Superior performance of liquid-based versus conventional cytology in a population-based cervical cancer screening program.

OBJECTIVE: Liquid-based cytology may offer improvements over conventional cytology for cervical cancer screening. The two cytology techniques were compared in a group of 86,469 women who participated in a population-based screening program. Using a nation-wide pathology database containing both cervical cytology and histology records for all patients, we compared the outcome of the two screenings methods with regard to the detection rate of histological proven abnormalities and the determination of the true false-negative rates for both methods. METHODS: Two cohorts of women living in the same geographical region were used. Cohort 1 (n=51,154 women) was analysed using conventional cytology (conventional cohort) and cohort 2 (liquid cohort) (n=35,315 women) was analysed using liquid-based cytology (SurePath). The samples were processed in one laboratory. The results of histological follow up were available via a central database. RESULTS: The rate of unsatisfactory slides was significantly lower using liquid-based cytology (0.13% vs. 0.89%, p<0.0001). Detection of ASCUS+ (Atypical squamous cells of unknown significance or higher abnormalities) was significantly higher using liquid-based cytology (2.97% vs. 1.64%, p<0.0001), mainly due to the increase in the ASCUS category. The percentage of histological abnormalities within the ASCUS samples was approximately equal in both cohorts, indicating that more true abnormal cases were detected using liquid-based cytology. The sensitivity for detection of a histological proven lesion is significantly higher in the liquid cohort compared to the conventional cohort (96.2% vs. 92.0%), with only a slight difference in specificity (97.8% vs. 98.2%). CONCLUSION: This population study confirmed previous institution-based reports of decreased numbers of unsatisfactory samples based on liquid-based cytology and showed an increased sensitivity for the detection of cytological abnormalities that was validated by subsequent histological investigation.

Herniation of the gall bladder through the abdominal wall.

We present a case of an 81-year-old woman, without medical history, with a swelling in the right lateral abdominal wall. Ultrasound and multislice CT were sufficient to confirm the diagnosis of a herniated gall bladder through the abdominal wall. This is the first case in which MRI proved to be a useful modality to exclude malignant characteristics and revealed an accurate differentiation between the gall bladder and the different layers of the abdominal wall. The gall bladder, including three stones, was removed laparoscopically. Histopathological research revealed signs of a chronic cholecystitis. Herniation of the gall bladder through the abdominal wall is rare. It was previously described in a few cases, but they were associated with the presence of an incisional hernia or carcinoma infiltration.

[Follow up after an abnormal pap smear: time interval acceptable, nature of follow up leaves room for improvement]. / Vervolgonderzoek na een afwijkend uitstrijkje: tijdsinterval acceptabel, aard van het vervolgonderzoek vaak niet.

OBJECTIVE: To investigate whether the interval between an abnormal Pap smear and follow-up is too long and whether the guidelines for histological follow-up after an abnormal Pap smear are being followed. DESIGN: Descriptive. METHOD: Data on all Pap smears of a minimum Pap class 3a (moderate dysplasia) from the national cervical-cancer screening programme in the Rotterdam area of the Netherlands were acquired from the Pathological Anatomical National Automated Archive (PALGA). The test results from each woman were arranged chronologically and the nature of the follow-up cervical examinations (cytological and histological) was recorded. The observation period was 360 days. The average interval in days between Pap smear and follow-up as well as the nature of the follow-up were analysed. RESULTS: In total, data on 156 women were analysed. In 93% of women follow-up was done during our observation period. The average interval was 60 days. In 80% of the women follow-up took place within 3 months and in 90% within 6 months. In 32% of women in the follow-up group the Pap smear was repeated at their first follow-up visit and in the remaining cases, a histological examination was performed according to the guidelines. In 7% of cases no cytological or histological follow-up at all took place within the year. CONCLUSION: The average interval between an abnormal Pap smear and follow-up is acceptable because of the slow natural course of cervical carcinoma. Attention should be focused on the incorrect repetition of the cytological test and on the fact that in a number of cases no follow-up at all is done within 1 year.

