Synchronous Cervical Minimal Deviation Adenocarcinoma, Gastric Type Adenocarcinoma and Lobular Endocervical Glandular Hyperplasia Along with STIL in Peutz-Jeghers Syndrome: Eliciting Oncogenesis Pathways
Azfar NEYAZ1, Nuzhat HUSAIN1, Manish DEODHAR2, Rohini KHURANA3, Saumya SHUKLA1, Aditi ARORA1
1Department of Pathology, Dr Ram Manohar Lohia Institute of Medical Sciences, LUCKNOW, INDIA
2Department of Radiology, Dr Ram Manohar Lohia Institute of Medical Sciences, LUCKNOW, INDIA
3Department of Radiation Oncology, Dr Ram Manohar Lohia Institute of Medical Sciences, LUCKNOW, INDIA
Keywords: Peutz-Jeghers syndrome, Minimal deviation adenocarcinoma, Uterine cervical neoplasm, Gastric type adenocarcinoma, Lobular endocervical glandular hyperplasia
We describe an unusual case of a Peutz-Jeghers syndrome associated with a composite synchronous cervical neoplasia comprising precursor
“lobular endocervical glandular hyperplasia (LEGH)”, “minimal deviation adenocarcinoma (MDA)” and “gastric-type adenocarcinoma (GTA)”
along with a serous tubal intraepithelial lesion (STIL) in the right fallopian tube. A 24-year-old woman presented with a white mucoid discharge
and bleeding per vaginum for one year. Histopathological evaluation showed MDA & GTA in FIGO grade III with pelvic lymph node metastasis
despite a deceptively bland tumour morphology and low Ki-67 index, indicating an aggressive tumour course and poor prognosis. Diagnostic
marker profile in the cervix showed gastric type mucin and positive expression of CK-7, CK-20 (patchy), CEA, and negative CDX-2, p16,
ER and PR. Further an attempt at eliciting the oncogenesis pathway in view of the p16 and HPV negative nature of the gastric type cervical
adenocarcinoma showed negativity for p53 but activation of cyclin D1. Growth factors including Her2 and EGFR were negative while VEGFR
was over-expressed. She was treated by radical hysterectomy and pelvic radiation. She was free from recurrence at the 12-month follow-up. This
is a first-time report of a STIL in the fallopian tube which was validated by a unilateral mutant type p53 expression and increased Ki67 index,
associated with synchronous gastric type adenocarcinoma of the cervix in all stages of evolution.
Peutz-Jeghers syndrome (PJS) is an autosomal dominant
inherited disorder that is characterized by hamartomatous
polyps of the gastrointestinal tract and mucocutaneous
melanin pigmentation and is often accompanied with a
higher incidence of other malignancies, such as breast
cancer, adenoma malignum of the uterine cervix and sex
cord tumor with annular tubules in the ovary. The cumulative
cancer risk for a PJS patient is 85% by age 70 (control
population risk 18%)1
. Serous tubal intraepithelial lesion
(STIL) in the fallopian tube has not been described in PJS in
the literature. We describe a very unusual case of PJS with
a right unilateral STIL in the fallopian tube associated with
a composite synchronous cervical malignancy comprising
a range of mucinous lesions of the uterine cervix from
precursor lobular endocervical glandular hyperplasia
(LEGH), minimal deviation adenocarcinoma (MDA) to
gastric-type adenocarcinoma (GTA).
A 24-year old G1P0 woman presented with white mucoid
discharge and bleeding per vaginum for one year. Her past
medical history was unremarkable. On investigation, USG
abdomen revealed a multicystic mass replacing the uterine
cervix. Pelvic magnetic resonance imaging (MRI) revealed
expansion of the cervix with a multilocular cystic mass
having thin septae appearing hypointense on T1WI and
hyperintense on T2WI and containing a fluid-fluid level
due to dependent layering (Figure 1A-D
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|Figure 1: Preoperative pelvic MRI scan shows A) Sagittal T1WI and B) T2WI demonstrating a complex cystic mass (*) containing fluid-fluid levels involving the cervix. C-D) Coronal T2WI demonstrates the ovaries separate from the cystic mass. E) Non-contrast and F) contrast enhanced follow-up CT scans performed with bowel opacification show multiple enhancing bowel polyps.
