Terminology in Gynaecological Cytopathology: Report of the Working Party of the British Society for Clinical Cytology

Home , Dyskaryosis, Karyorrhexis

J Clin Pathol: first published as 10.1136/jcp.39.9.933 on 1 September 1986. Downloaded from J Clin Pathol 1986;39:933-944

Review article Terminology in gynaecological cytopathology: report of the Working Party of The British Society for Clinical Cytology

D M D EVANS (CHAIRMAN),* E A HUDSON (SECRETARY),t C L BROWN,tt M M BODDINGTON,¶T H E HUGHES,¶ E F D MACKENZIE,** T MARSHALL§ From *St David's Hospital, Cardiff, tNorthwick Park Hospital, Harrow, ttThe London Hospital, ¶Royal Berkshire Hospital, Reading, ¶Glasgow Royal Infirmary. **Southmead General Hospital, Bristol, §Central Pathology Laboratory, Stoke on Trent

SUMMARY The report defines and recommends terms for use in cervical cytology.

Most cervical smear reports are received by medical firm prediction of CIN 3 because the cytologist can- practitioners who do not have specialised knowledge not reliably exclude a microinvasive or invasive of pathology or gynaecology. Therefore it is lesion. The histological prediction is more accurately important that the report is not only scientifically recorded on the National Cytology Form, HMR accurate but also easily understood so that the patient 101/5 (1982), where severe dysplasia or carcinoma in copyright. receives appropriate management and advice. To situ-(C-IN 3), or-carcinoma in situ (CIN 3) or? invasive promote these aims the British Society for Clinical carcinoma are the alternatives provided. Cytology set up a working party to make recommen- dations on the reporting of cervical smears and the INFLAMMATORY NUCLEAR CHANGES AND terms used. It was suggested that common use of a DYSKARYOSIS small but clearly defined vocabulary would improve A continuous range of nuclear abnormalities occurs, the communication of results to users of the cytology from minor changes that are usually associated with services and provide an accurate basis for wider inflammatory conditions and which are believed to be reference. essentially benign, through to more striking nuclear http://jcp.bmj.com/ abnormalities that correlate with CIN. Cytologists The cytology report should be encouraged to say precisely what abnormality is present in as many cases as possible, but The cytology report on abnormal findings should there will be some in which the abnormality is on the consist of a concise description of cells in precisely borderline. These abnormalities may be referred to as defined and generally accepted cytological terms. This "borderline nuclear abnormalities." In these circum- may be followed, ifappropriate, by a prediction of the stances follow up with repeat smears usually allows a on October 2, 2021 by guest. Protected histological condition based on the overall picture more exact cytological diagnosis to be made. and should include a recommendation for the further The morphological abnormalities of the nucleus management of the patient. comprise a combination of any number of the follow- When a prediction of histology is included as a sup- ing: plementary statement to a description of the cytology (1) disproportionate nuclear enlargement; use of the terminology, cervical intraepithelial neo- (2) irregularity in form and outline; plasia (CIN) is preferred: it has the advantage of (3) hyperchromasia; relating the histological report more clearly to the (4) irregular chromatin condensation, appearing as prognosis and management than the artificial sepa- stippling, clumps, or strands, and sometimes as con- ration implied by classification into dysplasia and car- densation beneath the nuclear membrane producing cinoma in situ. Caution is advised, however, in the apparent irregularities in thickness of the nuclear membrane; Accepted for publication 18 March 1986 (5) abnormalities of the number, size, and form of 933 J Clin Pathol: first published as 10.1136/jcp.39.9.933 on 1 September 1986. Downloaded from 934 Evans, Hudson, Brown, Boddington, Hughes, Mackenzie, Marshall

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Fig I Normal superficial and intermediate squamous cells. Both cell types have abundant translucent cytoplasm with angular borders. Nuclei ofboth intermediate squamous cells have evenly distributedfinely granular chromatin, whereas three superficial cells have smaller pyknotic nuclei. (Papanicolaou.) Original magnification x 1.60, enlarged x 5. copyright. http://jcp.bmj.com/ on October 2, 2021 by guest. Protected