The morbidity of treatment for patients with Stage I endometrial cancer: results from a randomized trial.

PURPOSE: To compare the treatment complications for patients with Stage I endometrial cancer treated with surgery and pelvic radiotherapy (RT) or surgery alone in a multicenter randomized trial. METHODS AND MATERIALS: The Postoperative Radiation Therapy in Endometrial Carcinoma (PORTEC) trial included patients with endometrial cancer confined to the uterine corpus, either Grade 1 or 2 with more than 50% myometrial invasion, or Grade 2 or 3 with less than 50% myometrial invasion. Surgery consisted of an abdominal hysterectomy and oophorectomy, without lymphadenectomy. After surgery, patients were randomized to receive pelvic RT (46 Gy), or no further treatment. A total of 715 patients were randomized. Treatment complications were graded using the French-Italian glossary. RESULTS: The analysis was done at a median follow-up duration of 60 months. 691 patients were evaluable. Five-year actuarial rates of late complications (Grades 1-4) were 26% in the RT group and 4% in the control group (p < 0.0001). Most were Grade 1 complications, with 5-year rates of 17% in the RT group and 4% in the control group. All severe (Grade 3-4) complications were observed in the RT group (3%). Most complications were of the gastrointestinal tract. The symptoms resolved after some years in 50% of the patients. Grade 1-2 genitourinary complications occurred in 8% of the RT patients, and 4% of the controls. Bone complications occurred in 4 RT patients (1%). Seven patients (2%) discontinued their RT due to acute RT-related symptoms. Patients with acute morbidity had an increased risk of late RT complications (p = 0.001). The 4-field box technique was associated with a lower risk of late complications (p = 0.06). CONCLUSION: Pelvic RT increases the morbidity of treatment in Stage I endometrial cancer. In the PORTEC trial, severe complications occurred in 3% of treated patients, and over 20% experienced mild (mostly Grade 1) symptoms. Patients with acute RT-related morbidity had an increased risk of late complications. As pelvic RT in Stage I endometrial carcinoma was shown to significantly reduce the rate of locoregional recurrence, but without a survival benefit, its use in the adjuvant setting requires careful patient selection (treating those at increased risk of relapse), and the use of treatment schemes with the lowest risk of morbidity.

The screening history of women with cervical cancer in the Rotterdam area.

OBJECTIVE: In order to gain insight into the diagnostic effectiveness of the screening program on cervical cancer in the Rotterdam area, the history of women with cervical cancer was studied. Three questions were asked: (1) What percentage of women were invited to the screening program, and what percentage participated. (2) What percentage of women had had a negative smear within 3 years before cancer was diagnosed, and (3) What percentage of women encountered inadequate follow-up. METHODS: All the cytological and histological results of women who were diagnosed with cervical carcinoma between 1992-1994 were studied. RESULTS: Within 3 years of the diagnosis, 42% of the 165 women with cervical cancer were invited for the cervical screening program. A total of 47% were too old to be invited and 10% were too young. A total of 37% of the women who were invited participated in the screening program. A total of 33 (20%) of 165 women with cervical carcinoma had had a negative smear within three years preceding the diagnosis. For women under 34 years of age this was 41% (n = 7), and for women over 56 years 8% (n = 6). A total of 7% of all women with cervical cancer encountered inadequate follow-up. CONCLUSION: Many women with a diagnosis of cervical cancer are too old to be invited for the cervical screening program. Relatively few of the women with cervical cancer who were invited for the screening program actually participated in this program.

Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma.

