Human papillomavirus (HPV) in condylomatous lesions of cervix.

Ninety-seven cervical condylomata classified histologically as flat condyloma (planum), papillary condyloma (acuminatum), and endophytic condyloma were studied by transmission electron microscopy (TEM) and by immunoperoxidase technique (IPT) for the presence of human papillomavirus (HPV) particles and antigen, respectively. Both techniques localized HPV chiefly in nuclei of koilocytotic cells. HPV particles were found in 25% of the cases by TEM and HPV antigen was detected in 48% of the cases by IPT. All cases positive by TEM were also positive by IPT, thus confirming the specificity of the immunological staining. The viral antigen was detected in 56% of 68 flat condylomata, 35% of 26 papillary condylomata, and in none of 3 cases of endophytic condylomata. However, when histiotypes of virus-positive condylomata were controlled for the intraepithelial extent of koilcytotic cells, the prevalence of HPV correlated with the extent of koilocytosis rather than with the histiotype. The immunologic technique will be of value for the further characterization of cervical condylomata and of the relationship between HPV infection and cervical intraepithelial neoplasia.

Condylomata of the uterine cervix and koilocytosis of cervical intraepithelial neoplasia.

In 202 women with koilocytotic atypia in cervical smears, 136 had predominantly small condylomata of the uterine cervix, and 66 had cervical intraepithelial neoplasia (CIN) of varying degree either with koilocytosis of the neoplasia or associated with condylomata. Koilocytosis correlated well with the histological diagnosis of condylomata, but occasionally it obscured the cytological evidence of CIN. Human papilloma virus particles were found in the cells of condylomata in 10 cases and in those of CIN II with koilocytosis in two cases of 21 examined ultrastructurally. There was evidence that the condyloma of the uterine cervix is a well-defined morphological entity and also that cytopathie changes similar to those seen in condylomata are present in some cases of CIN.

Human papillomavirus lesions in association with cervical dysplasias and neoplasias.

A series of 620 cervical biopsy specimens (precancerous and malignant) was assessed morphologically with special reference to the concomitant appearance of human papillomavirus lesions. Tissue samples from 346 of these biopsy specimens were stained for human papillomavirus antigens using the immunoperoxidase-peroxidase-anti-peroxidase (PAP) technique. Papillomavirus lesions were found in 55.6% of the biopsy specimens associated with all degrees of epithelial atypia. The mean age of the women with papillomavirus (condylomatous) changes was significantly lower (P less than .0001) than that of women without these lesions, ie, those who had dysplasia/neoplasia without concomitant papillomavirus changes. Flat and inverted condylomas were most frequent between the ages 20 and 39 and were accompanied by more severe dysplasias than the papillomatous condylomas. In immunoperoxidase-PAP staining, 56% of the papillomavirus lesions were positive, the positivity being inversely related to the degree of epithelial atypia, and bearing some correlation with the condyloma type (papillary 100%, inverted 70%, and flat 52%). Although the results show a clear-cut association of human papillomavirus lesions with premalignant, and to a lesser extent with malignant squamous cell lesions of young sexually active women, thus suggesting a relationship between the virus and cancer, a careful follow-up study is needed to fully elucidate this relationship.

Nuclear inclusions of tonofilaments and keratohyalin granules in the condyloma acuminatum.

Electron-microscopic investigations of the condyloma acuminatum show different nuclear inclusions in keratinocytes of the granular layer or the layer immediately below. Fibrous structures were indentified as tonofilaments and irregularly shaped electron-dense substances as keratohyalin. However the question remains as to whether there is a connection between the viral infection and the occurrence of such intranuclear inclusions.

[Comparison of the epidermodysplasia verruciformis Lewandowsky-Lutz with the other Papova virus acanthomas by light and electron microscopy (author's transl)]. / Die Epidermodysplasia verruciformis Lewandowsky-Lutz in licht- und elektronenoptischem Vergleich mit den übrigen Papova-Virus-Akanthomen.

Based on histology and electron microscopy, a series of Papova virus acanthomas consisting of 300 common warts and Condylomata acuminata as well as primary efflorescences of 7 typical and 7 questionable cases of Epidermodysplasia verruciformis have been classified. Four cytological types expressing different cytopathogenic viral actions were established. Typ 4 ("basophilic foamy giant keratinocytes") seems to be specific for Epidermodysplasia verruciformis which thus can be differentiated histologically against ordinary warts (type 1-3).

