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Pathogenesis of cervical cancer

Cervical cytology (Up to date, 2016)

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4. Pathogenesis of cervical cancer

CIN and squamous cell cervical carcinoma
It is widely accepted that invasive squamous cell carcinoma of the cervix, which is the commonest
histological type, is preceded by a pre-invasive stage of the disease, where the abnormal cells are
conned to the epithelium. This stage of non-invasive disease is known as cervical intraepithelial
neoplasia (CIN) and is directly related to the processes of infection and integration of HPV as
described in the previous chapter. [Link to Chapter 3 Epidemiology and aetiology]
The development of CIN involves a progression from early changes (CIN1) involving the deeper
layers of the epithelium to full thickness involvement at its most severe (CIN3) equating to carcinoma
in situ (Figure 4.1).

Figure 4.1. Schematic representation of the development of CIN (taken from Figure 1 in Kelloff & Sigman 2007)

CIN1, CIN2 and CIN3 have increasing risk of progression to

invasion and decreasing likelihood of natural regression
The three-tier concept of CIN has to be modied by the
understanding that CIN1 usually represents reversible
infection with human papillomavirus (HPV)

Figure 4.2 (a-c). CIN1

FIGURE
(a) CIN1 in a cervical biopsy; (b) LSIL in a Pap smear; (c) LSIL with koilocytosis (see Figures 9c-2a and
9c-3b in Chapter 9c and scanned slides linked to that chapter).

CIN1 overlaps with HPV infection and usually resolves spontaneously within 9-12 months. There
are numerous follow-up studies of CIN1 showing a highly variable risk of progression to CIN2-3 and
a consequent risk of invasive cancer in a small minority of patients (Ostr 1993; Holowaty 1999;
Bansal et al. 2008).
A large retrospective follow-up study of mild, moderate and severe dysplasia by Holowaty et al.
showed that the majority of cases of mild (62.2%) and moderate dysplasia (53.7%) regressed (two
negative smears within 2 years) while progression to moderate dysplasia or worse was
approximately 25% within 5 years, which is consistent with other studies.

Progression of mild dysplasia (from

Holowaty et al.)
Moderate

Severe+

Within 2 years

11.1%

2.1%

Within 5 years

20.4%

5.5%

Within 10 years

28.8%

9.9%

Likelihood of progression depends on persistence of HPV, its integration into the host genome and
its type (Jaisamrarn et al. 2013).
HPV16 and 33 have the highest risk of progression to CIN3
HPV16 and 31 to have the least likelihood of regression

High-grade CIN
CIN2 and CIN3 are managed as high-grade CIN and usually treated by excision or ablation when
diagnosed at colposcopy.
CIN2 is an intermediate lesion and there is evidence from the ALTS trial that around 40% resolves
spontaneously but was less likely to do so when HPV16-related (Castle et al. 2009).

The

retrospective study by Holowaty et al. (1999) showed that the majority of moderate dysplasia
regressed dysplasia regressed (53.7%) while progression was more likely than for mild dysplasia.

Progression of moderate
dysplasia (from Holowaty et
al.)
Severe+
Within 2 years

16.3%

Within 5 years

25.1%

Within 10 years

32.0%

The cumulative actuarial rate of progression at 5 years per 100 women of moderate dysplasia (1.2) to
invasive cancer was intermediate between mild (0.4) and severe dysplasia (3.9). (See Holowaty et al.
1999 for complete data with condence intervals.)
CIN2 is dened by nuclear pleomorphism with mitotic activity extending to the upper two-thirds of
the epithelium. There is usually little or no koilocytosis.
Figure 4.3 (a-b). CIN2 (moderate dysplasia): intermediate risk of progression

FIGURE
(a) HSIL, favour CIN2, on a LLETZ; (b) HSIL (favour CIN2) (see Figure 9c-7b and scanned slides linked
to Chapter 9c)
In view of its intermediate position between CIN1 and CIN3 in terms of risk of progression and the
clinical importance of deciding whether CIN2 should be managed as a high-grade precancerous
lesion, immunohistochemistry using the cyclin-dependent kinase inhibitor p16INK4A is now
recommended in the US to improve consistency of diagnosis and dene high-grade CIN (Galgano et
al. 2010; Darragh et al. 2012).

P16INK4A staining helps distinguish CIN2 from

1. CIN1 in immature metaplasia

2. Non-neoplastic mimics such as immature squamous metaplasia,
atrophic metaplasia and repair

CIN3 is dened by nuclear pleomorphism involving the full thickness of the squamous epithelium
with mitotic activity at all levels. CIN3 (and severe dysplasia) equates to carcinoma in situ, which
term is seldom used nowadays.

Risk of progression is highest for CIN3 and inter-observer variation is considerably less than for
CIN1 or CIN2 (Stoler et al. 2001). Microinvasive carcinoma is almost always seen in a background of
widespread CIN3 further demonstrating its malignant potential. The exact risk is difcult to
calculate because most CIN3/carcinoma in situ is treated when diagnosed.
Figure 4.4 (a-c). CIN3 and occult cancer

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