Cervix

2.1 LOW-GRADE SQUAMOUS INTRAEPITHELIAL LESION (LSIL) VS. NONDIAGNOSTIC SQUAMOUS ATYPIA

	Low-Grade Squamous Intraepithelial Lesion (LSIL)	Nondiagnostic Squamous Atypia
Age	Wide age range, from teenage to postmenopausal years	Wide age range, from teenage to postmenopausal years
Location	Cervix, transformation zone, ectocervix	Cervix, transformation zone, ectocervix
Symptoms	None	None
Signs	Abnormal Pap, high-risk HPV variably detected, acetowhite changes or other abnormal findings at colposcopy	Abnormal Pap, abnormal findings at colposcopy
Etiology	HPV, low- and high-risk types	Variety of conditions, often normal glycogenation of the squamous epithelium
Histology	1. Epithelial thickening is usually present	1. Epithelium is variably thickened
	2. Widening of the parabasal zone; slight disorganization of parabasal zone can be seen (Figs. 2.1.1 and 2.1.2)	2. Quiescent parabasal zone; mitotic figures are infrequent (Fig. 2.1.6)
	3. Intermediate and superficial layer cells with nuclear enlargement (Fig. 2.1.3); occasionally with mitotic figures in the lower third (Fig. 2.1.2)	3. Normal cell maturation, nuclear size decreases progressively from the parabasal layers to the epithelial surface (Fig. 2.1.7)
	4. Superficial layer cells with perinuclear cytoplasmic clearing and nuclear enlargement (koilocytes) (Figs. 2.1.1 2.1.2, 2.1.3, 2.1.4)	4. Cytoplasmic clearing and perinuclear “halo” in cells with normal nuclear size
	5. Hyperchromasia; irregular nuclear membranes (Fig. 2.1.5); prominent nucleoli are not typical	5. Vesicular chromatin and prominent nucleoli can be seen, particularly in cases with intraepithelial inflammation or small hyperchromatic nuclei (Fig. 2.1.8)
	6. Koilocytotic atypia is often limited to a distinct focal lesion	6. Diffuse ill-defined areas with cytoplasmic clearing
Special studies	• Not particularly helpful in this differential	• Not particularly helpful in this differential
	• Ki-67 labeling is increased in parabasal intermediate layers with occasional cells labeled in superficial layers	• Ki-67 labeling is generally low, mild increase can be seen
	• Diffuse “block-like” expression of p16 can be seen in some lesions or patchy to negative staining	• p16 is negative or weak and focal/patchy
Treatment	None required; follow-up with repeat cervical cytology and colposcopy	None required; treatment of underlying cervicitis if present
Prognosis	Most regress spontaneously without intervention; lesions harboring high-risk HPV can develop persistent infection and high-grade squamous intraepithelial lesions	Unremarkable

Figure 2.1.1 Low-grade squamous intraepithelial lesion. Widened parabasal zone and prominent koilocytotic atypia.

Figure 2.1.2 Low-grade squamous intraepithelial lesion. Nuclear enlargement in the intermediate layers, disorganization of the parabasal zone with occasional parabasal mitosis.

Figure 2.1.3 Low-grade squamous intraepithelial lesion. Nuclear enlargement and hyperchromasia; some cells with cytoplasmic clearing.

Figure 2.1.4 Low-grade squamous intraepithelial lesion. Prominent koilocytotic change.

Figure 2.1.5 Low-grade squamous intraepithelial lesion, higher magnification. Nuclear enlargement, hyperchromasia, and nuclear membrane irregularities.

Figure 2.1.6 Nondiagnostic squamous atypia. Diffuse cytoplasmic clearing in the superficial and intermediate layers. Hyperchromasia, but no nuclear enlargement.

Figure 2.1.7 Nondiagnostic squamous atypia. The parabasal zone appears widened due to tangential sectioning. Mildly enlarged uniform nuclei in the intermediate layers.

Figure 2.1.8 Nondiagnostic squamous atypia. Squamous mucosa with inflammation. Enlarged nuclei with smooth nuclear membranes and small nucleoli.

