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Objective We evaluated the distribution of histological diagnoses in pregnant women with atypical cytology or cervical malignancy signs, as well as the usefulness of the Swede score colposcopic scoring system to reduce the need for diagnostic cervical biopsy. Design Prospective clinical study. Setting and population The study comprised 261 pregnant women undergoing colposcopic investigation because of atypical cervical cytology, dysplastic biopsy changes, recurrent non-obstetric bleeding or pathological appearance of the cervix. Methods Five colposcopic variables (acetowhiteness, margins plus surface, vessel patterns, lesion size and iodine staining) were scored with 0, 1 or 2 points. Colposcopically directed biopsies or loop electrosurgical excision biopsies were taken from all lesions. Histology was compared with the colposcopic score. Sensitivity and specificity were calculated for each variable, and the combination of all five variables, with high-grade lesions (i.e. cervical intraepithelial neoplasia (CIN2, CIN3 or adenocarcinoma-in-situ (AIS)) as endpoints. Main outcome measures Colposcopic score (Swede score) and histology (CIN1, 2, 3; AIS; cancer). Results The specimens consisted of normal tissue in 19.5% of cases, low-grade lesions (i.e. CIN1, koilocytosis, glandular dysplasia of lower grade than AIS) in 26.1%, high grade lesions in 52.9% and cancer in 1.5%. All high grade lesions and cancers had total Swede scores of ≥ 5 and ≥ 8, respectively. Vessel patterns, lesion size and margins plus surface were most important for high grade lesion detection. Conclusion The Swede score seems to be a useful tool in evaluating atypical cervical cytology in pregnant women and may reduce the need for diagnostic biopsies.

A substantial proportion of women with cervical cancer that have participated in cervical screening have a history of an abnormal cytology result. Our objective was to assess the impact of histological investigation and treatment of women with abnormal cytology on the subsequent risk of invasive cervical cancer. All invasive cervical cancer cases in Sweden 1999-2001 and five population-based control women per case were investigated. Clinical investigations and treatment were analysed in case women (N = 143) and control women (N = 176) below 67 with abnormal cytology results 0.5-6.5 years before the cases' diagnosis. Cervical cancer risk in relation to investigation [histology or not, punch biopsy, cervical curettage or cone/large loop excision of the transformation zone (LLETZ)], and treatment (treatment or not, excisional or ablative) was estimated as odds ratios (ORs) using logistic regression. Absence of histological assessment was associated with increased cancer risk, both after low-grade [OR 2.37; 95% confidence intervals (CI): 1.27-4.43] and high-grade squamous atypia (8.26; 2.37-28.8). Among women with histology, absence of treatment was associated with increased cancer risk (3.68; 1.53-8.84), also when biopsy showed low-grade atypia or normal findings (3.57; 1.18-10.8). Ablative therapy associated with increased risk compared with excisional (3.82; 1.01-14.4), and laser conisation associated with decreased risk compared with LLETZ (0.06; 0.01-0.36). In conclusion, low-grade as well as high-grade squamous atypical cytology results may warrant histological investigation, treatment reduced cancer risk even when histology was negative or showed low-grade atypia indicating a need for improvements in the diagnosis of high-grade lesions, and laser conisation was the most effective treatment.

We have performed fine-needle biopsies from solid or ascites-growing mouse tumours. The biopsies were taken via striated muscle or the peritoneal cavity of healthy mice syngeneic with the tumours and the tumour-bearing animals. The incidence of tumour takes in these new mice were compared with the intramuscular or intraperitoneal transplantability of the tumours. In order to estimate more accurately the number of seeded cells, we also performed aspiration biopsy through the leg muscles of healthy animals into ascites-growing tumours labelled with 125IUDR. The resulting radioactivity in the leg muscle was compared with the radioactivity of the ascites tumour cells. The studies indicate that one may seed 10(3)-10(4) cells, and sometimes more, into the needle track with fine-needle aspiration biopsy from extremely cellular and dedifferentiated tumors.

The need for syngenic tumors to elucidate factors in lymphoma dissemination prompted us to induce new lymphomas in a series of inbred C57B1/6J mice. The method of induction, immunosuppression and simultaneous immunostimulation, had a high mortality rate, but gave us 2 transplantable lymphomas. These tumors are described and compared in the present paper, with emphasis on their dissemination patterns. Both tumors disseminated rapidly from tail transplants to lymphoid organs, lungs and liver. They were characteristically dissimilar, however, in their s.c., i.p. and i.v. transplantabilities.

We have studied four syngeneic murine tumors, a fibrosarcoma, a squamous cell carcinoma and their two ascites-converted counterparts, by transmission electron microscopy. The ascites tumors were investigated both as cell suspensions (AA-tumor) and as solid tumor (AS-tumor). We have also studied the ascites tumors, enzymatically produced cell suspensions of the AS-tumors and solid original tumors by scanning electron microscopy. The two ascites tumors are totally de-differentiated and lack intercellular junctions. This, we think, is a prerequisite for ascites growth. But the ascites tumors show no peculiar ultrastructural features in comparison with other undifferentiated malignant tumors. We found no morphological cell alternations by the enzymatical dissociation procedure used to bring the solid tumors into suspension. Differences between the AS and AA tumors can be ascribed to differences in proliferation rates.

Background The effectiveness of cervical cancer screening programs differs widely in different populations. The reasons for these differences are unclear. Routine and comprehensive audits have been proposed as an ethically required component of screening. We performed a nationwide audit of the effectiveness of the Swedish cervical cancer screening program. Methods We identified all invasive cervical cancer cases that were diagnosed in Sweden from January 1, 1999, through December 31, 2001, and had been reported to the Swedish Cancer Registry (n = 1230 cases). We verified the diagnoses by histopathologic rereview and matched each case subject to five (population-based) age-matched control subjects who were identified from the National Population Register. The Pap smear screening histories for case and control subjects were reviewed for a 6-year period using the National Cervical Cancer Screening Register, which contains data on essentially all relevant cytological and histological diagnoses in Sweden. Odds ratios (ORs), and their 95% confidence intervals (CIs), of cervical cancer according to screening history were calculated in conditional logistic regression models. All statistical tests were two-sided. Results Women who had not had a Pap smear within the recommended screening interval had higher risk of cervical cancer than women who had been screened (OR = 2.52, 95% CI = 2.19 to 2.91). This risk was similarly increased for all age groups ( P homogeneity = .96). The risk for nonsquamous cell cervical cancers (OR = 1.59, 95% CI = 1.20 to 2.11) was also increased. Women who had not had a Pap smear within the recommended screening interval had a particularly high risk of advanced cancers (OR = 4.82, 95% CI = 3.61 to 6.44). Among women who had been screened within the recommended interval, those with abnormal Pap smears had a higher risk of cervical cancer than those with normal smears (OR = 7.55, 95% CI = 5.88 to 9.69) and constituted 11.5% of all women with cervical cancer. Conclusions Nonadherence to screening intervals was the major reason for cervical cancer morbidity. The screening program was equally effective for women of all ages and was also effective against nonsquamous cancers.

