Benign Tumors

Epithelial Tumors (Figs. 91-94)

Squamous papillomas [8052/0] of the ectocervix (Figs. 91-94) occur predominantly in young women and are mainly caused by infection with low-risk HPV (LR-HPV) types, such as types 6 and 11 (Ward et al. 1992; see Table 3). Some may be inverted, hence their surfaces are flat. Histologically they consist of thick layers of stratified squamous epithelium with elongated rete pegs that extend deeply into the lamina propria (Fig. 91). The basal membrane is intact, the epithelial layers are well differentiated, and acantho-sis is usually pronounced. Some lesions may also contain koilocytes in the upper layers. Mitoses are rare. Besides the flat, inverted type of papilloma, others may present as exophytic condylomatous lesions [7672/0] and closely resemble the condylomata of the vulva and vagina (Fig. 92) or form verrucae covered by parakeratosis or hyperkeratosis (Fig. 93). These papillomas may be sessile or pedunculated. Since these lesions reflect acute virus-producing infections of low-risk type, they may display all morphological features of active papillomavirus replication (see HPV infection, p. 61).

■ Differential Diagnosis. On gross examination the condylomatous papillomas may resemble an invasive carcinoma. Histologically,they can be distinguished by lack of cellular atypia, absence of mitoses, and the intact basal membranes. Ectocervical papilloma, depending on the type of HPV causing it, may later become malignant, whereas condylomas of the vulva and vagina usually due to infection by LR-HPV types almost invariably remain benign (Willett et al. 1989).

The previously introduced term "flat condyloma" for inverted papilloma should be avoided, as it may mislead the clinician. These lesions may represent infection with LR-

Table 3. Classification systems of HPV-associated intraepithelial lesions of the cervix

Term

HPV risk

Three-tiered

Two-tiered

SIL

category

(Bethesda

CIN

CIN

like)

Exophytic condyloma

Low risk

-

-

LGSIL

Squamous papilloma

Low risk

-

-

LGSIL

Flat condyloma

Low and high risk

-

-

LGSIL

Mild dysplasia

Low and high risk

CIN 1

Low-grade CIN

LGSIL

Moderate dysplasia

High risk

CIN 2

High-grade CIN

HGSIL

Severe dysplasia

High risk

CIN 3

High-grade CIN

HGSIL

Carcinoma in situ

High risk

CIN 3

High-grade CIN

HGSIL

High Grade Dysplasia
Fig. 91b. Papilloma of the ectocervix, advanced stage. H&E
Mullerian Papilloma Vagina
Fig. 93. Papilloma of the ectocervix, verrucous surface. H&E
Papilloma StageSquamous Cell Ectocervix
Fig. 94. Focal staining pattern of p16INK4a in papilloma of the ectocervix. p16INK4a immunostain

HPV types (e.g., HPV 6 and 11) that cause koilocytic alterations histologically classified as CIN 1. They may, however, also be induced by high-risk HPV types (see Table 3),rep-resenting the acute stage of the infection and eventually persist or progress to highgrade dysplasia or carcinoma.

In unclear cases it is important to determine the type of the underlying HPV infection. If HR-HPV types were identified, high-grade dysplasia may be present or may develop, whereas lesions that only harbor LR-HPV types do not progress to invasive carcinoma. The use of p16INK4a as a dysplasia-associated antigen is very useful in the differentiation of benign condylomas and premalignant lesions induced by persistent papillomavirus infections (Fig 94). Strong diffuse expression of p16INK4a in the basal and parabasal cell layers is restricted to lesions induced by HR-HPV (see Figs. 110,111), whereas the condylomatous lesions induced by LR-HPV types may display focal p16INK4a staining in the intermediate or superficial cell layers, but never show a diffuse staining in the basal or parabasal cell layers (see Fig. 94). p16INK4a immunostaining is the simplest way to distinguish benign condylomatous lesions from true dysplastic lesions induced by HR-HPV types (Sano et al. 1998; Klaes et al. 2001; von Knebel Doeberitz 2002; Negri et al. 2004).

In many cases, however, both groups of HPV types are found concomitantly in one lesion. Here surveillance of the patients is particularly mandatory.

Besides diffuse or focal adenomatous hyperplasia (see p. 49), circumscribed benign adenomas may rarely develop from metaplastic foci. A villous adenoma (Mullerian papilloma) (Michael et al. 1986) derived from intestinal metaplasia of the endocervical epithelium occurs almost exclusively in young children (Smith et al. 1998).

Mesenchymal Tumors (Fig. 95-97)

Leiomyomas [8890/0] (Fig. 95) consist of smooth muscle cells more or less intermingled with fibroblasts and abundant blood vessels of various sizes. These leiomyomas resemble in most respects those of the myometrium (Tiltman 1998).

Hemangiomas (Fig. 96) of the cervix are rare (Gusdon 1965). They consist of compact tangles of venules (Fig. 96) or capillaries that through their growth often cause a bulging of the surface.

Blue nevi [8780/0] (Fig. 97) very rarely occur in the endocervix (Patel and Bhagavan 1985). They are composed of slender,wavy dermal melanocytes with long dendritic processes. These cells, either grouped or dispersed among variable numbers of melano-phages, fibroblasts, and collagenous fibers, are usually laden with fine granules of melanin.

Other benign mesenchymal tumors, such as rhabdomyoma, neurinoma, neurofibro-ma,and lipoma are rare, compared with their counterparts in other tissues (Nielsen and Young 2001).

Nevus Cervix
Fig. 95. Leiomyoma of the cervix. H&E
Benign Tumors The Cervix
Fig. 97. Blue nevus of the cervix. H&E

Mixed Tumors (Figs. 98,99)

Papillary adenofibromas [9013/0] (Figs. 98, 99) are shaped like large endocervical polyps with fingerlike projections at their surface. The covering epithelium is of the en-docervical type, single layered, and inconspicuous. Their stroma is very cellular and dense, consisting of fibroblasts, occasionally intermingled with leiomyoblasts. Mitoses are rare (Abell 1971). These tumors are seen almost exclusively in postmenopausal women. They recur frequently, and after several recurrences, their stroma may undergo malignant change to become an adenosarcoma (see Figs. 231,232).

■ Differential Diagnosis. Endocervical polyps can be distinguished by their either loose, edematous or fibrous, acellular stroma. Adenosarcomas are recognized by their high mitotic activity, their periglandular cuffs, and the polymorphism of their stromal cell nuclei.

Adenomyomas [8932/0] rarely arise within the cervix (Gilks at al. 1989). Polypoid ad-enomyomas of the endometrium may occasionally prolapse and protrude from the endocervical canal, giving the impression that they have arisen there.

Mullerian Adenofibroma
Fig. 99. Papillary adenofibroma of the endocervix. H&E, higher magnification

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