Endocervical adenocarcinoma diagnostic challenges

1. Presented by
Dr. Priti Toppo
Dr. Ruchi Singh
Resident
Dept of Pathology
Gandhi medical college
Moderated by
Dr. Archana Shrivastava
Associate Professor
Dept of Pathology
Gandhi medical college
Gandhi Medical College

2. Recent advances in Histopathology
25th edition
Diagnostic challenges in Endocervical Adenocarcinoma
Chapter 5
Authors: Jaime Prat, Emanuela D Angelo

3. Embryology and anatomy of the female genital tract

6. P. Dey, Color Atlas of Female Genital Tract Pathology,
https://doi.org/10.1007/978-981-13-1029-4_3

7. Introduction
The 2020 WHO classification, following the recommendation of the International Endocervical Adenocarcinoma
Criteria and Classification (IECC), separates endocervical adenocarcinomas into two different types based on HPV
relationship.
1.HPV-associated carcinomas USUAL TYPE (75% of endocervical adenocarcinomas)
VILLOGLANDULAR VARIANT,
MUCINOUS TYPE -NOS,
-Intestinal,
-Signet- ring cell
-Invasive stratified mucin-producing carcinomas (SMCs).
2.HPV independent adenocarcinomas GASTRIC,
CLEAR CELL,
MESONEPHRIC, AND
ENDOMETRIOID TYPES.
This classification is in accord with clinical features, pl6 immunoreaction and HPV status, prognosis, and response
to treatment.
As in other anatomic locations such as the oropharynx and the vulva, it has been demonstrated that
HPV-independent cervical adenocarcinomas are usually more aggressive than HPV-associated carcinomas.

8. Endocervical adenocarcinomas represent a diverse group of tumours and screening strategies are less
effective in detecting precancerous glandular lesions as compared to squamous cell carcinoma
precursors.
• HPV-associated precursors of glandular tumours include the endocervical adenocarcinoma in situ
(AIS) of the usual type and the stratified mucin-producing intraepithelial lesions (SMILE).
• HPV-independent precursor lesions are atypical lobular endocervical glandular hyperplasia (LEGH)
and gastric-type AIS (gAIS).
• Mesonephric carcinomas are frequently associated with mesonephric remnants or mesonephric
hyperplasia which are benign.
Pre cancerous glandular lesions

9. Adenocarcinoma in situ shows substitution of glandular epithelium by cytologically malignant
epithelial cells with maintenance of the glandular architecture and is related to infection by high-
risk HPV.
Etiology The following findings are in favour of AIS being a precursor of invasive
adenocarcinoma:
 The age of the patients with AIS is about 10-15 years younger than that of patients with
Invasive Adenocarcinoma.
 AIS is frequently encountered in the proximity of invasive adenocarcinoma.
 Most frequently HPV16 and HPV18, but also HPV45, are equally identified in both AIS and
Invasive Adenocarcinoma.
Adenocarcinoma in situ- HPV associated

10.  10-20% of cervical adenocarcinomas.
 In contrast to HSILs, AIS is much less frequent reported
 Prevalence of invasive glandular lesions is higher than that of noninvasive glandular
lesions.
 The median age in a recently reported large series of cases was 35 years compared with
41 years for patients with invasive adenocarcinoma.
 Asymptomatic but have abnormal cervical smears.
 Associated with HPV-DNA mainly 16 and 18 types
Adenocarcinoma in situ- General features

11.  AIS is neither grossly visible nor it shows a characteristic colposcopic pattern like squamous
intraepithelial lesion (SIL).
 Involves both surface and glandular epithelium of the transformation zone in 65% of cases and is
mainly unifocal.
 It can extend upwards for up to 3 cm into the endocervical canal.
 AIS coexists with SIL or invasive squamous cell carcinoma in 24-75% of case and the shedding
atypical cells lead to clinical examination helping to detect AIS.
Adenocarcinoma in situ- General features

12. Histologically, AIS grows along the
endocervical surface and does not
extend beyond normal glands.
There is neither destructive stromal
invasion nor desmoplasia.
The AlS glands appear lined by
stratified epithelium exhibiting
elongated, cigar-shaped
hyperchromatic nuclei, increased
number of mitotic figures and
apoptotic bodies.
Adenocarcinoma in situ- Pathology

13. Adenocarcinoma in situ (arrow) showing dark
glands with atypical, enlarged nuclei adjacent to a
normal, pale endocervical gland.
Normal architecture of the gland is
preserved
• Interglandular papillary projections or
cribriform appearance may be seen
• Pseudostratification of the cells forming
two to multiple rows
• Nuclei show:
–– Enlargement –– Elongated nuclei give
cigar shaped appearance –– Coarse
chromatin –– Nucleolar prominence ––
Granular eosinophilic cytoplasm with
mucin production
The most important feature: Absent tumour
diathesis
Adenocarcinoma in situ- Pathology

