Screening for carcinoma in situ of the contralateral testis in patients with germinal testicular cancer.

Two hundred and fifty biopsy specimens from the contralateral testis in patients with unilateral germinal testicular cancer were analysed by light microscopy for carcinoma-in-situ changes. Changes were found in 13 (5.2%) patients. One-third of patients with an atrophic contralateral testis (volume less than or equal to 12 ml) and one-fifth of patients with a history of cryptorchidism had changes in the remaining testis. In the present series 85% of cases with carcinoma-in-situ changes would have been diagnosed if the one-fifth of the patients having an atrophic testis or a history of cryptorchidism or both had been screened. Since the natural course of carcinoma in situ in the contralateral testis of patients with germinal testicular cancer has not been established, the patients are being re-evaluated frequently. To date two patients with carcinoma in situ have developed a second cancer.     

Carcinoma in situ of the testis: aneuploid cells in semen

The content of cellular DNA in ejaculates from eight patients with carcinoma in situ of the testis and 26 controls without evidence of testicular neoplasia was studied by flow cytometry. An aneuploid cell population with a ploidy value similar to that found for carcinoma in situ cells was detected in seminal fluid from four of the eight men with carcinoma in situ but in none of the controls. One year after orchidectomy or local irradiation in these four men no aneuploid cells were found in the semen.These findings show that a detectable proportion of malignant germ cells may be released into the seminal fluid of patients with carcinoma in situ of the testis. Analysis of seminal fluid may therefore aid in screening for early neoplasia of the testis.     

Immunohistochemical expression analysis of Cx43, Cx26, c-KIT and PlAP in contralateral testis biopsies of patients with non-seminomatous testicular germ cell tumor

Non seminomatous testicular germ cell tumors (NSTGCTs) express fetal stem cell markers and display dysregulation of connexin 43 expression. Persistence of fetal spermatogonial characteristics was implicated in the emergence of testicular germ cell tumors. The objective of this study was to analyze the tubular architecture in contralateral testes of patients with NSTGCT. We studied morphologic alterations, expression patterns of markers for the integrity of the germinal epithelium (gap junction proteins connexin 43 and 26), as well as of the embryonic markers c-KIT and placental alkaline phosphatase (PlAP), both established markers to detect carcinoma in situ (CIS). In all samples, tubules showing maturation of germ cells up to spermatozoa were observed. In addition, tubules with alterations in tubular architecture and with impaired spermatogenesis occurred. In tubules showing aberrant spermatogenesis, connexin 43 (Cx43) signal was down-regulated and a shift of signal from gap junctions to the cytoplasm occurred. Concomitantly, Cx26 was found highly up-regulated in tubules with incomplete and aberrant germ cell maturation. All testes exhibited single spermatogonia with positive reaction for c-KIT and a significant positive correlation was found between the mean number of c-KIT positive spermatogonia per tubule and the percentage of tubules presenting severely impaired spermatogenesis. Our data show alterations of the normal architecture of the germinal epithelium and disturbances of spermatogenesis in the contralateral testes of patients with NSTGCT in all cases evaluated. The concomitant occurrence of c-KIT positive spermatogonia and defects in tubular architecture is in line with the hypothesis that patients with NSTGCT suffer from disturbed germ cell development.     

Occult breast carcinoma in reduction mammaplasty specimens: 14-year experience

Reduction mammaplasty is commonly performed for bilateral macromastia, congenital asymmetry, or as a contralateral symmetry procedure in breast reconstruction following mastectomy for cancer. Occult carcinoma has been detected in 0.06 percent to 0.4 percent of breast reduction specimens. The purpose of this study was to examine the incidence of breast cancer in breast reductions performed in one institution over a 14-year period. The authors reviewed their experience with 800 reduction mammaplasties performed between 1988 and 2001. Six cancers were detected (0.8 percent). Of these cancers, three were invasive (0.4 percent) and three were ductal carcinoma in situ (0.4 percent). Stratified by indication for surgery, there was a trend toward higher detection rates in the reconstruction group (1.2 percent) compared with the macromastia (0.7 percent) or congenital asymmetry (0 percent) groups. Mammography was performed preoperatively in these patients and all results were negative for masses or suspicious microcalcification. Pathological diagnosis was guided by gross specimen evaluation in two patients and specimen radiography in one patient. Reduction mammaplasty has a small but definite risk of finding cancer in the resection specimen.     

Prevalence of carcinoma in situ of the testis in 207 oligozoospermic men from infertile couples: prospective study of testicular biopsies.