2.2 LOW-GRADE SQUAMOUS INTRAEPITHELIAL LESION (LSIL) VS. HIGH-GRADE SQUAMOUS INTRAEPITHELIAL LESION (HSIL)

	Low-Grade Squamous Intraepithelial Lesion (LSIL)	High-Grade Squamous Intraepithelial Lesion (HSIL)
Age	Wide age range, from teenage to postmenopausal years	Wide age range, from teenage to postmenopausal years
Location	Cervix, transformation zone, ectocervix	Cervix, transformation zone, ectocervix
Symptoms	None	None
Signs	Abnormal Pap, high-risk HPV variably detected, acetowhite changes or other abnormal findings at colposcopy	Abnormal Pap, high-risk HPV usually detected, acetowhite changes or other abnormal findings at colposcopy
Etiology	HPV, low- and high-risk types	High-risk HPV, types 16 and 18 are most common
Histology	1. Preserved epithelial maturation; some expansion of parabasal zone can be seen (Fig. 2.2.1), particularly with tangential sectioning (Fig. 2.2.2)	1. Loss of epithelial maturation except for very superficial keratinocyte layer (Fig. 2.2.5)
	2. Intermediate and superficial layer cells with nuclear enlargement, hyperchromasia	2. Expansion of immature parabasal-like cells for at least 2/3 of the epithelial thickness (Fig. 2.2.6)
	3. Superficial layer cells with perinuclear cytoplasmic clearing and nuclear enlargement (koilocytes) (Fig. 2.2.3)	3. “Disorganization” of parabasal zone, nuclei pointing in different directions (Figs. 2.2.7 and 2.2.8)
	4. Enlarged hyperchromatic nuclei with irregular contours, but nucleocytoplasmic ratio is not increased (Fig. 2.2.4)	4. Enlarged hyperchromatic nuclei and scant to moderate amount of cytoplasm, increased nucleocytoplasmic ratio (Fig. 2.2.7)
	5. Occasionally with increased mitotic activity in the lower third of the epithelium	5. Mitotic figures in the intermediate layers (Fig. 2.2.8)
Special studies	• Negative, patchy, or diffuse p16; diffuse “block-like” expression of p16 does not preclude diagnosis of LSIL	• Strong, diffuse “block-like” expression of p16
	• Ki-67 labeling is increased in parabasal intermediate layers with some cells in superficial layers labeled	• Significant increase in Ki-67 labeling throughout epithelial thickness
Treatment	None required; follow-up with repeat cervical cytology and colposcopy	Cervical excision, LEEP, or conization; close follow-up can be considered in young women
Prognosis	Most regress spontaneously without intervention; lesions harboring high-risk HPV can develop persistent infection and high-grade squamous intraepithelial lesions	Some cases will progress to invasive carcinoma if untreated

Figure 2.2.1 Low-grade squamous intraepithelial lesion. Widened parabasal zone and prominent koilocytotic atypia.

Figure 2.2.2 Low-grade squamous intraepithelial lesion. Parabasal area appears widened around stromal papillae, but the maturation is preserved, and there is prominent koilocytotic change.

Figure 2.2.3 Low-grade squamous intraepithelial lesion. Parabasal zone shows atypia and disorganization. Maturation is preserved in the upper 2/3 of the epithelium.

Figure 2.2.4 Low-grade squamous intraepithelial lesion. No notable koilocytosis. Nuclear enlargement in the intermediate layers. Immature cells with increased nucleocytoplasmic ratio are confined to the parabasal zone.

Figure 2.2.5 High-grade squamous intraepithelial lesion. Marked widening of the parabasal zone to more than 2/3 of the epithelial thickness. Preserved maturation in the very superficial epithelial layers.

Figure 2.2.6 High-grade squamous intraepithelial lesion. Atypical parabasal-like cells extend to the intermediate layers. Mitotic figures are seen above the parabasal zone.

Figure 2.2.7 High-grade squamous intraepithelial lesion. Significant nuclear atypia is present throughout entire epithelial thickness, while cells retain moderate amount of eosinophilic cytoplasm.

Figure 2.2.8 High-grade squamous intraepithelial lesion. Atypical immature cell proliferation with marked disorganization involving more than 2/3 of the epithelial thickness. Mitotic figures are seen in the intermediate layers.

