Inflammatory Lesions

Nonspecific Ecto- and Endocervicitis (Figs. 70-76)

Nonspecific cervicitis may be chemically induced or caused by trauma in the presence of a "locus minoris resistentiae," such as postmenopausal atrophy of the ectocervical epithelium, or eversion of the vulnerable endocervical mucosa onto the ectocervix (ectropion) during the reproductive age.

Acute and subacute ectocervicitis (Figs. 70-72) is characterized by vascular congestion, edema, and infiltration of inflammatory cells, mainly neutrophilic granulocytes. When the inflammation is mild, the overlying epithelium remains intact (Fig. 70). With more severe inflammation, the epithelium is destroyed, sloughed off, leading to an erosive or ulcerative ectocervicitis (Fig. 71,72).

Acute and subacute endocervicitis (Figs. 73-75) presents similar signs of inflammation (Figs. 73,74) and occasionally ulceration (Fig. 75).

Chronic Endocervicitis
Fig. 70. Chronic ectocervicitis, mild. H&E
Parabasal Cells
Fig. 72. Subacute ulcerative ectocervicitis. Positivity for MIB-1 in parabasal cell layer of squamous epithelium and in lymphocytic infiltrate in stroma. MIB-1 immunostain
Chronic Endocervicitis
Fig. 74. Subacute endocervicitis. H&E, higher magnification
Chronic Endocervicitis
Fig. 75. Subacute ulcerative endocervicitis. H&E
Histology Endocervicitis
Fig. 76. Follicular endocervicitis. H&E

In chronic ecto- and endocervicitis, rather dense subepithelial infiltrates of predominantly lymphocytes and plasma cells are found, often accompanied by proliferating capillaries and fibroblasts. The overlying epithelium is usually intact. In prolonged or severe chronic endocervicitis, lymphoid follicles may develop (follicular endocervicitis, Fig. 76), and the overlying columnar epithelium may show polymorphic,hyperchromat-ic, and depolarized nuclei. When detected in cervical smears, such reactive nuclear changes may be misinterpreted by the screening cytologist and lead to false-positive readings.

■ Differential Diagnosis. Severe subacute and chronic follicular and ulcerative cervicitis may be misdiagnosed as lymphoma when large lymphoid cells, immunoblasts, and mitoses are found. However, surface ulceration and a polymorphic inflammatory infiltrate with neutrophils and plasma cells are rarely seen in lymphomas, which show instead an extensive, monomorphic infiltrate of lymphoid cells (Fig. 235; Young et al. 1985).

Specific Inflammations (Figs. 77-89)

Viral Infections

Viral infections of the ecto- and endocervix can cause characteristic morphological changes, by which they can be recognized. The accompanying inflammatory infiltrate may be scant (as with HPV infection) or extensive (as with herpes virus infection).

Infection with HPV usually starts at the basal or parabasal cells and may initiate here a latent infection that remains morphologically inapparent. If the infection changes to the productive phase, strong viral gene expression and production of new virus particles are observed in the intermediate and superficial layers of the epithelium, resulting in characteristic morphological changes that are typical for HPV infections (Middleton et al. 2003). These include koilocytosis of the ectocervical (Fig. 77,78) and endocervical epithelia (Fig. 121), and may also lead to less specific changes such as acanthosis, papil-lomatosis, giant nuclei, multinucleated cells, monocellular keratinization, hypergranulation, and superficial ortho- and/or parakeratosis. Because of these cellular and nuclear alterations, they have to be classified as mild (reversible) dysplasia (CIN i,see p. 87).

A koilocyte is a dyskaryotic epithelial cell with a deformed, often angulated, hyper-chromatic nucleus surrounded by a swollen cytoplasm, which shows a clear perinucle-ar halo and a thickened cytoplasmic membrane (Fig. 78). Both signs, the atypical degenerating nucleus and the clear, blown-up cytoplasm, are essential features of a true koilocyte. Sometimes other agents may cause similar but nonspecific koilocyte-like cellular changes. For example, clear cells with ballooned cytoplasm and a normal nucleus may be seen after a gestagen-predominant hormonal stimulation, whereby glycogen accumulates in the cytoplasm (Fig. 79). In contrast, the cytoplasm of true koilocytes is devoid of glycogen. A degenerative vacuolation of the cytoplasm may occur in other nonspecific inflammatory lesions. Koilocytes can also be observed in columnar epithelial cells (Fig. 121) of the endocervix. Viral DNA is reproduced in the nuclei of koilocytes, and in the cytoplasm viral particles are accumulated.

Persisting infection with HR-HPV (see Table 4, p. 83) may in some cases result in dys-plastic transformation of the epithelium that is reflected by higher-grade cervical intra-

epithelial neoplasia (CIN 2/3) or even progression to invasive cancer. HR-HPV infection resulting in carcinogenesis is discussed therefore at greater length in "Premalignant Lesions" (p. 82 ff). Infections with LR-HPV types, however, in almost all cases regress spontaneously within several months (Ho et al. 1998; Wang and Hildesheim 2003).

