Frequent RET rearrangements in thyroid papillary microcarcinoma detected by interphase fluorescence in situ hybridization.

Papillary thyroid microcarcinomas (measuring 1 cm or less in diameter) are very common thyroid tumors, which are present in 10% to 35% of post-mortem histopathological examinations of individuals whose death was due to a cause other than thyroid cancer. The molecular basis of this tumor is still poorly understood. Somatic mutations are better characterized in clinically evident papillary thyroid carcinomas (PTCs), the most common involving the proto-oncogene RET, which maps to 10q11.2. Molecular alterations of RET always lead to intra- or interchromosomal rearrangements. In this study we have investigated the status of RET in 21 microcarcinomas, by means of interphase fluorescence in situ hybridization (FISH). RET was rearranged in 52% of microcarcinomas, a statistically significant higher frequency than that found previously in clinically evident PTCs using the same technique. Moreover, interphase FISH allowed us to detect a putative novel type of rearrangement in a microcarcinoma, and we observed trisomies of chromosome 10 and other chromosomes in two adenomas surrounding two of the microcarcinomas. The strikingly high frequency of RET rearrangements in microcarcinomas strongly suggests that RET plays a role in the initiation of thyroid tumorigenesis but does not seem to be necessary for the further progression of the tumor.     

Genomic amplification of the human telomerase gene (TERC) in pap smears predicts the development of cervical cancer

Invasive cervical carcinomas almost invariably carry extra copies of chromosome arm 3q, resulting in a gain of the human telomerase gene (TERC). This provided the rationale for the development of a multicolor fluorescence in situ hybridization (FISH) probe set as a diagnostic tool for the direct detection of TERC gains in Pap smears. We previously used this probe set to show that cervical intraepithelial neoplasia (CIN) 2 and CIN3 lesions could be distinguished from normal samples, atypical squamous cell of undetermined significance (ASCUS) and CIN1, with a sensitivity and specificity exceeding 90%, independent of the cytomorphological assessment. In the current study, we explored whether gain of 3q and amplification of TERC could predict progression from CIN1/CIN2 to CIN3 and invasive carcinoma. We applied our probe set to a series of 59 previously stained Pap smears for which repeat Pap smears and clinical follow-up were available. The samples included CIN1/CIN2 lesions that progressed to CIN3 (progressors), CIN1/CIN2 lesions that regressed spontaneously (regressors), and normal Pap smears from women who subsequently developed CIN3 or cervical cancer. Here, we show that progressors displayed a gain of 3q whereas none of the regressors showed this genetic aberration. These data suggest that 3q gain is required for the transition from CIN1/CIN2 to CIN3 and that it predicts progression. Of note, 3q gain was found in 33% of cytologically normal Pap smears from women who were diagnosed with CIN3 or invasive cervical carcinoma after a short latency. The sensitivity of our test for predicting progression from CIN1/CIN2 to CIN3 was 100% and the specificity, ie, the prediction of regression, was 70%. We conclude that the detection of 3q gain and amplification of TERC in routinely collected Pap smears can assist in identifying low-grade lesions with a high progression risk and in decreasing false-negative cytological screenings.     

The role of HER2/neu overexpression/amplification in the progression of ductal carcinoma in situ to invasive carcinoma of the breast.