14. AIS changes may be limited to part or all the epithelium lining the glands or the endocervical surface.
Based on cytoplasmic features, four types of AlS have been described:
1.Endocervical type
2. Intestinal type, with goblet cell differentiation
3. Endometrioid type
4. SMILE type
Endometrioid type of AIS probably represents endocervical type with depleted mucin.
The term endometrioid no longer applies to the spectrum of HPV-associated endocervical carcinoma.
Even if the biologic significance of these histologic types is questionable, their recognition helps the pathologist
to identify AIS.
Adenocarcinoma in situ- Pathology

15. The most common type of AIS is the endocervical type, in which
the
• cells resemble those of the endocervix, and
• glands show nuclear atypia and pseudostratification,
• scant amounts of juxtaluminal cytoplasm containing mucin,
• scattered mitoses (normal and/ or abnormal),
• and apoptotic bodies.
Usually, there is a clear demarcation of
AIS from closely uninvolved glands and
from the uninvolved epithelium of the
same gland.
Adenocarcinoma in situ- Pathology

16.  When these findings are prominent, a diagnosis of adenocarcinoma
with nondestructive invasion should be considered.
 Intestinal- type AlS is a form of intestinal metaplasia exhibiting
goblet cells.
 In these cases, nuclear atypia is often not evident as the mucin
globules compress the nuclei reducing the degree of nuclear
enlargement and pseudostratification.
Adenocarcinoma in situ- Pathology
The glands of AlS can focally show
outpouchings, complex papillary
infoldings and even a cribriform
pattern.

17. P16- diffuse
nuclear
block type
or every cell
and/or
cytoplasmic
positivity
Ki 67/MIB1
nuclear
overexpression
However, a subset of
intestinal-type AIS that
occurs in older patients is
not associated with HPV
and may show variable
reaction with antibodies
to pl6 and Ki67
Adenocarcinoma in situ- IHC

18. Adenocarcinoma in situ- IHC
P16 Ki67 diffuse
+
Bcl-2 focal+/-
Vimentin - P53 focal +
IHC panel
Adequate application of these markers may clarify whether an atypical glandular lesion is a
reparative condition or a precursor to endocervical glandular cancer; however, the mainstay of
AIS diagnosis should be careful morphologic haematoxylin and eosin (H&E) examination.

19.  Crowded sheets of endocervical columnar cells with palisading.
 Feathering of nuclei at group edges,
 Pseudostratification and gland openings within the sheets.
 Rosettes are also a typical feature.
 Mitoses and apoptosis are helpful if seen.
 Chromatin is often coarse and dark but can appear clearer on
liquid-based preparations.
Adenocarcinoma in situ- Cytological findings
Cases showing some features suggestive but not diagnostic of AlS should be diagnosed as are 'atypical endocervical
cells, favours neoplasm.
Pap tests have a high false negative rate for the detection of AIS (60%) whereas patients have a concurrent positive
HPV test.

20. Adenocarcinoma in situ- Cytological findings

21. Adenocarcinoma in situ- Differential diagnosis
1. Tubo-endometrial metaplasia
2. Superficial cervical endometriosis
3. Arias stella reaction
4. SMILE Stratified Mucin
producing intraepithelial lesion
 Endocervical cells are replaced by ciliated columnar cell.
 Lack nuclear atypia and mitoses
 Apoptotic bodies are inconspicuous.
 Endometrioid- type stroma.
 Bland nuclei without significant mitotic activity.
IHC Bcl-2
pl6INKAA
CD10
low Ki67/MIB1.
Tubo endometrial metaplasia

22. Adenocarcinoma in situ- Differential diagnosis
 Confined to the inner third of the cervical wall.
 Widely spaced cystic endocervical glands
 Glands lined by cells with large pleomorphic nuclei,
 Cytoplasm is finely vacuolated or granular.
 Loss of nuclear polarity
 Dispersed chromatin
Arias Stella reaction
 10% of gravid uterus.
 Superficial glands are more commonly
involved than deep glands.
 Involved glands usually have a single layer
of enlarged hyperchromatic pleomorphic
that protrude into the lumen producing a
'hobnail' appearance.
 Mitoses are extremely rare or absent
Superficial Cervical Endometriosis

