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High grade squamous intraepithelial lesion (HSIL) (Fig 1) is a term used in the Bethesda system for reporting cervical or vaginalÂ cytologicÂ diagnosis to describe a spectrum of noninvasive cervical epithelial abnormalities, including moderate and severe dysplasia, carcinoma in situ, and cervical intraepithelial neoplasia (CIN) grades 2 and 3. The presence of HSIL in patient does not mean of any cancer, but it is more to precancer stage. However if it is not treated, the precancer can progress to cancer that could lead to fatal or death. During the diagnosis of HSIL, the screener needs to know the age and history of the patient. The screener also needs to know the pitfalls of HSIL that can lead to wrong diagnose.
The diagnostic characteristics of HSIL are high nucleus to cytoplasmic (N/C) ratio with scanty cytoplasm, irregular nucleus membrane and absent of nucleoli. The problem arises when other dysplasia or other abnormalities give similar morphological cell as the HSIL. Pitfalls in diagnosing the HSIL mean the wrong diagnosis that happen during the interpretation of HSIL. These due to the cell that can mimicking the characteristics of it. Few cells that will be discussed below showing the mimicking cell of HSIL such as endometrial cell, histiocyte, immature squamous metaplastic, endometrial cell exfoliated due to an IUCD (intrauterine cell device), Follicular cervicitis and endocervical cell, mild and moderate dyskaryosis.
Immature Metaplastic Cell
Metaplastic cell (Fig 2) can be found in transformation zone. It arises in between the transition of the columnar cell to squamous epithelial cells. Nucleus of the metaplastic are slightly enlarged from the normal cells and appears as round to oval in shape uniformity with the presence of single nucleolus. However, it's become difficult to diagnose the HSIL when the immature metaplastic present in the smear.
(M.D., m. A., 1999)
The problem occur when the immature metaplastic shows hyperchromatic cell with clumped chromatin that mimicking the HSIL. Koilocytes sometimes may present in the immature metaplastic cell. However, there are certain characteristics that can be used to differentiate the HSIL from immature metaplastic. Although the N/C ratio for both HSIL and immature metaplastic cells are higher, they differ in cytoplasm characteristic. For HSIL, the cytoplasm is scanty, while in immature metaplastic, the cytoplasm is abundant. Thus, the nuclear membrane of HSIL is thick and irregular compared to immature metaplastic cells. Therefore, it is necessary to observe the whole cells based on their nuclear shape, chromatin pattern, and the cytoplasm.
(M.D., m. A., 1999)
Intrauterine Cell Device (IUCD) cells
Intrauterine cell device (IUCD) (Fig 3) cells are consistent with changes associated with the present of intrauterine device (IUD). Usually these cell found in endometrium in the present of IUCD. The present of IUD is associated with shedding of endometrial cell at a mid cycle which can cause severe cytologic changes to the endometrial cells. The IUCD is a single cell with high N/C ratio, finely vacuolated cytoplasm, smooth nuclear membrane and uniform nuclei. Usually single cell with this type of changes may be confused with HSIL. These cells can be distinguished from HSIL by the presence of rare abnormal cells, lack of nuclear membrane irregularity, hyperchromatism, syncytial fragment and cytoplasmic vacuolation.
(Malcolm Potts Ph.D., M. B., 2005)
Follicular cervicitis (Fig 4) or lymphocytic cervicitis is one of the pitfalls in diagnosis HSIL. Follicular cervicitis defined as polymorphous of benign lymphocytes, 'tingible' body macrophages, mitoses, differential diagnosis includes malignant lymphoma which shows monomorphic lymphocytes and no 'tingible' body macrophages. 'Tingible' body macrophages are macrophages that contain many phagocytized, apoptotic cells in various states of degradation. In other source, the follicular cervicitis may result in streaks of lymphocyte cells in a smear. The cells often focally but sometimes dominating large areas or even the whole of a smear. The cells characteristically are dispersed, include larger follicle centre cells which may show mitotic figures, small lymphocytes and mature plasma cells with coarse chromatin, and macrophages containing tangible bodies.
In the pitfalls in diagnosis of HSIL situation, usually follicular cervicitis is readily recognized in well-preserved preparation but there are confused with other small cell lesions for example HSIL. The problem occurs when there is poor preservation or degeneration. Furthermore, small lymphocytes with their characteristics, very small nuclei should not mistake for HSIL. However, larger germinal centre lymphocytes may be mistaken for HSIL. Germinal centre cells are often accompanied by tingible body macrophages. They also do not have membrane notching of HSIL and have a more coarsely granular chromatin pattern compared to HSIL.
Histiocyte (Fig 7) is known as macrophage in the body tissue, while in the bloodstream it is known as monocytes. General morphology of histiocytes is round to reniform or bean shaped nuclei, scant cytoplasm and fine to coarse chromatin and uniformly distributed. By observation under microscope, the smear shows that histiocytes usually appear as single cells. Only on certain cases they may appear in clusters especially if they are numerous, as in the late menstrual "exodus smear". The term "exodus smear" is used to describe histiocytes that may shed at the end of menstruation. Histiocytes in this smear may show degenerative changes that make them extremely difficult to differentiate from small cell severe dyskaryosis or HSIL.