2.3 PAPILLARY IMMATURE SQUAMOUS METAPLASIA (IMMATURE CONDYLOMA) VS. PAPILLARY SQUAMOUS CELL CARCINOMA

	Papillary Immature Squamous Metaplasia (Immature Condyloma)	Papillary Squamous Cell Carcinoma
Age	22-41 years	43-80 years, most cases are in fifth to sixth decade
Location	Cervix, often proximal (high) in the endocervical canal	Cervix, vagina
Symptoms	Often asymptomatic	Vaginal bleeding, discharge, constitutional symptoms and abdominal pain in advanced stage cases
Signs	Abnormal Pap, abnormal colposcopy findings	Abnormal Pap, abnormal colposcopy findings, cervical mass
Etiology	Most contain low-risk HPV (6 and 11 types)	High-risk HPV (type 16, most common)
Histology	1. Papillary fronds lined by immature squamous epithelium (Figs. 2.3.1 2.3.2, 2.3.3)	1. Papillary fronds lined by immature squamous epithelium (Figs. 2.3.6 and 2.3.7)
	2. No invasion into underlying cervical stroma; extension into endocervical glands can be seen	2. Invasion is present (unless “papillary squamous cell carcinoma in situ”); invasive component has typical appearance of squamous cell carcinoma. Base of the lesion must be completely examined to evaluate for presence and depth of invasion
	3. Some increase in nucleocytoplasmic ratio (Fig. 2.3.3)	3. Increased nucleocytoplasmic ratio
	4. Uniform bland nuclei; small nucleoli can be seen (Fig. 2.3.4)	4. Atypical nuclei with some degree of pleomorphism; hyperchromasia (Figs. 2.3.8 and 2.3.9)
	5. Absent to rare parabasal mitoses	5. Brisk mitotic activity in the upper epithelial layers (Fig. 2.3.10)
Special studies	• Patchy or negative p16 (Fig. 2.3.5, left)	• Strong diffuse expression of p16
	• Low to absent Ki-67 proliferative activity (Fig. 2.3.5, right)	• Elevated Ki-67 proliferative activity throughout the epithelial thickness
	• Lack of high-risk HPV by in situ hybridization; low-risk HPV is detected	• High-risk HPV, detected by in situ hybridization; the assay has imperfect sensitivity, false-negative cases can be seen
Treatment	For lesions located high in the endocervical canal, excision/conization may be required for definitive diagnosis (to ensure complete removal)	Conization to evaluate the extent of the tumor/depth of invasion; subsequent treatment depending on the tumor stage including modified radical hysterectomy or chemoradiation
Prognosis	Benign, considered a variant of immature condyloma; however, a coexisting high-grade squamous intraepithelial lesions (HSIL) can be present in a proportion of cases	Stage dependent

Figure 2.3.1 Papillary immature squamous metaplasia. Multiple detached papillary fragments. No extension into cervical stroma is seen in a separate fragment (left).

Figure 2.3.2 Papillary immature squamous metaplasia. Same case as in Figure 2.3.1, higher magnification. Papillae lined by immature cells.

Figure 2.3.3 Papillary immature squamous metaplasia. Fused papillae lined by stratified immature epithelium.

Figure 2.3.4 Papillary immature squamous metaplasia. Same case as in Figure 2.3.1, higher magnification. Papillary frond lined by monotonous immature cells with mild atypia; mitoses are not seen.

Figure 2.3.5 Papillary immature squamous metaplasia. Essentially absent expression of p16, left, and very low Ki-67 labeling, right.

Figure 2.3.6 Papillary squamous cell carcinoma. Multiple detached and fused papillary structures.

Figure 2.3.7 Papillary squamous cell carcinoma. Fused papillae lined by stratified immature epithelium.

Figure 2.3.8 Papillary squamous cell carcinoma. Same case as in Figure 2.3.6, higher magnification. Stratified epithelium shows disorganization and brisk mitotic activity.

Figure 2.3.9 Papillary squamous cell carcinoma. Thickened epithelium with increased nucleocytoplasmic ratio and nuclear pleomorphism.

Figure 2.3.10 Papillary squamous cell carcinoma. Moderately increased nucleocytoplasmic ratio and mitotic figures in the superficial layers.

