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Metaplasia of Female Genital Tract

Recent Advances Date- 27/8/13

DR GAURAV PAWAR PRESENTER GUIDE- DR K. MALUKANI

Definition and Pathogenesis of Metaplasia


Metaplasia is a condition in which there is a change of one type of differentiated tissue into another type of similar differentiated tissue or as the abnormal transformation of an adult, fully differentiated tissue of one kind into a differentiated tissue of another kind. The mullerian derived epithelium which lines most of the female genital tract is well known for its capacity to differentiate into various types of epithelium such as, ciliated, mucinous, endometrioid, transitional and squamous types. The metaplasias of the uterine corpus and cervix are the most common sites of metaplasia. Metaplasia occasionally can occur in other parts of the female genital tract such as mucosa of the fallopian tube and the vagina.

Endometrial epithelial metaplasia


Is a group of non-neoplastic lesions, often coexisting with endometrial hyperplasia or adenocarcinoma.

International society of Gynecological Pathologist ,classification of Endometrial epithelial metaplasia


Squamous metaplasia and morules Mucinous metaplasia (including intestinal ) Ciliary change Hobnail cell change Clear cell change Eosinophilic cell change(including oncocytic) Surface syncytial change Papillary proliferation Arias stella change

Classification of Cervical metaplasia


Cervical squamous metaplasia is extremely common in the cervix. Before full maturation is reached, there are stages of reserve cell hyperplasia and immature squamous metaplasia, both of which may cause diagnostic difficulty.

Squamous metaplasia occurring in the squamo-columnar junction (transformation zone) of the cervix begins as a patchy process, the foci of squamous metaplasia enlarging and eventually fusing. The metaplasia involves both the surface epithelium and underlying crypts.
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Cervical epithelial metaplasia may further be subdivided into:


Reserve cell hyperplasia Immature and mature squamous metaplasia Transitional metaplasia Tubal metaplasia Tuboendometrial metaplasia and endometriosis Cervical microglandular hyperplasia Intestinal metaplasia and oxyphil metaplasia .

Metaplasias elsewhere in the female genital tract are relatively very rare and can be transitional and mucinous metaplasia of the fallopian tube.6 The abdominal and pelvic peritoneum, as part of the secondary Mullerian system, may undergo metaplasia into various Mullerian epithelia. Nonneoplastic secondary mullerian lesions, which are in many cases a form of metaplasia, comprise endometriosis, endosalpingiosis and endocervicosis. When occurring in combination, they have been termed as mullerianosis. It is recognized that probably most cases of abdominal and pelvic endometriosis are not truly metaplastic but are the result of retrograde menstruation.

SQUAMOUS METAPLASIA WITH MORULES


Squamous metaplasia is the commonest form of metaplasia in the endometrium. Although this may be focal finding, it may be widespread and involve most of the endometrium. Microscopically, it is composed of bland squamous cells with eosinophilic cytoplasm. Central necrosis may be present and has no sinister connotation. Squamous metaplasia is common in endometrioid adenocarcinoma and in endometrial hyperplasia: these conditions should be excluded by careful examination of the glandular elements. The World Health Organization (WHO) categorises adenocarcinoma with squamous differentiation as a variant of endometroid adenocarcinoma and no longer accepts terms such as adenoacanthoma and adenosquamous carcinoma.

Morules differ from mature squamous metaplasia in that they lack keratinisation and intercellular bridges. Morules and foci of mature squamous elements, metaplasia often co-exist. An endometrial lesion in which squamous elements, usually in the form of morules, are extremely common and prominent is an atypical polypoid adenomyoma. Extensive squamous metaplasia of the endometrium also occur in association with pyometra, endometritis, cervical stenosis or an intra-uterine device. Endometrial squamous metaplasia occurs secondary to progestogen therapy.