Background Subtyping of human papilloma virus (HPV) may enhance the precision of vaginal cytological assessments and will be important for investigating the effect of the recently introduced vaccine against types 16 and 18. Objectives and study design To evaluate an in-house real-time PCR targeting HPV types 16–18–31–33–35–39–45–51–52–56–58–59–6–11, by analysing 107 liquid-based cytology specimens representing various degrees of dysplasia. Results In all, 71 samples were HPV positive, with multiple types present in 37 (52%). Comparison with Roche Linear Array on a subset of 24 of these 71 samples showed a good agreement. One or several types were detected in 17/17 (100%) samples with cervical intraepithelial neoplasia grade 2–3 (CIN 2–3), 16/19 (84%) with CIN 1, 32/43 (74%) with Atypical Squamous Cells of Undetermined Significance (ASCUS), and in 6/28 (21%) with benign cytology. Estimates of mean viral load were lower in CIN 1–3 than in ASCUS (≈4000 vs. ≈25,000 copies/1000 cells), and clearly lower in samples with benign cytology (≈50 copies/1000 cells). Conclusion The HPV rates in groups with different degrees of dysplasia agrees with previous reports and support a strong link between types 16/18 and severe dysplasia. The high rate of multiple type infection might influence the outcome of HPV vaccination. The possible importance of viral load should be further studied.

Background Screening for cervical cancer based on testing for human papillomavirus (HPV) increases the sensitivity of detection of high-grade (grade 2 or 3) cervical intraepithelial neoplasia, but whether this gain represents overdiagnosis or protection against future high-grade cervical epithelial neoplasia or cervical cancer is unknown. Methods In a population-based screening program in Sweden, 12,527 women 32 to 38 years of age were randomly assigned at a 1:1 ratio to have an HPV test plus a Papanicolaou (Pap) test (intervention group) or a Pap test alone (control group). Women with a positive HPV test and a normal Pap test result were offered a second HPV test at least 1 year later, and those who were found to be persistently infected with the same high-risk type of HPV were then offered colposcopy with cervical biopsy. A similar number of double-blinded Pap smears and colposcopies with biopsy were performed in randomly selected women in the control group. Comprehensive registry data were used to follow the women for a mean of 4.1 years. The relative rates of grade 2 or 3 cervical intraepithelial neoplasia or cancer detected at enrollment and at subsequent screening examinations were calculated. Results At enrollment, the proportion of women in the intervention group who were found to have lesions of grade 2 or 3 cervical intraepithelial neoplasia or cancer was 51% greater (95% confidence interval [CI], 13 to 102) than the proportion of women in the control group who were found to have such lesions. At subsequent screening examinations, the proportion of women in the intervention group who were found to have grade 2 or 3 lesions or cancer was 42% less (95% CI, 4 to 64) and the proportion with grade 3 lesions or cancer was 47% less (95% CI, 2 to 71) than the proportions of control women who were found to have such lesions. Women with persistent HPV infection remained at high risk for grade 2 or 3 lesions or cancer after referral for colposcopy. Conclusions The addition of an HPV test to the Pap test to screen women in their mid-30s for cervical cancer reduces the incidence of grade 2 or 3 cervical intraepithelial neoplasia or cancer detected by subsequent screening examinations.

We followed a population-based cohort of 5696 women, 32–38 years of age, by registry linkage with cytology and pathology registries during a mean follow-up time of 4.1 years to assess the importance for CIN2+ development of type-specific HPV DNA positivity at baseline. HPV 16, 31 and 33 conveyed the highest risks and were responsible for 33.1, 18.3 and 7.7% of CIN2+ cases, respectively. Women infected with HPV 18, 35, 39, 45, 51, 52, 56, 58, 59 and 66 had significantly lower risks of CIN2+ than women infected with HPV 16. After adjustment for infection with other HPV types, HPV types 35, 45, 59 and 66 had no detectable association with CIN2+. In summary, the different HPV types found in cervical cancer show distinctly different CIN2+ risks, with high risks being restricted to HPV 16 and its close relatives HPV 31 and HPV 33.

Objective Evaluation of colposcopic and histopathological findings in women screened for cervical human papillomavirus deoxyribonucleic acid persistence. Study design A total of 12 527 women, aged 32 to 38 years old, attending the population-based cervical cancer screening program in Sweden were randomized 1:1 to mock testing or human papillomavirus deoxyribonucleic acid testing by general primer 5+/6+ polymerase chain reaction and subsequent typing. Human papillomavirus deoxyribonucleic acid–positive women with a normal Papanicolaou smear (n = 341) and an equal number from the control group were human papillomavirus tested on average 19 months later. One hundred nineteen women with type-specific human papillomavirus persistence and 111 controls were referred to colposcopy, and 84.8% attended. Results Histopathology from colposcopically directed biopsies confirmed cervical intraepithelial neoplasia grade 2 or 3 in 28 of 100 of the women with human papillomavirus deoxyribonucleic acid persistence and in 2 of 95 among controls. Conclusion Among women with normal Papanicolaou smear attending population-based screening, the positive predictive value of human papillomavirus deoxyribonucleic acid persistence for detection of biopsy-confirmed cervical intraepithelial neoplasia 2 or 3 was 29%.