BACKGROUND: Postoperative radiotherapy for International Federation of Gynaecology and Obstetrics (FIGO) stage-1 endometrial carcinoma is a subject of controversy due to the low relapse rate and the lack of data from randomised trials. We did a multicentre prospective randomised trial to find whether postoperative pelvic radiotherapy improves locoregional control and survival for patients with stage-1 endometrial carcinoma. METHODS: Patients with stage-1 endometrial carcinoma (grade 1 with deep [> or =50%] myometrial invasion, grade 2 with any invasion, or grade 3 with superficial [<50%] invasion) were enrolled. After total abdominal hysterectomy and bilateral salpingo-oophorectomy, without lymphadenectomy, 715 patients from 19 radiation oncology centres were randomised to pelvic radiotherapy (46 Gy) or no further treatment. The primary study endpoints were locoregional recurrence and death, with treatment-related morbidity and survival after relapse as secondary endpoints. FINDINGS: Analysis was done according to the intention-to-treat principle. Of the 715 patients, 714 could be evaluated. The median duration of follow-up was 52 months. 5-year actuarial locoregional recurrence rates were 4% in the radiotherapy group and 14% in the control group (p<0.001). Actuarial 5-year overall survival rates were similar in the two groups: 81% (radiotherapy) and 85% (controls), p=0.31. Endometrial-cancer-related death rates were 9% in the radiotherapy group and 6% in the control group (p=0.37). Treatment-related complications occurred in 25% of radiotherapy patients, and in 6% of the controls (p<0.0001). Two-thirds of the complications were grade 1. Grade 3-4 complications were seen in eight patients, of which seven were in the radiotherapy group (2%). 2-year survival after vaginal recurrence was 79%, in contrast to 21% after pelvic recurrence or distant metastases. Survival after relapse was significantly (p=0.02) better for patients in the control group. Multivariate analysis showed that for locoregional recurrence, radiotherapy and age below 60 years were significant favourable prognostic factors. INTERPRETATION: Postoperative radiotherapy in stage-1 endometrial carcinoma reduces locoregional recurrence but has no impact on overall survival. Radiotherapy increases treatment-related morbidity. Postoperative radiotherapy is not indicated in patients with stage-1 endometrial carcinoma below 60 years and patients with grade-2 tumours with superficial invasion.

Positive diagnostic values and histological detection ratios from the Rotterdam cervical cancer screening programme.

BACKGROUND: In organized screening programmes for cervical cancer, pre-cancerous lesions are detected by cervical smears. However, during follow-up after a positive smear these pre-cancerous lesions are not always found. The purpose of the study is to analyse positive diagnostic values of smears of at least mild dysplasia, made under the organized screening programmes in the Rotterdam area (1979-1991), and detection ratios of histologically confirmed CIN > or =3, among women participating in these screening programmes. METHODS: Positive diagnostic values and histological detection ratios, by age and history of previous smears, recorded during the national screening programme (1989-1991), were compared with those of the experimental cervical cancer screening project (1976-1984). RESULTS: The positive diagnostic value of a smear with at least severe dysplasia (histologically confirmed CIN > or =3) remains approximately 78%. For smears with mild and moderate dysplasia only lower limits of the diagnostic value could be determined. This was 9% for a smear with mild dysplasia obtained during the national screening programme and 25% and 35% for smears with moderate dysplasia taken during the experimental and national screening programmes respectively. Histological detection ratios for CIN > or =3 in the three rounds of the experimental screening project were 4.7, 2.9 and 1.9. In the first round of the national screening programme the ratio was 4.7, and about three times higher in younger compared to older women. CONCLUSION: Immediate referral for colposcopy after a smear showing moderate dysplasia seems questionable. Whether the increased detection ratio among young women indicates a rise in the risk of cervical cancer is unclear.

Hypereosinophilic syndrome presenting with diarrhoea and anaemia in a patient with systemic lupus erythematosus.

We describe a patient with quiet systemic lupus erythematosus who developed a hypereosinophilic syndrome. The patient presented with gastrointestinal eosinophilia which caused diarrhoea, malabsorption and anaemia due to deficiencies of vitamins. The hypereosiniphilic syndrome completely resolved after treatment with prednisone.

Accuracy of the Jamshidi trocar biopsy in the diagnosis of bone tumors.