Isolated Squamous Morule

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MUCINOUS METAPLASIA
This is a rarer form of endometrial metaplasia. The diagnosis should be reserved for cases in which the endometrial epithelial cells are replaced by cells with abundant mucincontaining cytoplasm, which resemble endocervical cells. Rarely, intestinal metaplasia has been described in the endometrium, in which the mucinous epithelium contains goblet cells. This is also the case in the cervix. As with other types of endometrial metaplasia, mucinous metaplasia can co-exist with endometrial hyperplasia. As mucinous metaplasia of the endometrium can have a complex growth pattern, it can be difficult to distinguish between mucinous metaplasia and well-differentiated adenocarcinoma, especially in endometrial biopsy tissue.
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In biopsy tissue, a diagnosis of mucinous adenocarcinoma should be considered in a lesion resembling cervical microglandular hyperplasia in a postmenopausal patient, although cervical microglandular hyperplasia rarely occurs in this age group.

Vimentin staining may be of use: adenocarcinoma usually stains positively and microglandular hyperplasia is negative. Rarely, mucinous metaplasia in the endometrium is accompanied by mucinous lesions elsewhere in the female genital system.

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Mucinous differentiation in Endometrium

Endometrium showing combined Mucinous and Squamous Metaplasia

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ARIAS-STELLA CHANGE
Seen In pregnancy or trophoblastic disease, and occasionally with hormone therapy: rarely, there is no association.

Histologically, there may be cellular stratification, secretory activity and enlargement of the epithelial cell nuclei and cytoplasm.

Nuclei show considerable atypia and occasional mitotic figure may be present.

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Arias Stella change of Endometrium

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Arias- Stella Change


Recently five histological variant have been described: minimally atypical, early secretory pattern, hypersecretory pattern, regenerative pattern, and monstrous cell pattern. Differential diagnosis is clear cell carcinoma but the diagnosis of Arias-Stella change is usually straightforward if there is a history of pregnancy or if other morphological features of pregnancy are present.

In addition, the Arias-Stella change involves pre-existing endometrial glands and there is no evidence of stromal infiltration.

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PAPILLARY SYNCYTIAL METAPLASIA


Papillary syncytial metaplasia in most cases represents a reparative phenomenon after menstrual shedding or recent endometrial sampling. It is one of the commoner forms of endometrial metaplasia. Histologically it is characterised by a syncytium of endometrial epithelial cells which have small glandular lumina and papillae which lack fibrovascular stromal cores. The cells usually have eosinophilic cytoplasm and there is often a heavy neutrophil infiltrate.

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The most important differential diagnosis of papillary syncytial metaplasia is papillary adenocarcinoma of endometriod or serous type. The changes of papillary syncytial metaplasia are limited to the surface and are often associated with signs of breakdown.

A lesion recently described in detail by Lehman and Hart which is most frequently seen in endometrial polyps is characterised by papillary proliferations with fibrovascular cores. This lesion is like papillary syncytial metaplasia, it has a papillary appearance and so could be misdiagnosed as papillary endometrial carcinoma.
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Ichthyosis uteri
Another rare entity that appears to be declining in incidence,
ichthyosis uteri is a benign process in which the endometrial lining has been replaced by a cytologically benign stratified proliferation of cells with squamous differentiation. It has been associated with chronic endometritis and with heat ablation of the endometrium.

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Ichthyosis uteri

Ichthyosis Uteri

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CLEAR CELL METAPLASIA


Clear cell metaplasia is characterized by replacement of endometrial epithelial cells by cells with abundant clear cytoplasm. This may be found in the endometrium in pregnancy. Especially when florid, clear cell metaplasia may be misdiagnosed as clear cell carcinoma. Distinction is based on the bland nuclear features and the fact that in clear cell metaplasia the endometrial glands are normal in architecture and distribution. When clear cell metaplasia involves architecturally complex glands, the distinction from clear cell carcinoma may be very difficult, especially when clear cell carcinoma may be cytologically bland.
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Other features favoring clear cell metaplasia over clear cell carcinoma include focality of lesion, absence of visible tumor on hysterectomy, absence of stromal invasion and presence of estrogen receptor positivity.

