Optimal breast cancer pathology manifesto.

This manifesto was prepared by a European Breast Cancer (EBC) Council working group and launched at the European Breast Cancer Conference in Glasgow on 20 March 2014. It sets out optimal technical and organisational requirements for a breast cancer pathology service, in the light of concerns about variability and lack of patient-centred focus. It is not a guideline about how pathology services should be performed. It is a call for all in the cancer community--pathologists, oncologists, patient advocates, health administrators and policymakers--to check that services are available that serve the needs of patients in a high quality, timely way.

Expression of LRIG1 is associated with good prognosis and human papillomavirus status in oropharyngeal cancer.

BACKGROUND: The incidence of human papillomavirus (HPV)-associated oropharyngeal cancer has increased rapidly during the past decades. HPV is typically associated with a favourable outcome; however, a need exists for new and more effective prognostic and predictive markers for this disease. Leucine-rich repeats and immunoglobulin-like domains (LRIG)-1 is a tumour suppressor protein that belongs to the LRIG family. LRIG1 expression has prognostic significance in various human cancers, including cervical cancer, where HPV is a key aetiological agent. METHODS: The prognostic value of LRIG1 and LRIG2 immunoreactivity was investigated in tumour specimens from a Swedish cohort of patients with tonsillar and base of tongue oropharyngeal cancers, including 278 patients. RESULTS: LRIG1 immunoreactivity correlated with disease-free survival and overall survival in univariate and multivariate analyses. Notably, patients with HPV-positive tumours with high LRIG1 staining intensity or a high percentage of LRIG1-positive cells showed a very good prognosis. Furthermore, LRIG1 expression correlated with HPV status, whereas LRIG2 expression inversely correlated with HPV status. CONCLUSIONS: Taken together, the results suggest that LRIG1 immunoreactivity could be a clinically important prognostic marker in HPV-associated oropharyngeal cancer.

Disease Extent ≥4 cm Is a Prognostic Marker of Local Recurrence in T1-2 Breast Cancer.

Despite improvements of the therapy for breast cancer, a proportion of the patients still get local recurrence. The status of the surgical margins is the most often used parameter for decision regarding additional treatment. However, a negative margin is not a guarantee that there is not residual cancer left in the breast; additional parameters are needed to better predict the risk of local recurrence. The disease extent was evaluated in the surgical specimen from 313 women after breast-conserving therapy using large-section histology and was correlated to the incidence of local recurrence. A disease extent ≥4 cm was shown to be an independent marker for local recurrence; the cumulative 10-year local relapse rate for the group with a disease extent ≥4 cm was 20.5%, and for the rest 6.7%. We conclude that disease extent ≥4 cm seems to be an important factor when evaluating the risk for local recurrence.

Primary adenocarcinoma of the seminal vesicle.

Primary adenocarcinomas of the seminal vesicle (SVC) are very rare and poorly understood neoplasms with only somewhat more than 50 histologically confirmed cases reported in the literature. We demonstrate a case of SVC and discuss the problems related to diagnosis in this tumor.

LRIG1 and squamous epithelial uterine cervical cancer: correlation to prognosis, other tumor markers, sex steroid hormones, and smoking.

The aim is to evaluate LRIG1 as a prognosis predictor and correlations to cofactors in squamous cell cervical cancer. LRIG1 expression was studied in 128 cervical carcinomas and was compared with expression of nine other tumor markers. Smoking history was registered and pretreatment serum estradiol and progesterone levels were evaluated in 79 women. At clinical stage IB, 58% of the tumors showed LRIG1 expression, but there was a decline by increasing stage (33% in stage IV). Ninety percent of women with stage IB cancer and LRIG1 positivity survived, as compared to 64% without expression (P = 0.02). LRIG1 expression did not predict prognosis in advanced stages, but in stage IIA there was a marked relative difference, with 75% survival in tumors expressing LRIG1, as compared to 43% in those without. No correlation was found between LRIG1 and the other nine tumor markers studied. A high serum progesterone and smoking correlated to absent LRIG1 expression. We conclude that LRIG1 appears to be a significant prognosis predictor in early-stage cervical cancer, independent of the other tumor markers that were studied. Diminished expression in advanced stages and the inverse correlation to serum progesterone and smoking indicates that LRIG1 is a tumor suppressor in cervix.

Prediction of extracapsular extension of prostate cancer based on systematic core biopsies.