HER2/neu overexpression/amplification is seen more frequently in ductal carcinoma in situ, particularly high-grade ductal carcinoma in situ (50-60%), than in invasive ductal carcinoma of the breast (25-30%). To date, however, the role of HER2/neu in the progression of in situ to invasive disease has not been clarified. Two hundred fifty-one breast tumors were retrieved from the pathology files at Mount Sinai Hospital. These included 91 cases of ductal carcinoma in situ, 136 cases of invasive ductal carcinomas with associated ductal carcinoma in situ, and 24 cases of pure invasive carcinomas. All cases were reviewed and stained with two monoclonal antibodies to HER2/neu (CB11 and TAB250). Immunohistochemical staining was recorded using a semiquantitative scoring system (1). Representative cases were also investigated using fluorescence in situ hybridization. HER2/neu protein overexpression (defined as immunohistochemical staining with score of >or=5) was seen in 34% of cases of pure ductal carcinoma in situ, 17% of invasive carcinomas with associated ductal carcinoma in situ, and 12.5% of pure invasive carcinomas (P =.01). Sixty percent of cases of high-grade ductal carcinoma in situ showed HER2/neu protein overexpression, versus 29% of high-grade invasive carcinomas with associated ductal carcinoma in situ and 22% of high-grade pure invasive ductal carcinomas (P =.02). The concordance between the immunohistochemical staining in the in situ and invasive components of individual tumors was 90%. Thirty-three cases were also evaluated by fluorescence in situ hybridization and showed concordance between the immunohistochemical results and the degree of gene amplification in 91% of cases, whereas 3 of 33 cases showed HER2/neu gene amplification (HER2/CEP17 = 2.3-3.7) by fluorescence in situ hybridization in the absence of positive immunohistochemical staining. One case showed HER2/neu gene amplification in the associated ductal carcinoma in situ (HER2/CEP17 ratio = 6.5), with no evidence of gene amplification in the invasive tumor (HER2/CEP17 ratio = 1.14). Multiple genetic events are required for the development of an invasive phenotype. The findings from this study suggest that the genetic event of HER2/neu gene amplification/protein overexpression may not play a key role in the progression of ductal carcinoma in situ to invasive carcinoma and that other molecular alterations may be more important in the initiation of invasion in ductal carcinoma of the breast.     

Fine needle aspiration cytology in young women with breast cancer: diagnostic difficulties

BACKGROUND: Breast carcinoma is the most common malignancy in women worldwide. Though fine needle aspiration cytology (FNAC) plays an important role in preoperative diagnosis, there may be diagnostic delays in affected young women due to a lower index of suspicion. METHODS: The files of the Departments of Pathology, Singapore General Hospital, Singapore, and Prince of Wales Hospital, Hong Kong, were searched for cases of breast carcinoma in women aged 35 years or less. Those with prior FNA procedures comprised our study group. The FNA smears were reviewed and classified into five categories: inadequate, benign, equivocal, suspicious, malignant. The findings were correlated with subsequent histology. RESULTS: Thirty-four women aged 35 years and below underwent 35 FNACs, with one woman having bilateral FNA procedures. Upon review, one (2.9%) was classified as inadequate, one (2.9%) benign, five (14.3%) equivocal, five (14.3%) suspicious, 21 (60%) malignant and slides were not available for review for two (5.6%) cases. For six benign and equivocal cytological diagnoses, subsequent histology disclosed pure ductal carcinoma in situ (DCIS, 1 case), mucocoele-like lesions with DCIS (2 cases), invasive and in situ ductal carcinoma with neuroendocrine features (1 case) and two cases of invasive ductal carcinoma. CONCLUSION: Diagnostic difficulties in cytological interpretation of aspirates from breast carcinoma in young women may lead to unwanted delays, which occurred in six (17.6%) of 34 women in our series. Low grade cancers posing a pitfall in cytological diagnosis have to be considered.     

Biological tissue markers in benign and malignant disease of the human prostate

Summary Immunoperoxidase techniques were used to study, the distribution of peanut agglutinin receptors, blood group isoantigens and several epithelial antigens in hyperplasia, adenosis, microcarcinoma and well differentiated adenocarcinoma of the prostate. Intraluminal and luminal surface PNA receptors were seen in all well differentiated carcinomas, 53% of microcarcinomas and 50% of adenosis, while no such sites could be demonstrated in benign hyperplasia. The expected blood group isoantigen was expressed in 75% of benign hyperplasias. When compared to the hyperplastic epithelium nearby, appropriate ABH expression was seen in 60% of adenosis, 47% of microcarcinomas and 25% of well differentiated carcinomas. A keratin antibody specifically labelling the basal cells in the normal prostate identified a subset of well differentiated carcinomas with preferential staining of the apical cytoplasm while microcarcinomas and adenosis were consistently negative. Our study establishes a highly ordered PNA receptor distribution in prostatic epithelia; it confirms early changes in the expression of ABH isoantigens in epithelial proliferative disorders of the prostate; it identifies a subset of keratin-positive well differentiated carcinomas, possibly of different ontogeny.     

