Hpv aspcirani razlika so hpv ne asociranj na cervix SMILE, sto e vazno klinicki, patogeneza na gastricen

The term endocervical glandular dysplasia has been used to describe a “glandular lesion characterized by significant nuclear abnormalities that
are more striking than those in glandular atypia, but fall short of the criteria for adenocarcinoma in situ. The 2014 WHO classification discusses
the term endocervical glandular dysplasia which it states is synonymous with low-grade CIGN but further comments that it is a poorly
reproducible diagnosis for which criteria are not well defined. It also recommends that IHC be performed and if the profile matches that of AIS
that the lesion be classified as AIS for management purposes. The distribution of AIS in the cervix is important for determining the clinical
management. AIS typically involves both the epithelial surface and endocervical glands or crypts, but in some cases it can be limited to the
glands and rarely it can be limited to the surface epithelium. Cases confined to the surface epithelium present at a younger average age than
cases that involve endocervical glands or crypts, and it has been postulated that they may represent the earliest form of AIS. AIS confined to
the surface can be quite easily overlooked since they are often small and have less pronounced cytologic atypia and mitoses than the AIS that
involves endocervical glands or crypts. In 65% of cases, AIS involves the transformation zone and in the majority of cases it is unifocal.
However, AIS can extend for a distance of up to 3 cm into the endocervical canal and occasionally it can be multicentric with skip lesions in
the endocervical canal where foci of AIS are separated from each other by normal endocervical tissue. The identification of AIS in biopsies and
on ECC can be challenging. One of the first large case series of AIS found that despite colposcopy, cervical biopsy, and ECC, almost a third of
the cases were only identified after conization .
Pathologic Findings
This section describes the appearance of “usual” type AIS which is the type that is associated with HPV. A more recently recognized variant,
gastric type AIS, is not associated with HPV and is discussed later. AIS is characterized by the presence of endocervical glands lined by
atypical columnar epithelial cells that cytologically resemble the cells of invasive adenocarcinoma but which occur in the absence of invasion.
These cells have elongated, cigar-shaped, hyperchromatic nuclei with coarse granular chromatin. The amount of cytoplasm is greatly reduced
and there is only minimal intracellular mucin. This produces an increased nuclear: cytoplasmic ratio. The cells are crowded and
pseudostratified, forming two or more rows. AIS may involve glands either focally, multifocally, or diffusely. Typically, some glands show an
abrupt transition between normal epithelium and AIS. Mitotic figures including AMFs are common and apoptotic bodies are also commonly
seen in the epithelium, usually subadjacent to the nucleus. Architecturally, the glands of AIS can have numerous outpouchings and complex
papillary infoldings and may display a cribriform pattern focally. However, since the lesion is confined to the preexisting normal endocervical
structures, it retains a lobular architecture.
Several histological variants of AIS have been described. Ostor et al. identified two histological variants of which one is the typical or “usual”
endocervical-type variant of AIS described above . The usual endocervical variant can be pure (58% of cases) or admixed with other variants.
The other variant has features of an intestinal, as opposed to endocervical, mucosa with goblet cells and sometimes Paneth cells. The colonic
variant is uncommon and usually occurs in association with the usual endocervical AIS variant. The goblet cells in colonic AIS contain O-
acetylated sialomucin which is a marker of intestinal differentiation. Some intestinal types of AIS also contain argentaffin and Paneth cells .