OBJECTIVE: To evaluate the clinical utility of transrectal ultrasound-guided systematic sextant or octant biopsies for the prediction of extracapsular extension (ECE) at radical prostatectomy. MATERIAL AND METHODS: We performed a retrospective analysis of 84 patients who underwent preoperative staging and transrectal ultrasound-guided systematic sextant (n=60) or octant (n=24) biopsy. The presence of ECE was correlated with the number of positive biopsies on each side of the prostate by chi(2) analysis. Sensitivity, specificity and positive and negative predictive values were calculated for both positive (two or three positive biopsies per side) and negative (none or one positive biopsy per side) test results. The number of positive cores was thereafter combined with two other parameters: prostate-specific antigen (PSA) level and Gleason score. RESULTS: ECE was evidenced at radical prostatectomy in 24% of patients (20/84). chi(2) analysis demonstrated a significant correlation between the number of positive biopsies and the presence of ECE. Analysis of the 168 prostate sides and dominant sides revealed that systematic needle biopsies had positive predictive values of 46.7% and 37%, respectively and negative predictive values of 89% and 94%, respectively. Use of a combination of parameters (biopsy Gleason score > or =7 vs <7; PSA >10 vs < or = 10 ng/ml; and >1 positive core vs none or one positive cores) identified patients at high or low risk of ECE. At the extremes, none of the 10 patients in the low-risk group had ECE at radical prostatectomy, compared to 77% of those in the high-risk group. CONCLUSION: The probability of ECE at radical prostatectomy can be accurately predicted based on the number of positive sextant and octant biopsies, either alone or in combination with other parameters.

Unclassified sex cord/gonadal stromal testis tumor with predominance of spindle cells.

Unclassified sex cord/gonadal stromal tumors (SCSTs) of the testis comprised predominantly of spindle cells are extremely rare. It is important to differentiate these tumors from other testicular neoplasms, especially other types of sex cord/gonadal stromal tumors. In addition to histological criteria, immunohistochemistry plays an important role in the differential diagnosis. We describe a single case of this rare tumor type and discuss the differential diagnostics options based on a review of the related literature. The problem of the lack of reliable morphological prognostic factors is also addressed.

Cytokeratins 20 and 7 as biomarkers: usefulness in discriminating primary from metastatic adenocarcinoma.

Metastatic adenocarcinoma from an unknown primary site is a common clinical problem. The use of cytokeratins 20 (CK20) and 7 (CK7) was proposed to identify the primary sites in this situation. In this review, the results of 29 studies were summarised and the difficulties of data comparison described. Most tumours retained the CK20 phenotype during metastasis, but lung, non-mucinous ovarian, and gastric adenocarcinomas showed statistically significant differences in CK20 expression in the reported primary and metastatic cases. Ductal breast carcinomas, lung and non-mucinous ovarian adenocarcinomas showed significant differences in CK7 expression when primary and metastatic tumours were compared. CK20 positivity alone indicates metastatic spread of adenocarcinoma in several organs. CK7 negativity is consistent with metastases of adenocarcinomas in the lungs, ovaries, liver or serous membranes. CK20/7 phenotyping of adenocarcinomas is a useful diagnostic tool if based on algorithmic and probabilistic approaches and a detailed database.

The value of cytokeratins 20 and 7 in discriminating metastatic adenocarcinomas from pleural mesotheliomas.