[Viral acanthomas and specialized forms of keratinosome "membrane coating granules" (author's transl)]. / Virusacanthome und besondere Formen von Keratinosomen "Membrane Coating Granules".

In the case of viral acanthomas, the stratum spinosum and granulosum presents ballooned cells which contain all transitional stages from multivesicular bodies (MVB) to keratinosomes. A particularity in condylomata acuminata are the "wagon-wheel" bodies. These structures are typical for the non keratinazed squamous epithelium. The participation of intercellular extruded "wagon-wheel" bodies, MVB and atypical keratinosomes on an irregular baso-apical diffusion-barrier in the epidermis of cases with viral acanthomas has been discussed. On the basis of the relation seen between MVB and the Golgi-apparatus, their transition to partially atypical keratinosomes in cases of viral acanthomas and their "expulsion" into the intercellular space could indicate that in keratinozytes the enzymatically regulated feed-back between the cellular surface and the capability to synthesize is changed by viral agents. The interference appears to manifest itself in the Golgi-apparatus and also appears to be "specified" by the terrain present.

[Viral acanthomas and specialized forms of keratinosome "membrane coating granules" (author's transl)]. / Virusacanthome und besondere Formen von Keratinosomen "Membrane Coating Granules".

In the case of viral acanthomas, the stratum spinosum and granulosum presents ballooned cells which contain all transitional stages from multivesicular bodies (MVB) to keratinosomes. A particularity in condylomata acuminata are the "wagon-wheel" bodies. These structures are typical for the non keratinazed squamous epithelium. The participation of intercellular extruded "wagon-wheel" bodies, MVB and atypical keratinosomes on an irregular baso-apical diffusion-barrier in the epidermis of cases with viral acanthomas has been discussed. On the basis of the relation seen between MVB and the Golgi-apparatus, their transition to partially atypical keratinosomes in cases of viral acanthomas and their "expulsion" into the intercellular space could indicate that in keratinozytes the enzymatically regulated feed-back between the cellular surface and the capability to synthesize is changed by viral agents. The interference appears to manifest itself in the Golgi-apparatus and also appears to be "specified" by the terrain present.

Cytology of condyloma of the uterine cervix.

The presence of the koilocyte as well as other dyskeratotic cells in the routine gynecologic smear is often the earliest indication of an abnormality in an otherwise asymptomatic patient. These cells have now been shown to be infected by the human papillomavirus and for many women represent a transient event. The term condyloma has become associated with them and, by inference, a benign clinical course. But these cells should not be regarded solely as a manifestation of a viral infection, for nearly half are associated with a significant precancerous lesion and, in a few, invasive carcinoma. The behavior of the so-called condyloma of the cervix is unlike that of condyloma acuminatum of the external anogenital area.

A rapid method for the detection of papillomavirus in warts: the frequency of virus detection in various types of warts.

A rapid method was devised for the detection of virus particles in wart specimens. The upper layer of warts was cut perpendicularly to the surface, and the freshly cut surface was lightly touched to an electron microscope grid. The grid was then stained with a small drop of phosphotungstate and observed electron microscopically. On the specimen grid thus prepared, papillomavirus particles were easily discriminated from tissue debris. Papillomavirus particles were detected in 71% of verrucae plantares, 78% of verrucae palmares, 50% of verrucae vulgares and 75% of condylomata acuminata by the present method.

Submicrostructure and typing of female genital condylomata.

Thirty biopsies from female genital condylomata were examined by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) to study structural characteristics and typing of condylomata. It was found that cytoplasmic clearing was marked in acuminate condylomata, diffuse interstitial and epithelial proliferation in nodular condylomata (flat condylomata), and invagination of the lesions into the interstitial tissue or glandular ducts in endophytic condylomata. In nodular condylomata, SEM also showed some structural features similar to those of intra-epithelial neoplasia. Microridges on the surface of squamous cells had villiform of granular changes. On the surface of a percentage of squamous or columnar cells, there were holes with a diameter of about 3 to 5 microns. A number of giant cells were seen among other cells. The cervical squamatization zone contained groups of special cells covered with dense microvilli. TEM of nodular condylomata revealed some pictures resembling active proliferation of tumor cells, such as enlarged or irregular nuclei (large N/C ratio), evaginated or invaginated nuclear membranes, condensed chromatin attached to the inner part of the nuclear membrane, transparent nucleoplasm, and frequent nucleosomes and karyokinesis. Virus particles with the morphological characteristics of HPV (naked hexagon-like particles with an average diameter of 45-50 nm) were seen in some nuclei with markedly condensed chromatin. It is suggested that HPV-induced genital condylomata, especially nodular one (flat condylomata), entail a potential progression to malignancy.