Molecular phenotypes of matched in situ and invasive components of breast carcinomas

The current system of pathologic classification of human breast cancers does not take into account the biologic determinants of prognosis, nor is there a consensus regarding the progression from in situ to invasive carcinoma. The present study compared the molecular phenotypes of in situ and invasive components of breast cancer in the same sample. We built a series of 189 in situ and invasive carcinomas using tissue microarrays and classified them according to their immunoprofiles regarding estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, epidermal growth factor receptor, cytokeratin 5, P-cadherin, and the antigen Ki-67 into luminal A and B, human epidermal growth factor receptor 2 overexpressing, and basal-like carcinomas. We also correlated the subgroups of carcinomas with some of the classical prognostic factors such as histologic grade, tumor size, and lymph node metastasis, as well as with the age of the patient at diagnosis. The overall concordance on the molecular phenotypes between in situ and invasive components was 94%. For the in situ component, 63% of the cases were luminal A; 15%, luminal B; 12%, human epidermal growth factor receptor 2 overexpressing; and 7%, basal-like. Regarding the invasive component, 61% of the cases were luminal A; 16%, luminal B; 12%, human epidermal growth factor receptor 2 overexpressing; and 8%, basal-like. The present study allowed the identification of different immunoprofiles of in situ and invasive breast carcinomas using a specific panel of biomarkers and showed that in most cases, there is a concordance between in situ and invasive component profiles, supporting the theory of parallel disease in breast tumorigenesis.     

Early acquisition of gelatinolytic activity in carcinogenesis of the uterine cervix.

Film in situ zymography is a newly developed technique for detecting in situ gelatinolytic activity. Using the film in situ zymography method to stamp preparations, we evaluated the gelatinolytic activity in early stage cervical neoplasia and invasive squamous cell carcinoma. To determine the sensitivity of film in situ zymography for detecting gelatinase expression, slides made from stamps of 50 specimens resected from the uterine cervix, including early invasive carcinoma (FIGO Ia1 and Ib1) and cervical intraepithelial neoplasia (CIN) were examined by film in situ zymography. The specimens were also examined immunohistochemically with regard to mitotic activity and gelatinase expression. Gelatinolytic activity was subdivided into two patterns, the homogeneous pattern and the heterogeneous pattern. The homogeneous pattern consisted of circumscribed areas around atypical cell clusters; these areas were composed of homogenously digested full-thickness collagen, whereas the heterogeneous pattern consisted of spottily digested areas of superficial collagen around atypical cell clusters. All invasive carcinomas (8/8 cases) and carcinoma in situ (14/14 cases) were positive for gelatinolytic activity, and 33.3%(5/15 cases) of the specimens of CIN-1, CIN-2, and severe dysplasia were also positive. All invasive carcinomas and 6 of 14 carcinoma in situ (43%) showed homogenous pattern, and the other positive specimens showed heterogenous pattern. The MIB-1 index was 33.8% in invasive carcinoma, increasing stepwise from dysplasia to carcinoma. Matrix metalloproteinase-2 immunostaining was positive in 4 of 8 cases of invasive carcinoma and generally stained the stromal area around the tumor nest. These results indicated that matrix metalloproteinases are functionally activated even in carcinoma in situ and in cervical intraepithelial neoplasia of the uterine cervix not showing invasive growth histologically. Film in situ zymography can detect with sensitivity the invasive potential of carcinoma in situ and cervical intraepithelial neoplasia. An analysis combining cytological examination and film in situ zymography is a potentially useful tool for estimating invasive activity.     

Immunohistochemical comparison of p16 expression in actinic keratoses and squamous cell carcinomas of the skin.

There are approximately 200,000 new cases of cutaneous squamous cell carcinoma diagnosed each year in the United States, with between 1300 and 2300 deaths per year from metastatic disease. The tumor suppressor p16, encoded by the CDKN2/INK4a locus, has been reported mutated in >or=24% of squamous cell carcinomas. Mutations of the p16 gene have also been found in actinic keratoses, the first identifiable lesion in the continuum from normal skin to squamous cell carcinoma. We hypothesized that there may be an appreciable difference in expression of p16 between normal skin, actinic keratoses, squamous cell carcinoma in situ, and invasive squamous cell carcinoma. Ten actinic keratoses, 10 in situ squamous cell carcinomas, and 10 invasive squamous cell carcinomas were examined using the immunoperoxidase method with antigen retrieval for anti-p16(INK4a) antibody. All 10 actinic keratoses were positive for weak to moderate p16 staining in the lower third to lower half of the epidermis (especially the basal keratinocytes). This staining was significant when compared with the lack of staining seen in normal skin controls. Twenty percent of in situ squamous cell carcinomas had moderate to strong staining in only the lower half to lower two thirds of the epidermis, whereas 70% of the in situ squamous cell carcinomas exhibited full-thickness p16 staining, with no staining in the dermis. Thirty percent of invasive squamous cell carcinomas had full-thickness staining of the in situ component of the lesion, and 100% of invasive squamous cell carcinomas exhibited moderate to strong staining of the invasive component of the lesion. These findings indicate correlation between the increased expression of p16 during the progression of skin from actinic keratosis to in situ squamous cell carcinoma to invasive squamous cell carcinoma. These data may lend further support to the view of the actinic keratosis as a precursor lesion to squamous cell carcinoma.     