OBJECTIVE: To investigate the prevalence of carcinoma in situ of the testis in a group of oligozoospermic men from infertile couples. DESIGN: A consecutive group of oligozoospermic men from infertile couples were offered bilateral testicular biopsy. The observed prevalence of carcinoma in situ was compared with the expected prevalence of testicular cancer in a corresponding age matched population of Danish men, assuming all untreated cases of carcinoma in situ progress to tumour stage. This calculation was based on data from the Danish Cancer Registry. SUBJECTS: 207 men aged 18-50 years who had sperm density below 10 million/ml in two samples within the previous 2 years or sperm density below 20 million/ml in two samples within the previous 2 years and a history of cryptorchidism or one or two atrophic testicles (orchidometer volume less than 15 cm3), or both. INTERVENTIONS: Bilateral testicular biopsies. MAIN OUTCOME MEASURES: Carcinoma in situ in the biopsy specimen. RESULTS: No case of carcinoma in situ was found among the 207 men. The expected number in a normal age matched population of corresponding size was 0.8. CONCLUSIONS: There is no increase in risk of carcinoma in situ of the testis in moderately oligozoospermic men of couples referred because of infertility.     

Role of screening in detection of clinically localized prostate cancer

The aim of this study was to confirm the role of screening by determining the percentage of clinically localized prostate cancer (stage A and B) in patients with prostate cancer detected on screening and in those presenting to urologic clinic for the symptoms of urination impairment or ostalgia. During the study, 1,000 men aged > or = 50 from the community of Cepin and village of Josipovac near Osijek were examined. The subjects with elevated concentration of total prostate specific antigen and/or digital rectal examination suspect of carcinoma underwent transperineal biopsy of the prostate. Clinical staging was performed in patients with prostate cancer detected on screening, and data on clinical staging for prostate cancer patients treated during the 1996-1997 period were retrieved from patient files of the Department of Urology, University Hospital "Osijek". On screening, 28 (80%) patients with localized prostate cancer and seven (20%) patients with metastases were detected. In the group of patients examined on an outpatient basis for the signs and symptoms of prostatism, there were 30 (83.4%) patients with metastases and only six (16.6%) patients with localized prostate cancer. Study results indicated that an early diagnosis of prostate cancer could be made by use of noninvasive and inexpensive methods that cause no major discomfort to the patient. Accordingly, these results appear to strongly support such screening in men, if not in all those aged over 50, then at least in the otherwise healthy, 50-70 age group.     

Antigen-driven oligoclonal expansion of tumor-infiltrating B cells in infiltrating ductal carcinoma of the breast

The objective of this study was to determine whether tumor-infiltrating B cells (TIL-B) of infiltrating ductal carcinoma (IDC) of the breast represent a tumor-specific humoral immune response. Immunohistochemical analysis of three Her-2/neu-negative IDC tumors from geriatric patients showed that TIL-B cluster in structures similar to germinal centers containing CD20(+) B lymphocyte and CD3(+) T lymphocyte zones with interdigitating CD21(+) follicular dendritic cells, suggesting an in situ immune response. A total of 29, 31, and 58 IgG1 H chain clones was sequenced from the three IDC tumors, respectively. Intratumoral oligoclonal expansion of TIL-B was demonstrated by a preponderance (45-68%) of clonal B cells. In contrast, only 7% of tumor-draining lymph node and 0% of healthy donor PBL IgG H chains were clonal, consistent with the larger repertoires of node and peripheral populations. Patterns and levels of TIL-B IgG H chain somatic hypermutation suggested affinity maturation in intratumoral germinal centers. To examine the specificity of TIL-B Ig, a phage-displayed Fab library was generated from the TIL-B of one IDC tumor. Panning with an allogeneic breast cancer cell line enriched Fab binding to breast cancer cells, but not nonmalignant cell lines tested. However, panning with autologous tumor tissue lysate increased binding of Fab to both tumor tissue lysate and healthy breast tissue lysate. These data suggest an in situ Ag-driven oligoclonal B cell response to a variety of tumor- and breast-associated Ags.     