Obtaining a histologic diagnosis is crucial in patients presenting with a tumor or a tumorous condition of the bone. The incisional surgical and the closed trocar biopsy are the most frequently used techniques for obtaining a representative tissue sample for histologic evaluation. This study reports on the reliability of 270 Jamshidi trocar biopsies performed on 258 patients with osseous tumors and tumorlike lesions. All patients were evaluated clinically and radiographically by a team consisting of an orthopaedic surgeon, a radiologist, and a surgical pathologist. In nearly all cases the biopsy and the resection were performed by the same orthopaedic surgeon. The biopsy site was determined in accordance with the planned subsequent resection surgery. Overall, an accurate diagnosis could be reached in 90.7% of the total number of 270 Jamshidi biopsies and in 95% of the 258 patients. The failure rate of the 270 biopsies was 9.3%. No specific contraindications with regard to the kind of lesion were found. Except for the pelvis, the localization of the lesion did not influence the rate of success. The high accuracy of the trocar biopsy, combined with the advantages of this technique over the incisional surgical biopsy, makes it a safe, fast, and adequate technique for obtaining a histologic sample of a bone tumor.

Isolated liver perfusion with mitomycin C in the treatment of colorectal cancer metastases confined to the liver.

We evaluated the technical feasibility of isolated liver perfusion (ILP) in the treatment of patients with colorectal cancer metastases confined to the liver, and investigated whether ILP allows exposure of the tumor to high concentrations of mitomycin C (MMC). Furthermore, survival time and tumor response were studied. Nine patients were treated with 30 mg/m2 MMC recirculated for one hour in the isolated circuit. The MMC concentration in the perfusate and plasma was measured using a high-performance liquid chromatography assay. All complications directly related to the surgical procedure were treated effectively (no mortality). The peak concentration of MMC in the perfusate was 5 to 11 times higher than that measured in the plasma of patients treated with 20 to 60 mg/m2 MMC i.v., and the concentration remained significantly higher during the whole perfusion period. In contrast, the peak concentration of MMC in plasma was approximately two thirds of the lowest peak plasma level measured after i.v. administration of 10 mg/m2 MMC. No systemic toxicity was observed in any of our patients. However, four patients developed veno-occlusive disease of the liver which was mild in three but lethal in one. One of the eight evaluable patients had an objective complete response (25 months), one an objective partial response and five others a clear reduction in tumor size (25-50%). The median survival time was 17 months. This study demonstrates that ILP is technically feasible in patients, and in comparison with systemic therapy allows exposure of hepatic metastases to much higher concentrations of MMC, while systemic toxicity is absent. Remarkably, this single exposure to a high concentration of MMC resulted in a complete response and a median survival time comparable to that in recently published hepatic artery infusion studies with floxuridine and leucovorin. However, due to the hepatotoxicity we are continuing our studies with melphalan to further exploit the possible therapeutic benefit of ILP.

[Follow-up not according to guidelines after an abnormal cervix smear]. / Follow-up na een afwijkend cervixuitstrijkje niet conform de adviezen.

OBJECTIVE: To investigate whether the recommendations for the follow-up after a positive cervical smear test, made within the Dutch national screening programme on cervical cancer, are followed in practice. DESIGN: Descriptive. SETTING: The Rotterdam Municipal Health Services Area. METHOD: All cytological and clinical-histological findings on women who had a Pap smear of at least Pap class IIIA in the period 1989-1991, were collected from the Pathological Anatomical National Automised Archives (PALGA). Per smear test result, the cervix-cytological and histological examinations that took place after the screening programme were arranged in order of occurrence. RESULTS: 61% of the women with Pap class IIIA had been followed according to the recommendations, in 12% no follow-up had been done. Repeat cytology was often done much later than after three months as recommended. After Pap class IIIB, IV or V smear test outcome the recommendations were followed in respectively over half, about three-quarters, and all cases. In 9% of women with Pap class IIIB or IV, no follow-up was recorded in the PALGA data base. CONCLUSION: Often, the recommendations for follow-up after a positive smear were followed poorly. Further research into the problems in the follow-up route is necessary.

Results of curettage for postmenopausal vaginal bleeding in women treated with tamoxifen and megestrol acetate for progressive metastatic breast carcinoma.