Galectin-3 expression in papillary microcarcinoma of the thyroid

AIMS: Galectin-3 is a beta-galactoside binding protein, recently recognized as a promising molecular marker of thyroid malignancy. As reported in several studies, galectin-3 is highly expressed in papillary thyroid carcinoma, but its expression has not been investigated in papillary microcarcinoma, which is a variant of papillary thyroid carcinoma. METHODS AND RESULTS: Using a monoclonal antibody to galectin-3 and the avidin-biotin-peroxidase complex (ABC) immunohistochemical technique, we analysed galectin-3 expression in 63 cases of papillary microcarcinoma. The results showed immunohistochemical reactivity for galectin-3 in 51 (80.9%) cases. Intensity of staining varied from strong or moderate to weak. Galectin-3 localization was mostly cytoplasmic, but also membranous or nuclear in some cells. Immunohistochemical expression of galectin-3 was not found in 12 (19.1%) cases. Most galectin-3 negative microcarcinomas (10/12) were of the non-classical type, i.e. without papillary architecture. Neither the frequency nor the intensity of a positive reaction was related to tumour size. CONCLUSIONS: Galectin-3 gene is expressed at the protein level in most papillary microcarcinomas, although with slightly lower frequency than that reported for clinically evident papillary thyroid carcinoma. The presence of galectin-3 in clinically silent microcarcinomas may indicate that galectin-3 is not related to growth or aggressiveness of papillary thyroid microcarcinomas but rather plays some other role in thyroid tumour biology.     

Fine-needle aspiration of breast lesions: role and accuracy in a review of 7,495 cases

In the past 10 years, 7,495 cytological breast fine-needle aspirations (FNAs) were performed (4,756 FNAs of solid nodes and 2,739 of cystic nodes). Of these, 2,099 cases underwent surgery; 650 (31%) had histologically proven carcinoma. Sensitivity was 83.9%, specificity was 99.5%, the predictive value for negative results was 93.2% and for positive results was 98.6%, and the accuracy was 94.6%. Inadequate (13.3%) and doubtful samples (8.1%) were excluded from calculation. False-negative results (82 cases) mainly resulted from sampling errors. False suspicious results (six cases) lessened with increasing experience in breast pathology and with the application of strict diagnostic criteria, but most likely they will never reach zero. Frozen-section diagnosis could be bypassed only in selected cases. Guidelines on the role of FNA in management of solid breast lesions are given. FNA deserves further evaluation in diagnosing early stages of breast carcinoma: sensitivity was 7.5% in 57 carcinomas in situ, 67.5% in 55 minimally invasive carcinoma, and 92.7% in 538 nonminimally invasive carcinomas.     

Detection rate and clinical significance of monoclonal gammopathy in different age groups in the population of Northern Jutland, Denmark

All serum protein electrophoresis performed in the period 1 May 1979-30 April 1982 in the county of Northern Jutland, Denmark, were studied to find the annual detection rate and the clinical significance of a monoclonal gammopathy (MG) in different age groups. A monoclonal gammopathy was found in 325 persons (185 males and 140 females). The average annual detection rate of MG per 100,000 individuals increased with age in both sexes (p less than 0.01, Kolmogorov test). The lowest and highest detection rate for males/females were 2.8/3.3 (age group less than 50 years) and 236.8/100.3 (age group greater than or equal to 80 years) per 100,000 individuals, respectively. Monoclonal gammopathy was associated with a B-cell malignancy in 28 percent (95% confidence limits 23.9-32.4%) of the persons irrespective of sex and age.     