Recurrence following treatment of ductal carcinoma in situ with skin-sparing mastectomy and immediate breast reconstruction

Skin-sparing mastectomy with immediate breast reconstruction can provide an excellent cosmetic result. Despite its increasing popularity, few studies have assessed the risk of recurrence when the procedure is used for the treatment of ductal carcinoma in situ. To evaluate the oncologic safety of skin-sparing mastectomy used for the treatment of ductal carcinoma in situ, the recurrence rate was analyzed. Patients with ductal carcinoma in situ or invasive carcinoma or both who underwent skin-sparing mastectomy with immediate breast reconstruction between 1985 and 1994 and had a follow-up period of at least 6 years were included in this retrospective analysis. The recurrence rates were determined for invasive carcinoma (with or without foci of ductal carcinoma in situ) and ductal carcinoma in situ alone. A total of 221 patients were included, 177 patients with invasive carcinoma and 44 patients with ductal carcinoma in situ alone. The immediate breast reconstructions were performed with transverse rectus abdominis muscle (TRAM) flaps in 62 percent of patients, implants in 34 percent of patients, and latissimus dorsi myocutaneous flaps (with or without implants) in 4 percent of patients. The local recurrence rate was zero of 44 for patients with ductal carcinoma in situ and 5.6 percent (10 of 177) for patients with invasive carcinoma during a mean follow-up period of 9.8 years. There was a 6.8 percent (12 of 177) metastatic recurrence rate in the invasive carcinoma group. All recurrences were invasive ductal carcinoma. Of the patients with ductal carcinoma in situ alone, none developed metastatic disease. The combined metastatic and local recurrence rates for the invasive carcinoma group (n = 177) with each type of reconstruction were 13 percent (14 of 110), 12 percent (seven of 60), and 14 percent (one of seven) for TRAM flaps, implants, and latissimus dorsi flaps, respectively. The risk of recurrence following skin-sparing mastectomy and immediate breast reconstruction for ductal carcinoma in situ is low during this follow-up period. Therefore, skin-sparing mastectomy with immediate breast reconstruction seems to be a safe oncologic treatment option for ductal carcinoma in situ; however, a longer follow-up period is important to determine the long-term risk of recurrence.     

Marker features for malignancy in ectocervical cells. Statistical evaluation

Marker features for malignancy have recently been observed in ectocervical cells, even in cells that are visually normal in appearance. This study assessed the statistical significance of these marker features using a mixed-model nested-design analysis of variance (ANOVA). Features in blue intermediate cells from patients with normal cytology, moderate dysplasia, and severe dysplasia/carcinoma in situ, nonkeratinizing cells from patients with moderate dysplasia, severe dysplasia/carcinoma in situ, and invasive cancer, and dysplastic cells from areas of metaplasia from patients with moderate dysplasia, severe dysplasia/carcinoma in situ, and invasive cancer were tested. ANOVA clearly demonstrated that the marker features differentiate between cells of the same cell type originating from patients in different diagnostic categories. In every instance, the differences owing to the diagnostic category were statistically significantly greater than those caused by patient-to-patient variability. Although the discriminating marker features in the intermediate cells were almost exclusively spectral features reflecting staining differences, morphometric features were also marker features in the dysplastic cells.     

Immunohistochemical profile of ovarian inclusion cysts in patients with and without ovarian carcinoma

Summary The expression of cytokeratin, epithelial membrane antigen, Leu-M1, B72.3, carcinoembryonic antigen, human placental lactogen, proliferating cell nuclear antigen, p53, and ovarian carcinoma-associated antigen OC-125 was evaluated in inclusion cysts in contralateral ovaries of patients with unilateral ovarian carcinoma. The findings were compared with the findings in inclusion cysts in ovaries of patients without ovarian carcinoma. Although there was more frequent expression of tumour markers B72.3 and CEA in patients with ovarian carcinoma, these differences did not reach statistical significance.     

Clinical evaluation of a bleomycin-group antitumor antibiotic bleomycetin

The efficacy of bleomycetin or bleomycin A5 was studied in 128 patients with different malignant neoplasms. The antibiotic was used as a systemic or intracavitary chemotherapeutic agent. Bleomycetin was effective in 75-80, 81.8, 58.3, 70 and 50 per cent of the cases with disseminated derminogenic tumor of the testicle, squamous cell carcinoma of the head and neck, cancer of the penis, carcinoma of the skin and lymphogranulomatosis, respectively. When used intracavitarily the drug was effective in 41.2 per cent of the patients with cancer of the ovaries and lungs, teratoblastoma of the ovaries, cancer of the mammary gland and sarcoma of the soft tissues. Hyperthermia and focal hyperkeratosis as the adverse reactions were observed in 40.6 and 5.4 per cent of the patients, respectively. No toxicity with respect to the lungs was registered.     