The cytologic criteria of synovial sarcoma in fine-needle aspirates were defined by a retrospective examination of 37 primary tumors. Irrespective of subtype, a typical pattern at low power was found, provided the yield was rich. The typical pattern was a mixture of dispersed cells with the presence of striped nuclei and cell-tight tumor tissue fragments with irregular borders. Often a branching network of vessels was present in the fragments, imitating a true vascular tumor. Except in poorly differentiated synovial sarcomas, the tumor cells were, small to medium in size, with rounded, ovoid, or fusiform bland nuclei with inconspicuous nucleoli. In the biphasic variant, small glandular- or acinar-like structures were present, although not in all cases. In the poorly differentiated type, however, the cellular pleomorphism was marked with the presence of cells with irregular nuclei and rhabdomyoblast-like cells, corresponding to the pleomorphic variant. The Ewing's sarcoma-like and the atypical spindle cell variants of poorly differentiated synovial sarcoma were not diagnosed in the material. An unequivocal diagnosis of sarcoma is possible when the yield is rich. However, ancillary diagnostics are necessary for a correct diagnosis, to avoid important pitfalls, such as other sarcomas with bland tumor cells and vessel-rich tumor fragments, in particular, solitary fibrous tumor and true hemangiopericytoma. Electron microscopic and/or molecular genetic analyses were better diagnostic adjuncts than immunocytochemistry.

Carcinoma ex pleomorphic adenoma (CexPA) is a carcinoma developing within a pre-existing benign pleomorphic adenoma (PA). Here we describe the identification and characterization of a series of genetic events leading to translocation, deletion/amplification, and overexpression of the HMGIC and MDM2 genes in a CexPA at an early stage of development. The tumor had a pseudodiploid stemline karyotype with a del(5)(q22–23q32–33) and a t(10;12)(p15;q14–15). In addition, there were several sidelines with double minute chromosomes (dmin) or homogeneously staining regions (hsr). Fluorescence in situ hybridization (FISH) mapping revealed that the 12q14–15 breakpoint was located centromeric to HMGIC and that the entire gene was juxtaposed to the der(10) chromosome. Detailed analysis of cells with dmin and hsr revealed that HMGIC and MDM2 were deleted from the der(10) and that the dmin and hsr were strongly positive for both genes. Southern blot analysis confirmed that both HMGIC and MDM2 were amplified and that no gross rearrangements of the genes had occurred. Immunostaining revealed that the HMGIC protein was highly overexpressed particularly in the large polymorphic cells within the carcinomatous part of the tumor. These findings suggest that amplification and overexpression of HMGIC and possibly MDM2 might be important genetic events that may contribute to malignant transformation of benign PA.

BACKGROUND Pilomatrixoma (PMX) is a benign skin neoplasm of hair matrix origin. The fine-needle aspiration (FNA) features of PMX frequently lead to a misdiagnosis of carcinoma. METHODS Nine cases of PMX in which a preoperative FNA was performed were reviewed. The cytologic features were compared with the histologic appearance of corresponding surgical specimens as well as with cytologic features of tumors that arose in the differential diagnosis. RESULTS Unequivocal benign diagnoses were rendered in three cases; the correct preoperative diagnosis of PMX was rendered in two of these cases and considered in an additional case. In four additional cases, carcinoma was diagnosed or could not be excluded. A noncommittal diagnosis of epithelial tumor, most likely of skin adnexal origin, was rendered in an additional single case. Retrospective review of the FNA smears in all nine instances disclosed cytologic features that corresponded well with the histologic components of PMX. Diagnostic cytologic features included cellular aspirates; clusters of small, primitive-appearing basaloid epithelial cells; a high nuclear-cytoplasmic ratio; evenly dispersed chromatin; prominent nucleoli; pink, fibrillary material enveloping clusters of basaloid cells; multinucleated giant cells; and sheets of ghost cells. CONCLUSIONS The FNA cytologic diagnosis of PMX may be extremely difficult; its distinction from various primary cutaneous carcinomas is most problematic. Recognition of a unique constellation of cytologic features in FNA smears in the appropriate clinical context is most helpful in making this distinction. Cancer (Cancer Cytopathol) 2001;93:252–256. © 2001 American Cancer Society.

The major cause of mortality in the long-term in lung transplant recipients is chronic rejection. This is a fibroproliferative process in the small airways leading to obliterative bronchiolitis and progressive loss of lung function, both constituting the clinical entity bronchiolitis obliterans syndrome (BOS). Granulocyte activation has been implicated as one factor behind BOS. Granulocyte markers in bronchoalveolar lavage (BAL) fluid were prospectively and longitudinally studied in order to identify possible association with BOS. BAL fluid from 266 bronchoscopy procedures performed in twelve single lung, eight bilateral lung and five heart/lung transplant recipients were analysed. The majority (19 of 25) were studied for a period of 2 yrs after surgery. Myeloperoxidase (MPO), eosinophil cationic protein (ECP) and interleukin-8 (IL-8) levels were used as indirect markers of activation and attraction of granulocytes. Five patients developed BOS. Ninety-eight episodes of acute rejection, nine of bacterial infection, 19 of cytomegalovirus pneumonitis, nine of Pneumocystis carinii infection, two of aspergillus infection and two of respiratory syncytial virus infection were diagnosed. BOS patients had significantly higher mean levels of MPO, ECP and IL-8 compared to patients without BOS, irrespective of acute rejection status. Over time, the five patients with BOS had significantly elevated BAL fluid levels of MPO and ECP as well as neutrophil percentages, and in four patients this increase preceded the clinical diagnosis of BOS by several months. Elevated bronchoalveolar lavage fluid neutrophil percentage as well as levels of the granulocyte activation markers myeloperoxidase and eosinophil cationic protein appear to be early signs of development of BOS in lung transplant recipients.