23. Adenocarcinoma in situ- Differential diagnosis
 The SMILE exhibits stratified epithelium resembling SIL but with
conspicuous production of mucin.
 Mucin is present all over the epithelium, varying from indefinite
cytoplasmic clearing to distinct vacuoles.
 The lesion shows a rounded contour at epithelial-stromal interface
and a high Ki67/MIBI index.
 SMILE is frequently as associated with SIL, AIS, or invasive carcinoma
SMILE

24.  Conisation or hysterectomy.
 Recurrence- conisation > hysterectomy
 Hysterectomy - definitive therapy.. for AIS.
 In a meta-analysis, 27% of patients treated with conisation where the surgical margins were
free of tumour had residual AIS in the subsequent hysterectomy specimen
Adenocarcinoma in situ- Biologic behavior and t/t

25.  10-25%
 Before 1970- represented only 5% of cervical carcinomas.
 Decrease in invasive squamous cell carcinoma, readily identified in its preinvasive stages by cytologic
examination than adenocarcinoma.
 Primary HPV-based screening improves prevention of adenocarcinoma over cytology.
 60% of cervical adenocarcinomas are associated with SIL or invasive squamous cell carcinoma.
 HPV-16, HPV 45, and particularly HPV-18 have a significant role in the causation.
 Identified in adenocarcinomas and adenosquamous carcinomas with a frequency of >80%
 HPV status is not predictive of disease outcome
Endocervical adenocarcinoma HPV associated

26.  Adult life.
 Rare in the first decade and uncommon in the second decade.
 Average age ranges from 47-50years.
 AUB in 80-90% of cases.
 Asymptomatic in up to 20%
 Abnormal Pap test.
 Adenocarcinomas of the cervix may cause diagnostic difficulties because of their relative rarity, their varied
patterns, and the potential for confusing them with several non-neoplastic lesions.
 Some variants are associated with a distinctive biologic behaviour.
 A classification of these tumours is presented next slide includes new described histologic variants such as SMC
and those with micropapillary feature (micropapillary adenocarcinoma)
Endocervical adenocarcinoma HPV associated

27. WHO classification
Endocervical
Adenocarcinoma
• HPV associated
• Usual type
• Mucinous type
• NOS
• Intestinal
• Signet ring cell
• Invasive stratified mucin-producing carcinoma (SMC)
• Adenocarcinoma NOS
• HPV independent
• Gastric
• Clear cell
• Mesonephric
• Endometrioid type
• Adenocarcinoma NOS

28. Non-HPV adenocarcinoma, gastric type
Non-HPV adenocarcinoma, endometrioid type
Non-HPV adenocarcinoma, clear cell type
Non-HPV adenocarcinoma, mesonephric type
Non-HPV adenocarcinoma, serous type
2. Non-HPV related adenocarcinoma
Adenocarcinoma NOS

29. Usual type adenocarcinoma
 While cervical adenocarcinoma is often referred to as 'mucinous adenocarcinoma’ not always overtly mucinous.
 In fact, it is commonly mucin-poor due to less than a high degree of differentiation and instead is composed of cells
with eosinophilic cytoplasm.
 Therefore the designation 'endocervical adenocarcinoma of usual type' is used.
It is defined as an adenocarcinoma in which the tumour cells resemble those lining the endocervical glands and contain
varying amounts of cytoplasmic mucin (up to 50%). These neoplastic glandular cells are related to infection by high-risk
HPV and invade the cervical stroma.

30. Usual type adenocarcinoma-Gross
 Exophytic, often with a polypoid or papillary growth pattern.
 Nodular, with diffuse enlargement or ulceration, and
 Barrel-shaped cervix.
 Small and not visible, usually because of their location within the endocervical canal.
 May infiltrate deeply into the wall.
Generally, the gross appearance is not helpful in predicting the histologic appearance.
Diffuse enlargement of the
endocervical canal

31. Usual type adenocarcinoma-Microscopy
 Well to moderately differentiated and show little intracytoplasmic mucin;
 The tumour glands resemble those of endometrioid carcinoma or exhibit a mixed endocervical and
endometrioid appearance.
 This has led to confusion, with these tumours being regarded as endometrioid adenocarcinomas.
Irregular tumour
glands composed
of mucin depleted
cells in abundant
fibrous stroma.
The glands show a
mixed
endocervical and
endometrioid
appearancce
Pg13
article
briggiti
mage

32. Usual type adenocarcinoma-Microscopy
Gland size may vary from small to cystic, and the glands may be wide spaced or closely packed, often with a
cribriform pattern. Stroma is fibrous
One tumour gland shows
cribriform pattern

33. Papillae may be present but rarely conspicuous.
Numerous mitoses and apoptosis are present.
Usual type adenocarcinoma-Microscopy

34. Grading of endocervical adenocarcinomas follows the the Internation
Federation of Obstetrics and Gynaecology (FIGO) system for glandular
tumours as described elsewhere for endometrium and ovary.
 Grade 1 tumours (well-differentiated tumours) grow in glandular formations with <5% of areas
being solid.
 Grade 2 tumours (moderately-differentiated tumours) 5-50% solid areas.
 Grade 3 tumours (poorly differentiated tumours) are >50% composed of solid tumour nests.