Immunohistochemical diagnosis of preinvasive germ cell cancer of the testis

The aim of the study was to identify testicular carcinoma in situ (CIS), a precursor of germ cell tumours (GCT), in patients from the high risk groups, using classic and alternative immunohistochemical methods. 70 patients with 46,XY karyotype were examined. Whole gonads or biopsy specimens were fixed in Bouin's fluid. In cases with dysgenetic male pseudohermaphroditism (DMP), gross histopathology revealed sex cord tumour gonadoblastoma in 4 and malignant dysgerminoma in 1 out of 23 patients. In all patients, paraffin sections were treated with antibodies against placental-like alkaline phosphatase (PLAP), a classic immunohistochemical marker of GCT and CIS. CIS was detected immunohistochemically in 10 out of 23 cases with DMP (43.5%), in 1 out of 10 cases with androgen insensitivity syndrome (10%), in 3 out of 18 cases operated previously because of already developed GCT in contralateral testis (16.6%) and in 1 out of 3 patients with cryptorchidism in anamnesis (33.3%). CIS was not found in 16 examined adult infertile men with azoospermia. In addition to PLAP investigation, 12 cases with DMP and 6 cases with GCT were examined using M2A and TRA-1-60 antibodies, the alternative immunohistochemical markers of CIS. While in DMP positive reactions for M2A and TRA-1-60 accompanied PLAP reaction in 1/3 of cases, M2A accompanied PLAP in all cases with GCT. The positive reaction for TRA-1-60 accompanied PLAP and M2A in 1 case with GCT. The results indicate that among different risk groups the highest incidence of CIS occurs in DMP. Screening for CIS is of importance also in cryptorchidism, androgen insensitivity syndrome and in men who underwent gonadectomy because of unilateral GCT. The immunostaining for PLAP seems to be more discriminative procedure. The positive staining of CIS cells with M2A and TRA-1-60 antibodies may be indicative for more advanced neoplastic transformation.     

High level of endostatin in epididymal epithelium: protection against primary malignancies in this organ?

Rete testis and epididymis are rare locations for primary tumors or metastasis. Assuming that this may be related to expression level of angiogenic inhibitors, we focused our study on the expression pattern of collagen 18/endostatin. In situ hybridization and immunohistochemistry for collagen 18 and endostatin were carried out on sections of human rete testis and epididymis as well as on epididymal adenoma and human testicular tissue with or without carcinoma in situ (CIS). In situ hybridization revealed strong expression of collagen 18 mRNA in rete testis, efferent ducts and epididymal duct. Immunostaining showed collagen 18 in epithelium and basement membrane as well as in blood vessels of rete testis. Further, in both efferent ducts and epididymal duct, collagen 18 was mainly localized in the basement membrane of these ducts and of the blood vessel wall. Endostatin immunostaining was localized in the epithelium of rete testis, efferent ducts and epididymal duct. This pattern of endostatin staining was absent in epididymal adenoma tissue while tumor associated blood vessels exhibited strong endostatin staining. No endostatin staining was detectable in normal germinal epithelium and CIS cells while Leydig cells exhibited strong endostatin staining. High endostatin expression in epididymis may protect this organ against tumor development. Gene therapeutic strategies providing high expression of endostatin in normal epithelia may be useful to prevent tumor development.     

Trial of the clinical use of mithramycin in treating testicular cancer

The data on efficacy of mitramycin, an antitumor antibiotic in treatment of 32 patients with cancer of the testicle are presented. The objectively pronounced effect was observed in 37.5 per cent of the cases, mitramycin being effective in patients with tumors resistant to bleomycin, vinblastin and cis-dichlordiaminoplatinum. Nausea and vomiting were the most frequent side effects of mitramycin use. The hemorrhagic syndrome was recorded in 2 patients. The regimen of the mitramycin intravenous administration in a dose of 25--30 microgram/kg once in 2 days was well tolerated by the patients and may be recommended for the treatment of testicle cancer.     