Fig 2 Endocervical cells. These columnar epithelial cells are seen lined up in characteristic palisade pattern andfrom an alternative aspect in a sheet with nuclei surrounded by narrow rim ofcytoplasm. Nuclei appear vesicular apartfrom one or more prominent nucleoli. (Papanicolaou.) Original magnification x 160, enlarged x 5. J Clin Pathol: first published as 10.1136/jcp.39.9.933 on 1 September 1986. Downloaded from Terminology in gynaecological cytopathology 935 I

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Fig 3 Normalparabasal squamous cells. These cells usually have rounded outlines with opaque cytoplasm and vesicular nuclei. Chromatin pattern isfinely granular but nucleoli may be prominent. (Papanicolaou.) Original magnification x 160, enlarged x 5. copyright. V Wt:- -'NI( 4

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Fig 4 Inflammatory changes in parabasal squamous cells. Inflammatory nuclear changes may beparticularly pronounced in smearsfrom atrophic cervical squamous epithelium, as shown here. Hyperchromasia is striking and chromatin is coarsely clumped but clumps are evenly distributed. An impression ofanisonucleosis is created by coexistence ofreactive and degenerative changes in nuclei. (Papanicolaou.) Original magnification x 160, enlarged x 5. J Clin Pathol: first published as 10.1136/jcp.39.9.933 on 1 September 1986. Downloaded from 936 Evans, Hudson, Brown, Boddington, Hughes, Mackenzie, Marshall nucleoli; those associated with inflammation alone. Irregu- (6) multinucleation associated with any of the above. larity of chromatin distribution is the most important Figs I and 3 show examples of normal squamous change in nuclear morphology. It may be accom- cells; fig 2 shows glandular cells. panied by irregularity of form and outline, multinucleation, further disproportionate nuclear enlarge- Inflammation ment, and hyperchromasia. Artefactual cell distortion Inflammation alone causes minor nuclear abnormal- must be distinguished from dyskaryosis. ities (fig 4). These are usually disproportionate The Working Party endorses the recommendation nuclear enlargement with or without hyperchromasia. by Spriggs et al' that "dyskaryosis" and "dys- Wrinkling of the nuclear membrane due to degener- karyotic" should be used to describe the nuclear ative change may also be associated with inflam- abnormalities seen in cells from CIN and it recognises mation but must be distinguished from the irregu- that some cases of invasive carcinoma exfoliate simi- larities of form and outline of dyskaryosis. lar cells. Karyorrhexis and pyknosis must also be dis- The term dyskaryosis is appropriate when referring tinguished from nuclear abnormalities with malig- to both squamous and endocervical cell abnormalities nant potential. There is no need to report simple with the same implication of intraepithelial or inflammatory changes. invasive carcinoma.

Dyskaryosis CLASSIFICATION OF DYSKARYOTIC CELLS Dyskaryosis literally means "abnormal nucleus" and Spriggs et al' recommended a classification that is liable to be used in different ways-for example, by depends on the cytoplasmic characteristics of the dys- some to describe abnormal cells expected to be karyotic squamous cells. Thus superficial cell, inter- obtained from CIN 1 or CIN 2, and by others it is mediate cell, and parabasal cell dyskaryosis were only used for severely abnormal cells expected to described. After considerable deliberation this Work- come from CIN 3. ing Party prefers to emphasise the overriding Dyskaryosis should be used to describe nuclear importance of nuclear abnormalities. This does not abnormalities more numerous or more severe than exclude cytoplasmic changes from cell assessment, copyright.

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Fig 5 Mild dyskaryosis. Nuclei are enlarged and hyperchromatic. Clumps and ridges ofchromatin are unevenly distributed and there are alsofolds in some ofthe nuclear membranes. Three cells are binucleate. Abnormal nuclei occupy less than half area ofcytoplasm ofmost ofthese cells. Cytoplasm retains translucent quality ofnormal, superficial, or intermediate squamous cells. (Papanicolaou.) Original magnification x 160, enlarged x 5. J Clin Pathol: first published as 10.1136/jcp.39.9.933 on 1 September 1986. Downloaded from Terminology in gynaecological cytopathology 937

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Fig 6 Nuclear abnormalities associated with human papiloma virus infection. These koilocytes show typical central clearing andperipheral condensation ofcytoplasm. It is impossible to be certain whether uneven chromatin pattern in larger nucleus is dyskaryotic or degenerate: patient would therefore befollowed up. (Papanicolaou.) Original magnification x 160, enlarged x copyright. 5.