Tamoxifen and megestrol acetate are used as a hormonal treatment for metastatic breast carcinoma. It is suggested that the use of tamoxifen may induce endometrial cancer. In this article we describe nine patients under hormonal treatment for metastatic breast cancer with, firstly, tamoxifen and, later, megestrol acetate. These nine patients all had symptoms of postmenopausal vaginal blood loss during therapy with megestrol acetate, an indication to perform a diagnostic dilatation and curettage. By histopathological examination the curettings showed a decidualized stroma with an infiltration of lymphocytes, some plasma cells and many eosinophils. In none of the patients was atypical hyperplasia or malignancy found. The dilatation and curettage had also a therapeutic effect, since only one of the patients still had complaints, while the other eight did not complain of postmenopausal bleeding again. We review the literature and discuss the value of a diagnostic dilatation and curettage.

High levels of DNA index heterogeneity in advanced breast carcinomas. Evidence for DNA ploidy differences between lymphatic and hematogenous metastases.

BACKGROUND: The aim of this study was to investigate DNA ploidy status and DNA index heterogeneity of lymphatic and hematogenous metastases of advanced breast carcinomas and the relations among the various tumor sites. METHODS: DNA ploidy status was analyzed by flow cytometry on frozen and paraffin-embedded tissue blocks taken from primary and metastatic tumor sites in 18 patients with advanced breast cancer. RESULTS: Presumably because of the extensive sampling, high percentages of DNA aneuploidy, DNA multiploidy, and DNA index heterogeneity were found in primary breast carcinomas as well as in lymph node and distant metastases. DNA aneuploid tumor stemlines were frequently accompanied by DNA diploid tumor stemlines. Most of the DNA tumor stemlines found in the primary tumors recurred in lymph node (55%) and distant (59%) metastases, even after 17 years of relapse-free survival. DNA tumor stemlines found in distant metastases, however, often differed from those in lymph node metastases (61%). CONCLUSIONS: A marked DNA index heterogeneity can be found in primary and metastatic tumor sites when appropriate sampling is applied. There were no DNA ploidy subclasses, notably absent in either type of metastasis, indicating similar metastatic capacities of both DNA aneuploid and DNA diploid tumor stemlines in advanced breast carcinomas. The difference in DNA ploidy status between lymphatic and hematogenous metastases suggest that these metastases can be generated independently.

Flow cytometric and histomorphometric analysis of limitations of clinical breast cytomorphometry.

The clinical value and limitations of a previously described cytomorphometric method, based on nuclear size and anisonucleosis, for evaluation of routine fine-needle aspiration of the breast were assessed in a series of 313 histologically investigated primary breast lesions. Limitations were analyzed by histomorphometry and DNA flow cytometry in 116 consecutive cases of histologically confirmed breast carcinoma. Eighty per cent of histologically proven malignant tumours were classified cytomorphometrically as malignant and no false-positive results were encountered. For benign lesions a benign cytomorphometric classification was reached in 66% of the cases. Histomorphometry showed that on the whole the assignment of histologically malignant tumours to a non-malignant cytomorphometric classification was determined by smaller nuclei and not by sampling error. Tumours assigned to a malignant cytomorphometric classification had on average significantly higher DNA indices than did tumours not assigned to a malignant cytomorphometric classification (P less than 0.001). The mean-nuclear areas in cytomorphometry and histomorphometry were strongly correlated with DNA indices indicated by DNA flow cytometry (P less than 0.001 for both). The present findings show that this cytomorphometric method is appropriate for routine quality control of a cytological diagnosis of malignancy in FNA of the breast. However, an inconclusive result in 15-25% of the tumours is inevitable.

DNA ploidy of primary breast cancer and local recurrence after breast-conserving therapy.