BACKGROUND: Immunohistochemistry is a useful method in the differential diagnosis between pleural mesotheliomas and metastatic adenocarcinomas to the pleura. Cytokeratin (CK) 5-6 is one of the most specific mesothelioma-associated antibodies. Cytokeratin 20 and CK7 have been used successfully in studies determining primary location of adenocarcinomas from metastases. In the current study, the value of these CKs in differential diagnosis of malignant pleural lesions was examined. METHODS: Ninety-three autopsy-verified cases (14 mesotheliomas and 79 adenocarcinomas including 42 primary lung tumors and 37 adenocarcinomas metastatic to the pleura) were stained on CK20, CK7, and CK5-6 with commercially available primary antibodies. The staining was conducted in an automated immunohistochemical system. The results were analyzed statistically at different positivity thresholds: 10% and 0%. RESULTS: None of the mesotheliomas stained positively for CK20 at the 10% positivity level, but 3 cases showed focal positivity in < 10% of the tumor cells. Eighty-six percent (12 of 14) of these tumors were CK7+ and 64% (9 of 14) were CK5-6+. None of the mesotheliomas expressed the CK20+/7- pattern. Lung adenocarcinomas, both primary and metastatic, and breast carcinomas were very similar to mesotheliomas with regard to expression of CK20 and CK7 but differed significantly with regard to expression of CK5-6. Conversely, gastrointestinal adenocarcinomas and pancreaticobiliary tumors expressed CK20 positivity in a high proportion, 86% (13 of 15) and 77% (7 of 9), respectively. The gastrointestinal tumors stained positively for CK7 in only 20% (3 of 15) of cases and differed significantly from the other adenocarcinomas in this aspect. The CK20+/7- pattern was typical for gastrointestinal tumors. CONCLUSIONS: Adding CK20 and CK7 to the panel of antibodies in the differential diagnosis of pleural mesothelioma versus metastatic adenocarcinomas is useful because diffuse CK20 positivity seems to be an indicator of metastasis. Furthermore, CK7 negativity most often is associated with metastases, and the CK20+/7- pattern, typical of colorectal adenocarcinomas, is absent in pleural mesotheliomas.

The pressing need for better histologic-mammographic correlation of the many variations in normal breast anatomy.

Mammography screening calls for a reevaluation of the working relationship between physicians dealing with the diagnosis and treatment of breast diseases. In this new era, histologic-mammographic correlation needs to be extended to correctly describe the deceptive mammographic findings that correspond to variations in normal breast tissue. Progress in histologic-mammographic correlation can only be made by overcoming the limitations inherent to the traditional histologic technique by examining a histologic specimen of greater length, width, and depth. There are several distinct advantages to using the large-section histology technique in the diagnosis of breast diseases. The subgross (three-dimensional) histology technique serves to bridge the gap that separates the pathologist and radiologist, bringing them to a common ground for a better understanding of breast morphology. These improvements in communication between the members of the diagnostic team will serve to optimize the sensitivity and specificity of breast cancer diagnosis.

The role of cytokeratins 20 and 7 and estrogen receptor analysis in separation of metastatic lobular carcinoma of the breast and metastatic signet ring cell carcinoma of the gastrointestinal tract.

Metastatic signet ring cell carcinomas of unknown primary site can represent a clinical problem. Gastrointestinal signet ring cell carcinomas and invasive lobular carcinomas of the breast are the most common sources of these metastases. Immunohistochemical algorithms have been successfully used in the search for the unknown primary adenocarcinomas. In the present study a series of primary invasive lobular breast carcinomas (79 cases) and their metastases and a series of gastrointestinal signet ring cell carcinomas (22 primary and 13 metastases) were stained with monoclonal antibodies for cytokeratin (CK) 20 and CK7 and for estrogen receptors (ER). The staining was evaluated as negative (no staining), focally (less than 10% of the tumor cells stained) or diffusely positive. All the primary and metastatic gastrointestinal signet ring cell carcinomas proved to be CK20 positive, while only 2/79 (3%) of the primary and 1/21 metastatic lobular carcinomas (5%) stained positively for this CK. None of the gastrointestinal carcinomas and the majority of the lobular carcinomas expressed ER. The majority of the tumors were CK7+. Using CK20 alone, 33 of 34 metastases could be properly classified as gastrointestinal (CK20+) or mammary (CK20-). ER identified 31/34 of breast cancer metastases. By combining the results of CK20 and ER staining all the metastases could be properly classified as the CK20+/ER- pattern identified all the gastrointestinal tumors.

The Swedish Two-County Trial twenty years later. Updated mortality results and new insights from long-term follow-up.

The benefit of invitation to mammographic screening observed in this trial is maintained as a highly significant 32% reduction in breast cancer mortality. Mammographic screening for breast cancer continues to save lives after up to 20 years. Screening derives this benefit by improving the distribution of tumors diagnosed with respect to prognostic categories based on node status, size, and histology of tumors. There is potential for modern screening programs with shorter interscreening intervals to achieve even greater improvements in prognostic category and greater reductions in breast cancer mortality. Mammography can discriminate a subpopulation of high-risk cases, those displaying casting-type calcifications on the mammogram, among very small tumors, with fundamental implications for diagnosis and treatment.

The cytokeratin profile of medullary carcinoma of the breast.

