Lobular intraepithelial neoplasia: previously unexplored aspects assessed in 775 cases and their clinical implications

Lobular intraepithelial neoplasia (LIN) is currently considered a risk factor for the development of invasive breast cancer of varying morphologies (ductal or lobular) and prognoses in either breast. The reason for the high frequency (50%) of subsequent development of invasive ductal cancers remains unclear and the issue unexplored. A total of 775 LIN cases were retrieved from the Armed Forces Institute of Pathology files and separated into three groups using our three-tiered grading system. The presence or absence of simultaneous invasive cancer (ductal or lobular type) and various grades of ductal intraepithelial neoplasia (DIN) were noted for each case and correlated with the grade of LIN. Of the 775 cases, 80% qualified as LIN 2, with the other 20% being relatively evenly split between LIN 1 and LIN 3. Of the 775 cases, 163 cases were pure LIN, while invasive carcinoma was present in 140 cases. The remaining 472 cases were associated with various grades of DIN. The frequency of associated invasive carcinomas (ductal and lobular) increased from 14% in LIN 1 to 23% in LIN 3. Remarkably, while the frequency of invasive lobular carcinoma increased dramatically from 11% in LIN 1 to 86% in LIN 3, the frequency of invasive ductal carcinoma markedly decreased with advancing grade of LIN from 89% in LIN 1 to 14% in LIN 3. Among the cases of LIN unassociated with invasive carcinoma, DIN was present in 75% of LIN 1, 75% of LIN 2, and 66% of LIN 3 cases. The grade of DIN was directly proportional to the grade of LIN. Based on the higher frequency of invasive lobular carcinoma associated with LIN 3, biopsies with LIN 3 should be evaluated diligently for the presence of an associated invasive lobular carcinoma. Furthermore, an excisional biopsy should be performed when LIN 3 is observed in a core biopsy. The high frequency of DIN associated with LIN might suggest that the subsequent invasive ductal carcinomas originate from the associated DIN and that some of this may represent a different phenotype of the same cells that form the LIN lesion. It is also possible that the neoplastic cells may reflect or retain stem cell characteristics with plasticity and the capacity to attain or progress into either a ductal or lobular invasive phenotype.     

Combined E-cadherin and high molecular weight cytokeratin immunoprofile differentiates lobular,ductal, and hybrid mammary intraepithelial neoplasias

The terminal duct-lobular unit is the origin of 2 distinct variants of intraepithelial neoplasia traditionally separated into ductal and lobular types based on a combination of cytologic and architectural features. In general, distinction of the fully developed or classic lobular intraepithelial neoplasia (LIN) from various grades of ductal intraepithelial neoplasia (DIN) is not a problem. An increasing number of lesions that appear to have intermediate, overlapping ductal and lobular features are being sent to us for consultation because of the distinctly different clinical implication of the 2 diagnoses. We have separated and designated these as MIN (mammary intraepithelial neoplasia, not otherwise specified), whereas others have categorized them into either a definitive ductal or lobular subtype. The recent findings that LIN lacks immunoreaction for E-cadherin coupled with significantly diminished to absent expression of the high molecular weight (HMW) cytokeratins in more than 90% of grade 1b or higher DIN prompted us to evaluate intraepithelial neoplasias for a possibly more precise immunohistochemical categorization. One hundred and ten examples of intraepithelial neoplasias, consisting of 40 classic LIN, 20 unequivocal DIN 1c to DIN 3 (ductal carcinoma in situ), and 50 MIN, were acquired from the files of the Armed Forces Institute of Pathology. These specimens were tested with an antibody to E-cadherin and with antibody 34ssE12 reactive against HMW cytokeratins 1, 5, 10 and 14. All samples of LIN showed complete absence of reactivity with anti-E-cadherin, whereas all cases of DIN displayed a positive immunoreaction. In contrast, the DIN lesions displayed little or no reactivity with 34ssE12, whereas the lobular lesions showed cytoplasmic reactivity, often in a distinct perinuclear pattern. Twenty-three of the morphologically indeterminate cases could be classified as either ductal or lobular based on the immunoprofile, and 27 demonstrated an immunoprofile that differed from either typical DIN or classic LIN. Among the 27 MIN, 11 were negative for both markers (negative hybrids), whereas 16 were positive for both markers (positive hybrids). These 2 antibodies in combination are extremely useful in distinguishing lobular and ductal lesions and clarifying the nature of some of the morphologically intermediate cases. Also, they have confirmed the presence of a group of intraepithelial lesions (MIN) with not only overlapping morphologic features, but also immunoprofiles distinctly different from either DIN or LIN. These MIN lesions may reflect either a transient stage in the development of DIN and LIN (the immediate post-stem cell stage) or a plastic group in transition from one type to the other. This group needs further evaluation for better understanding of its significance, pattern of progression, and behavior.     