The first excisional biopsy was reported as mucinous
adenocarcinoma. Subsequently, the patient underwent
radical hysterectomy with bilateral salpingo-oophorectomy,
vaginal reconstruction and bilateral pelvic lymph node
On macroscopic examination, the cervix was infiltrated
by an ill-defined ulcero-infiltrative growth measuring
4.0x3.0x3.0 cm and involving the endocervix, ectocervix and isthmus. The tumour was seen to be infiltrating the
entire thickness of the cervix. The ovaries, fallopian tubes
and parametrium appeared free in gross evaluation.
Macroscopic metastases to pelvic lymph nodes were
evident. The cervix was extensively sectioned. Sections
from bilateral fallopian tubes were also taken as per the
Sectioning and Extensively Examining of the Fimbriated end (SEE-FIM) protocol2. Microscopically, complete
effacement of cervical stroma by three distinct histological
patterns was noted. The majority of the tumor was composed
of dilated irregularly shaped glands lined by single-layer
of columnar cells without atypia. These well differentiated
glands lined by columnar cells displayed basally located
bland nuclei along with abundant intracytoplasmic mucin.
Mitosis, atypia or necrosis was not apparent. Some of the
glands showed complex branching and distortion. These
microscopic findings were consistent with a diagnosis
of minimal deviation adenocarcinoma (Figure 2A-C).
Encroachment of the blood vessels and nerve fibers added
further support for stromal invasion. The other histological
pattern in spatial continuity with the first type constituted
irregularly shaped glands revealing moderate atypia and
stromal desmoplasia. These ill-defined neoplastic glands
showed moderate anisonucleosis with nuclear stratification,
coarse chromatin, occasional prominent nucleoli and large
to abundant amount of eosinophillic to clear cytoplasm
reflecting morphological features of gastric type mucinous adenocarcinoma of the cervix (Figure 2D-F). Cytochemical
staining highlighted neutral mucin (Figure 2G).
Accompanying lobular endocervical glandular hyperplasia
consisting of proliferating moderately sized endocervical
glands confined within the superficial cervical stroma was
discernible at places (Figure 2H). Synchronous existence
of three diverse histological morphologies prompted the
diagnosis of composite cervical adenocarcinoma composed
of minimal deviation of adenocarcinoma and gastric type
adenocarcinoma. The tumour involved full thickness of the
cervix lip. Foci of perineural invasion and lympho-vascular
invasion were also observed. Tumour was seen extending
to lower uterine segment and anterior vaginal wall. Bilateral pelvic lymph nodes showed metastasis and hence, was
staged as FIGO IIIA. Serous tubal intraepithelial lesion
(STIL) was noted in right fallopian tube, characterised by
non-ciliated epithelium displaying nuclear enlargement,
hyperchromasia, irregularly distributed chromatin and
nucleolar prominence (Figure 3A-B). Strong p53 overexpression
was evident (Figure 3C) with Ki-67 index of
approximately 8% (Figure 3D). The lesion was evident in
the distal half of the tube and at the fimbrial end. Other tube
showed no morphological atypia with wild type p53, low
Ki67. The ovaries did not show any neoplastic pathology.
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|Figure 2: A) Two histologically distinct components, MDA and GTA identified (H&E; x100). B) Irregular neoplastic glands displaying complex branching (H&E; x100). C) Tumour glands lined by single layer of columnar cells with basally located bland nuclei, suggesting MDA (H&E; x400). D-F) Irregularly shaped dilated glands with moderate atypia and prominent infoldings and neoplastic glands with nuclear pseudostratification, enlarged centrally placed nuclei, prominent nucleoli and abundant foamy cytoplasm, features suggestive of GTA (H&E; x100 ; x100 ;x200). G) Combined Alcian blue & PAS-D highlights the neutral mucin (Alcian blue&PAS-D; x200). H) Lobular endocervical glandular hyperplasia consisting of proliferating moderately sized endocervical glands (H&E; x40). I) Hamartomatous GI polyp composed of complex arborizing glandular architecture lying on slips of smooth muscle (H&E; x40).
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|Figure 3: A-B) Serous tubal intraepithelial lesion (STIL) characterised by stratified epithelium displaying increased nuclear/cytoplasmic ratio, nuclear atypia (H&E; x200; x400). C) Mutant type p53 over-expression in STIL (p53; x200). D) Ki-67 index at 8% in STIL lesion (Ki-67; x 400).