AIMS: The cytokeratin (CK) phenotype and vimentin expression of 31 medullary carcinomas was studied using commercially available antibodies on archived material. Comparing the phenotype of typical and atypical tumours and the phenotype of metastases, the biological significance of cytokeratin and vimentin expression in medullary carcinomas of the breast was determined. METHODS AND RESULTS: Antibodies to CK4, CK5 and 6, CK7, CK14, CK8 and 18, CK19, CK20 and to vimentin were used. All the typical and atypical medullary carcinomas and the metastases (10 cases) stained negatively for CK4 and positively for CK8-18 (CAM5.2). Almost all the tumours were CK7 and CK19 positive and CK20 negative. Twelve per cent of the tumours contained CK14. Twenty-five per cent of the typical, 43% of the atypical and 20% of the metastatic medullary carcinomas showed CK5-6 positivity. No association between the cytokeratin-vimentin profile of the tumours and axillary node metastases, tumour size or oestrogen receptor status was found but instability of CK expression was demonstrated by comparing the primary tumours with their metastases. CONCLUSIONS: : Medullary carcinomas of the breast express all the glandular type CKs including CK19 and additionally a proportion of the tumours expresses some of the CKs typical for myoepithelial cells. There was no correlation with prognostic factors.

Patterns of distribution of cytokeratins 20 and 7 in special types of invasive breast carcinoma: a study of 123 cases.

Metastatic adenocarcinomas of unknown primary site are a common clinical problem. Invasive ductal carcinomas of the breast and some special types of invasive breast carcinoma are common sources of metastases. Immunohistochemical algorithms, such as a combination of cytokeratins 20 and 7, can be helpful in this situation. Detailed phenotyping of the different types and subtypes of primary invasive carcinomas and their metastases is an essential prerequisite for a successful search for an unknown primary tumor. A series of 123 primary invasive breast adenocarcinomas of special type and of 27 lymph node metastases was analyzed. Sections of selected blocks were stained with two monoclonal cytokeratin antibodies (CK20 and CK7) and evaluated as negative (no staining), focally positive or diffusely positive. Of the 123 carcinomas, 113 (92%) proved to be CK20 negative. Three of 82 (4%) invasive lobular carcinomas, three of 11 (27%) mucinous carcinomas, one of 10 (10%) tubular carcinomas, and one invasive papillary carcinoma stained diffusely with CK20. Additionally, a tubulolobular carcinoma and a medullary carcinoma showed focal CK20 positivity. One hundred twenty (98%) of the 123 tumors were CK7 positive, five of them only focally. One of the four solid invasive lobular carcinomas, one medually carcinoma, and one invasive papillary carcinoma were completely negative for CK7. Only two cases, one mucinous and one invasive papillary carcinoma, exhibited the CK20(+)/CK7(-) ("colorectal") pattern. One of the lymph node metastases was CK20(+); another was CK7(-). Like their ductal counterparts, invasive breast carcinomas of special type are usually CK20(-)/CK7(+); they generally retain this phenotype in their metastases. However, there are CK20-positive special-type breast carcinomas that can be confused with gastrointestinal or pancreaticobiliary carcinoma in metastases, especially if they are mucinous or invasive lobular.

Adenocarcinomas metastatic to the liver: the value of cytokeratins 20 and 7 in the search for unknown primary tumors.

BACKGROUND: Metastatic adenocarcinoma in the liver with an unidentified primary tumor site is a common clinical problem. Pathologists often are asked to identify the primary tumor site. The histologic picture itself usually is not helpful, because the histology may be similar in the metastases of tumors with different primary localizations. Immunohistochemistry can be helpful, but the previously recommended antibody panels are too complicated for everyday use. METHODS: A simple immunohistochemical algorithm with two monoclonal cytokeratin (CK) antibodies, CK20 and CK7, was tested on 93 autopsy cases of adenocarcinomas metastatic to the liver. Sections of the liver metastases were stained automatically and evaluated as negative (no staining), focally positive, or diffusely positive. Statistical comparison of the staining results for a single antibody was calculated as an odds ratio. RESULTS: Thirty-six of 93 (39%) metastases proved to be CK20 positive (+). In this group, the CK20+/CK7 negative (-) pattern was highly characteristic for colorectal localization of the primary tumor, having been observed 17 of 21 of the cases (81%). The CK20+/CK7+ pattern of the metastatic liver adenocarcinomas was highly suggestive of primary localization in the pancreas or biliary tract (11 of 14 cases; 79%). Exclusion of the tumors originating in the stomach raised these values to 94% and 92%, respectively. The statistically calculated predicted probability of primary tumor site being in the colon or rectum for CK20+/CK7- metastasis was 78,41%, the probability of a primary tumor being located in the pancreas or biliary tract was 74,85%, if calculated for the whole study group. CONCLUSIONS: The tested simple algorithm proved to be useful in CK20 positive (+) cases, predicting a primary tumor localization in the colon, rectum, pancreas, or biliary tract with high accuracy. The CK20- group was too heterogeneous to be classified adequately by these two antibodies.