Screening for cervical cancer by testing for human papillomavirus (HPV), the major cause of the disease, reportedly increases the sensitivity of detecting high-grade (grade 2 or 3) cervical intraepithelial neoplasia (CIN). It is not clear, however, whether this reflects protection against future high-grade CIN or cervical cancer, or whether it represents over-diagnosis. This Swedish population-based screening program randomly assigned 12,527 women ranging in age from 32 to 38 years to have either an HPV test plus a Pap test (n = 6257, the intervention group) or a Pap test alone (n = 6270, the control group). Those having a positive HPV test and a normal Pap test were offered a second HPV test at least 1 year later, and those persistently infected with the same high-risk type of HPV were offered colposcopy with cervical biopsy. A similar number of double-blinded Pap smears and colposcopies with biopsy were done in randomly selected control women to avoid ascertainment bias. The average follow-up interval was 4.1 years. Initially, 51% more women in the intervention group than in the control group had grade 2 or 3 CIN or cancer. On subsequent screening, the proportion of women in the intervention group who had grade 2/3 lesions or cancer was 42% less, and the proportion with grade 3 lesions or cancer was 47% less than the proportion of control women having such lesions. The increased incidence of grade 2 lesions found at initial screening in the intervention group was not followed by a significant reduction of such lesions at later screening. Women with persistent HPV infection remained at high risk of grade 2 or 3 lesions or cancer after being referred for colposcopy. Five women in the control group and one in the intervention group were found to have invasive squamous-cell carcinoma. Four in each group developed adenocarcinoma in situ or adenocarcinoma. All of these women with advanced changes were HPV-positive at baseline. The improved sensitivity of HPV testing in women in their mid-30s who are screened for cervical cancer is not solely a result of over-diagnosis. It can be ascribed-at least in part-to the earlier diagnosis of cervical lesions that do not regress on follow-up screening.

The purpose of this study was to investigate whether Epstein-Barr virus (EBV) is associated with acetowhite lesions of the portio cervix, demonstrating koilocytosis and/or cervical intraepithelial neoplasia (CIN) I-III. The study group comprised 37 women admitted to the Department of Gynaecology and Obstetrics, Sahlgrenska University Hospital, Go teborg because of pathological colposcopy or cytology of the portio cervix. Colposcopically, all exhibited acetowhite lesions of the portio cervix. Cells were sampled with a cytobrush for examination for EBV and human papillomavirus (HPV) DNA by polymerase chain reaction (PCR) and a biopsy was taken for histopathology. Biopsies from 5 patients positive for EBV by PCR in cervical cell samples were examined by an in situ hybridization technique for EBER (Epstein-Barr virus encoded RNA), RNAs expressed in latent EBV infection. The control group consisted of women attending the Department of Dermato-Venereology at the same hospital for STD check-up. These had a normal cytology and no signs of acetowhiteness of the portio cervix. In the study group, EBV DNA was found in 30% and HPV DNA in 51%. In the control group 57% exhibited EBV DNA and 23% HPV DNA. EBV was not found to be a predictive factor in the development of koilocytosis and/or CIN I-III. HPV was a predictive factor in acetowhite, koilocytotic lesions. No expression of EBER was found in the 5 biopsies examined by in situ hybridization.

Lung transplantation has become an accepted therapy for end-stage lung disease. Acute rejection of the transplanted lung still remains a major clinical problem since it decreases graft survival. Eosinophil cationic protein (ECP) from activated eosinophils, hyaluronan (HYA) from fibroblasts, and circulating intercellular adhesion molecule 1 (ICAM-1) have been associated with acute rejection in kidney and liver grafts. We investigated whether these, as well as other molecules, were increased in acute rejection of lung allografts. Serum and BAL fluid from 38 bronchoscopies performed in 9 single lung, 2 bilateral lung, and 4 heart-lung transplant patients were studied. Differential cell counts were made from the BAL fluid. Levels of ECP, myeloperoxidase (MPO), and HYA were used as indirect markers for activation of eosinophils, neutrophils, and fibroblasts, respectively. In addition, levels of circulating ICAM-1, cVCAM-1, and cE-selectin were analyzed. Twenty-two episodes with acute rejection were diagnosed. Of these, 7 were minimal, 13 were mild, and 2 were of moderate character. We found increased levels of ECP and HYA in BAL fluid during mild acute rejection of the allograft. Numbers of eosinophils were also increased. Activation of neutrophils or neutrophil numbers were not significantly increased. Levels of circulating ICAM-1, cVCAM-1, and cE-selectin did not differ between the groups. This retrospective study shows that measurements of ECP and HYA can give information about the inflammatory process present during acute rejection in patients who have undergone lung transplants. Analysis of cCAMS, however, appears to be of limited value as markers for acute rejection.

We evaluated the distribution of histological diagnoses in pregnant women with atypical cytology or cervical malignancy signs, as well as the usefulness of the Swede score colposcopic scoring system to reduce the need for diagnostic cervical biopsy.Prospective clinical study.The study comprised 261 pregnant women undergoing colposcopic investigation because of atypical cervical cytology, dysplastic biopsy changes, recurrent non-obstetric bleeding or pathological appearance of the cervix.Five colposcopic variables (acetowhiteness, margins plus surface, vessel patterns, lesion size and iodine staining) were scored with 0, 1 or 2 points. Colposcopically directed biopsies or loop electrosurgical excision biopsies were taken from all lesions. Histology was compared with the colposcopic score. Sensitivity and specificity were calculated for each variable, and the combination of all five variables, with high-grade lesions (i.e. cervical intraepithelial neoplasia (CIN2, CIN3 or adenocarcinoma-in-situ (AIS)) as endpoints.Colposcopic score (Swede score) and histology (CIN1, 2, 3; AIS; cancer).The specimens consisted of normal tissue in 19.5% of cases, low-grade lesions (i.e. CIN1, koilocytosis, glandular dysplasia of lower grade than AIS) in 26.1%, high grade lesions in 52.9% and cancer in 1.5%. All high grade lesions and cancers had total Swede scores of ≥ 5 and ≥ 8, respectively. Vessel patterns, lesion size and margins plus surface were most important for high grade lesion detection.The Swede score seems to be a useful tool in evaluating atypical cervical cytology in pregnant women and may reduce the need for diagnostic biopsies.