[Molecular and ultrastructural study on the relationship between human papillomavirus and female genital condyloma in China].

From the results of DNA hybridization, it has been shown that there is a close relationship between HPV 16 and human uterine cervical carcinoma in China, and also that the viral DNA is integrated into the cancer cell genome. Genital condyloma revealed a high positive hybridization rate with HPV 11 DNA, and the viral DNA presented as an episome apart from the cell genome. Under the electron microscope, the inter and perichromatin granules as well as nuclear bodies were observed in all biopsies with positive hybridization, but no HPV particle was found in cancer cells, besides these two kinds of chromatin granules. Human papillomavirus nucleocapsid particles were observed in the nuclei of some genital condyloma cells. Electron-dense matrix aggregates of different sizes were seen in the perinuclear cytoplasm and in the nuclei. This kind of structure may be related to the process of HPV maturity, but its nature remains to be studied.

[A rare complication of ulcerative colitis: Bowen's disease in perianal condyloma acuminatum]. / Colitis ulcerosa ritka szövödménye: Bowen-kór, perianalis condyloma acuminatumban.

Discharging, itching perianal pointed condyloma acuminatum in a 35 years old male patient who had been suffering from ulcerative colitis for 20 years. Two years following its development the condyloma was excised. Histological examination revealed in the perianal condyloma in situ cancer, characteristic of Bowen's disease. With electronmicroscopic examination the tumor cells were found to be keratinocytes of medium differentiation. Virus could not be detected in the tumor cells. The author was the first to describe in the literature the development of perianal Bowen's disease on the ground of ulcerative colitis. On the basis of literary data the author emphasizes the importance of the radical removal and regular control.

Ultrastructure of Buschke-Loewenstein tumor.

A 44-year-old man suffered a Buschke-Loewenstein tumor that was treated by distal penectomy. Ultrastructurally, this tumor showed widened intercellular spaces, prominent microvilli, decreased numbers of and incompletely developed desmosomes, decreased tonofilaments, cytoplasmic dense bodies, enlarged nucleoli and annular nuclear bodies. These ultrastructural features are quite similar to those of squamous carcinoma but are dissimilar to those of condyloma acuminatum and, to a lesser extent, verrucous carcinoma. These data suggest that electron microscopy may be useful in differentiating the neoplastic Buschke-Loewenstein tumor from large condyloma acuminatum.

Condylomata acuminata with pigmented papular lesions.

5 cases of condylomata acuminata with pigmented papular lesions were examined. By light microscopy, the pigmented papules showed benign basaloid cell proliferation and papillomatosis with only a few vacuolizations of the keratinocytes. Although mitotic figures increased in number, cellular atypia and disorderly arrangement were rarely observed. Electron microscopy revealed only benign epidermal cell proliferation. From these findings, the pigmented papules may be regarded as an initial stage or a forme fruste of condylomata acuminata. These papules are clinically very similar to the lesions of so-called multicentric pigmented Bowen's disease and the relationships between these two conditions are discussed.

Superficial nuclear enlargement without koilocytosis as an expression of human papillomavirus infection of the uterine cervix: an in situ hybridization study.

Nuclear enlargement of the superficial cervical epithelial cells in the absence of koilocytosis is frequently observed. The purpose of this study was to investigate whether this change represents human papillomavirus (HPV) infection. We reviewed 257 cervical biopsies with the diagnosis of "suggestive of condyloma," mild or moderate dysplasia, or both. Of the 257 consecutive biopsies, 23 fulfilled the two criteria: the superficial cells had a nuclear diameter of at least twice that of the basal nuclei, and complete absence of koilocytosis was seen. Parallel sections from each paraffin block were hybridized with biotinylated probes for HPV 6/11, 16/18, and 31/35/51 under high-stringency conditions. The cases that were negative at high-stringency conditions were then hybridized under low-stringency conditions with a mixture of the three HPV probes. Twelve of the 23 cases (52.17%) were positive for HPV, including one positive for HPV 16/18 in one area and for HPV 31/35/51 in another area, four positive for HPV 31/35/51, two positive for HPV 16/18, two positive for HPV 6/11, and three positive for HPV probe mixture at low-stringency conditions. The positive in situ hybridization was located predominantly in the enlarged nuclei in the superficial layers. In conclusion, HPV infection can be expressed as nuclear enlargement in the superficial layers of the cervical epithelium in the absence of koilocytosis.