Positioning of necrotic lobular intraepithelial neoplasias (LIN,grade 3) within the sequence of breast carcinoma progression

Lobular intraepithelial neoplasia Grade 3 (LIN3) is a recently recognized variant of intraepithelial lobular neoplasia (LIN) of the breast composed of either uniform, generally small cells with massive lobular distension, pleomorphic cells, signet‐ring cells, or any cell type with necrosis. In contrast to classic forms of LIN, there is no consensus on therapeutic strategies for LIN3. In part this is due to the paucity of molecular data that could assist in defining the relationship of LIN3 to classic LIN and carcinomas. In this study we have employed array comparative genomic hybridization to determine the patterns of chromosomal aberrations in nine LIN3 lesions. By comparison to array CGH data of 13 classic LIN lesions, we demonstrate that classic LIN and LIN3 share several recurrent changes, in particular gains of 1q and losses of 16q. Both aberrations are known to appear early in tumorigenesis and to be associated with good prognosis. However, apart from this overlap, there were a number of karyotypic features that were observed exclusively in LIN3. Clearly, this lesion was characterized by a significantly higher number of DNA copy number changes (9 vs. 31 on average), a considerable complexity of chromosomal rearrangements with more than 16 breakpoints in one chromosome and overlapping high copy amplifications encompassing a number of known oncogenes. Our data suggest that, at the genetic level, LIN3 represents a highly advanced lesion with considerable resemblance to carcinomas and, therefore, might represent the transition state from an intraepithelial neoplasm to breast carcinoma. © 2010 Wiley‐Liss, Inc.     

Tubular carcinoma of the breast and associated intra-epithelial lesions: a comparative study with invasive low-grade ductal carcinomas

Ductal intra-epithelial lesions of the breast are associated with invasive neoplasms and comprise a large spectrum of histological patterns. We have examined 23 cases of pure tubular carcinomas (TCs) of the breast and 53 cases of invasive ductal low-grade carcinomas to determine the relationship and distribution of intra-epithelial lesions, mainly of ductal in situ carcinoma type, but including also lobular intra-epithelial neoplasia (LIN) in both entities. Eleven cases of TC showed flat epithelial atypia (FEA) (47.8%), and, in 14 and 6 cases, micropapillary and cribriform low-grade ductal carcinoma in situ (DCIS) were present (60.7 and 26.1%, respectively). On the opposite, in ductal grade I invasive carcinomas, the most frequent architectural pattern was low-grade DCIS growing in arcades in 26 cases (49%). While absent in TCs, low-grade DCIS of solid type was found in five (9.4%) cases of ductal invasive carcinomas, where FEA were present in seven (13.2%) cases. LIN lesions were present in four (17.4%) cases of TC, whereas they represented 7.5%, as reported by Carstens et al. (Am J Clin Pathol 58:231–238, 1972), of cases of low-grade carcinomas. These results suggest that invasive pure TC and low-grade ductal carcinomas of the breast are different lesions, and support the fact that TC, of low histopathological grade, is a particular distinct tumoural entity.     

Flat epithelial atypia (DIN 1a, atypical columnar change): an underdiagnosed entity very frequently coexisting with lobular neoplasia

AIMS: Flat epithelial atypia of the breast [FEA; synonyms: ductal intraepithelial neoplasia (DIN) 1a, atypical columnar change] is increasingly recognized by pathologists and shows distinct genetic alterations. The aim of this study was to determine its biological significance as an incidental finding in breast biopsy specimens. METHODS AND RESULTS: On the assumption that both FEA and lobular neoplasia (LN) derive from progenitor cells in the terminal ductal-lobular unit, we investigated the association between FEA and LN semiquantitatively in 111 excisional breast biopsy specimens which contained LN, but did not contain ductal carcinoma in situ (DCIS) or invasive carcinoma. Ninety-six cases (86.5%) revealed coexistence of LN and FEA (P < 0001). The distribution of LN was focal in 41 cases (37%), multifocal in 50 (45%) and extensive in 20 (18%) cases. FEA was identified as focal, multifocal and extensive in 29 (26%), 42 (38%) and 25 (23%) cases, respectively. Distribution patterns of LN and FEA showed no statistically significant correlation. CONCLUSIONS: Due to the striking association between LN and FEA in our material, one may speculate that these two lesions are biologically related and that FEA is an early but non-obligate precursor lesion similar to LN. Based on this assumption, regular clinical and mammographic follow-up of patients with FEA would be prudent.     