Background: Given the high burden of cervical cancer in low-income settings, there is a need for a convenient and affordable method for detecting and treating pre-cancerous lesions. Methods: Samples for comparing the accuracy of cytology, virology and histology were collected. Identification of HPV E6/E7 mRNA was performed using PreTect HPV-Proofer. HPV DNA detection was performed by GP5+/6+ PCR, followed by reverse line blot (RLB) for typing. Results: A total of 343 women, aged 25–60 years, attending gynaecological polyclinics in DR Congo were included for sample enrolment. The test positivity rate was conventional and liquid-based cytology (LBC) at cutoff ASCUS+ of 6.9 and 6.6%, respectively; PreTect HPV-Proofer of 7.3% and consensus DNA PCR for 14 HR types of 18.5%. Sixteen cases of CIN2+ lesions were identified. Of these, conventional cytology identified 66.7% with a specificity of 96.2%, LBC identified 73.3% with a specificity of 96.9%, all at cutoff ASCUS+. HR-HPV DNA detected all CIN2+ cases with a specificity of 85.9%, whereas PreTect HPV-Proofer gave a sensitivity of 81.3% and a specificity of 96.6%. Conclusion: Both HPV detection assays showed a higher sensitivity for CIN2+ than did cytological methods. Detecting E6/E7 mRNA from only a subset of HR HPVs, as is the case with PreTect HPV-Proofer, resulted in a similar specificity to cytology and a significantly higher specificity than consensus HR HPV DNA (P

BACKGROUND: Primary cervical screening with both human papillomavirus (HPV) DNA testing and cytological examination of cervical cells with a Pap test (cytology) has been evaluated in randomized clinical trials. Because the vast majority of women with positive cytology are also HPV DNA positive, screening strategies that use HPV DNA testing as the primary screening test may be more effective. METHODS: We used the database from the intervention arm (n = 6,257 women) of a population-based randomized trial of double screening with cytology and HPV DNA testing to evaluate the efficacy of 11 possible cervical screening strategies that are based on HPV DNA testing alone, cytology alone, and HPV DNA testing combined with cytology among women aged 32-38 years. The main outcome measures were sensitivity for detection of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) within 6 months of enrollment or at colposcopy for women with a persistent type-specific HPV infection and the number of screening tests and positive predictive value (PPV) for each screening strategy. All statistical tests were two-sided. RESULTS: Compared with screening by cytology alone, double testing with cytology and for type-specific HPV persistence resulted in a 35% (95% confidence interval [CI] = 15% to 60%) increase in sensitivity to detect CIN3+, without a statistically significant reduction in the PPV (relative PPV = 0.76, 95% CI = 0.52 to 1.10), but with more than twice as many screening tests needed. Several strategies that incorporated screening for high-risk HPV subtypes were explored, but they resulted in reduced PPV compared with cytology. Compared with cytology, primary screening with HPV DNA testing followed by cytological triage and repeat HPV DNA testing of HPV DNA-positive women with normal cytology increased the CIN3+ sensitivity by 30% (95% CI = 9% to 54%), maintained a high PPV (relative PPV = 0.87, 95% CI = 0.60 to 1.26), and resulted in a mere 12% increase in the number of screening tests (from 6,257 to 7,019 tests). CONCLUSIONS: Primary HPV DNA-based screening with cytology triage and repeat HPV DNA testing of cytology-negative women appears to be the most feasible cervical screening strategy.

The objectives of the study were to evaluate 1) the diagnostic sensitivity and specificity of p16INK4a as a marker for high-grade cervical lesions, 2) the results of a real-time polymerase chain reaction detecting high-risk human papillomavirus, and 3) the interobserver variability of the p16INK4a interpretation. A total of 232 ThinPrep samples were stained for p16INK4a, and HPV-DNA PCR was performed on 107 specimens with inclusion of both benign and abnormal cytology. Histological follow-up information was collected. The diagnostic sensitivity of ASC+ with CIN2+ in histology as endpoint was 96% for p16INK4a and 100% for HR-HPV DNA PCR, and the diagnostic specificity was 41% and 27%, respectively. If p16INK4a had been used for triage of the ASC samples, then 18 patients (42%) could have been spared unnecessary follow-up procedures compared to six patients (21%) with the HR-HPV DNA test. Diagn. Cytopathol. 2008;36:453–459. © 2008 Wiley-Liss, Inc.

BACKGROUND. The objective of this study was to evaluate whether liquid-based cytology (LBC) can improve high-standard cervical cancer screening cytology further. The primary endpoint was histopathologic high-grade lesions in current and subsequent screening rounds. The secondary endpoints were cytologic diagnosis and inadequate samples. METHODS. Women were randomized to smear taking by conventional Papanicolaou (Pap) smear or LBC according to the time of appointment. Eight thousand eight hundred ten conventional Pap smears and 4674 LBC samples were included. Evaluations of atypical cytology and referral to colposcopy and treatment were performed as routine procedures. Histopathologic diagnoses were retrieved from a regional database 8 months after the study was closed. The mean follow-up was 2 years and 9 months. RESULTS. Inadequate samples were observed in 0.3% of LBC samples versus 0.7% of Pap smears (P = .002). The total fraction of nonbenign diagnoses in cytology was 4.5% versus 3.5%, respectively (P < .001). Histopathologic evaluation was made on 570 patients constituting 4.6% of the LBC samples and 4% of the Pap smears. Forty percent more high-grade lesions were identified as a result of LBC sampling (1.20% vs 0.85%; P = .05). The influence of the sampling method was significant for all variables (odds ratio [OR], 1.60; 95% confidence interval [95% CI], 1.12–2.28) for high-grade lesions that were identified by histology when adjusting for age and screening unit in a logistic regression model. At the second follow-up 2 years and 1 month later, the OR was decreased only slightly (1.51; 95% CI, 1.13–2.01). CONCLUSIONS. In the ongoing cervical screening program of western Sweden, liquid cytology produced a significantly higher yield of histologic high-grade lesions compared with conventional Pap smears. Cancer (Cancer Cytopathol) 2007. © 2007 American Cancer Society.

Background Women once treated for high grade cervical dysplasia have a high long term risk for developing new dysplasia or cancer. Objectives To investigate if human papilloma virus (HPV)-negativity after treatment of cervical dysplasia reduces the need for frequent long term follow up. Design Case/control study based on archival smears. Methods Women with cervical intraepithelial neoplasi (CIN)2-3, treated for dysplasia and with recurrence of CIN2+ more than 2 years after treatment were compared with controls without recurrence, matched for age and date of treatment. High risk-HPV-DNA were analysed with PCR from two archival smears per woman. Mean follow up time was 14.6 years. Results 24% (45/189) of cases and 11% (43/378) of controls were HPV-positive in any of two smears. Odds ratio (OR) = 2.5 (1.6–3.8). Conclusion HPV-status 6–12 months after treatment of high grade dysplasia is of limited value for the design of long term follow up.