35. Pattern A (non-
destructive
invasion)
Pattern B
(early/focally
destructive
invasion)
Pattern C (diffusely
destructive
invasion)
Well-demarcated glands with rounded contours.
No single cells or cell detachment.
Complex intraglandular growth allowed (ie. cribriform and papillae).
No solid growth or high-grade cytology.
No lymphovascular invasion.
Irrelevant relationship to large cervical vessels or depth of the tumour.
Individual or small clusters of tumour cells, separated from the rounded glands, usually in an inflamed or
desmoplastic stroma.
Foci may be single, multiple, or linear at the base of the tumour.
No solid growth
Lymphovascular invasion (present/absent)
Infiltrative glands that are variable in shape and size, often angulated or interconnected.
Confluent growth: Glands or papillary structures with little intervening stroma or mucin lakes with tumour cells
within the cervical stroma.
Solid: Poorly differentiated component (architecturally high grade) with sheets of large malignant cells
Lymphovascular invasion (present/absent)
Invasive HPV-associated adenocarcinomas may have a destructive or nondestructive (AIS-1like) growth pattern and a system
to assess the pattern of invasion has recently been developed and validated.
The Pattern-based classification (Silva system)

36. Invasive human papilloma virus–
associated adenocarcinoma, pattern
A
Proliferation of neoplastic
glands focally with lobular
architecture The proliferation
extends deep into the cervical
stroma
The glands have rounded
contours
Nuclei are elongated and
pseudostratified and lack high-grade
cytologic atypia

37. Source
The Silva Pattern-based Classification for HPV-associated Invasive Endocervical Adenocarcinoma and the
Distinction Between In Situ and Invasive Adenocarcinoma: Relevant Issues and...
International Journal of Gynecological Pathology40:S48-S65, March 2021.
Invasive human papilloma virus–associated adenocarcinoma, pattern B.
Diffuse proliferation of neoplastic glands with a
rounded contour and focal intraglandular papillary
architecture, and small gland with focal inflammation,
square (A), higher magnification shows a small gland
with flattened epithelium indicating early destructive
invasion, arrow (B
Mostly diffuse proliferation of neoplastic
glands extending into the ectocervix (C) and
with focal lymphovascular invasion, square
(D).

38. The Silva Pattern-based Classification for HPV-associated Invasive Endocervical Adenocarcinoma and the
Distinction Between In Situ and Invasive Adenocarcinoma: Relevant Issues and...
International Journal of Gynecological Pathology40:S48-S65, March 2021.
Invasive human papilloma virus–associated adenocarcinoma, pattern C.
Diffuse proliferation of variably sized and
shaped glands, many of them angulated, in a
desmoplastic stroma (A), some of the glands
are elongated and with flattened epithelium,
microcystic, elongated and fragmented–like
(B).
Interconnected glands in a desmoplastic
stroma (C), confluent glands with
intraglandular papillary growth filling a 4×
field (5 mm) (D)

39.  The Silva system is applicable to HPV-associated but not HPV- independent adenocarcinomas.
 A prerequisite for its application is the histologic examination of the entire tumour.
 Thus, pattern assignment is best done in a cone or loop electrosurgical excision procedure
(LEEP) specimen with negative margins, or alternatively in a hysterectomy or trachelectomy
specimen.
 Biopsy material is not suitable for pattern assignment.
 Conversely, it has been shown that the Silva pattern of invasion in LEEP and cone material is
highly predict the overall pattern of residual tumour in hysterectomy.
 The Silva system has been included in the current FIGO or AJCC grading systems.
The Pattern-based classification (Silva system)

40. P16 overexpression Negative ER
Usual type adenocarcinoma-IHC
Negative for Vimentin

41. Difference between endocervical adenocarcinoma and
Endometrial adenocarcinomas of the corpus
Endocervical Adenocarcinoma Endometrial Adenocarcinoma
Intracellular mucin +++ +
Fibrous stroma Abundant Scanty
Villoglandular architecture + +++
HPV DNA + -
P16 +++ -
Estrogen receptor - Or + +++
Vimentin - ++
SIL + -