2.4 HIGH-GRADE SQUAMOUS INTRAEPITHELIAL LESION (HSIL) VS. IMMATURE SQUAMOUS METAPLASIA

	High-Grade Squamous Intraepithelial Lesion (HSIL)	Immature Squamous Metaplasia
Age	Wide age range, from teenage to postmenopausal years	Wide age range, more common in young reproductive-age women
Location	Cervix, transformation zone, ectocervix	Cervix, transformation zone
Symptoms	Often asymptomatic	Asymptomatic or vaginal discharge
Signs	Abnormal Pap, high-risk HPV usually detected, acetowhite changes or other abnormal findings at colposcopy	Abnormal Pap usually triggers colposcopic examination and cervical biopsy; high-risk HPV may be detected coincidentally, abnormal findings at colposcopy may be present
Etiology	High-risk HPV, types 16 and 18 are most common	Normal evolution of the cervical transformation zone
Histology	1. Loss of epithelial maturation except for very superficial keratinocyte layers; extension into endocervical glands can occur (Figs. 2.4.1 2.4.2, 2.4.3)	1. Loss of epithelial maturation; extension into endocervical glands is common (Figs. 2.4.5 2.4.6, 2.4.7)
	2. Expansion of immature parabasal-like cells for at least 2/3 of the epithelial thickness (Fig. 2.4.2)	2. Expansion of immature parabasal-like cells
	3. “Disorganization” of parabasal zone, nuclei pointing in different directions	3. Parabasal zone retains orderly arrangement of the nuclei (Fig. 2.4.6)
	4. Enlarged hyperchromatic nuclei with nuclear membrane irregularities; increased nucleocytoplasmic ratio (Fig. 2.4.4)	4. Mild nuclear enlargement; round nuclei with finely dispersed chromatin and inconspicuous nucleoli; mild increase in nucleocytoplasmic ratio (Fig. 2.4.7)
	5. Mitotic figures in the intermediate and superficial layers	5. Mitotic figures can be occasionally seen in the parabasal zone
Special studies	• Strong, diffuse “block-like” expression of p16	• Focal/patchy or negative staining for p16 (Fig. 2.4.8. left)
	• Significant increase in Ki-67 labeling throughout epithelial thickness	• Variable Ki-67 proliferative activity, but generally it is not markedly increased (Fig. 2.4.8. right)
Treatment	Cervical excision, LEEP or conization; close follow-up can be considered in young women	None needed
Prognosis	Some cases will progress to invasive carcinoma if untreated	Benign/normal variant; cervical cancer screening should continue based on other findings (previous abnormal Pap, high-risk HPV detection)

Figure 2.4.1 High-grade squamous intraepithelial lesion. Full-thickness immature cell proliferation with metaplastic-like appearance. The cells retain a moderate amount of cytoplasm. Hyperchromatic enlarged nuclei with some degree of pleomorphism.

Figure 2.4.2 High-grade squamous intraepithelial lesion, metaplastic type.

Figure 2.4.3 High-grade squamous intraepithelial lesion with endocervical gland involvement.

Figure 2.4.4 High-grade squamous intraepithelial lesion. Atypical nuclei with some degree of pleomorphism pointing in different directions.

Figure 2.4.5 Immature squamous metaplasia. Mild atypia and some increase in nucleocytoplasmic ratio.

Figure 2.4.6 Immature squamous metaplasia. Endocervical gland involvement with residual endocervical glandular epithelium remaining.

Figure 2.4.7 Immature squamous metaplasia. Thickened epithelium composed of immature cells with uniform nuclei and moderate amount of cytoplasm.

Figure 2.4.8 Immature squamous metaplasia. Same case as in Figure 2.4.7. Essentially absent expression of p16, left, and some increase in Ki-67 labeling, right.

2.5 HIGH-GRADE SQUAMOUS INTRAEPITHELIAL LESION (HSIL) VS. TRANSITIONAL CELL METAPLASIA/ATROPHY

	High-Grade Squamous Intraepithelial Lesion (HSIL)	Transitional Cell Metaplasia/Atrophy
Age	Wide age range, from teenage to postmenopausal years	Postmenopausal women, mean age 60-68 years
Location	Cervix, transformation zone, ectocervix, vagina	Ectocervix, transformation zone, occasionally vagina
Symptoms	Asymptomatic	Asymptomatic or vaginal discharge
Signs	Abnormal Pap, high-risk HPV usually detected, acetowhite changes or other abnormal findings at colposcopy	Abnormal Pap, high-risk HPV can be detected coincidentally, abnormal findings at colposcopy can be occasionally seen
Etiology	High-risk HPV, types 16 and 18 are most common	Unknown, related to atrophy
Histology	1. Loss of epithelial maturation except for superficial keratinocyte layers (in some cases); keratinocytes may appear “spindled” (Figs. 2.5.1 and 2.5.2)	1. Involves full thickness of the epithelium (Figs. 2.5.5 and 2.5.6)
	2. Expansion of immature parabasal-like cells for at least 2/3 of the epithelial thickness (Fig. 2.5.3)	2. Immature parabasal-like cells resembling urothelium
	3. “Disorganization” of parabasal zone, nuclei pointing in different directions (Fig. 2.5.4)	3. Haphazard orientation of the nuclei can be seen (Fig. 2.5.7)
	4. Enlarged hyperchromatic nuclei and scant amount of cytoplasm, increased nucleocytoplasmic ratio (Fig. 2.5.4)	4. Mild nuclear enlargement; ovoid to spindled uniform, hyperchromatic nuclei with occasional nuclear grooves; smooth nuclear membranes (Fig. 2.5.8)
	5. Mitotic figures in the intermediate and superficial layers	5. Mitotic figures are not seen
Special studies	• Strong, diffuse “block-like” expression of p16	• Patchy or negative staining for p16 (Fig. 2.5.9, left)
	• Significant increase in Ki-67 labeling throughout epithelial thickness	• Low to absent Ki-67 proliferative activity (Fig. 2.5.9, right)
Treatment	Cervical excision, LEEP, or conization; close follow-up can be considered in young women	None needed
Prognosis	Some cases will progress to invasive carcinoma if untreated	Benign

Figure 2.5.1 High-grade squamous intraepithelial lesion. Immature cells occupy entire epithelial thickness. Atypical squamous cells appear somewhat spindled. Occasional markedly enlarged nucleus is seen.