Analysis of chromosome aneuploidy in breast carcinoma progression by using fluorescence in situ hybridization

Nonisotopic fluorescence in situ hybridization by using alpha satellite centromeric probes was performed on intact tissue sections of 12 breast carcinomas to compare the pattern of aneuploidy for chromosomes 7, 8, 16, and 17 between foci of residual in situ carcinoma (DCIS) and a representative area of coexisting invasive neoplasm. Most hybridization pairs (58%) showed a gain in chromosomal copy number between the in situ and corresponding invasive area, whereas 29% showed no apparent change and 13% showed loss in copy number. Hybridizations from areas of invasive carcinoma, thus, were more frequently characterized by tumor cells with trisomy/polysomy (78%) than neoplastic cells from residual DCIS (50%) and less frequently characterized by cells with monosomy (10% versus 16%, p = 0.01). Even when DCIS cells exhibited chromosome trisomy, 65% of hybridizations demonstrated a significantly greater proportion of trisomic cells in the corresponding invasive population. The hybridization pairs (n = 7) initially showing apparent loss in chromosome copy number from in situ to invasive growth were all from two cases that demonstrated morphologic heterogeneity. Enumeration of cells from histologically distinct areas of these cases revealed different patterns of aneusomy, in keeping with karyotypic diversity. However, comparison of histologically similar areas of DCIS and invasive neoplasm demonstrated a pattern of chromosome copy gain with invasive growth, similar to morphologically homogeneous tumors. We conclude that invading cells in breast carcinomas differ from residual in situ populations with respect to degree of chromosome aneuploidy and that tumor progression from preinvasive to an invasive phenotype in human breast carcinoma is characterized by a significant increase in the degree of genetic instability. The observed pattern of chromosome copy number gain, moreover, is consistent with a common cellular level genetic mechanism underlying early breast tumor progression.     

Carcinoma Arising in Microglandular Adenosis: An Immunohistochemical Analysis of 20 Intraepithelial and Invasive Neoplasms

Microglandular adenosis (MGA) of the breast is an uncommon, benign lesion that may mimic invasive carcinoma and has recently been recognized as having significant premalignant potential. When carcinomas arise in MGA, there is often a transition from ordinary MGA to atypical MGA (AMGA) to carcinoma. Nineteen cases of carcinoma arising in MGA are reported: 7 invasive carcinomas, 7 intraductal carcinomas (DCIS), and 5 with both invasive and intraductal carcinoma. A single case of AMGA without carcinoma is also reported. The 20 patients ranged in age from 36 to 81 years (mean 52). The most common clinical presentation was either a palpable mass (13 patients) or a mammographic abnormality (4 patients). All 20 cases contained AMGA, and in some cases AMGA was the predominant lesion. In 18 of the 19 cases with carcinoma, there was a clear transition from AMGA to the carcinoma. Twelve cases contained ordinary MGA, but in only 2 cases was MGA a prominent component of the lesion. In contrast to ordinary MGA, the glands of AMGA were more irregularly shaped, closely packed, and cytologically atypical and tended to lack secretions. A solid, occlusive proliferation of cells in the tubules was seen in 10 cases. All 12 examples of in situ carcinoma were either grade 2 or 3 and typically showed a solid proliferation of severely atypical cells within the glands; a cribrifrom pattern was also present in 1 case. The invasive carcinomas were morphologically diverse and included 2 with a basaloid morphology and 2 metaplastic carcinomas. Various immunostains were performed, and each lesion (AMGA, in situ, and invasive carcinoma) was separately assessed for immunoreactivity. As expected, S-100 was positive in the vast majority of AMGA and in situ carcinomas and in all 12 invasive carcinomas. S-100beta was also positive in the majority of cases although the staining was weaker. Laminin and type IV collagen highlighted the basement membrane around the AMGA and in situ carcinoma and are useful stains in difficult cases. Except for a single case, ER and PR were negative in all lesions. Cytokeratin 7 (CK 7) was positive, while cytokeratin 20 (CK 20) was negative in all cases. Immunostains for CK903 showed no reactivity in any of the invasive carcinomas, in situ carcinomas, or atypical MGA but was focally present in the associated MGA in 2 of the 8 cases studied. Immunostains for MIB-1 and p53 were semiquantitatively assessed and both were positive in AMGA but tended to show a more intense staining in the carcinomas. Five cases were also studied for immunoexpression of alpha-1 antitrypsin (AAT), alpha-1 antichymotrypsin (ACTP), lysozyme, and salivary gland amylase. All 5 invasive carcinomas were positive for ACTP, though the staining was very focal in about 10% of the cells in a basaloid carcinoma. The in situ carcinoma as well as the AMGA in 4 of the 5 cases were positive for ACTP. Three of the 5 invasive carcinomas were positive for AAT in 10% to 40% of the cells. The most intense positivity for AAT and ACTP was in cells with coarsely granular apocrine appearance evident in 2 of the 5 cases. Four of the 5 invasive carcinomas were positive for lysozyme in 10% to 50% of the cancer cells; the in situ carcinoma and the associated AMGA showed similar immunoreaction in each case. None of the 5 cases showed convincing positivity for salivary gland amylase. The MGA in all 5 cases was negative for AAT and ACTP; the MGA in 1 of the 5 cases was positive for lysozyme. This study confirms the potential of MGA to develop into an invasive carcinoma, more clearly defines the features of AMGA, highlights the importance of AMGA in the evolution of carcinoma from MGA, and expands our knowledge of the immunophenotype of AMGA and the carcinomas arising from it. The diagnostic criteria briefly noted previously for diagnosis of AMGA and carcinoma arising in MGA are expanded and formally proposed. Int J Surg Pathol 8(4):303-315, 2000     