Desmoid tumors have a tendency to recur locally, and traditionally they have been treated surgically. No treatment is sometimes indicated, however; this requires a morphological diagnosis that is not based on a surgical specimen. In this study we aimed to identify the diagnostic accuracy of needle and core biopsy for the morphological diagnosis of desmoid.We compared the diagnostic accuracy of fine-needle aspiration (FNA) and core needle biopsy (CNB) in 69 and 26 patients, respectively, who had had surgical resections for desmoid. We also reviewed 15 additional cases that had been incorrectly diagnosed as desmoid on FNA but which had different diagnoses after surgery.FNA-based diagnoses of desmoid/fibromatosis were rendered in 35 of 69 cases, and other benign spindle cell proliferations in 26 cases and spindle cell sarcoma in the remaining 4 cases. All 26 CNBs were either suggested to correspond to desmoid (24) or other benign spindle cell lesions (2). Of the 15 FNAs incorrectly diagnosed as desmoid, 2 were found to be sarcomas.FNA is fairly reliable for recognition of the benign nature of desmoids. Occasional over- and under-diagnosis of malignancy can occur, however. CNB appears to be more reliable.

Objective Celiac disease (CD) is characterized by chronic inflammation of the small intestinal mucosa with disturbed epithelial transport. The fatty acid (FA) composition of intestinal membranes is important for epithelial function, and disturbances may contribute to the pathophysiology of the disease. We aimed to evaluate whether the intestinal mucosal FA status was reflected in serum phospholipids of patients with CD. Patients and methods Samples were obtained from 7 pediatric patients with active CD showing mucosal atrophy, 6 pediatric patients with CD in remission, and 11 control pediatric patients with morphologically healthy intestinal mucosa. Small intestinal biopsies were obtained using a Watson biopsy capsule under fluoroscopic control. Blood samples were collected on the same morning after an overnight fast. Tissue phospholipids were isolated by high-performance liquid chromatography, and FAs were analyzed by capillary gas-liquid chromatography. Results Serum phospholipid FA showed marginal differences between the patients with CD and the controls. Significant differences were observed in mucosa with active CD compared with controls. Linoleic acid (18:2n-6) level was decreased, whereas those of its derivatives were elevated, indicating increased transformation of n-6 FA. Mead acid (20:3n-9) level was increased, with an increased ratio of Mead acid to arachidonic acid (20:4n-6) levels, suggesting essential fatty acid deficiency. The n-3 FA levels were not significantly changed. During remission, the FA pattern of the intestinal mucosa was mainly similar to that in controls. Conclusions The FA abnormality of intestinal mucosa in patients with active CD was not reflected in serum values. Altered FA content may contribute to the pathophysiology of the disease because FAs are important for enzymes and for the transport and receptor functions of epithelial membranes.

Human papillomavirus (HPV) persistence is the major cause of cervical cancer, but most HPV infections will not persist and risk factors for HPV persistence are not well known. Chlamydia (C.) trachomatis infection seems to also be associated with cervical cancer. We investigated whether C. trachomatis infection is a risk factor for HPV persistence. In a cohort of 12,527 women participating in a population-based HPV screening trial in Sweden, 6,418 women completed testing for HPV DNA by general primer PCR and typing by reverse dot blot hybridization. On average 19 months later, 303 women that had been HPV-positive and had normal cytology at enrollment completed a new HPV test. Environmental exposures were assessed by an 87-item questionnaire. Previous sexually transmitted infections were also investigated by serology. At follow-up, 44% of the women were positive for the same type of HPV DNA as at enrollment. Persistence correlated with length of follow-up (p < 0.01) and condom use seemed to protect against HPV persistence (p < 0.05). The most significant risk factor for persistent presence of HPV DNA was self-reported history of previous C. trachomatis infection (relative risk in multivariate model = 2.09; 95% confidence interval = 1.05-4.18). We conclude that persistence of oncogenic HPV infections is more likely among women with a previous C. trachomatis infection.

The cytologic criteria of synovial sarcoma in fine-needle aspirates were defined by a retrospective examination of 37 primary tumors. Irrespective of subtype, a typical pattern at low power was found, provided the yield was rich. The typical pattern was a mixture of dispersed cells with the presence of striped nuclei and cell-tight tumor tissue fragments with irregular borders. Often a branching network of vessels was present in the fragments, imitating a true vascular tumor. Except in poorly differentiated synovial sarcomas, the tumor cells were, small to medium in size, with rounded, ovoid, or fusiform bland nuclei with inconspicuous nucleoli. In the biphasic variant, small glandular- or acinar-like structures were present, although not in all cases. In the poorly differentiated type, however, the cellular pleomorphism was marked with the presence of cells with irregular nuclei and rhabdomyoblast-like cells, corresponding to the pleomorphic variant. The Ewing's sarcoma-like and the atypical spindle cell variants of poorly differentiated synovial sarcoma were not diagnosed in the material. An unequivocal diagnosis of sarcoma is possible when the yield is rich. However, ancillary diagnostics are necessary for a correct diagnosis, to avoid important pitfalls, such as other sarcomas with bland tumor cells and vessel-rich tumor fragments, in particular, solitary fibrous tumor and true hemangiopericytoma. Electron microscopic and/or molecular genetic analyses were better diagnostic adjuncts than immunocytochemistry.

Human papillomavirus (HPV) DNA testing can be used to identify women at risk of the development of cervical cancer. The cost-effectiveness of HPV screening is dependent on the type-specific HPV prevalence in the general population. The present study describes the prevalence and spectrum of high-risk HPV types found in a large real-life population-based HPV screening trial undertaken entirely within the cervical screening program offered to middle-aged Swedish women. Cervical brush samples from 6,123 women aged 32-38 years were analyzed using a general HPV primer (GP5+/6+) polymerase chain reaction-enzyme immunoassay (PCR-EIA) combined with reverse dot-blot hybridization for confirmation and HPV typing by a single assay. In this study, 6.8% (95% CI 6.2-7.5) (417/6,123) were confirmed as high-risk HPV positive. Infections with 13 different high-risk HPV types were detected, of which HPV 16 was the most prevalent type (2.1%; 128/6,123), followed by HPV 31 (1.1%; 67/6,123). Any one of the HPV types 18, 33, 35, 39, 45, 51, 52, 56, 58, 59, or 66 was detected in 3.6% (223/6,123) of the women. Infection with two, three, and five types simultaneously was identified in 32, 5, and 1 women, respectively. The combination of PCR-EIA as a screening test and reverse dot-blot hybridization as a confirmatory test, was found to be readily applicable to a real-life population-based cervical screening. The type-specific HPV prevalence found support in previous modeling studies suggesting that HPV screening may be a favorable cervical screening strategy.