The value of DNA-flow cytometry and clinico-pathological prognostic factors for the prediction of local recurrences after breast-conserving therapy (BCT) were evaluated in a retrospective study. Thirty-one patients with a local recurrence were compared with 31 matched patients without a local recurrence. Morphology and DNA-indices of the local recurrences and their corresponding primary tumours were compared. Ductal carcinoma in situ was present significantly more often in the group with a primary recurring tumour, than in the matched group (P less than 0.001), and the same holds for lobular carcinoma (n = 5). Half of the tumours that recurred had macroscopically positive surgical margins compared to about one-fourth of the matched group. Fifty-six per cent of the DNA-aneuploid stemlines in cases with local recurrence were present in the corresponding primary tumour as well (confidence limits 45%-75%), an indication that the majority of local recurrences are true recurrences and not independently developed tumours. The lack of similarity of DNA stemlines between some primary DNA-aneuploid tumours and their local recurrences indicates that these tumours had developed independently. The percentage of DNA-aneuploid cases in the group with local recurrence (89%) did not differ significantly from that in the matched group (70%). However, the findings suggest a selective recurrence of DNA-diploid stemlines. This might indicate increased resistance of DNA-diploid tumour cells to radiotherapy as compared with the resistance level in DNA-aneuploid cells.

Cytomorphometry as quality control for fine needle aspiration. A study in 321 breast lesions.

Material collected by fine needle aspiration (FNA) in 321 histologically examined primary breast lesions of previously untreated patients was analyzed by morphometry. The mean nuclear area (MNA) and its standard deviation (SD) were calculated for 50 cells in each case. Four subclasses were defined on the basis of the MNA and SD: benign (less than 10% probability of malignancy), doubtful benign (10% to 49%), doubtful malignant (50% to 90%) and malignant (greater than 90% probability of malignancy). FNA samples showing signs of acute inflammation or only apocrine metaplastic cells were not suitable for analysis by this morphometric method and were excluded. In 274 (85.4%) of the cases, the measurements allowed a definite morphometric conclusion, with predictive values of 99.5% and 100% for the histologically malignant and benign aspirates, respectively. The probability of malignancy in the doubtful malignant group was almost 86%. The morphometric method described is quick, easy to perform and well suited for use in routine daily practice; furthermore, it does not require expensive equipment. The ease of the technique and its high predictive value make this method appropriate for use as a quality control procedure in FNA cytology.

Flow cytometric analysis of DNA stemline heterogeneity in primary and metastatic breast cancer.

Flow cytometric DNA-ploidy analysis was used to investigate intratumor DNA stemline heterogeneity in primary breast carcinomas and lymph node metastases (LNM). The study was done in tumor specimens from 44 patients 35 of whom had LNM. In all, measurements were done in 214 different samples of primary tumors and 211 lymph nodes. Sixty-one percent (27/44) of the primary tumors were found to have multiple DNA aneuploid stemlines when the data of the separate samples per tumor (mean 4.9) were compared. Only five of 44 (11%) primary tumors were DNA diploid; two of these had DNA aneuploid metastases. Statistical analysis of these results indicated that, on average, four samples are needed for reliable determination of the DNA ploidy status of primary tumors by flow cytometry. In the majority of the cases (26/35), distinct tumor DNA stemlines found in LNM were also present in the primary tumor, which suggests that the generation of DNA ploidy diversity may have taken place prior to metastasis. Multiploidy was not related to tumor size but, particularly for LNM, was significantly correlated with age (r = 0.40, P = 0.02). The results of this study support the view that breast cancer is an extremely heterogeneous disease and that underestimation of this factor might account for the disagreement in literature about the prognostic value of DNA ploidy determinations.

Multilocular renal cyst associated with transposition of the inferior vena cava and malrotation of the bowel.

A case is presented of an adult male patient with a heavily calcified multilocular renal cyst (Permann's tumor), transposition of the inferior vena cava and reversed rotation (malrotation) of the bowel. Because of the synchronous embryological development of the forementioned structures, a possible congenital etiology of the multilocular renal cyst is suggested.

Melanin production in black medullary thyroid carcinoma (MTC).

Melanin production by two medullary carcinomas of the thyroid is reported and discussed. In both tumours, melanin and calcitonin could be detected in the same cells.