Most ovarian clear cell carcinomas are estrogen receptor negative.

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Clear cell metaplasia endometrium

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EOSINOPHILIC (OXYPHIL,ONCOCYTIC )METAPLASIA


The cytoplasm is granular,abundant and eosinophilic.
Some degree of cytoplasmic eosinophilia is commonly found in endometrial epithelial cells and does not alone warrant a diagnosis of eosinophilic metaplasia. Differential diagnosis, especially when there is architectural complexity, is the eosinophilic or oxyphilic variant of endometrioid adenocarcinoma. Distinction from adenocarcinoma is made on the absence of a visible lesion on hysteroscopy, absence of severe cytological atypia, and absence of stromal invasion.
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Eosinophilic cell change

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CILIATED OR TUBAL METAPLASIA


Ciliated endometrial epithelial cells are normal phenomenon, so a diagnosis of ciliated metaplasia should be made only when one or more endometrial glands are lined predominantly by ciliated cells. Ciliated cells often have very eosinophilic cytoplasm. Isolated ciliated cells are commonly found in endometrial adenocarcinoma and a ciliated adenocarcinoma has been described which is a variant of endometrioid adenocarcinoma in which the tumour is composed predominantly of ciliated cells.
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Tubal or Ciliated metaplasia of endometrium

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HOBNAIL CELL METAPLASIA


Hobnail cell metaplasia is characterized by the presence of rounded atypical blebs Hobnail cell metaplasia is a reparative phenomenon after endometrial biopsy ,it also occurs in pregnancy Hobnail are also characteristic of clear cell carcinoma and this may enter into the D/D , especially if there is accompanying clear cell metaplasia.

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Endometrial mesenchymal metaplasia


1] Smooth muscle metaplasia- Most common type of metaplasia in endometrium. It is thought that multipotent cell exists in the uterus which has capacity to differentiate into stroma and smooth muscles. This is shows an IHC overlap between endometrial stromal and smooth muscle neoplasm that hybrid exist. 2] Cartilaginous and osseous metaplasia- Rarely , foci of bone or cartilage are found within endometrium. It is likely that these foci are fetal origin. Benign osseous or cartilaginous metaplasia in endometrium carcinoma should not be mistaken for the sarcomatous component of a carcinosarcoma. These tissues are found in endometrium of a young women with past history of abortion.

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Conti..
3]Glial metaplasia- Glial tissue is rare and the chief D/D is a teratoma. It is presumed to a consequence of previous abortion.

4] Adipose metaplasia- Adipose tissue may be rarely seen in the stroma of endometrial polyp. It is found in an endometrial biopsy or curretage specimen, so perforation must be suspected.Other explanation of adipose tissue presence include lipoma, lipoleiomyoma,rare uterine hamartogenous like lesions.
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Smooth muscle metaplsia at center and right

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Conti.
5]Extramedullary hematopoiesis- Extramedullary hematopoiesis, recognized by the presence of megakaryocytes, erythroid and myeloid precursors, is occasionally seen.

If extramedullary hematopoiesis is identified in the endometrium in the absence of other tissues, and underlying hematological disorder should be considered and investigated.

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CERVICAL EPITHELIAL METAPLASIA


In late fetal life, the cervical canal is lined by columnar epithelium and the ectocervix by non-keratinised stratified squamous epithelium. The junction between the two is known as the original squamouscolumnar junction. Later the columnar epithelium close to the original squamouscolumnar junction undergoes metaplastic change into squamous epithelium. This area is known as the transformation zone of the cervix and persists into adult life. Squamous metaplasia occurring in the transformation zone of the cervix begins as a patchy process, the foci of squamous metaplasia enlarging and eventually fusing. Squamous metaplasia is extremely common in the cervix and should be seen as a normal phenomenon rather than an abnormal pathological process. Before full maturation is reached, though, there are stages of reserve cell hyperplasia and immature squamous metaplasia, both of which may cause diagnostic difficulty.