Figure 2.5.2 High-grade squamous intraepithelial lesion. Full-thickness atypical immature epithelium; occasional mitotic figure (arrow) in the intermediate zone.

Figure 2.5.3 Attenuated high-grade squamous intraepithelial lesion in a suboptimally oriented epithelial fragment lacking stroma in an endocervical curettage.

Figure 2.5.4 High-grade squamous intraepithelial lesion. Cells with atypical, hyperchromatic, and variably shaped nuclei occupy entire epithelial thickness.

Figure 2.5.5 Transitional cell metaplasia/atrophy. Tangentially oriented cellular fragments in an endocervical curettage.

Figure 2.5.6 Transitional cell metaplasia/atrophy. Attenuated epithelium appears basophilic.

Figure 2.5.7 Transitional cell metaplasia/atrophy. Same case as in Figure 2.5.5, higher magnification. Disorganized mildly hyperchromatic nuclei; increased nucleocytoplasmic ratio; nuclear membranes are smooth, and chromatin is fine. Mitoses are not seen.

Figure 2.5.8 Transitional cell metaplasia/atrophy. Same case as in Figure 2.5.6, higher magnification. Mildly hyperchromatic elongated nuclei with occasional nuclear grooves.

Figure 2.5.9 Transitional cell metaplasia/atrophy. Same case as in Figure 2.5.6. No expression of p16, left, and absent Ki-67 labeling, right.

2.6 ATTENUATED HIGH-GRADE SQUAMOUS INTRAEPITHELIAL LESION (HSIL) VS. ATYPICAL IMMATURE SQUAMOUS METAPLASIA

	Attenuated High-Grade Squamous Intraepithelial Lesion (HSIL)	Atypical Immature Squamous Metaplasia
Age	Wide age range, from teenage to postmenopausal years; however, attenuated forms are more common in older women	Wide age range
Location	Cervix, transformation zone	Cervix, transformation zone
Symptoms	Often asymptomatic	Often asymptomatic
Signs	Abnormal Pap, high-risk HPV usually detected, acetowhite changes or other abnormal findings at colposcopy	Abnormal Pap, high-risk HPV may be detected, abnormal findings at colposcopy
Etiology	High-risk HPV, types 16 and 18 are most common	Not a specific biologic entity; a morphologically ambiguous lesion concerning for but not definitively diagnostic of HSIL
Histology	1. Hyperchromatic epithelial fragments; loss of epithelial maturation except for very superficial keratinocyte layers in some cases	1. Loss of epithelial maturation; metaplastic-appearing epithelium
	2. Expansion of immature parabasal-like cells for at least 2/3 of the epithelial thickness (Figs. 2.6.1 and 2.6.2)	2. Expansion of immature parabasal-like cells (Figs. 2.6.6 and 2.6.7)
	3. “Disorganization,” nuclei pointing in different directions (Fig. 2.6.3)	3. Some “disorganization” can be seen
	4. Enlarged hyperchromatic nuclei with nuclear membrane irregularities; increased nucleocytoplasmic ratio (Figs. 2.6.2 and 2.6.4)	4. Nuclear features are concerning for HSIL, but not unequivocal (Figs. 2.6.7 and 2.6.8)
	5. Mitotic figures in the intermediate and superficial layers	5. Mitotic figures in parabasal layers; no abnormal forms
Special studies	• Strong, diffuse “block-like” expression of p16 (Fig. 2.6.5, left)	• Variable expression of p16 (Fig. 2.6.9, left); strong and diffuse expression strongly favors HSIL
	• Significant increase in Ki-67 labeling throughout epithelial thickness (Fig. 2.6.5, right)	• Variable Ki-67 proliferative activity (Fig. 2.6.9, right)
Treatment	Cervical excision, LEEP, or conization	Close follow-up with repeat cervical cytology and colposcopy with biopsies or cervical excision
Prognosis	Some cases will progress to invasive carcinoma if untreated	Some cases are diagnosed as HSIL in follow-up specimens

Figure 2.6.1 High-grade squamous intraepithelial lesion (HSIL). Attenuated hyperchromatic poorly oriented fragments in an endocervical curettage.