Immunohistochemical evaluation of the cervical
adenocarcinoma and the metastasis in the lymph nodes
was carried out to study the expression of recognised
markers such as CK-7, CK-20, CDX-2, CEA, p16, p53, ER, PR and Ki-67 as well as Her 2, Cyclin D1, EGFR,
VEGFR and β-catenin to elicit pathways of carcinogenesis.
Strong or diffuse immunoreactivity was observed for CK-
7, CEA, Cyclin D1 and VEGFR while CDX-2, p16, p53,
Her-2, EGFR, ER and PR were negative (Figure 4A-L).
CK-20 showed focal expression. Ki-67 in the MDA, GTA
component and lymph node metastasis was 3-4%. Uniform
marker expression was observed in the primary lesion and
the lymph node metastasis, and in the latter the phenotype
was predominantly MDA.
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|Figure 4: A) Positive immunoreactivity for CK-7 (CK-7; x100). B) Focal positivity for CK-20 (IHC; x100). C) Negative immunoreactivity for CDX-2 (IHC; x200). D) Positive immunoreactivity for CEA (IHC; x100). E) Negative immunoreactivity for p16 (IHC; x100). F) Negative immunoreactivity for ER (IHC; x200). G) Negative immunoreactivity for PR (IHC; x200). H) Negative immunoreactivity for p53 (IHC; x200). I) Positive immunoreactivity for VEGFR (IHC; x100). J) Positive immunoreactivity for Cyclin D1 (IHC; x100). K) Negative immunoreactivity for Her-2 (IHC; 200). L) Ki-67 index was 3-4% (IHC; x200).
Follow-up imaging by CT scan showed no residual mass
in the pelvis. However, numerous polyps were incidentally
detected in the small and large intestines. An upper and
lower gastrointestinal endoscopy was done, disclosing
multiple polyps throughout the duodenum, colon and rectum (Figure 1E,F). Polypectomy was done from the
largest rectal polyp. Histological examination exhibited
complex arborizing glandular architecture lying on slips of
smooth muscle supporting aggregates of benign cystically
dilated glands suggestive of hamartomatous polyp (Figure
2I). Features of concomitant dysplasia or malignancy were
Clinical examination disclosed mucocutaneous pigmentation
in the peri-oral area. However, no significant family
history could be elicited. The patient was treated by radical
hysterectomy and pelvic radiation on a LINAC at 45 gy in
25 sittings of radiation followed by brachytherapy to the
vault. She was free from recurrence during the 12 month
We report an interesting rare composite lesion in the
uterine cervix with a morphologic spectrum of LEGH
and malignant cervical mucinous lesions exhibiting
gastric differentiation including MDA and GTA existing
in synchronous continuous transition in a case of Peutz-
Jeghers syndrome. We are reporting for the first time an associated STIL in fallopian tube in PJS. In an extensive
literature review, we have not come across any reports of
serous intraepithelial lesions of the tube associated with
PJS. Rare reports of mucinous lesions of the fallopian tube
have been reported in association with other mucinous
lesions of the female genital tract in GTA, MDA and with
. It was interesting to note
that STIL was unilaterally present in right fallopian tube.
The diagnosis was validated using a diagnostic algorithm
recommended by Vang et al. coordinating the histology
and immunohistochemical expression of p53 and the Ki67
. STIL and STIC are known to be associated with
serous carcinomas of peritoneal, ovarian, or endometrial
origin and not with any other non-serous lesions such as
endometrioid, clear cell, or mucinous carcinomas5
cases with concordant STICs and ovarian or pelvic high
grade serous carcinomas, identical TP53 mutation in both
STICs and the associated ovarian neoplasms has been
however it is significant to note in our
case that the cervical malignancy was p53 negative while
STIL was p53 positive denoting multifocal unrelated
neoplastic change in association with PJS.