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Squamo-columnar junction view

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RESERVE CELL HYPERPLASIA


This is the first stage in the metaplastic process which eventually results in the transformation of columnar epithelium into mature squamous epithelium. Reserved cell hyperplasia is characterised by the presence of a layer of cuboidal or low columnar cells with clear cytoplasm situated immediately beneath the normal endocervical cells but separated from the stroma by basement membrane. This results histological double cell layer. Occasionally the presence of double layer may be confusing and result in consideration of cervical glandular intra-epithelial neoplasia (CGIN). However, the histological appearances the characteristic and CGIN can be excluded if attention is paid to the nuclear details.
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Reserve Cell Hyperplasia

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Immature and mature Squamous metaplasia


The progression of reserve cell hyperplasia results in the development of a multilayered epithelium with features of both squamous and glandular differentiation. Squamous features are usually most prominent near the base of the epithelium while towards the surface , glandular is in the form of cytoplasmic mucin. As the process continues, the immature metaplastic squamous epithelium is converted to mature squamous epithelium. Immature sq. metaplasia may be mistaken for (CIN) and the term atypical immature metaplasia been used for cases with nuclear atypia.

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To differentiate Immature Sq.metaplasia from CIN. Presence of uniform population of cells with scanty cytoplasm and nuclei which lack significant pleomorphism . The nuclei are not hyperchromatic and abnormal mitosis may not be seen. The presence of mucin on the surface of cells may be useful . A minor degree of nuclear atypia is acceptable in immature Sq. metaplasia. When grading of CIN is difficult, a diagnosis CIN unclassified should be made with a statement on whether this is likely to be low gd(CIN 1) or high (CIN 2-3). Koilocytosis may also involve Immature metaplastic Sq. epithelium and result in atypical changes. Using HPV typing with careful follow-up, have shown that some cases of atypical immature sq. metaplasia are probably a variant of high gd CIN.

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Squamous metaplasia in cervix

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Squamous metaplasia of the Cervix

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Stratified mucinous intra-epithelial lesion

This lesion involves the surface epithelium and underlying endocervical crypts and is characterized by a multilayered epithelium resembling CIN.

Stratified mucinous intra-epithelial lesion is associated with more extreme pleomorphism and hyperchromasia and higher proliferation index, demonstrable by MIB1 staining, than immature sq. metaplasia.
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Stratified mucinous intra-epithelial lesion

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In addition, stratified mucinous intra-epithelial lesion is almost always associated with CIN or CGIN and commonly with an invasive carcinoma which may be squamous ,glandular or adenosquamous in type.

It has been considered that stratified mucinous intra-epithelial lesion is a form of reserve cell neoplasia and a marker of phenotypic instability

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Transitional Metaplasia
Trasitional cell metaplasia of the cervix is uncommon and is usually an incidental finding in postmenopausal women. It may involve both the surface epithelium and underlying Endocervical glands and is more common on the ectocervix. Histologically it may show cells with pale, uniform ,ovoid to spindle-shaped nuclei which may contain grooves. A useful Diagnostic feature , not always present, is that in the deeper layers of the epithelium the nuclei are usually oriented at right angles to the basement membrane whereas superficially they are parallel to it. The main problem in diagnosis is the superficial resemblance to CIN 3,especially in those cases with tightly packed nuclei and low N:C ratio.

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Ectocervix showing Transitional cell Metaplasia

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Tubal metaplasia ,Tubo-endometrial and Endometriosis


Tubal metaplasia ,Tubo-endometrial , are very common in cervix. In some cases the epithelium has predominantly tubal differentiation with abundant cillia while in other cases there is a more endometrioid appearance with non-ciliated cuboidal and columnar epithelial cells. When tubo-endometrial metaplasia occurs in the region of the transformation zone of Cx ,especially when florid ,it is often a reparative phenomenon secondary to a previous procedure such as loop or cone Bx. The presence of cillia is always a useful pointer towards a non-neoplastic lesion.