BACKGROUND Hibernoma is a rare, benign lipomatous tumor with features of brown fat. The preoperative diagnosis of hibernoma is difficult at times because its clinical, radiographic, and fine-needle aspiration (FNA) characteristics overlap with those of liposarcoma. METHODS The preoperative FNA findings of eight surgically excised hibernomas from seven patients (three men and four women, ages 24–60 years) were reviewed. The cytologic features were compared with the histologic features of the corresponding surgical specimens as well as lipomatous tumors and other lesions that may cause confusion in the differential diagnosis. RESULTS The FNA cytologic features of the hibernomas were found to correspond well with their histologic appearance. The FNA findings included small, round, brown fat-like cells with uniform, small cytoplasmic vacuoles and regular, small, round nuclei; delicate branching capillaries; and variable numbers of mature fat cells. CONCLUSIONS The FNA cytologic features of hibernoma are characteristic and useful in the preoperative investigation of lipomatous tumors, particularly with regard to excluding a diagnosis of liposarcoma. Cancer (Cancer Cytopathol) 2001;93:206–210. © 2001 American Cancer Society.

BACKGROUND The prognosis of patients with chordoma of the sacrum and mobile spine has been reported to be dismal and attributable in the majority of cases to intralesional surgery. The purpose of this study was to evaluate the clinical outcome of these patients using modern surgical principles aimed at complete resection and to identify prognostic factors. METHODS The clinical and morphologic features, type of surgery, and follow-up of 39 consecutive patients with chordoma were reviewed and analyzed statistically. RESULTS Thirty sacral and 9 mobile spine chordomas (size range, 3–20 cm; mean, 8 cm) occurring in 22 women and 17 men (median age, 55 years) were analyzed. The preoperative morphologic diagnosis was based on fine-needle aspiration (FNA) biopsy, core needle biopsy, or incisional biopsy. The final surgical margins were wide in 23 patients and marginal or intralesional in 16. The mean follow-up was 8.1 years (range, 0.1–23 years). Seventeen patients (44%) developed local recurrences and 11 patients (28%) developed metastases. The estimated 5-, 10-, 15-, and 20-year survival rates were 84%, 64%, 52%, and 52%, respectively. Local recurrence was associated significantly with an increased risk of metastasis and tumor-related death (P < 0.001). CONCLUSIONS New surgical techniques have improved local control and survival of patients with sacral or spinal chordoma significantly and have decreased progressive neurologic deterioration. Larger tumor size, performance of an invasive morphologic diagnostic procedure outside of the tumor center, inadequate surgical margins, microscopic tumor necrosis, Ki-67 > 5%, and local recurrence were found to be adverse prognostic factors. FNA is the preferred method for establishing the preoperative morphologic diagnosis of chordoma. Cancer 2000;88:2122–34. © 2000 American Cancer Society.

Acute rejection of the transplanted lung is a clinical problem, since it decreases graft survival and predisposes the patient to chronic rejection and obliterative bronchiolitis (OB). In an earlier study, we had indications that eosinophil cationic protein (ECP) from activated eosinophils and hyaluronan (HYA) from fibroblasts were associated with acute pulmonary rejection. This prospective longitudinal study was designed to investigate whether molecules from activated inflammatory cells in bronchoalveolar lavage (BAL) fluid could serve as clinically useful diagnostic markers for acute rejection. BAL fluid from 138 bronchoscopies performed in 10 single lung, four bilateral lung and five heart-lung transplant recipients were analysed. Nine patients were studied for a period of more than 1 yr (mean 13.4 months) after surgery. Differential cell counts were made from the BAL fluid. ECP, myeloperoxidase (MPO), HYA and interleukin-8 (IL-8) were used as indirect markers for activation and attraction of eosinophils, neutrophils and fibroblasts, respectively. Fifty four episodes of acute rejection were diagnosed. Two patients developed OB. Nine episodes of bacterial infection, 13 episodes of cytomegalovirus (CMV) pneumonitis, three of Pneumocystis carinii infection and one of respiratory syncytial virus (RSV) infection were diagnosed. The mean levels of ECP, MPO, HYA and IL-8 were all higher during rejection episodes, but differences were not statistically significant compared to no rejection, when the confounding factors of time, concomitant infection, and repeated measures in the same individual had been accounted for. We could not confirm that measurements of eosinophil cationic protein, myeloperoxidase, hyaluronan and interleukin-8 in bronchoalveolar lavage fluid can be used as diagnostic markers for acute rejection in the postoperative follow-up of lung transplant recipients.

To determine whether detection of invasive cervical cancer by screening results in better prognosis or merely increases the lead time until death.Nationwide population based cohort study.Sweden.All 1230 women with cervical cancer diagnosed during 1999-2001 in Sweden prospectively followed up for an average of 8.5 years.Cure proportions and five year relative survival ratios, stratified by screening history, mode of detection, age, histopathological type, and FIGO (International Federation of Gynecology and Obstetrics) stage.In the screening ages, the cure proportion for women with screen detected invasive cancer was 92% (95% confidence interval 75% to 98%) and for symptomatic women was 66% (62% to 70%), a statistically significant difference in cure of 26% (16% to 36%). Among symptomatic women, the cure proportion was significantly higher for those who had been screened according to recommendations (interval cancers) than among those overdue for screening: difference in cure 14% (95% confidence interval 6% to 23%). Cure proportions were similar for all histopathological types except small cell carcinomas and were closely related to FIGO stage. A significantly higher cure proportion for screen detected cancers remained after adjustment for stage at diagnosis (difference 15%, 7% to 22%).Screening is associated with improved cure of cervical cancer. Confounding cannot be ruled out, but the effect was not attributable to lead time bias and was larger than what is reflected by down-staging. Evaluations of screening programmes should consider the assessment of cure proportions.