Follicular lesions of the thyroid: a retrospective study of 1,348 fine needle aspiration biopsies

Fine needle aspiration (FNA) has proven to be an effective tool in management of patients with thyroid nodules. However, the diagnosis of follicular patterned lesions can be challenging. The surgical and cytopathology computer database at a large referral medical center was searched for cases that had both cytologic and histologic thyroid accessions from January 2004 to November 2008. A total of 1,255 histologic thyroid specimens and 2,776 thyroid FNA biopsies were retrieved for review. Histologically, 272 overt malignancies were identified; 20 (7.4%) were follicular carcinomas. Cytologically, 1,348 cases were follicular-patterned lesions, comprising 1,044 cases of "benign follicular nodules" (BFN), 137 cases of "follicular lesions of undetermined significance" (FLUS), and 167 cases of "suspicious for follicular neoplasm" (SFN). Seventy-nine (7.5%) of BFN, 23 (16.8%) of FLUS, and 65 (38.9%) of SFN cases had histologic follow-up. Overt malignancy, a cystic papillary carcinoma, was identified histologically in only one case of BFN, for a negative predictive value of 98.7%. Overt malignancy was identified histologically in two cases of FLUS, both follicular variant of papillary carcinoma, for a positive predictive value of 8.7%. Overt malignancy was identified histologically in 14 cases of SFN, for a positive predictive value of 21.5%. Five follicular carcinomas were identified histologically in the SFN category, all minimally invasive. Incidental ("occult") papillary microcarcinoma were identified histologically in all three categories. In this study, the risk of overt malignancy increases from 1.3%, to 8.7%, to 21.5% for BFN, FLUS, and SFN, respectively. All follicular carcinomas identified histologically occurred in the SFN category and all were minimally invasive. Papillary microcarcinomas can occur in any of the three diagnostic categories.     

Stereotactic fine needle aspiration biopsy (SFNB) of breast: preliminary results in Perth with the TRC mammotest machine. Cytological aspects.

Stereotactic fine needle aspiration biopsy (SFNB) was carried out on 404 mammographically detected impalpable breast lesions from 389 women between October 1988 and January 1990. Seventy-three lesions were excised, and 38 were carcinomas. Thirty-six of the 38 carcinomas had been diagnosed as atypical, suspicious or malignant by cytology; in the remaining 2 only fat and fibrous tissue were present in smears. The sensitivity of cytological diagnosis in detecting malignancy was therefore 94.8% (36 of 38 cases). A cytological diagnosis of malignancy was made in 23 cases (5.7%) and in 5 (1.2%) the findings were suspicious of malignancy. All of these were confirmed as carcinoma histologically; the predictive value of a positive cytological diagnosis was therefore 100%. In 32 cases (7.9%) the cytological findings were atypical but inconclusive. Twenty-three of these lesions were excised, and 8 proved to be carcinoma (34.8%). No case assessed radiologically and cytologically as benign has subsequently proven to be malignant. Twenty-two of 28 cases of invasive carcinoma were given an unequivocal cytological diagnosis of malignancy; 2 were suspicious of malignancy, and in 3 the findings were atypical but inconclusive. Of the 10 pure duct carcinoma-in-situ (DCIS) lesions, (26.3% of the cancers) 1 was diagnosed cytologically as malignant, 3 as suspicious of malignancy, and 5 as atypical. The sensitivity of SFNB in detecting DCIS lesions was therefore similar to invasive carcinomas, but cases of DCIS were more likely to be given a suspicious or atypical diagnosis rather than a definite diagnosis of malignancy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Expression of poly-ADP-ribose polymerase (PARP) in endometrial adenocarcinoma: Prognostic potential