Endometrioid variants of AIS and more rarely, adenosquamous, and clear cell AIS also occur . Some precursor lesions have both squamous and
mucinous differentiation. This is thought to reflect the multipotential nature of the cells in the transformation zone. These uncommon lesions
with both squamous and mucinous differentiation have been referred to as stratified mucin-producing intraepithelial lesion (SMILE) and
contain cells with prominent mucin droplets. SMILE usually show a high Ki-67 labeling index and strong diffuse staining with p16. These
lesions are often found in association with both HSIL and AIS. In the original description, 9 of 18 cases of SMILE were associated with
invasive lesions . In the larger more recent series, SMILE coexisted with HSIL in 93% of cases, AIS in 42%, and invasive carcinoma in 10%
Because of their mixed histologic appearance and association with both HSIL and AIS, it is difficult to classify the lesions as either squamous
or glandular in origin. These lesions were initially felt to be a variant of AIS arising in reserve cells of the transformation zone and the
squamous differentiation was considered a marker of phenotypic instability recently, several case reports and one small case series have been
published identifying a rare variant of AIS referred to as gastric AIS (gAIS). This lesion may be a potential precursor to gastric type cervical
adenocarcinomas. Like cervical gastric type mucinous carcinoma, these lesions are HPV . negative and have a gastric phenotype. They tend to
occur in older women than the usual AIS with an average age of 53 years . Gastric AIS typically arises in the transformation zone and can
extend into the endocervical canal and even into the endometrium . The normal endocervical cells are replaced by columnar cells with abundant
eosinophilic or pale-pink cytoplasm and basally located nuclei. Small numbers of goblet cells can be present. Occasionally the cytoplasm can
have a foamy appearance. Compared to the usual variant of AIS, gAIS frequently has less nuclear atypia and nuclear stratification as well as
fewer mitoses and apoptotic bodies. However, this not always the case and some gAIS can have considerable nuclear atypia and nuclear
stratification. Since gAIS is not caused by HPV, it does not stain positively for p16, but it may show patchy p16 staining similar to what can be
seen with normal endocervical glands. Like the usual variant of AIS, gAIS stains positively for carbonic anhydrase-IX . The eosinophilic
cytoplasm contains neutral mucin that stains predominantly red with Alcian blue/periodic acid Schiff (PAS) stain. The mucus also stains with
immunohistochemical markers such as MUC6 and HIK1083 that react with pyloric gland mucin. Immunohistochemical analysis for ERs and
PRs is usually negative and occasional cases show a mutant p53 expression pattern (diffuse staining or complete absence of staining) as
opposed to the usual high-risk HPV-related variant of variant AIS which shows a wild-type p53 expression pattern.
Early Invasive Adenocarcinoma
Definition
It is important to emphasize that recognizing early invasive, stage IA adenocarcinoma is often problematic, and less is known about the
behavior of early invasive adenocarcinoma compared to squamous cell carcinoma. When referring to early invasive adenocarcinoma, four
histologic tumor types are considered, namely, endocervical, intestinal, endometrioid, and villo-glandular. No systematic information is
available for early invasive rare tumor subtypes including gastric, clear cell, serous, and mesonephric adenocarcinoma.
Microscopic Findings
Most patients with early invasive adenocarcinoma have coexisting adenocarcinoma in situ and some also have HSIL. The irregular distribution
and architecture of the normal endocervical crypts in the cervical stroma makes it difficult to differentiate between adenocarcinoma in situ and
early stromal invasion. In addition, in cases with admixed adenocarcinoma in situ and superficially invasive adenocarcinoma, the depth of the
invasion may be difficult to measure. Several growth patterns differentiate early invasive carcinoma from adenocarcinoma in situ and include
(1) small, densely packed, confluent glands that appear more crowded than adjacent benign glands; (2) architecturally complex, branched,
jagged, or dilated glands with shapes that are more irregular than adjacent normal glands; (3) cribriform growth of neoplastic epithelium devoid
of stroma within dilated gland profiles; (4) papillary growth; (5) neoplastic glands below the deep margin of normal glands and adjacent to
large caliber vessels; and (6) desmoplastic stromal response around neoplastic glands. The assessment of normal gland architecture in cervical
mucosa is very important for identifying early invasive glands since they stand out from the background with their markedly abnormal shapes
or crowded, confluent growth. On rare occasion, however, benign conditions such as tunnel clusters, laminar endocervical hyperplasia,
microglandular hyperplasia, and mesonephric duct hyperplasia may also show crowded, confluent growth; nevertheless, these lesions are
usually circumscribed and lack the cytologic features of neoplasia.
