologic features, we were able to render a diagnosis of GCA or consistent with GCA in small surgical specimens. Interpretation was limited by specimen size in only 8% of cases due to scant, fragmented and/or well-differentiated morphology.

The differential diagnosis of well-differentiated forms of GCA includes benign and premalignant gastric-type glandular lesions which are often incidental findings in hysterectomy specimens. The most common benign mimic of GCA is type A tunnel clusters, a lobular proliferation of endocervical glands composed of small, non-cystic tubular structures with bland cytology.18, 38 Diffuse laminar endocervical glandular hyperplasia is usually confined to the inner third of the cervical wall, and is composed of a laminar proliferation of closely packed rounded glands sharply demarcated from underlying stroma and lined by columnar to mucinous epithelium with bland, basally located nuclei.39, 40 LEGH can present as a well-demarcated mass or cystic lesion, sometimes with watery or mucoid discharge. LEGH is usually confined to the inner half of the cervical wall, and is composed of a lobular proliferation of small to medium-sized rounded glands lined by gastric-type epithelium, often with a central larger gland.24, 27, 40 A subset of LEGH exhibits cytologic and/or architectural atypia, including epithelial infolding or papillary structures with delicate fibrovascular cores, enlarged irregular nuclei with coarse chromatin and distinct nucleoli, loss of polarity, mitotic figures, luminal apoptotic bodies or nuclear debris.19.18 These cases known as "atypical LEGH" may fall into the spectrum of gastric-type adenocarcinoma in situ, possibly representing a precursor to GCA.41, 42 The immunophenotype of LEGH is similar to that of GCA.24, 27, 40 The presence of even mild cytologic atypia (increased nuclear/cytoplasmic ratio, conspicuous nucleoli, mitotic figures) in endocervical glands exhibiting pyloric metaplasia should raise concern for GCA, particularly in small biopsies.

The main differential diagnoses for moderately- to poorly-differentiated forms of GCA are endometrial endometrioid adenocarcinoma and endocervical adenocarcinoma of usual type, which exhibits pseudoendometrioid features, i.e. tumor cells have eosinophilic, mucin-poor cytoplasm resembling endometrioid adenocarcinoma. GCA can also be mistaken for endometrioid adenocarcinoma because it often involves the upper endocervix in the area of the lower uterine segment and is HPV and p16 negative. This has serious repercussions as it could result in the incorrect surgical procedure being performed (simple rather than radical hysterectomy). Finding the typical histologic features described herein can be crucial for diagnostic accuracy. Differentiating from endocervical adenocarcinoma of usual type is somewhat less problematic since apical (“floating”) mitotic figures and apoptotic bodies are easily appreciable at scanning magnification in most cases of endocervical adenocarcinoma of usual type.15 Tumors with mixed features of GCA and endocervical adenocarcinoma of usual type have been described, with 23% of these cases harboring HPV.43 Needless to say, these tumors can be especially challenging. Thus morphologically ambiguous cases may require ancillary studies including Alcian-blue/Periodic acid Schiff (AB/PAS) stain and immunohistochemistry to confirm gastric differentiation.44, 45 In our cohort, ancillary studies were performed on 74% of cases to assist in the diagnosis.

Gastric differentiation is characterized by the presence of neutral mucin rather than acidic mucin typical of benign endocervical glands. Neutral mucin stains predominantly red/magenta with combined AB/PAS, in contrast to normal endocervical glands that stain dark blue-purple.45 Neutral mucin can also be recognized by IHC using HIK1083 antibody.19, 46 However, HIK1083 is not available in most laboratories and is not consistently positive in GCA especially as the tumors become more poorly differentiated. The immunophenotype of GCA is typically absent or patchy p16 (with rare exceptions), negative estrogen and progesterone receptors, and aberrant expression of p53 in up to 50% of cases.15, 20, 31, 40, 47 Other positive stains include CK7 and CEA, while CK20 may be focally positive.36 In our cohort, negative or patchy p16 and negative in situ hybridization for high risk HPV subtypes were the most important pertinent negatives.