BackgroundIn the United States endometrial carcinoma is the most common female gynecologic malignancy. An average of more than 60,000 new cases of endometrial carcinomas have been diagnosed yearly over the past 5 years, with a higher incidence occurring in the central Appalachian states of Ohio and West Virginia. In the U.S., the national average of newly diagnosed endometrial carcinomas is 26.8 in every 100,000 women, while in the states of Ohio and West Virginia the average is 30.5 and 31.1 in every 100,000 women, respectively. This notable increase in the incidence of endometrial carcinomas may be due a variety of elevated risk factors including but not limited to: tobacco use, obesity, and genetic predisposition of the predominant demographic. The American Cancer Society estimates that approximately 55,000 new cases of endometrial carcinoma will be diagnosed in 2020 yet, this disease is widely considered understudied and under-represented in mainstream cancer research circles.MethodsThe aim of this study was to quantitate the co-expression of two DNA repair proteins poly-ADP-ribose polymerase 1 and 2 (Parp-1 and Parp-2) by enzyme- linked immuno-sorbent assay (ELISA) in 60 endometrioid endometrial tumor samples and compare their expression to matched non-malignant endometrial tissue from the same corresponding donors from central Appalachia.ResultsWe found that Parp-1 was significantly overexpressed in endometrial carcinoma relative to corresponding normal tissue. This overexpression implicates Parp inhibition therapy as a possible treatment for the disease. Our results also found a protective effect of native Parp-2 expression in non-malignant endometrial tissue with each 1 ng/mL increase in PARP-2 concentration in normal tissue was associated with a 10 % reduction in the hazard of tumor progression (HR = 0.90; p = 0.039) and a 21 % reduction in the hazard of death (HR = 0.79; p = 0.044).ConclusionsThis study demonstrated the over-expression of the druggable target Parp-1 in endometrial adenocarcinoma and observed a strong negative correlation of native Parp-2 expression and disease progression via the quantification of the Parp proteins using enzyme- linked immuno-sorbent assay (ELISA) assays.     

Structural characteristics of the tumor and the state of the surrounding tissue in middle-aged and elderly breast cancer patients

Investigations of mammary glands of 241 patients of 50-70 years of age or older suffering from carcinoma and having been is menopause for 10 years or more established that the main histological form of carcinoma was infiltrating carcinoma of glandular, solid, solid-scirrhous structure of various degrees of malignancy (I, II, III) (81.3%), irrespective of the age and duration of menopause. The main forms of carcinoma were observed in occasional cases, most frequently it was lobular invasive carcinoma (8.3%). In 65% of the patients carcinoma was detected in the presence of involutive processes and changes corresponding to nonproliferating mastopathy. In one-third of the patient carcinomas developed in the presence of proliferative processes, half of these patients showing transition from proliferation of the epithelium of ducts and lobules to cancer in situ and its invasion into the surrounding tissues of mammary glands.     

Detection of amplified int-2/FGF-3 gene in primary breast carcinomas using differential polymerase chain reaction.