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...~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~-..-1 Fig 7 Moderate dyskaryosis. Disproportionate nuclear enlargement is greater than that infig5 and morphological abnormalities ofnuclei more severe. Dyskaryosis is classified as moderate in most ofthe cells but could be called severe infew in which area ofnucleus exceeds two thirds ofarea ofcytoplasm ofcell. (Papanicolaou.) Original magnification x 160, enlarged x 5. J Clin Pathol: first published as 10.1136/jcp.39.9.933 on 1 September 1986. Downloaded from 938 Evans, Hudson, Brown, Boddington, Hughes, Mackenzie, Marshall

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Fig 8 Severe dyskaryosis. (a) Dyskaryotic cells show wide range ofnuclear abnormalities, ofwhich uneven chromatin distribution and irregularities ofnuclear membranes are most important. Differences in size and shape ofcells and their nuclei are striking in this example. Abnormal nuclei occupy more than two thirds ofall cytoplasm. (b) Uniformly small size ofthese severely dyskaryotic cells may cause diagnostic difficulty. Fig 8 continued opposite J Clin Pathol: first published as 10.1136/jcp.39.9.933 on 1 September 1986. Downloaded from Terminology in gynaecological cytopathology 939

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dk http://jcp.bmj.com/ 4, P. I 00 i 41 4 on October 2, 2021 by guest. Protected Aik 'I C. I k C (d} Fig 8 continued Irregular chromatin condensation is predominant abnormalfeature ofnuclei, although some show degenerative changes. Hyperchromasia is present but is not always afeature in this type ofabnormal cell. A few cells in which nucleus occupies less than two thirds could be classified as moderately dyskaryotic. (c) Cluster ofseverely dyskaryotic cells contrasts with single normal superficial squamous cell and both intermediate squamous cells. Although abnormal cells have irregular chromatin distribution patterns, size and shape is generallyfairly uniform. Nuclei are crowded together and this appearance contrasts with orderly pattern ofsheet ofendocervical cells seen infig 2. (d) Fragment ofepithelium is breaking up in characteristic manner to show severely dyskaryotic cells in clusters ofvarious sizes, single cells, and bare nuclei. Fig 8 continued overleaf J Clin Pathol: first published as 10.1136/jcp.39.9.933 on 1 September 1986. Downloaded from 940 Evans, Hudson, Brown, Boddington, Hughes, Mackenzie, Marshall

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Fig 8 continued (e) Abnormal nuclear chromatin pattern ofthese severely dyskaryotic cells distinguishes themfrom parabasal squamous cells. (f) Thesefour severely dyskaryotic cells with little cytoplasm show such gross aggregation ofchromatin that translucent areas are seen within nuclei. (Papanicolaou.)-Original magnification x 160, enlarged x 5. J Clin Pathol: first published as 10.1136/jcp.39.9.933 on 1 September 1986. Downloaded from