Figure 2.6.2 High-grade squamous intraepithelial lesion. Same case as in Figure 2.6.1, higher magnification. Full-thickness epithelial immaturity, hyperchromasia, and atypia in suboptimally oriented epithelial fragments without underlying stroma.

Figure 2.6.3 High-grade squamous intraepithelial lesion. Disorganized immature cell proliferation with atypia and hyperchromasia.

Figure 2.6.4 High-grade squamous intraepithelial lesion. Detached fragment; while the fragment is somewhat tangentially sectioned and suboptimally oriented, the degree of immaturity and atypia warrant the diagnosis of HSIL.

Figure 2.6.5 High-grade squamous intraepithelial lesion. Same case as in Figure 2.6.1. Diffuse p16 expression (left); markedly increased Ki-67 labeling throughout epithelial thickness (right).

Figure 2.6.6 Atypical immature squamous metaplasia. Hyperchromatic squamous epithelial fragments in an endocervical curettage.

Figure 2.6.7 Atypical immature squamous metaplasia. Same case as in Figure 2.6.6, higher magnification. The morphologic features raise concern for HSIL.

Figure 2.6.8 Atypical immature squamous metaplasia. Detached tangentially sectioned and suboptimally oriented fragment of atypical immature squamous epithelium. The fragment was depleted on the immunostained levels. HSIL cannot be excluded.

Figure 2.6.9 Atypical immature squamous metaplasia. Same case as Figure 2.6.7, patchy expression of p16, left, and some increase in Ki-67 labeling, right. Compare to Figure 2.6.5.

2.7 HIGH-GRADE SQUAMOUS INTRAEPITHELIAL LESION (HSIL) WITH EXTENSION INTO ENDOCERVICAL GLANDS VS. SUPERFICIALLY INVASIVE SQUAMOUS CELL CARCINOMA

	High-Grade Squamous Intraepithelial Lesion (HSIL) with Extension into Endocervical Glands	Superficially Invasive Squamous Cell Carcinoma
Age	Wide age range, from teenage to postmenopausal years	Most cases are between 40 and 55 years
Location	Cervix, transformation zone, ectocervix	Cervix, transformation zone
Symptoms	None	Vaginal bleeding or discharge
Signs	Abnormal Pap, high-risk HPV usually detected, acetowhite changes or other abnormal findings at colposcopy	Abnormal Pap; abnormal colposcopic findings, clinically visible cervical lesion is often not seen
Etiology	High-risk HPV, types 16 and 18 are most common	High-risk HPV, types 16 and 18 are most common
Histology	1. Surface HSIL is usually present	1. Background of HSIL with or without endocervical gland involvement is often seen (Figs. 2.7.5 2.7.6, 2.7.7, 2.7.8)
	2. Rounded outlines of the lesional nests (Figs. 2.7.1 and 2.7.2)	2. Irregularly shaped small nests and single cells in the stroma (Figs. 2.7.5 2.7.6, 2.7.7, 2.7.8)
	3. Normal/uninvolved endocervical glands are often seen in the vicinity; partial gland involvement can be seen (Figs. 2.7.2 and 2.7.3)	3. Normal endocervical glands can be seen in the vicinity
	4. Lesions cells within the glands with features similar to the surface lesion; some maturation can be seen in the center of the involved gland, but no paradoxical maturation at the periphery (Fig. 2.7.4)	4. Paradoxical maturation can be seen (Fig. 2.7.5)
	5. Loose stroma can be seen around the glands, but no true desmoplasia	5. Stromal desmoplastic response can be seen (Fig. 2.7.5)
Special studies	Not helpful in this differential diagnosis	Not helpful in this differential diagnosis
Treatment	Cervical excision, LEEP, or conization; larger volume excision may be required to achieve negative margins in cases with extensive endocervical gland involvement	Cases of superficially invasive carcinoma without angiolymphatic invasion can be treated with cervical excision; modified radical hysterectomy +/- lymphadenectomy for early-stage cases; chemoradiation for advanced stage cases
Prognosis	Some cases will progress to invasive carcinoma if untreated	Five-year survival approximately 95% (for superficially invasive squamous cell carcinoma)

Figure 2.7.1 High-grade squamous intraepithelial lesion (HSIL) with extension into endocervical glands. Nests of lesional epithelium with rounded outlines.

Figure 2.7.2 High-grade squamous intraepithelial lesion (HSIL) with extension into endocervical glands. Residual normal endocervical glandular epithelium is seen in the deep aspects of partially involved glands.

