Читать книгу Shear's Cysts of the Oral and Maxillofacial Regions - Paul M. Speight - Страница 33

There are very many publications reporting the expression of different proteins in odontogenic cysts. In most cases the purpose has been to shed light on the pathogenesis and mechanisms of growth of the lesions, but many papers have attempted to determine whether particular patterns of expression can provide accurate diagnostic markers for each cyst type. Studies of keratin expression and proliferation markers are particularly numerous and the odontogenic keratocyst has been the subject of the majority of studies. Overall, however, immunohistochemistry has only a very small role to play in the diagnosis of cysts of the maxillofacial regions. Although each cyst type may show a different pattern of cytokeratins, the expression demonstrated by immunohistochemistry merely reflects the type of keratinisation that is easily and clearly visible on examination of a routine H&E (haemotoxylin and eosin)‐stained section. The best example of this conundrum is the odontogenic keratocyst. Many studies have been undertaken to compare the cytokeratin profile of keratocysts with other cysts, but almost without exception, the specimens used have been selected as typical histological examples of each cyst type. It is not surprising therefore that if the features are typical, there is no need for any additional staining beyond a good H&E‐stained section to make the diagnosis. One key area of diagnostic difficulty is when the pathologist must examine a small biopsy of an inflamed cyst. When heavily inflamed, any cyst type, including a keratocyst, may become lined by proliferative epithelium identical to that seen in a radicular cyst. The lining becomes non‐keratinised and studies have not been able to identify immunohistochemical markers that can differentiate between an inflammatory cyst and an inflamed developmental cyst. This issue is discussed in detail in Chapter 7. Our experience, supported by a number of studies (Rao et al. 2015 ), suggests that a good H&E‐stained section is the most specific marker for patterns of keratinisation and is usually sufficient to make an accurate diagnosis.

Table 2.3 Characteristic histological features that assist in the diagnosis of cysts of the maxillofacial regions.