The term ‘lobular endocervical glandular hyperplasia’
(LEGH) has been shown to have a gastric-type IHC profile
and is considered to be a putative precursor lesion to MDA
and GTA. Approximately 10-15% of PJS cases develop
minimum deviation adenocarcinoma. Rare case reports
describe the presence of LEGH, a potential premalignant
lesion of MDA, and its evolution to more aggressive gastric
adenocarcinoma7. McCluggage et al. reported composite
carcinoma for the first time and identified common genetic
aberrations between MDA and GTA indicating a possible
link between these tumors. In their case, the MDA and
GTA occupied discrete areas in the cervix8. In contrast,
the MDA and GTA components in the current case as
well as the case reported by Peng et al. were continuous in
nature, and had similar immunophenotypes, favoring the
hypothesis that GTA may arise from dedifferentiation of
MDA9. MDA has been classified as an extremely well
differentiated form of GTA in the new WHO Classification
of Tumors of Female Reproductive Organs. Although P53
postitivty has been enumerated as one of the diagnostic
criteria for the tumour, Carleton et al. have shown “wildtype”
p53 in 58% and “mutation-type” staining in 41% of
the cases10. In the current case, p53 was negative while
cyclin D1 and VEGFR were strongly expressed in the
tumour nuclei and membrane respectively.
High-risk human papillomavirus (hr-HPV) is currently
considered to be implicated in the carcinogenesis of most
cervical adenocarcinoma and squamous cell carcinoma
with a detection rate reaching 85% in the former. Unlike
conventional endocervical adenocarcinoma, the presence
of hr HPV and diffuse p16 positivity, a surrogate marker for
HPV integration, is not associated with MDA and gastric
type adenocarcinoma. Mucinous cervical adenocarcinomas
appear to represent an oncogenic hr-HPV-independent
pathway of p16 overexpression and are therefore a potential
pitfall of HPV DNA testing and vaccination11. Our case
was also negative for p16 expression.
Immmunohistochemical support for a gastric phenotype
comes from studies demonstrating histochemical positivity
for gastric mucin and immunohistochemical positivity
for the gastric markers HIK1083 and MUC6. Histological
changes mimicking clear cell carcinoma have been reported
after neoadjuvant therapy but immunohistochemical
positive expression of CEA, cytokeratin 7 (diffuse),
and cytokeratin 20 (focal), positive HIK1083 stain or
negative/focal p16 stain favors gastric-type mucinous
adenocarcinoma of the cervix12. Immunophenotypic overlap with pancreaticobiliary adenocarcinomas exists but
PAX8 immunoreactivity may be useful to distinguish them.
The responsible gene in PJS is a tumor suppressor gene,
STK11/LKB1, that is located on the short arm of chromosome
19 (19p13.3). STK11/LKB1 is a 23-kb gene that encodes a
serine-threonine kinase of a 432-amino-acid protein and
consists of 9 coding exons and 1 non-coding exon13.
Cases with MDA in PJS, that is a STK11 mutation, have
a poorer prognosis than those without a STK11 mutation
(p = 0.039)14. There are no established guidelines for
screening for gynecologic neoplasia in PJS patients15.
Routine cervical cytology screening is recommended and
ideally the diagnosis of PJS should be communicated to the
reviewing cytotechnologist/cytopathologist so that careful
assessment for gastric type adenocarcinoma is done. Beyond
cervical cytology screening, some investigators advocate for
yearly pelvic examinations and/or ultrasound beginning in
young adulthood to detect ovarian neoplasia; however, this
recommendation has not been uniformly accepted15,16.
The treatment schedule for MDA is the same as that for
conventional adenocarcinoma at the same stage. Surgery
remains the main treatment for patients with early
stage lesions. Radiotherapy and/or chemotherapy are
recommended for patients with advanced disease. Our case
underwent a radical hysterectomy followed by radiation
Gastric-type adenocarcinoma and MDA have been
reported to have an aggressive clinical course. Carleton C
et al. reported in their review of 40 cases of GTA that 59%
were in the advanced stage (FIGO II-IV), 50% had lymph
node metastases, 35% had ovarian involvement, 20% had
abdominal disease, 39% had at least one site of metastasis
at the time of initial surgery and 12% of the patients
experienced distant recurrence10. The 5-year disease-free
survival rate of patients with gastric-type adenocarcinoma
(38%) was substantially lower than that of patients with
the usual type of uterine cervical adenocarcinoma (74%).
In the study by Kojima et al., gastric morphology and
immunophenotype (HIK1083-positivity) were found to be
independent predictive factors of disease recurrence and
decreased survival in stage I and II cervical adenocarcinoma17. The minimal deviation adenocarcinoma also has a less
favorable prognosis than the usual type of endocervical
adenocarcinoma. The 2-year survival rate of patients with
any stage of minimal deviation adenocarcinoma is 20-30%,
whereas that of patients with stage I disease is around 50%18.
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