Cytologic diagnosis of GCA can be challenging. The characteristic features include monolayer and honeycomb sheets with vesicular nuclei, prominent nucleoli, vacuolar to foamy cytoplasm and intracytoplasmic neutrophil entrapment.48 In this cohort of GCAs, we found a constellation of cytologic features including: polygonal or columnar tumor cells arranged singly and in cohesive clusters; mildly to moderately pleomorphic nuclei with finely granular/vesicular chromatin and conspicuous nucleoli; moderate to abundant amounts of pale, foamy and/or vacuolated cytoplasm with well-defined cytoplasmic borders; inflammatory diathesis in the background in some cases. The cytomorphologic features in gynecologic and non-gynecologic specimens showed considerable similarity. It is encouraging that the cytologic features of GCA do not depend on the type of specimen or preparation being evaluated, as it indicates that with sufficient familiarity with the diagnostic features and a high index of suspicion for GCA in a patient with cervical cancer, the diagnosis can be accurately rendered.

The diagnostic categories were variable but none were deemed to be benign and all cases were diagnosed as at least “atypical glandular cells” (Table 1). However, many cases had a prior diagnosis of GCA and/or concurrent surgical specimens available, which aided cytologic evaluation. Analysis of the histologic and cytologic diagnoses of GCA by year revealed that the frequency of a confident final diagnosis of GCA increased substantially since 2013 (72% versus 19%), reflecting increasing recognition of the features of GCA by pathologists.

Our findings are very similar to those reported previously in the literature.37, 48 For example, Ishii et al37 described the presence of variable degrees of cytologic atypia, corresponding to the degree of differentiation of the tumor (as determined by histologic examination). They also described a background of necrosis, inflammation and mucin from several cases, corresponding to our identification of tumor diathesis and neutrophil admixture with tumor cell groups.37 Kawakami et al48 investigated the cytologic features of cohorts of GCAs and HPV-associated endocervical adenocarcinomas of usual type and described very similar findings to our cases. Features that were found to be significantly more common in GCAs than in endocervical adenocarcinomas of usual type were: monolayer sheets of tumor cells, foamy and vacuolated cytoplasm, intracytoplasmic neutrophil entrapment (seen as neutrophil infiltration into tumor cell groups in our cases), vesicular nuclear chromatin, and conspicuous nucleoli. The nuclei in endocervical adenocarcinomas of usual type tend to show homogenous chromatin and hyperchromasia with inconspicuous nucleoli.48 Both studies described yellow-orange staining of cytoplasmic mucin with Papanicolaou stain, which contrasted with pink staining in the cytoplasm of endocervical cells; however, we did not appreciate this tinctorial difference in our samples, which may be related to differences in staining reagents and protocols.37, 48

When evaluating cervicovaginal and other cytologic specimens from patients with a history of cervical neoplasia, a high index of suspicion for this variant of endocervical adenocarcinoma should be entertained, particularly with specimens from unusual anatomic sites; for example, one of our positive samples was an FNA of a neck lymph node. The presence of atypical glandular cells with foamy/vacuolated cytoplasm, well-defined cytoplasmic borders, finely granular/vesicular nuclear chromatin, and conspicuous nucleoli should raise suspicion for GCA and prompt careful additional examination, clinical correlation, and the performance of ancillary tests. Given that a diagnosis of GCA was only suspected by the referring pathologist in 25% of surgical consultation cases, awareness of the diagnostic features of GCA, allied with a high index of suspicion, is extremely important for early recognition. In the remaining 75% of surgical cases, the diagnoses ranged from “suspicious for adenocarcinoma” to “invasive adenocarcinoma” with various descriptions of tumor morphology. GCA was not suspected by the outside pathologist in any of the 5 cytology consultation cases and the diagnoses ranged from negative for malignant cells to adenocarcinoma. The importance of early recognition is highlighted by the 5- and 10-year survival rates of patients with GCA - 42% and 31%, respectively, for all stages, compared to 62% and 62%, respectively, for stage I33.

In conclusion, diagnosis of GCA, particularly well-differentiated variants, in small-volume biopsy and cytology specimens can be challenging. Awareness of the morphologic features with ancillary studies (e.g. immunohistochemistry for markers of gastric differentiation and HPV testing) will allow recognition and accurate diagnosis of these aggressive tumors.

Supplementary Material

Responses to reviewer comments

Acknowledgments

This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748.

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