We sought to evaluate the management of women with abnormal cytology in terms of subsequent risk of invasive cervical cancer.The screening histories of all invasive cervical cancer cases diagnosed in Sweden 1999-2001 and of 5 population-based controls per case were reviewed. In all, 159 patients and 258 control subjects aged67 years had an abnormal smear result 0.5-6.5 years prior to cancer diagnosis. The cervical cancer risk was estimated in relation to management by calculating odds ratios.Histologic assessment of low-grade squamous abnormalities strongly reduced the risk compared to repeated cytology (odds ratio, 0.46; 95% confidence interval, 0.24-0.89). Delaying histologic assessment was also associated with a higher risk (odds ratio, 5.65; 95% confidence interval, 1.39-23.05). After high-grade squamous atypia, absence of any cytologic or histologic specimen was a major determinant of cancer risk (odds ratio, 12.52; 95% confidence interval, 1.42-infinitive).For adequate protection against invasive cervical cancer, further assessment with histology must be recommended also for women with low-grade squamous abnormalities.

An ascites tumor line, TA3 Ha, is allotransplantable i.p. while a sister line, TA3 St, has retained its strain specificity. This study shows that the allotransplantability of TA3 Ha, with very few exceptions, is restricted to the peritoneal cavity and is not operative s.c. or i.v.

Two ascites tumors in syngeneic CBA mice are described, viz., MCB 21-AA and MCB 31-AA, with their solid progenitors: A sarcoma (MCB 21-SS) and a squamous cell carcinoma (MCB 31-SC), induced by gastric feeding of 20-methylcholanthrene. The ascites tumor cells have certain characteristics in common, which they do not share with either cells from the solid tumors or even with cells from solid ascites tumors (-21-AS and -31-AS=ascites tumor transplanted s.c.). Presumably some of these differences, for instance, in PAS stainability, electrophoretic mobility and lectin agglutinability, are due to enzyme treatment required to bring solid tumors into suspension. Between the two ascites tumors there are certain differences in cell size, aggregability, and growth rate. They are similar, however, in requiring large cell doses for transplantation in syngeneic animals, which is also true for the solid (SS and SC) tumors. MCB 21 and -AA even required fewer cells for transplantation in allogeneic A mice than in syngeneic CBA mice. MCB 31-AA is also allotransplantable. The pattern of spread, after i.v. cell injection, is almost exclusively to the lungs for all tumor lines.

Cell debris is inevitably produced by the mechanical and enzymatic procedures used to dissociate solid tumors. We investigated the influence of such debris on the i.v. and s.c. transplantability of B16 melanoma cells. Cell suspensions were centrifuged on a Percoll cushion to remove the debris, and the purified preparations were compared to untreated control suspensions. The i.v. injection of a massive dose (10(6) cells) of unpurified cells killed the animals within a few minutes, while the same amount of purified cells left the animals unaffected. When 5 X 10(5) cells were given, animals receiving purified cell suspensions had more extrapulmonary tumors at their time of death than those given unpurified cells. However, with a lower cell dose, 2 X 10(4) cells, there were no such differences in tumor incidence or distribution.

Using five syngeneic tumor-host systems in mice, we studied the influence of fine-needle aspiration biopsy, incisional biopsy, and excisional biopsy on tumor death rates. Guided by results from pilot studies a very strict test protocol was developed which made possible a comparison between the tumor systems in spite of their differences in tumor growth rates and dissemination patterns. The compiled results from the experiments did not reveal any differences in tumor death rates, neither between the test groups and their controls, nor between the three biopsy methods: fine-needle aspiration biopsy, incisional biopsy, and excisional biopsy. Additional experiments confirmed, however, earlier observations that tumor cell seeding and tumor outgrowth by way of the aspiration needle track may occur under extreme test conditions.

The transplantabilities of trypsin and neuraminidase-treated 101-AA cells were compared with untreated cells. The cell doses required for growth were similar for enzyme-treated and control cells. Yet, trypsinized cells injected i.v. gave rise to less lung tumours and, in one experiment, they produced more extrapulmonary tumours than control cells or neuraminidase-treated cells. These findings were collated with some data on the effect of enzyme treatment on the tumour cell membranes, obtained by particle size analysis, cell electrophoresis, lectin agglutinability and sialic acid determinations. The importance of cell surface characteristics for specific metastasis patterns, in this case a peculiar "myotrophism", is discussed.

We have transformed two new MC-induced tumours, a sarcoma (MCB21-SS) and a carcinoma (MCB31-SC), into ascites form. When transplanted s.c. these ascites tumours grow as solid, quite undifferentiated tumours, (AS = ascites solid tumours). We compared the metastasizibility of the AS tumours with that of the parent tumours. In doing so. we used both the tail and the hind leg as transplantation sites. The tumours can be radically removed from both sites by amputation, which prolongs the survival time of the animals and permits metastases to grow into detectable sizes. As registered grossly and by microscopy, the AS tumours have a greater tendency of spread than the parent (SS/SC) tumours. MCB-21AS grows quicker than 21-SS and gives rise to more lymph node metastases. When transplanted to the tail the AS tumour also gives a higher incidence of lung metastases. We detected no such difference by leg-transplanted tumours. MCB31-SC did not produce any detectable metastases at all, while 31-AS, particulary from the tail, gave rise to numerous lymph node and lung metastases. There were no differences in tumour size or growth rate to account for this difference. Thus ascites conversion has changed the carcinoma MCB31-SC into an undifferentiated. metastasizing tumour, as detected by our procedure. The design of test protocols to detect metastasizibility is discussed.

A case of ancient neurilemoma (Schwannoma) is presented that, owing to a severe cell pleomorphism, was falsely interpreted as a malignant spindle-cell sarcoma by fine-needle aspiration cytology. Cytological features of the tumor are given together with its histopathology and electron microscopy findings. The usefulness of electron microscopy on material obtained by fine-needle aspiration biopsies in the diagnosis of soft-tissue tumors is discussed. Diagn Cytopathol 1986;2:244-247.