After confirming the presence of invasion, the depth of invasion and horizontal extent of the invasive component should be measured. In most
cases the depth of invasion is measured from the epithelial surface rather than from the point of origin in AIS, which may be impossible to
determine. For tumors in which the in situ and invasive components are intimately associated, it is recommended that the entire tumor
thickness, including both the in situ and invasive components, should be measured because it can be difficult or even impossible to determine
where the invasion begins .
In exophytic/papillary tumors, the entire tumor thickness should be reported. The horizontal dimension should be reported as the greatest
continuous span of the invasive area measured parallel to the surface. Similarly, for tumors in which the in situ and invasive components are
intimately associated, it is recommended that the entire horizontal extent, including both the in situ and invasive components, be measured. For
cases with multifocal invasion, the depth/thickness and horizontal extent/width of each focus should be measured individually and reported,
and the FIGO stage should be determined based on the measurement of the largest focus. In cases in which the invasive lesion spans adjacent
blocks of tissue and co-localizes in the contiguous sections, it is recommended that the third measurement of circumference be estimated by
multiplying the number of involved blocks by the approximate block thickness. In addition to tumor size, involvement of the margins and
presence or absence of LVSI should be reported.
Adenocarcinoma currently comprises ∼25% of all cervical carcinomas, representing an increase from 5%–10% in previous decades. They can be grouped, from an
etiologic perspective, into HPV-related and unrelated categories, as highlighted in the recently proposed International Endocervical Adenocarcinoma Classification and
Criteria (IECC) scheme. HPV-related adenocarcinoma is by far the most common (85%–90%); this group can be divided into morphologic subtypes, of which usual
endocervical adenocarcinoma is the most common (80% of all adenocarcinomas). HPV-unrelated tumors are less common (10%–15%) but clinically important, as they
can behave more aggressively; this group includes gastric-type, clear cell, mesonephric, and endometrioid carcinomas.
 EARLY INVASIVE ADENOCARCINOMA (FIGO STAGE IA)Most studies define early invasive
adenocarcinoma by depth of invasion (<5 mm from base of surface epithelium) or by volume
(<500 mm³). Early invasive adenocarcinoma occurs in patients with an average age of 39
years, approximately 7 years younger than the peak frequency of higher stage invasive
adenocarcinoma. Patients commonly present with an abnormal Papanicolaou smear that
shows atypical glandular cells or postcoital bleeding. It may represent an incidental finding in
conization or hysterectomy specimens. These lesions are, by definition, microscopic and not
visible on regular colposcopic exam.
PATHOLOGIC FEATURES
MICROSCOPIC FINDINGS
Pathologic criteria for the diagnosis of early invasive adenocarcinoma include the presence of
stromal invasion. This is seen as:
1) Destructive stromal invasion in the form of individual cells, clusters, and irregular glands
with angulated or incomplete borders lined by cytologically malignant appearing cells,
surrounded by a desmoplastic stromal reaction and inflammation . This form corresponds to
patterns B and C of invasion (defined later in this chapter).
3) Nondestructive growth in which neoplastic glands are round and well-defined but
significantly complex, branching and variably sized, exceeding the architecture expected for
the normal cervix/AIS glands . This form corresponds to pattern A of invasion (defined later in
this chapter). Measuring depth of invasion is often arbitrary and difficult, as the cells may
invade the stroma either from the surface or from underlying glands, and consequently, the
point of reference for measurement may not be clear. Therefore, the thickness of superficially
invasive adenocarcinoma can be reported, rather than the depth of invasion. The
circumferential extent of invasive carcinoma, as described previously, should also be
estimated.
DIFFERENTIAL DIAGNOSIS
Early invasive adenocarcinoma should be distinguished from adenocarcinoma in situ, which mirrors the normal endocervix in terms of glandular distribution and
density and therefore lacks the florid architectural complexity and stromal reaction of invasive adenocarcinoma. Architecture is extremely important in distinguishing
both entities, and thus when possible, neoplastic glands .