Reconstructive management of contralateral breast cancer in patients who previously underwent unilateral breast reconstruction

When a patient who has had unilateral breast reconstruction presents with a new cancer on the opposite side, the reconstructive management of the second breast can be unclear. This study was performed to determine whether reconstruction of the second breast is oncologically reasonable and to evaluate the reconstructive options available to these patients.Patients who had mastectomy with unilateral breast reconstruction between 1988 and 1994 and who had a minimal follow-up of 5 years from the initial breast cancer were reviewed. Of 469 patients reviewed, 18 patients (4 percent) were identified who developed contralateral breast cancer. Mean age at the initial breast cancer presentation was 43 years (range, 26 to 57 years), and mean age at presentation with contralateral breast cancer was 48 years (range, 36 to 67). The mean interval between the initial and contralateral breast cancer presentations was 5 years (range, 1 to 10 years). Mean follow-up from the time of contralateral breast cancer was 5 years (range, 1 to 9 years). In most cases, contralateral breast cancer presented at an early stage (13 of 18 patients; 72 percent), and a shift to an earlier stage at presentation of the contralateral cancer was evident compared with the initial breast cancer. Of the 18 patients who developed contralateral breast cancer, 16 (89 percent) had no evidence of disease, one was alive with disease, and one died. Reconstructive management after the initial mastectomy included 16 transverse rectus abdominis myocutaneous flaps (seven free and nine pedicled), one latissimus dorsi myocutaneous flap with implant, and one superior gluteal free flap. Surgical management of the second breast after contralateral breast cancer included breast conservation in two patients, mastectomy without reconstruction in four, and mastectomy with reconstruction in 12. Reconstruction of the second breast included one free transverse rectus abdominis myocutaneous flap, three extended latissimus dorsi flaps, two latissimus dorsi myocutaneous flaps with implants, three implants alone, two Rubens flaps, and one superior gluteal free flap. No major complications were noted after the reconstruction of the second breast. The best symmetry was obtained when similar methods and tissues were used on both sides.The incidence of contralateral breast cancer after mastectomy and unilateral breast reconstruction is low. In most cases, contralateral breast cancer presents at an earlier stage compared with the initial breast cancer, and the prognosis is good. In patients who develop a contralateral breast cancer after mastectomy and unilateral breast reconstruction, the reconstruction of the second breast after mastectomy is oncologically reasonable and should be offered to provide optimal breast symmetry and a better quality of life. The best result is obtained when similar methods and tissues are used on both sides.     

Early diagnosis of testicular cancer

PURPOSE: The authors analyze their 3-year results of the "educational and early detection program for testicular cancer". The goals of the program are to reduce the duration of symptoms and to improve early detection. METHODS: Advertisements were placed in the media describing the early signs of testicular cancer, the risks factors, the correct method of self-investigation and the importance of early detection. Between 1 April, 1995 and 1 April, 1998 5056 volunteers were examined. They underwent physical and ultrasound examination of the testicles, and in case of suspicious findings, tumor markers (alpha-fetoprotein, human choriogonadotropin) were checked. RESULTS: Testicular tumors were found in 1.28% of patients with symptoms (testicular enlargement or nodules). No tumor was found in the population that was symptom-free, or in patients with pain, sensitivity to palpation, or unrelated complaints. Of the patients with a palpable lump and swollen testicles, 4.5 and 3.9% were found to have tumors respectively. In total 32 testicular tumors were detected in 30 patients: 15 (2 bilateral) seminomas, 13 non-seminomas and 4 benign tumors. The occurrence of malignant testicular tumors was most frequent, 1.6% in the age group between 15 and 40 years. The stages were as follows: 9 I/A, 9 I/B, 1 I/S, 3 II/A, 1 II/B and 2 III/B. One patient was lost to follow-up after castration. All the other patients achieved complete remission. CONCLUSION: Despite the increasing incidence of testicular cancer screening of asymptomatic men does not lead to detection of tumors. The awareness of the early signs associated with cancer, self-examination, ultrasound examination of the testicle help in establishing an early diagnosis, nevertheless a widescale program for the early detection of testicular cancer is not justifiable. Effective early detection should be based on an educational program for the population at risk, the appropriate training of doctors and staff engaged in the health care of the young, and the initiation and facilitation of early ultrasound examination at the first symptoms. Serum markers play a limited role in early diagnosis.     

