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Potential false negatives

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Most false negatives are well-recognised types of HSIL, which will not be missed if cytologists are familiar with them.  


Small cell dyskaryosis

  • Essentially, this is typical ‘carcinoma in situ’ (CIN3) but the cells may be deceptively small and little larger than neutrophils.  
  • Attention to the nuclear chromatin pattern will allow this type of HSIL to be recognised even when very few abnormal cells are present as in the single cell below (Figure 10.1 (b), which was the only one on the slide. It was not a false negative and was correctly identified by a diligent screener.


Figure 10.1 (a) Small cell HSIL

(b) Isolated abnormal cell 


Pale dyskaryosis

Although HSIL is usually characterized by hyperchromasia, the nucleus may be pale, making it difficult to distinguish from immature squamous metaplasia – or from endocervical cells when the cells are large.  

Pale staining may be a feature of regressive Papanicolaou staining 


Figure 10.2 (a) Pale cell dyskaryosis (moderate).  This was correctly reported as moderate dyskaryosis and confirmed as CIN2 but would have justified an ASC-H report if these were representative of the abnormal cells or the only ones present.  Nuclear chromatin and nuclear membrane irregularity are only mildly abnormal in this case and NC ratio around 50% in most cells.
(b) Large pale cell HSIL (CIN3).  This appearance may be difficult to interpret because the friable cytoplasm is largely lost making NC ratio impossible to assess.  The nature of the cells can be determined from the abnormal chromatin pattern, disorderly arrangement of cells, variable cell size and density of nuclear staining.  This appearance is most often seen in CIN3 rather than CIN2.


In the BSCC Terminology Conference, approximately one-third of the respondents recognised Figure 10.2 (b) as severe dyskaryosis; one-third diagnosed follicular cervicitis and one-third ‘other reactive change’; 4% thought it was glandular neoplasia.

Small and pale cell HSIL as pitfalls in cervical cytology are described and illustrated in detail by Smith & Turnbull (1997).


Hyperchromatic crowded cell groups

Microbiopsies or hyperchromatic crowded cell groups of HSIL or even cancer can be overlooked at primary screening or misinterpreted on review. These cells may mimic endometrial cells, sheets of cells from the lower uterine segment or clusters of endocervical cells showing reactive changes.

Figure 10.3. a) An example of what has been described as ‘bland dyskaryosis’ and is reproduced from Figure 10 in Denton et al. 2008. The key to its recognition is the disorderly arrangement of cells in the group and the high NC ratio of cells that otherwise have some resemblance to endocervical cells. 
Figure 10.3.b) HSIL in this case from the BSCC Terminology Conference is only recognisable from separated cells at the margin of the cell group. 
Figure 10.3.c) This group of cells superficially looks like a cluster of benign endomtrial cells and has already been shown in Chapter 9c as an example of a problematic hyperchromatic crowded group of cells that could justify an ASC-H report.


If the cells are not recognised as HSIL, in these cell groups or elsewhere on the slide, false negatives may be avoided in any or all these cases by reporting them as ASC-H rather than normal or reactive


 ‘Inflammatory smears’

Misinterpretation of HSIL or even cancer as non-specific inflammation has been a hazard of misdiagnosis in the past. Careful attention to cellular detail on high-power examination should allow this pitfall to be avoided. 


Figure 10.4 HSIL+ with severe inflammation


Cytological changes at risk for false negative reports in   conventional and LBC slides

  • Conventional smears have been shown to be at risk for false negative reports if the cells are small, pale or few in number (Mitchell & Medley 1995; Demay 1996)
  • ‘Microbiopsies’ may be overlooked at primary screening (Robertson & Woodend 1993; Demay 2000).  Similar findings have been reported for liquid-based cytology using ThinPrep (Leung et al. 2008).
  • Sparse abnormal cells and microbiopsies/hyperchromatic crowded cell groups were found to be the commonest reasons for false negative and potential false negative cytology using SurePath (Gupta et al. 2013).


The main causes of false negative cytology

  • Small, sparse or pale dyskaryotic cells
  • Hyperchromatic crowded groups of cells
  • Dyskaryosis mistaken for or masked by inflammation


How to avoid false negative results

  • Careful examination of the whole slide
  • Familiarity with the main causes of false negatives
  • Attention to nuclear changes of dyskaryosis
  • Training, update and quality control