Figure 2.7.3 High-grade squamous intraepithelial lesion (HSIL) with extension into endocervical glands. Same case as in Figure 2.7.1, higher magnification. Nests of atypical epithelium with smooth contours. Residual glandular epithelium (arrow) confirms gland involvement.

Figure 2.7.4 High-grade squamous intraepithelial lesion (HSIL) with extension into endocervical glands. Same case as in Figure 2.7.1, higher magnification. Atypical epithelium forming round nest with morphologic features similar to HSIL on the surface. Numerous mitotic figures are noted.

Figure 2.7.5 Superficially invasive squamous cell carcinoma. Irregular squamous epithelial nests in the stroma (bottom) display eosinophilic cytoplasm (paradoxical maturation). Note surrounding stromal reaction. Compare to the broad basophilic nest with smooth contour within endocervical gland (top).

Figure 2.7.6 Superficially invasive squamous cell carcinoma. Irregular nests of carcinoma within the stroma (left). Compare to HSIL involving endocervical glands (right).

Figure 2.7.7 Superficially invasive squamous cell carcinoma. Small eosinophilic nest of carcinoma (arrow) with adjacent HSIL involving endocervical glands (left).

Figure 2.7.8 Superficially invasive squamous cell carcinoma. Small eosinophilic nest of carcinoma (arrow) arising from HSIL involving endocervical glands.

2.8 ADENOID BASAL EPITHELIOMA VS. HIGH-GRADE SQUAMOUS INTRAEPITHELIAL LESION (HSIL) WITH EXTENSION INTO ENDOCERVICAL GLANDS

	Adenoid Basal Epithelioma	High-Grade Squamous Intraepithelial Lesion (HSIL) with Extension into Endocervical Glands
Age	Wide age range, more common in postmenopausal women, mean age 64-71 years	Wide age range, from teenage to postmenopausal years
Location	Cervix	Cervix, transformation zone
Symptoms	Asymptomatic	Asymptomatic
Signs	Abnormal Pap or an incidental finding in the hysterectomy for other indications	Abnormal Pap, abnormal findings on colposcopy
Etiology	High-risk HPV, particularly in cases associated with HSIL or squamous cell carcinoma	High-risk HPV
Histology	1. Located superficial or deep in the cervical stroma (Fig. 2.8.1)	1. Within the range of distribution of endocervical glands (Fig. 2.8.6)
	2. Small basaloid nests with prominent peripheral palisading (Figs. 2.8.2 and 2.8.3)	2. The squamous nests often expand involved glands resulting in their size exceeding that of adjacent endocervical glands; smooth contours (Fig. 2.8.7)
	3. No association with adjacent endocervical glands; loose stroma around the nests (Fig. 2.8.3)	3. Atypical stratified squamous epithelium (HSIL) similar to the lesion seen on the mucosal surface extending into preexisting endocervical gland (Fig. 2.8.8); partial gland involvement can be seen (Fig. 2.8.9)
	4. Glandular/acinar differentiation is common (Fig. 2.8.4); squamous differentiation can be seen in the center of the nests	4. Associated adjacent adenocarcinoma in situ can be seen; true glandular differentiation is not present
	5. Uniform mildly atypical basaloid cells; cytoplasmic clearing can be seen (Figs. 2.8.3 2.8.4, 2.8.5)	5. Cytologic atypia, enlarged hyperchromatic nuclei, eosinophilic cytoplasm (Figs. 2.8.9 and 2.8.10)
	6. Mitoses are generally infrequent	6. Often brisk mitotic activity
Special studies	Not helpful in this differential; however, some studies suggested lack of high-risk HPV and p16 expression in small isolated lesions not associated with invasive carcinoma	Not helpful in this differential
Treatment	Cervical excision to exclude other components (adenoid basal carcinoma, squamous cell carcinoma, etc.)	Cervical excision, LEEP, or conization
Prognosis	Benign; however, may be associated with HSIL or invasive carcinoma	Some cases will progress to invasive carcinoma if untreated

Figure 2.8.1 Adenoid basal epithelioma. Proliferation of basophilic epithelial nests in the stroma below the level of normal endocervical glands.

Figure 2.8.2 Adenoid basal epithelioma. Basaloid epithelial nests with peripheral palisading.

Figure 2.8.3 Adenoid basal epithelioma. Solid basaloid nests composed of uniform cells.

Figure 2.8.4 Adenoid basal epithelioma. Basaloid nests with adenoid cystic-like features.

Figure 2.8.5 Adenoid basal epithelioma. Basaloid nests with cytoplasmic clearing.