Terminology in gynaecological cytopathology 941 but when nuclear abnormalities are particularly of single cells (figs 8c and d). Loss of normal regular severe they should outweigh any apparent cyto- arrangement (polarity) may distinguish neoplasia plasmic maturation. It is recommended that dys- from severe inflammation when the nuclear appear- karyotic cells are classified as mild, moderate, or ances are equivocal. Papillary processes, sheets of severe according to: metaplastic cells, fragments of CIN 3, and I The diversity of abnormal nuclear characteristics desquamated glands from adenocarcinoma provide listed above and the degree of morphological examples of the importance of intercellular relation in abnormality. interpretation (fig 9). 2 Cytoplasmic characteristics, which include quan- tity, density, shape, and staining quality. INVASIVE AND MICROINVASIVE CARCINOMA OF THE CERVIX Mild dyskaryosis Invasive carcinoma cannot be diagnosed reliably Mildly dyskaryotic cells usually have plentiful, thin, from a smear. There are cytological features, how- translucent cytoplasm with angular borders, resem- ever, which infer a strong possibility of a more bling superficial or intermediate squamous cells advanced abnormality than that suggested by CIN 3 (fig 5). The nucleus occupies less than half the total (fig I Oa). It may be useful to refer to these in the cytol- area of the cytoplasm. Mild dyskaryosis correlates ogy report to convey the more urgent need for biopsy. with cells from the surface of CIN 1. It is doubtful, The following characteristics, often several at once, however, if it can be reliably distinguished from the are associated with invasive tumours: nuclear abnormalities associated with human papillo- 1 Variation in size and shape of dyskaryotic cell mavirus infection (fig 6). nuclei beyond that usually associated with CIN 3 and often including unusually small cells of Moderate dyskaryosis bizarre shape. Moderately dyskaryotic cells have more disproportionate nuclear enlargement than 2 Aggregations of nuclear chromatin, so coarse that mildly translucencies appear. dyskaryotic cells, so that the nucleus occupies one copyright. half to two thirds of the total area of the cytoplasm 3 Large irregular sometimes multiple nucleoli in (fig7). The nuclear morphology tends to be more dyskaryotic cells. abnormal than that seen in mild dyskaryosis. The 4 Cytoplasmic keratinisation of dyskaryotic cells cytoplasm may resemble that of intermediate, para- and the presence of thick anucleate fragments of basal, or sometimes superficial type squamous cells. keratinised cytoplasm. 5 Irregularly shaped dyskaryotic squamous cells Severe dyskaryosis including fibre cells and tadpole cells as well as Severely dyskaryotic cells typically have a narrow rim other bizarre forms of thick dense cytoplasm and they are round, oval, (figs 10b and c). http://jcp.bmj.com/ polygonal, or elongated in shape (figs 8a-f). Thus the 6 Tissue fragments composed of dyskaryotic cells. abnormal nucleus practically fills the cell, or at least The term "malignant diathesis" is sometimes used two thirds of it. Occasionally, there are severely dys- to describe the necrotic debris, inflammatory exudate, karyotic cells in which there is plentiful abnormally and blood that predominate in smears from ulcerated shaped, often keratinised, cytoplasm accompanied by invasive tumours. These constituents may contribute abnormal nuclear morphology that is more pro- to an unreliable smear. They are insufficiently specific nounced in degree and diversity than that usually for diagnosis. on October 2, 2021 by guest. Protected associated with CIN I or CIN 2. Their correct inter- The term "malignant cells" may be read as pretation is facilitated by the presence of more char- implying invasive carcinoma. It is preferable to acteristic cells showing the changes described above. describe the cells as dyskaryotic, and a secondary In those cases the cells should be described as severely statement could be added to draw attention to char- dyskaryotic. In severe dyskaryosis the abnormal cells acteristics associated with an invasive tumour. It is may occur in clumps as well as singly. Severely dys- a long established custom of reporting at some karyotic cells correlate with cells from the surface of centres to mention malignant cells before suitable cervical epithelium showing CIN 3 or invasive car- diagnostic and therapeutic measures are undertaken, cinoma. even for an intraepithelial abnormality. The Working Party feels that this should be discouraged, unless Intercellular relation there is firm evidence of invasive tumour. Evaluation of sheets of epithelial cells in a smear requires slightly different criteria, which may be more SMEARS. SHOWING BORDERLINE ABNORMALITIES difficult to define than the diagnostic characteristics The report is made after careful scrutiny of all the J Clin Pathol: first published as 10.1136/jcp.39.9.933 on 1 September 1986. Downloaded from

942 Evans, Hudson, Brown, Boddington, Hughes, Mackenzie, Marshall

Fig 9 Severe dyskaryosis from endocervical adenocarcinoma. Desquamated gland shows characteristic rosette pattern. copyright. (Papanicolaou.) Original magnification x 160, enlarged x 5.