It is important to note that not all HPV infections result in detectable morphological changes (Fuchs et al. 1988). Samples taken from women between 15 and 50 years of age with normal cytologic smears harbor HR-HPV DNA in about 10% (de Villiers et al. 1987). The percentage of HPV-positive women with normal cytologic smears depends significantly on the women's age. In general the percentage of younger women with a HR-HPV-positive test result is significantly greater than that of older women (Schiff-man and Kjaer 2003). For a detailed description of the taxonomy and the epidemiological distribution of HPV infection, the reader is referred to de Villiers et al. (2004) and Munoz et al. (2003).

Infection with herpes virus (Figs. 80-83) involves chiefly herpes simplex virus (HSV) type 2. In the acute stage, the infection can be easily recognized cytologically by the large multinucleated epithelial cells with characteristic intranuclear, ground-glass, viral inclusions (Fig. 80). On histological examination, small or larger vesicles may be found within the ectocervical epithelium containing such giant cells with intranuclear viral inclusions (Fig. 81). These vesicles ultimately burst, forming confluent ulcers surrounded by cellular debris and dense inflammatory infiltrates (Figs. 82,83). During pregnancy, infection of the fetus or placenta may cause spontaneous abortion (Corey 1984).

Human Papillomavirus Infection Vagina
Fig. 77. Infection of ectocervical epithelium with human papillomavirus. H&E
Koilocytes
Fig. 79. Squamous epithelium with "false" koilocytes. H&E
Multinucleated Endocervical Cells
Fig. 80. Vaginal cytological smear with intranuclear inclusions of herpes virus. Papanicolaou
Vaginal Herpes Lesions
Fig. 81. Ectocervical epithelium with intranuclear inclusions of herpes virus. H&E
Hsv Lesions
Fig. 82. Florid ulcerative ectocervicitis caused by herpes virus. H&E
Herpes Lesion Vaginal
Fig. 83. Florid ulcerative ectocervicitis caused by herpes virus. H&E, higher magnification

■ Differential Diagnosis. Intraepithelial vesicles (bullae) may be seen in the ectocervix in patients with generalized pemphigus vulgaris, or as isolated small cysts (see below). These, however, lack the characteristic intranuclear viral inclusions of herpes. An ulcer-ative and necrotizing infection of the cervix may occasionally be caused by Chlamydia trachomatis, or by protozoa, such as Trichomonas vaginalis, or rarely by Entamoeba histolytica. Identification of the causative agent is essential for a definitive diagnosis. The cytoplasmic chlamydial inclusions can best be detected immunohistochemically; the most sensitive method to assess the presence of Chlamydia is the examination for chlamydial DNA, either by polymerase chain reaction (PCR) or with the hybrid capture technique. The motile protozoa are most readily identified in fresh native smears under phase-contrast microscopy.

Bacterial Infections

Tuberculous cervicitis (Fig. 84) almost always develops from an infection descending from tuberculous salpingitis or endometritis. The tuberculous granulomas can be recognized by aggregates of epitheloid cells and Langhans giant cells surrounded by lymphocytes. Caseation is rare in the cervix. Since similar granulomatous lesions of other causes may occur here, and some of them are even more common, the diagnosis of tuberculosis has to be verified by the demonstration of acid-fast mycobacteria (tuberculosis), with the Ziehl-Neelsen stain, or a modification of it.

■ Differential Diagnosis. Under low microscopic magnification, foreign body granulomas may appear very similar. They can often be distinguished from tuberculous granulomas by identifying intracytoplasmic inclusions of foreign material in multinucleated giant cells under polarized light. Most of these inclusions are double refractile under polarized light (such as talcum crystals or suture material). Infectious granulomas such as lues, lymphogranuloma venereum, granuloma inguinale, schistosomiasis, and sarcoidosis must be distinguished from tuberculosis by using special stains or bacteriological and immunological methods, since individual morphological features are often lacking.

Chlamydial cervicitis is being observed with increasing frequency (Winkler and Crum 1986) and is now the most common sexually transmitted infection in the Western world (Stamm and Holmes 1984). It is considered a cofactor to HPV in the etiology of cervical cancer (Smith et al. 2002). The causative agent, Chlamydia trachomatis, is sexually transmitted and has an affinity for cervical columnar cells or basal (reserve) cells. Concomitant infection of other tissues leads to urethritis, endometritis, salpingitis, and proctitis, which are common. Other infections, such as gonorrhea, often occur at the same time.