42. Invasive cervical adenocarcinoma share many features with AIS.
Features helpful in correctly predicting histological invasion are:
 Heavy bleeding and abnormal glandular epithelium
 Supercrowding of sheets, abnormal 3D groups
 Papillary clusters
 Tumour diathesis
 Single malignant cells with nuclear pleomorphism and macronuclei
 Mitotic figures
Liquid based cytology maybe more sensitive than conventional cytology in detecting cervical adenocarcinomas

43. Abundant discrete and cohesive clusters of
cells. No tumour diathesis is present.
Multiple three dimensional tight cohesive
clusters of cells along with many discrete cells.
Columnar strips of cells, enlarged pleomorphic
nuclei, small nucleoli
Cells are round with coarse chromatin and
prominent nucleoli

44. Differential diagnosis
 Benign glandular lesions including tunnel clusters (types A and B),
 Microglandular hyperplasia,
 LEGH,.
 Diffuse laminar endocervical glandular hyperplasia, and
 Deep nabothian cysts,
 Secondary adenocarcinoma metastatic to the cervix.
Features that favors a benign nature include
• Superficial location and
• lack of deep infiltration
• Lobulation
• Well-defined margins
• Bland nuclear features
• Inconspicuous mitotic and apoptotic activity
• Absence of a stromal reaction

45. Tunnel clusters
Definition: Collection
of benign endocervical
glands within the wall
of cervix
Mimics ECA micocystic
pattern
HP view to confirm
malignant nature
Aggregates of closely spaced
endocervical glands deep within the
stroma.
Variable sized glands
lined by mucus secreting
columnar cells

47. Proliferation of the endocervical
glands
Lobular architectural pattern of the
aggregated glands
Glands are lined by mucus secreting
columnar epithelial cells
Well differentiated adenocarcinoma: Stromal invasion,
desmoplastic reaction, nuclear atypia and mitosis are present
Lobular endocervical glandular hyperplasia

48. Villoglandular type
 Uncommon variant
 Well-differentiated villoglandular fronds resembling villoglandular adenoma of the colon.
 Average age, 35-45 years
 Excellent prognosis.
 OCP.
Grossly, the tumour typically appears as a broad-based, papillary, and friable cervical polyp.
Microscopically, it shows a
• Surface papillary component of variable thickness
• Papillae are long and slender,
• Occasionally short, and broad, and
• Covered by endocervical mucin-depleted (endometrioid-like), or
• Intestinal epithelia with at most mild to moderate cytologic atypia

49. Stroma in the villi may be
substantial or minimal,
Contains many acute and
chronic inflammatory cells.
The epithelium may be pseudostratified
but lacks tufting and solid areas.
Entirely exophytic or show only
superficial invasion, confined to the
inner third of the cervical. cells.
Associated SIL or AIS are common
Lymphatic or vascular invasion is
rarely observed
Lymph node metastases are rare

50.  A tumour should not be placed in this group if any adverse prognostic feature, eg presence of coexisting
serous carcinoma, is present.
 The differential diagnosis villoglandular adenocarcinoma also includes benign lesions such as Müllerian
papilloma and Müllerian adenofibroma.
 These lesions lack the degree of nuclear atypia that is present in villoglandular adenocarcinomas.
 Müllerian adenofibroma and Müllerian papilloma typically show more prominent stromal component.
 Villoglandular adenocarcinoma should also be distinguished from serous carcinoma of the corpus that has
extended to the endocervix.
 Serous carcinomas exhibit more irregular papillae which are lined by cells with nuclear anaplasia and
numerous mitoses.

51.  Large cohesive sheets, with crowded nuclei and
loss of the normal honeycomb structure.
 Most characteristics are true papillary structures
with stromal component covered by palisaded
columnar cells with intact cytoplasm.
 Nuclei are small, moderately hyperchromatic
and round to oval with minimal pleomorphism
and small or absent nucleoli.
 The nuclear features are not clearly malignant
and if close attention is not paid to the
architectural features, the diagnosis may be
missed.
Villoglandular adenocarcinoma cytology.