material on the smear and rarely depends on the METAPLASIA appearance of one cell. Some cells will be on the Smears may contain endocervical cells that have some borderline between the accepted definitions, but the squamous characteristics. These appearances cor- problem of classification can usually be resolved by relate with the surface of immature metaplastic epi- the time the whole specimen has been examined. In thelium from the transformation zone of the cervix. http://jcp.bmj.com/ the relatively few smears that remain equivocal a Sometimes the squamous features are so pronounced repeat smear for a mild abnormality or referral for that the cells cannot be distinguished from parabasal colposcopy and biopsy for more severe abnormalities squamous cells from immature primary squamous will be necessary to resolve the problem. epithelium. Dyskaryosis often occurs in these cells The Working Party has considered the use of the and should be reported and managed accordingly. term atypia or another single word for the equivocal

smear. It has decided against such a recommendation CYTOPATHIC CHANGES DUE TO WART VIRUS on October 2, 2021 by guest. Protected because the word can be used too often as a substitute The human papillomavirus causes a variety of for careful observation and definition. appearances in smears.2 These maymimic some char- Atypia has been used in a number of senses includ- acteristics of well differentiated squamous carcinoma ing that for which this report recommends dys- but the severe dyskaryosis of squamous carcinoma karyosis. It should be avoided because its previous will not be present. Wart virus changes accompanied loose and diverse application makes it unlikely that by dyskaryosis should be managed according to the users will adhere to any definition suggested now. degree of dyskaryosis.3 There are smears in which the evidence is such that it is impossible to decide if the cells are the product of NUMERICAL CLASSIFICATIONS inflammation or if they have neoplastic potential. It is The Papanicolaou classification of cytology reports suggested that the report should explain briefly the into classes I to V has been discouraged for some time diagnostic dilemma (bordering on mild dyskaryosis). because of the different interpretations which its This is more helpful than a word of uncertain broad definitions have been given. It is retained in meaning. some centres in which there is a clear understanding J Clin Pathol: first published as 10.1136/jcp.39.9.933 on 1 September 1986. Downloaded from Terminology in gynaecological cytopathology 943

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Fig 10 Severe dyskaryosisfrom invasive squamous carcinoma. (a) All ofthese cells are severely dyskaryotic. They appear in various shapes and there arefragments ofdegenerative cells in the background. (b) Elongated severely dyskaryotic cells are sometimes calledfibre cells. These and other bizarreforms are particularly characteristic ofinvasive carcinoma but may also be seen in smearsfrom CIN 3. rigingIII...1u coniinuea overteaj J Clin Pathol: first published as 10.1136/jcp.39.9.933 on 1 September 1986. Downloaded from 944 Evans, Hudson, Brown, Boddington, Hughes, Mackenzie, Marshall

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(c) This severely dyskaryotic cell has plentiful abnormally shaped keratinised cytoplasm accompanied by severely abnormal copyright. nuclear morphology. Elongated tail ofcytoplasm has led to description ofthis bizarreform as a tadpole cell. (Papanicolaou.) Original magnification x 160, enlarged x 5. between cytopathologist and gynaecologist about its endometrial cells exfoliated from a benign lesion or use but it lacks the precision necessary for wider refer- during menstruation. ence. Similarly, attempts to subdivide or redefine the References Papanicolaou classification or the introduction of other numerical or alphabetic shorthands will result I Spriggs AJ, Butler EB, Evans DMD, Grubb C, Husain OAN, Wachtel GE. Problems of cell nomenclature in cervical cytol- in varied interpretations. http://jcp.bmj.com/ ogy smears. J Clin Pathol 1978;31:1226-7. 2 Butler EB, Stanbridge CM. Condylomatous lesions of the lower ENDOMETRIAL CELLS female genital tract. Clin Obstet Gynaecol 1984;1 1:171-87. Endometrial cells can be identified in smears, but the 3 Kaufman R, Koss LG, Kurman RJ, et al. Statement of caution in smear is not a reliable test for endometrial the interpretation of papillomavirus-associated lesions of the cervical epithelium of the uterine cervix. Acta Cytol 1983;27:107-8. abnormalities. The cause of endometrial exfoliation may not be reflected in the morphology of the cells- Requests for reprints to: Dr E A Hudson, Department for example, cells from a well differentiated ade- Park of Histopathology, Northwick Hospital, Harrow, on October 2, 2021 by guest. Protected nocarcinoma may be barely distinguishable from Middlesex HAl 3UJ, England.