Histologically, severe nonspecific inflammation is typical, but in some cases chronic follicular endocervicitis is observed (Winkler and Crum 1986). Slight atypia of both columnar and metaplastic cells has been described. Only in a small number of cases can cytoplasmic inclusions, comprising aggregates of Chlamydia trachomatis organisms,be found in columnar or metaplastic basal cells of smears or sections (Fig. 85a, b). Recognition in vaginal PAP smears is difficult, since many degenerative cytoplasmic inclusions occurring in metaplastic epithelial cells closely resemble the various developmental stages of chlamydial inclusions. These consist of cytoplasmic vacuoles containing

Gononrrhea Cervicitis Photos
Fig. 84. Tuberculous cervicitis. H&E

few or numerous tiny particles. The most sensitive method to assess the presence of Chlamydia is the examination for chlamydial DNA, either by PCR or with the hybrid capture technique.

It is important to treat the patients as well as their male partners since chlamydial urethritis may be asymptomatic.

■ Differential Diagnosis. Distinction from severe subacute or chronic nonspecific cervicitis is virtually impossible on histological grounds alone. Many of these so-called nonspecific infections actually are unrecognized chlamydial cervicitis, as Paavonen et al. (1982) could show for follicular endocervicitis. Distinction from gonorrhea is possible bacteriologically, from trichomonal infection by vital cytology under phase-contrast microscopy (see below).

Parasitic Infections

Trichomonas cervicitis (Fig. 86) is caused by an ascending infection with Trichomonas vaginalis, a flagellated protozoon most easily recognized in a fresh vaginal smear under phase-contrast microscopy (Stoll 1969). In histological preparations an inflammatory infiltrate is seen, whereby the desquamating epithelial cells reveal nuclear swelling and chromatin clumping.

Endocervical Cell Change Chlamydia

Fig. 85a. Subacute endocervicitis with intracytoplasmic inclusions of Chlamydia trachomatis in metaplastic epithelial cells. H&E

Entamoeba Fluorescence
Fig. 85b. Intracytoplasmic inclusions of Chlamydia trachomatis showing uniform green fluorescence. Immunohistochemistry with specific antibodies
Follicular Cervicitis
Fig. 86. Endocervicitis caused by ascending infection with Trichomonas vaginalis. H&E

■ Differential Diagnosis. Nonspecific acute and subacute purulent cervicitis, follicular (chlamydial) cervicitis, granuloma inguinale, and lymphogranuloma can be distinguished by detecting the causing agent. Rare parasitic infections involving the cervix are: schistosomiasis (endemic in Africa), echinococcosis, and infections with Entamoeba histolytica.

Fungal Infections

Actinomycosis of the cervix (Fig. 87) may result from infectious trauma from an intrauterine device or surgical procedures (Burkman and Damewood 1985). Microscopically, a dense inflammatory infiltrate with abscess formation is seen, consisting mainly of neutrophils and histiocytes. Characteristic gram-positive rods arranged in a radial fashion, and located in the center of the abscess, are diagnostic.

■ Differential Diagnosis. Inspissated mucus or groups of autolytic, swollen, endocervi-cal epithelial cells arranged in a radial position may have a very similar appearance. Distinction is possible by immunohistochemical detection of Actinomyces organisms (Pine et al. 1985).

Infection with Candida albicans rarely involves the cervix and is secondary to involvement of vulva and vagina.

Infections of Unknown Etiology

In cervicitis emphysematosa, subepithelial cysts are found as dilated, empty spaces in the connective tissue without epithelial lining. The etiology is unknown. Intraepithelial cysts are occasionally observed (Fig. 88), which may have a similar cause.

Polyarteriitis nodosa (Fig. 89) can involve the cervix only, or appear as part of a generalized (autoimmune) disease.

Actinomyces Pap Smear

Fig. 87. Actinomycosis of the cervix. H&E

Fig. 87. Actinomycosis of the cervix. H&E

Detection Actinomycosis Tissue
Fig. 88. Cervicitis emphysematosa. H&E
Polyarteritis Nodosa Pictures
Fig. 89. Polyarteritis nodosa of the cervix. H&E

Irradiation Changes (Fig. 90)

After irradiation therapy, pre-existing glandular patterns become distorted (Fig. 90). The nuclei of the glandular epithelial cells are pleomorphic, hyperchromatic and enlarged due to replication of DNA without cell division. In the cytoplasm, damage of various organelles and destruction of lysosomal membranes may result in vacuolation. Similar cellular changes may be observed in the ectocervical epithelium resulting in postirradiation dysplasia.

Postoperative Spindle Cell Nodule

This reactive benign lesion develops at the site of a recent operation and consists of densely packed proliferating mesenchymal spindle cells, capillaries and inflammatory cells. Distinction from leiomyosarcoma is clinically important and will be facilitated by the clinical history of a previous operation at the site of the nodule (Nielsen and Young 2ooi).Rarely,a non-neoplastic traumatic neuroma [4977/0] may develop postoperatively at the site of cervical amputation. Retention of fetal glial tissue may follow a previous abortion.

Glial Cells Inclusions
Fig. 90b. Same as Fig. 90a. Pleomorphic nuclei and vacuolated cytoplasm of glandular epithelium.H&E
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