52. Villoglandular adenocarcinomas are associated with HPV 16 >18
KRAS and TP53 mutations absent.
Immunohistochemically,
Overexpress Ki-67/MIB1, show
normal P53 immunoreactivity
ER negative
PR negative.
Immunohistochemistry and somatic genetics
 Cone biopsy and careful follow-up good prognosis.
 Two cases of 'villous adenoma' of the uterine cervix associated with underlying invasive
adenocarcinoma have been reported.
 The presence of an underlying invasive carcinoma in these cases indicates that the finding of a
villoglandular lesion of the cervix, even if it is lined by only slightly atypical cells, should warrant
investigation to exclude an underlying infiltrating adenocarcinoma.
Biologic behaviour and treatment

53. Mucinous non gastric type adenocarcinoma
 This type accounts for approximately 10% of all endocervical adenocarcinomas.
 By definition, there is intracytoplasmic mucin in >_50% of tumour cells.
 A minor component of usual adenocarcinoma is frequently present.
The 2020 WHO classification subdivides the mucinous type into four variants:
1. Mucinous NOS adenocarcinoma
2. Intestinal adenocarcinoma
3. Signet-ring cell adenocarcinoma
4. Stratified mucin-producing carcinoma

54. Mucinous Adenocarcinoma NOS
In a usual-type background,
the tumour cells show
mucinous cytoplasm
resembling normal endocervix
with a pale-purple staining on
H&E
Resembles adenocarcinoma
but the tumour cells contains
obvious cytoplasmic mucin

55. Intestinal Adenocarcinoma
 Resemble adenocarcinoma of the large intestine.
 Intestine type change may be found diffusely only focally within a mucinous adenocarcinoma.
 Form glands with papillae or infiltrate throughout the stroma in a pattern like that of colonic adenocarcinoma
 Primary endocervical adenocarcinoma of intestinal generally reactive with antibodies to CK-7 and nonreactive with
antibodies to Pe is CDX-2 CD20.
 High-risk of HPV has been detected in the intestinal variant

56. Signet ring cell Adenocarcinoma
 Primary signet-ring cell adenocarcinomas occurring either in a pure form or as part of a poorly
differentiated endocervical or intestinal adenocarcinoma are uncommon.
 Typically, loose non-cohesive round cells
 Mucinous cytoplasmic vacuole and
 Eccentric nuclei growing singly, in clusters, nests or in columns, represent >_50% of the tumour.
 The differential diagnosis includes metastatic adenocarcinoma from the gastrointestinal tract

57. Stratified mucin producing Carcinoma
 Associated with adjacent SMILE
 Invasive nests of stratified columnar cellsVariable amounts of intracytoplasmic mucin and peripheral palisading.
 Moderately or poorly differentiated.
 It can occur in pure form or admixed with usual type or mucinous type HPV associated endocervical adenocarcinoma or
adenosquamous carcinomas.
 Poor prognosis

58.  Misdiagnosed as gastric-type endocervical adenocarcinoma and the
distinction may be particularly difficult with a small biopsy specimen.
 Easily detectable mitotic figures and apoptotic bodies at 40x to 100x
magnification,
 Mitoses and apoptotic bodies are typically rare in gastric-type tumours.
 Intestinal differentiation can occur in both types.
 pl6 and HPV testing can assist with diagnosis in problematic cases, but
pl6 is rarely negative in HPV associated carcinomas and rarely positive
in gastric type carcinomas.
HPV associated mucinous type
endocervical adenocarcinoma-
Differential diagnosis

59. HUMAN PAPILLOMAVIRUS-INDEPENDENT
CERVICAL LESIONS

60. HUMAN PAPILLOMAVIRUS-INDEPENDENT
PRECANCEROUS GLANDULAR LESIONS
Lobular endocervical glandular hyperplasia
(LEGH)
• Benign proliferations of edocervical glands.
• LEGH was originally considered a benign condition.
• But it shows spectrum of cytological atypia, ranging
from reactive changes or nuclear abnormalities to
high grade atypia.
• Now, considered to be intraepithelial carcinoma
Proliferation of small glands arranged in
lobular fashion around cystically dilated
endocervical glands.

61. Small glands arranged in a lobular
fashion around cystically dilated
endocervical glands
Glands lined by tall columnar
mucinous epithelium with bland
basally located nuclei.

62. • Gastric type adenocarcinoma in situ (gAIS)
• Normal endocervical gland architecture is preserved.
• It may be preceded by simple gastric metaplasia.
Replacement of preexisting mucin-
producing columnar cells by atypical
cells with abundant pale cytoplasm.