Amplification of int-2/FGF-3 gene was investigated by differential polymerase chain reaction (dPCR) in 440 archival primary breast carcinoma tissues. Of these, 23 were comedo ductal carcinoma in situ (DCIS), 18 were non-comedo DCIS, 41 were comedo DCIS with adjacent invasive ductal carcinomas, 19 were non-comedo DCIS with adjacent invasive ductal carcinomas, 270 were invasive ductal carcinomas, 33 were invasive lobular carcinomas, 21 were colloid carcinomas and 15 were medullary carcinomas. Int-2 was amplified in 22% (96/440) of the primary breast carcinomas. It was shown that int-2 was amplified in 13% (3/23) of the comedo DCIS, 17% (7/41) of the comedo DCIS and 29% (12/41) of the adjacent invasive ductal carcinomas, 26% (71/270) of the invasive ductal carcinomas, 18% (6/33) of the invasive lobular carcinomas, 10% (2/21) of the colloid carcinomas and 13% (2/15) of the medullary carcinomas. In contrast, int-2 was not amplified in non-comedo DCIS and invasive ductal carcinomas with adjacent non-comedo DCIS lesions. A significant association was observed between int-2 amplification in the in situ components and adjacent invasive lesion (P<0.05). All tumors with int-2 amplification in the in situ lesions (7/7) also demonstrated same degree of amplification in the adjacent invasive components. However, 9% (5/53) of the tumors with no amplified int-2 gene in the in situ components showed int-2 amplification in the adjacent invasive lesions. A significant relationship was noted between amplification of int-2 and lymph node metastases (P<0.05) and poorly differentiated tumors (P<0.05) but not with estrogen receptor status (P>0.05) and proliferation index (Ki-67 and PCNA) (P>0.05). In Malaysia, majority of the patients belong to younger age group (<50 years old) but a comparison of the age groups showed that the amplification of int-2 was not statistically associated with patient age (P>0.05). These observations indicate that amplification of int-2 tends to strengthen the view that int-2 may have the potential to be an indicator of poor prognosis regardless of the age of the patient. Moreover, the presence of int-2 amplification in preinvasive, preinvasive and adjacent invasive lesions, and invasive carcinomas suggest that int-2 could be a marker of genetic instability occurring in early and late stages of tumor development.     

Overexpression of clusterin in human breast carcinoma

Clusterin has been implicated in numerous processes including active cell death, immune regulation, cell adhesion and morphological transformation. The purpose of this study was to examine clusterin expression in a large series of breast carcinomas by immunohistochemistry and in situ hybridization. The study included 40 samples of non-neoplastic glandular epithelia, 42 benign lesions, 15 atypical intraductal hyperplasias, 35 carcinomas in situ, 114 invasive carcinomas, and lymph node metastases from 40 patients. Epithelial normal cells were always negative for clusterin expression and only 19% of the benign lesions presented positive staining. In contrast to the benign lesions, however, the frequency of clusterin positive samples increased in atypical hyperplasias (47%, P = 0.08), intraductal carcinomas (49%, P = 0.01) and invasive carcinomas (53%, P < 0.001). Positive staining presented a cytoplasmic pattern, except in 3 cases of invasive carcinomas which had nuclear staining. Clusterin mRNA by in situ hybridization confirmed the specific cellular pattern of clusterin expression by immunohistochemistry. Clusterin expression was associated with large tumor size (P = 0.04), estrogen and progesterone receptor negative status (P = 0.02 and P = 0.001, respectively) and with the progression from primary carcinoma to metastatic carcinoma in lymph nodes (80% metastatic nodes had positive expression) (P = 0.004). Ten of 15 (67%) primary carcinomas without clusterin expression became positive in lymph node metastases, while most (22 of 25, 88%) of the clusterin-positive primary carcinomas were also immunoreactive in metastases. In survival analysis, clusterin expression did not represent a prognostic indicator by uni- or multivariate analysis. The increased clusterin expression in breast carcinomas tended to correlate inversely with the apoptotic index (P = 0.09) which indicates that clusterin gene expression is not a prerequisite to cellular death by apoptosis. From these results, we suggest that clusterin may have a role in tumorigenesis and progression of human breast carcinomas.     

Sarcomatoid carcinoma of the urinary bladder. A clinicopathologic analysis of 12 cases and review of the literature

Twelve carcinomas of the urinary bladder with a prominent component of spindle-shaped cells (sarcomatoid carcinomas) that arose in patients from 60 to 83 (average, 71.5 years) years of age are reported. The seven male and five female patients typically complained of hematuria. Seven tumors were sessile and five were polypoid. On microscopic examination, the malignant spindle cells merged with in situ transitional cell carcinoma or various forms of invasive carcinoma, including transitional cell carcinoma (11 cases), adenocarcinoma (2 cases), squamous cell carcinoma (2 cases), and small cell undifferentiated carcinoma (2 cases). Immunocytochemical stains were performed in 11 cases; the spindle cells stained for cytokeratin, epithelial membrane antigen, and vimentin. Limited follow-up in this series does not allow for conclusions concerning differences in behavior between sarcomatoid carcinoma and conventional transitional cell carcinoma of similar grade and stage. However, the typically deep invasion of the former tumors and their histologic features indicate that they are highly aggressive neoplasms.