Histological feature	Cyst type(s)	Diagnostic utility	Figure references
Proliferative epithelium with an arcading pattern	Radicular cyst Inflammatory collateral cysts	Typical feature of radicular cyst and of inflammatory collateral cysts But proliferative arcading epithelium may be seen in any odontogenic cyst that is secondarily inflamed	Figures 3.7, 3.12 (radicular cyst), 4.7 (paradental cyst), 5.22 (dentigerous cyst)
The epithelial lining is attached to an unerupted tooth at the cementoenamel junction	Dentigerous cyst	Virtually diagnostic of dentigerous cyst. This feature may be seen on macroscopic examination of an intact specimen or in decalcified sections Note: there have been reports of odontogenic keratocyst or orthokeratinised odontogenic cyst attached at the cementoenamel junction, but this is very rare and is thought to be due to a tooth ‘erupting’ into a cyst (see discussion in Chapter 12)	Figures 5.18 and 5.19
Thin regular parakeratinised epithelium with a corrugated surface and prominent basal layer	Odontogenic keratocyst	Diagnostic of odontogenic keratocyst. This typical epithelium is not seen in any other jaw cyst	Figures 7.15–7.17
Epithelial plaques or thickenings with a whorling pattern	Lateral periodontal cyst Botryoid odontogenic cyst Gingival cyst of adults Glandular odontogenic cyst	Epithelial plaques are seen in all cases of lateral periodontal cyst and are diagnostic if the cyst is unilocular and no other features are noted If the cyst is multilocular, then diagnostic for botryoid odontogenic cyst Gingival cyst shows similar features but is extraosseous Glandular odontogenic cyst may show plaques in about 65% of cases, but must be accompanied by other features (see Table 10.3)	Figures 8.6, 8.7 (lateral periodontal cyst), 8.9 (botryoid odontogenic cyst), 9.4 (Gingival cyst), 10.8 (glandular odontogenic cyst)
Cuboidal or columnar cells at the luminal aspect of the cyst lining	Glandular odontogenic cyst	Typical feature and seen in up to 100% of glandular odontogenic cysts. Diagnostic when accompanied by other features (see Table 10.3). Similar cells are occasionally seen in other cyst types, including dentigerous cyst, but these lack other features	Figures 10.7 and 10.8
A simple cyst with ghost cells in the wall	Calcifying odontogenic cyst	This feature is diagnostic of calcifying odontogenic cyst. Note that the lining is ameloblastomatous and if ghost cells are not seen, a diagnosis of cystic ameloblastoma must be considered. Ensure the whole lining is examined (see discussion in Chapter 11). If the lesion is solid, then consider dentinogenic ghost cell tumour. Ghost cells may be seen in odontomas and rarely in ameloblastomas	Figures 11.8–11.10
Hyaline bodies	Various odontogenic cyst types	Hyaline (Rushton) bodies are often stated as being typical of radicular cyst. They are seen in about 10% of radicular cysts, but also in up to 10% of odontogenic keratocysts and dentigerous cysts (see discussion in Chapter 3). However, hyaline bodies are specific and diagnostic of odontogenic cysts	Figures 3.15 (radicular cyst), 7.20 (odontogenic keratocyst)
Cholesterol clefts	Radicular cyst	Cholesterol clefts result from an accumulation of cholesterol crystals as a results of long‐standing inflammations. They are therefore typical of radicular cyst and are seen in 30% or more of cases (Table 3.3) But they are not specific and may be seen in any cyst that has become chronically inflamed, in particular in inflamed dentigerous cysts or keratocysts	Figure 3.16
Mucous cells	Various cyst types	Mucous cells have been described in most types of odontogenic cyst and are not diagnostic. They are a result of metaplastic change and are seen in about 20% of radicular cysts, 25% of dentigerous cysts, and 2% of odontogenic keratocysts Note that mucous cells are not a diagnostic requirement for glandular odontogenic cyst and are seen in only about 70% of cases (Table 10.3). Mucous cells are seen in surgical ciliated cysts and in about 50% of nasopalatine duct cysts and nasolabial cysts	Figures 3.14 (radicular cyst), 5.23 (dentigerous cyst), 10.10, 10.11 (glandular odontogenic cyst), 13.10 (nasopalatine duct cyst), 14.5 (nasolabial cyst)
Sebaceous glands	Dermoid cyst	Sebaceous glands are rare in jaw cysts and when seen a diagnosis of dermoid cyst should be considered. If sweat glands and hair follicles are also present, then this is diagnostic for dermoid cyst. Sebaceous glands have rarely been reported in odontogenic keratocyst and orthokeratinised odontogenic cyst	Figures 18.2 and 18.3 (dermoid cyst)
Respiratory epithelium	Nasopalatine duct cyst Various cyst types	Among cysts in the jaws, respiratory epithelium is a typical feature of nasopalatine duct cyst and is seen in about 50% of cases However, this is not specific. Surgical ciliated cyst is lined by respiratory epithelium and metaplastic respiratory epithelium has been described in radicular cysts Among soft tissue cysts, nasolabial cyst, bronchogenic cyst, and thyroglossal duct cyst are lined by respiratory epithelium, and respiratory epithelium may be seen in cysts of foregut or branchial cleft origin (Boxes 18.2–18.4)	Figures 3.14 (radicular cyst), 13.9 (nasopalatine duct cyst), 14.5 (nasolabial cyst), 16.5 (surgical ciliated cyst), 18.5 (bronchogenic cyst), 18.6 (branchial cyst), 18.8 (thyroglossal duct cyst)

Despite these limitations, there are a few instances where immunohistochemistry can help establish a diagnosis and differentiate between lesions with similar histological features. A number of diagnostically useful applications are summarised in Table 2.4.

Molecular studies have provided much useful and interesting information relating to the pathogenesis of odontogenic lesions, especially with regard to the role of the PTCH gene in the odontogenic keratocyst and to the role of the SHH (hedgehog), WNT, and MAPK signalling pathways in a variety of cysts and tumours (Diniz et al. 2017 ; Bilodeau and Seethala 2019 ). Molecular tests, however, have not yet proven to be useful in routine diagnosis of cysts. The main exception to this is the identification of MAML2 rearrangements that can be helpful in differentiating between the glandular odontogenic cyst and intraosseous mucoepidermoid carcinoma (discussed in Chapter 10). Table 2.4 summarises a number of molecular techniques that may show some value as diagnostic markers.

Table 2.4 Immunohistochemical and molecular markers that might have diagnostic utility in the differential diagnosis of cysts.