63. ENDOCERVICAL ADENOCARCINOMAS HUMAN PAPILLOMAVIRUS-
INDEPENDENT
• They are of four types:
1. Gastric-type adenocarcinoma
2. Clear cell carcinoma
3. Mesonephric carcinoma
4. Endometrioid adenocarcinoma

64. ENDOCERVICAL ADENOCARCINOMAS
HUMANPAPILLOMAVIRUS-INDEPENDENT
Gastric-type adenocarcinoma
• Extremely well-differentiated tumour are designated MDA .
• An invasive adenocarcinoma exhibiting gastric (pyloric) differentiation.
• Clinical features:
• Represents approximately 25% of cervical adenocarcinomas.
• The age range of patients is 25-72 years (mean age, 42 years).
• Extremely well-differentiated tumours, round tend to develop synchronous or metachronous
benign or borderline mucinous tumours of the ovary, and some of them have the Peutz-Jeghers
syndrome.
• The most ommon presenting sign is abnormal vaginal bleeding.

65. .
Sagital section of the cervix and upper vagina shows
thickening by tan-white tumour tissue and mucin-filled
cysts
Gastric-type adenocarcinoma
Tumour may be polypoid or ulcerative and the cervical wall is typically firm or indurated.
In early lesions, the cervix may even look normal. On section, the cervix usually shows
thickening by yellow or tan-white tumour tissue and mucin-filled cysts are occasionally
prominent .

66. The tumour glands appear lined by a single layer of
columnar cells with mucinous apical cytoplasm and
basal uniform nuclei with inconspicuous nucleoli. The
cytoplasm is typically clear or eosinophilic and shows
distinct cell borders
The presence of tumour glands adjacent to
thick-walled blood vessels indicates that
stromal invasion has occurred
Gastric-type adenocarcinoma

67. • diagnosis of MDA may be impossible in small superficial biopsies; it
requires cone biopsy or hysterectomy specimen.
• Clearly malignant glands, vascular invasion, or perineural invasion which
help to confirm the diagnosis are present in approximately half of the cases.
• In cases of extremely well-differentiated adenocarcinomas, features that
help in arriving at the correct diagnosis are:
 Variability in gland shape and size, often exhibiting large branching glands
Desmoplastic or edematous stroma
 Mitotic figures
• The most reliable criterion to assess the malignant nature of extremely well-
differentiated gastric-type adenocaroimoma is the haphazard arrangement
of glands.

68. • Cytologic diagnosis
sheets of enlarged glandular cells with
retention of the honeycomb pattern
Nuclei can be enlarged but are uniform, with
smooth nuclear membranes, occasional
irregularities in shape and fine chromatin.
Small nucleoli may be present

69. • Immunohistochemistry
• Positive : MUC6 and/or HIK1083 antibodies which recognise pyloric gland
mucins .
• Negative : p16.
• Positive : PAX8, CK7, and CEA
• Focally positive : CK20 and CDX2
• ER and PR is uniformly negative and this finding helps to distinguish these
tumours from variants of normal endocervical glands.
• Gastric-type adenocarcinomas have a worse prognosis compared to the usual
type
• Associated with more frequent peritoneal and abdominal metastases.
• Despite histologically bland appearance, gastric-type adenocarcinoma invades
deeply and commonly metastasis to lymph nodes.

70. Differential diagnosis
• Tunnel clusters
• Deep Nabothian cysts
• Microglandular hyperplasia
• Mesonephric hyperplasia.

71. • Clear cell carcinoma
• Composed of uniform, cuboidal, clear or eosinophilic, flat or hobnail cells arranged
in tubulocystic, papillary, or solid patterns.
• Accounts for only 2-4% of cervical adenocarcinomas
• The tumour is associated in young women with a history of in utero exposure to
diethylstilbestrol (DES) .
• The occurrence of these tumours has decreased after withdrawal of DES from the
market about 40 years ago.
• Pathology
• Grossly :- Tumours may involve the ectocervix or the endocervix.
• Microscopically:- Most common patterns are Tubulocystic and papillary.
• In Pap smears, clear cell adenocarcinoma may display large nuclei with prominent
single nucleoli and variable hyperchromasia

72. Tubulocystic pattern : Tubules and cysts of
different size and shape lined by flat cells
Tubules and cyst lined by hobnail,
flat or clear cells with intraluminal
eosinophilic material
Clear cell carcinoma

73. Papillary pattern
Papillae with central hyaline fibrous
tissue core are lined by hobnail cells
with hyperchromatic nuclei
Clear cell carcinoma

74. • >85% of clear cell carcinomas are diagnosed at stage I or II.
• Survival of patients with stage I disease is about 90%.
• Metastasis to distant sites (lung or supraclavicular nodes) occurs more frequently
(36%) than with squamous cell carcinoma (10%).
• Immunohistochemistry
• Positive: HNF 1 beta and napsin A
• Positive: AMACR ,CK7 and PAX 8
• Negative: ER and GATA3

75. Differential diagnosis
• Microglandular hyperplasia : women of reproductive age, lacks severe nuclear
atypia.
• Arias-Stella reaction : Nuclei tend to be dark and homogeneous and there is no
mitotic activity.
• Yolk sac tumour of the cervix : contains clear cells and may be confused with
clear cell adenocarcinoma. The presence of a reticular pattern with Schiller-
Duval bodies, the positivity of a-fetoprotein, facilitate the diagnosis.