[An experimental model of ischemic lesions of the small intestine]. / Eksperimentalni model ishemicke lezije tankog creva.

Ischemic (necrotic) lesions of the small intestine are caused by the influence of elevated environment temperature on the rat. The initial change which was gained was a subnuclear vacuolization of the absorptive cells on the tips of the intestinal villi. Later on, the vacuoles blend into the subnuclear space which contains a serous exudate in some places. With the expansion of the subnuclear space the epithelium separates from the stroma, and after it's desquamation there comes to an autolysis of the denuded stroma of the intestinal villi. The lesions are comparable with lesions of the small intestine caused by hypothermia, shock, mesenterial blood vessel ligation in experimental models of other authors, and with ischemic lesions of the small intestine in humans as well. These changes can be considered as a nonspecific consequence of mesenterial ischemia in the appearance of which vascular factors play a key role.

[Sudden death due to dysplasia of the right ventricle]. / Nagla smrt izazvana displazijom desne komore.

The authors present two cases of arrhythmogenic right ventricular dysplasia in two young males, who had died by sudden death. A brief presentation is given of the clinical manifestation, uninvasive and invasive diagnostic possibilities, of the pathoanatomic finding and the pathohistological presentation, and the possibilities of treatment.

[Multiple gastrointestinal polyps]. / Multipla gastrointestinalna polipoza.

A case of a ten year old adopted girl is presented, who had gastrointestinal disturbances, anal pruritus and relapses of urticaria from her fourth year of age. By means of radiological and endoscopis analysis, multiple gastrointestinal polyposis was established. Pathohistological examination of the polyp indicated that tubular adenomas were in question, therefore in the case of this girl it can be stated that she has diffuse tubular gastrointestinal adenomatous polyposis, which is a characteristic of Gardner's syndrome. At the moment of the setting of the diagnosis, the girl had no skin changes nor did she have any radiological changes on the bones of her skull. The first skin changes appeared one year after the diagnosis was set, and they were in the form of maculopapular nodules, comedos of the closed and open type on the forehead and chin.

[Characteristics of colonic carcinoma in our material]. / Karakteristike karcinoma debelog creva na nasem materijalu.

By analyzing the characteristics of colonic carcinoma on the ten-year material of the Department for pathology of the Senta Hospital we came to a conclusion that this disease has a greater part in the mortality structure of the region along the river Tisa in relation to the Vojvodina average. Some morphologically prognostic elements (the tumor type, the intensity of peritumoral lymphocytic infiltration) do not show any significant deviations from literature facts, while tumor differentiation, the type of invasion and grading according to Dukes indicate a less favorable situation in our surroundings. An attempt was made to evidence the relation between colonic adenoma and carcinoma on the basis of classic morphology and the presence of nucleolar organizers. Our results indicate the insufficient discovering of precancerous states and early stadiums of colonic cancer in our surroundings.

[Results of laryngo-microscopic examinations over a 10-year period at the ORL Department of the Senta Hospital]. / Rezultati laringomikroskopskih ispitivanja na desetogodisnjem materijalu ORL odeljenja bolnice u Senti.

In the period from 1980-1989, 199 laryngomicroscopical examinations were conducted at our department. There were 20 cases of laryngeal carcinoma, 55 cases of keratosis with the presence of dysplasia in 21.8%, as well as 19 papillomas in adult individuals. In our material keratoses appear a few years before the onset of laryngeal carcinoma in an average statistical distribution. With one exception, the carcinomas were detected before the appearance of metastases. Our data indicate the exceptional benefit of laryngomicroscopy in the detection of precancerous lesions and carcinoma of the larynx.