Loss of p53 and acquisition of angiogenic microRNA profile are insufficient to facilitate progression of bladder urothelial carcinoma in situ to invasive carcinoma

Activation of oncogenes or inactivation of tumor suppressors in urothelium is considered critical for development of urothelial cancer. Here we report cloning of the urothelium-specific promoter uroplakin-II (UPK II) and generation of transgenic mice in which expression of SV40 large T antigen is driven by UPK II promoter. Inactivation of tumor suppressor p53 and pRb in urothelium by SV40 T antigen resulted in urothelial carcinoma, resembling human high-grade carcinoma in situ. Specific deletion of p53 in urothelial cells using the newly generated UPK II-Cre mice results in normal bladders without any evidence of cancer. The high-grade carcinoma in situ in the UPK II-SV40 mice is associated with significant activation of angiogenic signals consisting of hypoxia-inducible factor-1α (HIF-1α) and VEGF and a down-regulation of thrombospondin-1. Interestingly, such pro-angiogenic activity was not associated with progression to invasive cancer. Analysis of bladder-associated microRNAs in carcinoma in situ lesions reveals a pro-angiogenic profile, with specific overexpression of miR-18a and miR-19a and down-regulation of miR-107. A group of microRNAs (miRs) identified as associated with invasive human urothelial cancer remained unchanged in this mouse model. Collectively, our results support the notion that activation of angiogenesis and loss of p53 are not sufficient for progression to invasive cancer. Our studies identify a new mouse model for bladder cancer that can be used to study factors that determine progression to an invasive phenotype of bladder cancer.     

Estimation of proportion of the patients with a very low number of tumor cells from carcinoma in situ in the cervical smear

The proportion of patients with cervical carcinoma in situ exhibiting a very low number of tumor cells in cytologic samples from the female reproductive tract was assessed with a model based on a multivariate beta distribution. The results of the study indicate that it is highly unlikely that a case of carcinoma in situ will be missed when 50,000 cells are screened in a given sample. However, the study also shows the importance of sampling methodology in the design of screening systems for cervical cancer and the crucial role that the coefficient of variation between patients assumes.     

Morphological and molecular aspects of cancerogenesis in the lung

Morphology and some molecular aspects of hyperplastic (bronchial basal cell hyperplasia and alveolar cell hyperplasia), metaplastic (squamous metaplasia), preneoplastic and early neoplastic (dysplasia in squamous metaplasia, cancer in situ and atypical alveolar cell hyperplasia) changes were studied in 180 lungs resected due to non-small cell lung cancer: 106 cases (58.9%) of squamous cell carcinoma, 42 (23.3%) of adenocarcinoma and 32 (17.8%) of large cell carcinoma. P53 protein and PCNA expressions were detected immunohistochemically (using formalin-fixed, paraffin-embedded sections). DNA extracted from the microdissected P53-positive cells was analysed for point mutations in the P53 gene. No P53 immunostaining was observed in normal mucosa, hyperplasia of basal cells, squamous metaplasia without and with minor and moderate dysplasia of bronchial mucosa as well as alveolar cell hyperplasia. Overexpression of P53 protein occurred in 3 out of 12 (25%) cases of severe bronchial dysplasia, 5 out of 11 (45.5%) cases of intraepithelial carcinoma and 6 out of 45 (13.3%) cases of alveolar cell hyperplasia. Using direct sequencing, mutations in the P53 gene were detected in 11 out of 14 (87%) P53-immunopositive samples, including all severe dysplasias, all carcinomas in situ and 3 of 6 alveolar cell hyperplasias. A significant association was observed between PCNA expression and preinvasive as well as invasive lesions. The data clearly show that lung resected due to primary cancer ought to be treated as "field cancerization" in which one can find early morphologic events of multi-step cancerogenesis. P53 protein alterations and P53 gene mutations can occur before invasion and its frequency depends on the degree of dysplasia.     

Proliferation index and karyometric features of pancreatic intraductal proliferative lesions.

The increasing frequency and poor prognosis in pancreatic cancer prompt us to search for morphological lesions being a substrate for its development. Studies of autopsy and surgically resected material as well as recent molecular studies have proved that one of the possible pathways of pancreatic neoplasia is the intraepithelial proliferation--dysplasia--cancer sequence. In the present paper we studied the proliferative activity (Ki-67 index) in pancreatic intraepithelial proliferative lesions and its correlation with geometric features of cell nuclei as signs of increasing dysplasia. The studies were carried out in a group of 35 patients operated on for pancreatic cancer, chronic pancreatitis and other conditions not associated with the pancreas. We used immunohistochemical methods and basic morphometric parameters. The results of our studies indicate that the cell proliferative activity depends both on the type of epithelial proliferation and underlying pancreatic disease. The values of Ki-67 index are significantly different in low-grade proliferation (flat and papillary hyperplasia) and high-grade proliferation (atypical papillary hyperplasia and carcinoma in situ). A set of karyometric features correlates with Ki-67 index but there is no single feature which would have a diagnostic value.