76. Mesonephric carcinoma
• Mesonephric adenocarcinomas account for «1% of cervical adenocarcinoma.
• These tumour mainly originates from mesonephric remnants.
• In past, mesonephric carcinoma were confused with clear cell adenocarcinoma.
• Pathology
• These tumours usually arise in the lateral to posterior cervical wall and may be deeply
invasive.
• They involve the lower uterine segment more frequently than other cervical
adenocarcinomas
• Microscopically
• They exhibit a tubuloglandular pattern.
• Typically contain bright pink or red hyaline material which is PAS-positive and
mucicarmine-positive.

77. Tubuloglandular pattern
Mesonephric carcinoma
Glands are small and round, lined by
mucin-free cuboidal epithelium
,

78. • Immunohistochemistry
• Positive: CD10 and GATA 3
• Also positive for vimentin, calretinin, low-molecular-weight cytokeratins, and
EMA.
• Negative for napsin A, AMACR, ER, PR and CEA
Diffuse GATA3 positivity Luminal CD 10 positivity
.

79. • KRAS mutations are seen in most mesonephric adenocarcinomas of the cervix.
• Prognosis of mesonephric carcinomas was better than that of Mullerian
carcinomas at the same stage.
• It usually invades the cervical wall and mesonephric hyperplasia is present at the
periphery of tumours.
• However, a recent multi-institutional report claims that mesonephric
carcinomas are a clinically aggressive neoplasms that typically present at an
advanced stage with a predilection for pulmonary recurrence.

80. • Differential diagnosis
• The most difficult differential diagnosis of mesonephric carcinoma is with
mesonephric hyperplasia.
• Hyperplastic tubules may extend deeply into the cervical wall and even into the
uterine corpus.
• Back-to-back pattern of tabular glands is present, along with significant nuclear
atypia and mitotic activity.
• Mesonephric carcinoma must be distinguished from other adenocarcinomas of
the cervix such as gastric adenocarcinoma, endometrioid carcinoma, and clear cell
carcinoma.
• Rarely, mesonephric carcinoma may exhibit a second admixed patter such as
villoglandular adenocarcinoma.

81. • Endometrioid adenocarcinoma
• Endometrioid adenocarcinomas of the cervix resemble primary adenocarcinomas of the
uterine corpus.
• The reported frequency of cervical endometrioid adenocarcinoma ranges from 7 to 50%.
• Primary endometrioid adenocarcinoma of the cervix is rare and accounts for no >1% of all
endocervical adenocarcinoma.
• Endocervical-type adenocarcinomas that contain relatively little intracytoplasmic mucin
may resemble endometrioid adenocarcinomas of endocervical origin.
• Endocervical extension from an adenocarcinoma of the corpus, a far more frequent event,
has to be ruled out.
• By the time they extend to the cervix, carcinomas of the uterine corpus have frequently
invaded the myometrium and, therefore, uterine enlargement is present.

82. Endometrioid Adenocarcinoma
Tumour shows glandular
architectural complexity and
resembles primary adenocarcinoma
of uterus

83. • Immunohistochemistry
• Strong positive immunoreaction for vimentin and estrogen
receptors.
• Negative for p16 .
• These tumours are typically diffusely and strongly p16 positive
whereas tumours of endometrial origin have a patchy pattern of
p16 expression

84. • SUMMARY:
• Endocervical adenocarcinomas are a heterogeneous group of
tumours, which account for10-23% of all carcinomas of uterine cervix.
• They are divided into two major groups:
• (1) HPV-related cancers and
• (2) those that are HPV independent
• Invasive adenocarcinomas are often preceded by preinvasive forms of
carcinoma.
• The vast majority of endocervical adenocarcinomas are HPV-related
and show diffuse and moderate/strong immunoreaction for p16.
• Almost 60% of HPV -associated cervical adenocarcinomas are
associated with squamous intrepithelial lesion (SIL) or invasive
squamous cell carcinoma.

85. • Villoglandular and mucinous adenocarcinomas, which occur in several
variants, are less common forms of HPV related cervical
adenocarcinoma.
• Human papillomavirus-independent adenocarcinomas forming the
minority of endocervical adenocarcinoma include several entities:
• gastric,
• clear cell,
• Mesonephric,
• endometroid type carcinomas