(Mark H. Stoler, M.D. 1999)
Challenges occur when only a few high-grade cells are present in the background of the slide. These cells are often small and may approximate the size of a small histiocyte. To ensure that the cells are histocytes (not HSIL), some of the cells in the group at least, should have typical bean-shaped nucleus and recognizable dispersed histiocytes should be found elsewhere in the smear. If the characteristic of foamy cytoplasm and reniform nuclei cannot be observed, distinction of histiocytes from severely dyskaryotic squamous cell can be made by comparing with neighboring cells which show more distinctive characteristics.
It could be simplify that those histiocytes in an "exodus smear" mimicking dyskaryosis. Since histiocytes and severe dyskaryosis may both be present on the same smear, a careful observation and research should be made for dyskaryotic cells when degenerate histiocytes are found.
(Mark H. Stoler, M.D. 1999)
Exfoliated Endometrial Cells
Exfoliated endometrial (Fig 3) cells are commonly seen in specimens obtained during the menstrual cycle. Abraded endometrial cells from the lower uterine segment and cells that can be identified as histiocytic or stromal in origin should not be reported as endometrial cells as they do not carry the same risk for endometrial pathology. However, endometrial cells have been considered a potential harbinger of endometrial adenocarcinoma when seen in cervical cytology of postmenopausal women or outside of the proliferative phase of the menstrual cycle. In the first half of the menstrual cycle, endometrial cells often have a double contour with glandular cells surrounding a core of stromal cells.
(Mamatha Chivukula, 2007)
During observing the specimen, endometrial cells can be mistaken with HSIL. Normal endometrial nuclei are small, no larger than an intermediate nucleus, and are either round or bean-shaped. The chromatin pattern may be difficult to discern in the cell groups, but nucleoli are usually inconspicuous and nuclei may be degenerated. The cytoplasm is scanty, basophilic, and often wispy or occasionally vacuolated. Cell borders are ill-defined, and the cells frequently appear to be packed together. The background is often bloody and may contain histiocytes and endometrial stromal cells. In liquid based preparations, three-dimensional cell clusters are common, with the plane of focus often above the plane of the normal squamous cells. Single cells may be more commonly seen, and the background is usually clear with less blood. Nuclear chromatin detail may be more easily discerned, and single cell necrosis (apoptosis) is common within exfoliated cell groups. Usually they are not difficult to distinguish from cells of CIN or invasive carcinoma but it is necessary to be aware that clustered, and sometimes single cells from small cell non-keratinizing HSIL or invasive carcinoma may look similar to endometrial cells.
(Mamatha Chivukula, 2007)
The characteristics of endometrial cells that can be observed are small hyperchromatic nuclei with scanty cytoplasm and present in clusters. This can be wrong interpreting as HSIL. The presence of the characteristic of the biphasic endometrial cell groups is helpful to confirm endometrial exfoliation, but if there is a possibility of coexistent HSIL or carcinoma, further investigation should be necessary.
In cytology, it is a common serious error to make mistake between HSIL in crowded sheets for endocervical cells (Fig 5) or vice versa. Several characteristics that make the endocervical cells can be mistaken as HSIL in crowded sheets are when the columnar cell shapes are ill defined or absent and the sheets appear as syncytial as cell borders within the sheets are inconspicuous. Endocervical cells that mimicking HSIL cell sheets are nearly alwaysÂ three or more nuclei thick, while the normal endocervical cell sheets are almost always less than three nuclei thick.
(Renshaw et al.,2006)
Most of the factors that make the HSIL in crowded sheets can be mistaken as endocervical cells are when their cytoplasmic textures resemble to that of endocervical cells. The pale, fragile and foamy cytoplasm of the HSIL therefore can be dismissed as endocervical cells. Although cytoplasmic texture may resemble that of endocervical cells, the groups do not have long runs of smooth apical or luminal cytoplasmic edge, across several cells, and nuclei set back a constant distance, repeated, ordered 'six around one' honeycomb arrangements of nuclei. Nuclei in crowded HSIL sheets are often very crowded, reflecting a very high nuclear N/C ratio. This is a very conspicuous screening feature when present. However, the N/C ratio is not always high in endocervical-like HSIL sheets where the cytoplasm may be relatively abundant in some sheets or in part of a sheet.
(Renshaw et al. ,2006)
This seems to contradict the principle that high N/C ratio is an essential feature of a HSIL. However, the real basis of the 'High N/C ratio equates to High grade' principle is that high grade abnormal cells have scant cytoplasm because they have failed to mature normally.
We conclude that it is important to distinguishing HSIL from its mimics during reporting the result. HSIL cannot be agreeing if the fully characteristic found. By the way, getting adequate clinical information and continuous training to maintain competency and knowledge are some of the suggestion to reduce pitfalls. Thus, wrong diagnose of atypical glandular cells cause result over treatment. The diagnostic pitfalls of HSIL are endometrial cells, immature squamous metaplasia, endocervical cells, mild and moderate dyskaryosis, histiocyte, follicular cervicitis, and endometrial cell exfoliation due to an IUCD.