Figure 2.8.6 High-grade squamous intraepithelial lesion (HSIL) with extension into endocervical glands. Note residual endocervical glandular epithelium in the deep aspects of the glands.

Figure 2.8.7 High-grade squamous intraepithelial lesion (HSIL) with extension into endocervical glands. Large round basophilic nests in the stroma. Residual endocervical glandular epithelium is seen (bottom right).

Figure 2.8.8 High-grade squamous intraepithelial lesion (HSIL) with extension into endocervical glands. Epithelial nests with smooth contours and adjacent endocervical gland.

Figure 2.8.9 High-grade squamous intraepithelial lesion (HSIL) with extension into endocervical glands. Residual endocervical glandular epithelium remains at the periphery of the involved gland.

Figure 2.8.10 High-grade squamous intraepithelial lesion (HSIL) with extension into endocervical glands, higher magnification. The cells have atypical nuclei and moderate amounts of eosinophilic cytoplasm.

2.9 HIGH-GRADE SQUAMOUS INTRAEPITHELIAL LESION (HSIL) VS. STRATIFIED MUCIN-PRODUCING INTRAEPITHELIAL LESION (SMILE)

	High-Grade Squamous Intraepithelial Lesion (HSIL)	Stratified Mucin-Producing Intraepithelial Lesion (SMILE)
Age	Wide age range from teenage to postmenopausal years	23-57 years, mean 34 years
Location	Cervix, transformation zone	Cervix, transformation zone
Symptoms	Asymptomatic	Asymptomatic
Signs	Abnormal Pap, abnormal colposcopic findings	Abnormal Pap, abnormal colposcopic findings
Etiology	High-risk HPV	High-risk HPV, derived from the reserve cells of cervical transformation zone
Histology	1. Present on the surface or extends into endocervical glands (Figs. 2.9.1 2.9.2, 2.9.3)	1. Present on the surface or extends into endocervical glands (Figs. 2.9.4 2.9.5, 2.9.6)
	2. Stratified epithelium composed of immature cells with increased nucleocytoplasmic; squamous maturation can be preserved in the superficial layers	2. Stratified epithelium with mucin-containing columnar cells (Figs. 2.9.6 and 2.9.7)
	3. May undermine residual normal endocervical glandular columnar epithelium on the surface or within endocervical glands (Figs. 2.9.1 and 2.9.3)	3. Columnar cells with cytoplasmic mucin distributed throughout epithelial thickness (Figs. 2.9.6 and 2.9.7)
	4. Enlarged hyperchromatic nuclei with nuclear membrane irregularities; increased nucleocytoplasmic ratio (Fig. 2.9.3)	4. Some nuclear enlargement and atypia (Fig. 2.9.8)
	5. Mitotic figures in the intermediate and superficial layers; apoptotic bodies can be seen	5. Mitoses can be present, but often not frequent; apoptotic bodies can be seen
Special studies	• p63 positive	• p63 negative, except for the basal layer in some cases
	• Mucicarmine stain is negative; residual normal endocervical glandular cells on the surface can be positive	• Mucicarmine stain can be used to highlight cytoplasmic mucin throughout entire epithelial thickness
Treatment	Cervical excision, LEEP, or conization	Cervical excision, conization
Prognosis	Some cases will progress to invasive carcinoma if untreated	Considered a variant of adenocarcinoma in situ (AIS); commonly is associated with HSIL and usual-type AIS; greater risk of coexisting invasive carcinoma than HSIL. Stratified mucin-producing carcinoma has been described

Figure 2.9.1 High-grade squamous intraepithelial lesion (HSIL). Stratified immature epithelium composed of cells with moderate amounts of eosinophilic cytoplasm. Note residual normal endocervical glandular epithelium (right).

Figure 2.9.2 High-grade squamous intraepithelial lesion (HSIL) with endocervical gland involvement. Basaloid nests of lesional cells with residual glandular epithelium at the deep aspects.

Figure 2.9.3 High-grade squamous intraepithelial lesion (HSIL) with endocervical gland involvement. Lesional cells have moderate amounts of eosinophilic cytoplasm and oval hyperchromatic nuclei.

Figure 2.9.4 Stratified mucin-producing intraepithelial lesion (SMILE). Endocervical curettage; fragment of cellular mucosa at low power.

Figure 2.9.5 Stratified mucin-producing intraepithelial lesion (SMILE). Intraepithelial proliferation of cells with pale cytoplasm.

Figure 2.9.6 Stratified mucin-producing intraepithelial lesion (SMILE). Same case as in Figure 2.9.5, higher magnification. Cells with pale mucinous cytoplasm are present within surface epithelium and extend into endocervical gland.

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