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But recently a ciliated variant of CGIN has been described (designated AdenoCA in situ of tubal type). A panel of IHC stains comprising of MIB1,bcl2 and p16 may be of value.
MIB1 Tubo-endo metaplasia Endometriosis Microglandular hyperplasia High gr CGIN Negative or low Neg or low Intermediate or high Bcl2 diffuse Diffuse Negative Negative p16 Neg or focal Neg or focal Negative Diffuse 50

Cervical glandular hyperplasia


Microglandular hyperplasia is common within cervix and is usually associated with exogenous hormone use and pregnancy. Although not a metaplasia , but is best categorized with these. Histologically microglandular hyperplasia is characterized by closely packed glands, most of which are small but some are cystically dilated. Crypts are lined with cuboidal and low columnar cells which commonly have subnuclear supranuclear vacuolation.

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Typical microglandular hyperplsia

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Figure 1 Typical cervical microglandular hyperplasia (HE, ob. 10)

2 basal Endocervical microglandular Microglandular associated Figure with hyperplasia associate with basal hyperplasia (HE, ob. 6) hyperplasia

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Intestinal metaplasia
Intestinal metaplasia involving endocervical crypts has rarely been seen. It is characterized by the presence of goblet cells and sometimes Paneth cells. Co-existent appendiceal neoplasms were present and differential cytokeratin staining (CK7 and CK20) suggested metastasis from appendix by a transtubal route.

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Intestinal metaplasia

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Oxyphilic metaplasia
Oxyphilic metaplasia is characterized by replacement of the endocervical cryptal epithelium by cuboidal cells with eosinophilic cytoplasm. Often there is a degree of nuclear atypia and this lesion was originally designated atypical oxyphilic metaplasia . Its only significance is that it is mistaken as CGIN.

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Oxyphilic metaplasia

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Other miscellaneous metaplasia within the FGT


Metaplasias elsewhere within the female genital system are relatively rare. In the fallopian tube, transitional metaplasia, similar to that seen within cervix ,as well mucinous type also. The abdominal and pelvic peritoneum ,as part of secondary mullerian system ,may go under metaplasia into various mullerian epithelium. Mullerian potential of this tissue is consistent with its close embryonic relation with the mullerian ducts. Non-neoplastic secondary mullerian lesions, which are in many cases a form of metaplasia, compromise endometriosis, endosalpingiosis, endocervicosis.
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1] Endosalpingiosis is characterized by the presence of nonneoplastic glands lined by ciliated tubal type epithelium. It usually involves the peritoneum and the subperitoneal tissues including the surface of the ovaries. Endosalpingiosis is usually an incidental finding on microscope , but rarely may form cystic mass referred to as florid cystic endosalpingiosis. Psammoma bodies are often present in glandular lumina or the surrounding stroma. Endosalpingiosis is especially likely to be found in patients with ovarian serous neoplasms which may benign ,borderline and malignant. Occasionally, foci of endosalpingiosis have multilayering with papillary formation and mild cytological atypia.
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2] Endocervicosis is characterized histologically by the presence of non-neoplastic mucinous glands resembling endocervical glands. This is much less common then endometriosis or endosalpingiosis. Involved sites have included the peritoneum, pelvic lymph nodes, the urinary bladder, the uterine serosa, the cervix, and the vagina.

Especially when florid and involving the wall of the bladder cervix, a diagnosis of well differentiated mucinous adenocarcinoma , including cervical minimal deviation adenocarcinoma of mucinous type, may be considered.

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3] Another rare metaplastic lesion to arise from the secondary Mullerian system is diffused peritoneal leiomyomatosis. This condition is characterised by multiple small nodules of bland smooth muscle cells involving the peritoneum and omentum and is often associated with pregnancy or exogenous hormones

Diffuse peritoneal leiomyomatosis often shows positive immunohistochemical staining with progesterone receptor and persistent cases have been successfully treated with gonadotropin-releasing hormone agonists.

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THANKS
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