Immunohistochemistry
Antibody	Target	Diagnostic utility
CK10	Type I keratin, found mainly in cornified epithelia	CK10 stains keratinising epithelium and is positive in the superficial layers of odontogenic keratocyst and orthokeratinised odontogenic cyst. Of little value in histological sections, but has some utility in cytological smears from aspiration biopsies. Cells from keratocyst and orthokeratinised odontogenic cyst are positive, but dentigerous cysts and ameloblastomas are negative (August et al. 2000 ). Pan‐cytokeratin antibodies (AE1/AE3) may also stain keratin in smears from inflamed cysts (Vargas et al. 2007 ) (Figure 7.22)
CK18 and CK19	Keratin intermediate filaments. Both are widely expressed, but CK19 is seen typically in odontogenic epithelium	Use of both antibodies together has been shown to be useful to distinguish a glandular odontogenic cyst from central mucoepidermoid carcinoma (Pires et al. 2004 ; discussed in Chapter 10). Glandular odontogenic cyst is CK19+/CK18‐. Mucoepidermoid carcinoma is CK19‐/CK18+
Calretinin	Calretinin, a widely expressed calcium‐binding protein	Calretinin has been shown to be positive in up to 100% of ameloblastomas, including unicystic ameloblastoma. Odontogenic cysts including keratocysts are negative. Useful to differentiate cystic ameloblastoma from other cysts, especially in small biopsies from the posterior mandible region (Altini et al. 2000 ; Coleman et al. 2001 ; De Villiers et al. 2008; Jeyaraj 2019 ; Rudraraju et al. 2019 ; discussed in Chapters 5 and 7)
Maspin	Maspin, a member of the serine protease inhibitor superfamily	May be useful in the differentiation of glandular odontogenic cyst from central mucoepidermoid carcinoma, especially in small biopsies where not all features may be apparent. Maspin is widely expressed, but studies have shown much greater expression in the mucous cells of mucoepidermoid carcinoma than in glandular odontogenic cyst. Note that the differences relate only to mucous cells – other epithelial cells of the cyst lining are positive (Vered et al. 2010 ; Chapter 10, Table 10.4)
β‐catenin	Cell surface protein important in cell adhesion, but also in the regulation of the WNT signalling pathway	Intracellular expression of β‐catenin (cytoplasmic and nuclear) is characteristic of calcifying odontogenic cyst (and other ghost cell lesions – see CTNNB1 gene below) and is seen in all cases. However, it is not diagnostic, since it may also be seen in ameloblastomas
p16	p16 is a cyclin‐dependent kinase inhibitor, involved in regulation of the cell cycle	p16 antibodies are useful in the differentiation of branchial cleft cyst from a cystic metastasis in the lateral neck. p16 is activated by human papillomavirus (HPV) infection and strong expression, interpreted in context, is almost diagnostic of HPV‐associated oropharyngeal carcinoma. The majority of cystic metastases come from HPV‐associated squamous cell carcinomas and are p16 positive, but branchial cysts are negative. Note that positive staining must be carefully interpreted and the correct criteria must be used (Pai et al. 2009 ; Cao et al. 2010 ; Müller et al. 2015 ; Chapter 18, Figure 18.7)
Molecular markers
Gene	Alterations	Diagnostic utility
PTCH	Mutations or loss of heterozygosity (LOH) of PTCH gene	Alteration or loss of PTCH gene is seen in up to 80% of odontogenic keratocysts, but is not diagnostic because altered PTCH may be seen in other cyst types. However, biallelic loss of PTCH has been recorded in keratocysts and not in other odontogenic cysts, and this may be diagnostic
MAML2	Rearrangements of MAML2 gene, usually with CRCT1 or 3	MAML2 rearrangements are seen in mucoepidermoid carcinomas and their presence helps differentiate intraosseous mucoepidermoid carcinoma from glandular odontogenic cyst, which does not show the translocation (Bishop et al. 2014 )
CTNNB1	Mutations in the CTNNB1 (β‐catenin) gene	CTNNB1 mutations are seen in a wide range of neoplasms, but within the jaws are almost unique to ghost cell lesions (calcifying odontogenic cyst and dentinogenic ghost cell tumour). However, molecular analysis has not been used for diagnostic purposes. CTNNB1 mutation results in aberrant intracellular (cytoplasmic and nuclear) expression of β‐catenin protein (see β‐catenin above) (Gomes et al. 2019 ; Chapter 11)