COX-2 localization within plasma membrane caveolae-like structures in human lobular intraepithelial neoplasia of the breast

Cyclooxygenase-2 (COX-2) is highly expressed in human intraepithelial neoplasia of the breast and takes part in the molecular pathway implicated in progression of breast cancer. Recently, we demonstrated that COX-2 protein is mainly located in plasma membrane of lobular intraepithelial neoplasia (LIN) cells suggesting a localization in caveolae-like structures. The aim of the present study is to establish subcellular locations of COX-2 and its colocalization with caveolin-1 (CAV-1) to caveolae structures in LIN. To establish a relationship between COX-2 and CAV-1, 39 LINs were studied by immunohistochemistry and confocal microscopy analysis. COX-2 and CAV-1 expression was observed respectively in 79.5 and in 94.9% of LIN studied. A positive correlation was found between membrane COX-2 staining pattern and CAV-1 expression, while no correlation was found between cytoplasm COX-2 staining pattern and CAV-1. Confocal analysis showed that COX-2 localized to plasma membrane was strictly associated to CAV-1 suggesting that an amount of COX-2 protein is placed in caveolae-like structures. Our results show that COX-2 is localized within caveolae compartment and colocalized with CAV-1 protein in LIN lesions. Because caveolae are rich in signaling molecules, this COX-2 compartment may play an important role in diverse breast cancer carcinogenesis processes.     

Konzept und Problematik der lobulären Neoplasie

The term lobular neoplasia (LN) includes lobular carcinoma in situ (LCIS) and atypical lobular neoplasia (ALH). It is generally considered to be a risk lesion and a non-obligatory precursor for the subsequent development of an invasive carcinoma in the ipsilateral or contralateral breast. LN has also been termed lobular intraepithelial neoplasia (LIN). A grading system (LIN 1-LIN 3) has been suggested as a tool for a more precise estimation of the individual risk. When LN is the most significant finding in a core biopsy, the probability of a higher grade lesion is about 17% in the follow-up surgical biopsy, justifying follow-up surgery in the majority of cases. A higher risk of progression is attributed to LIN 3 (pleomorphic LN, extensive LN, and signet ring cell LN) compared to LIN 1 or LIN 2. These special forms of LN may have an unusual presentation clinically or histologically. Using immunohistology, LN are characterized by the loss of E-cadherin, low proliferative activity and by positive hormone receptor status. The molecular characteristics of LN are similar to those of invasive lobular carcinomas, indicating the nature of LN as a precursor lesion.     

Discrepancies in the diagnosis of intraductal proliferative lesions of the breast and its management implications: results of a multinational survey

To measure discrepancies in diagnoses and recommendations impacting management of proliferative lesions of the breast, a questionnaire of five problem scenarios was distributed among over 300 practicing pathologists. Of the 230 respondents, 56.5% considered a partial cribriform proliferation within a duct adjacent to unequivocal ductal carcinoma in situ (DCIS) as atypical ductal hyperplasia (ADH), 37.7% of whom recommended reexcision if it were at a resection margin. Of the 43.5% who diagnosed the partially involved duct as DCIS, 28.0% would not recommend reexcision if the lesion were at a margin. When only five ducts had a partial cribriform proliferation, 35.7% considered it as DCIS, while if ≥20 ducts were so involved, this figure rose to 60.4%. When one duct with a complete cribriform pattern measured 0.5, 1.5, or 4 mm, a diagnosis of DCIS was made by 22.6, 31.3, and 94.8%, respectively. When multiple ducts with flat epithelial atypia were at a margin, 20.9% recommended reexcision. Much of these discrepancies arise from the artificial separation of ADH and low-grade DCIS and emphasize the need for combining these two under the umbrella designation of ductal intraepithelial neoplasia grade 1 (DIN 1) to diminish the impact of different terminologies applied to biologically similar lesions.     

Flat DIN 1 (flat epithelial atypia) on core needle biopsy: 63 cases identified retrospectively among 1,751 core biopsies performed over an 8-year period (1992–1999)

Uniform management of flat DIN 1 (flat epithelial atypia) on core needle biopsy (CNB) concerning surgical excision or clinical follow-up are lacking. In a retrospective review of 1,751 CNB over an 8-year period, we found 63 cases with flat DIN 1 as the most advanced lesion; follow-up was available in 55 cases. Of the 63 patients, 24 had a subsequent biopsy for 15 days to 10 years after the initial CNB, an infiltrating carcinoma was found in nine (14.3%) patients, seven (11.1%) in the ipsilateral, and two (3.2%) in the contralateral breast. Five underwent an excisional biopsy of the ipsilateral breast within less than 3 months of the initial CNB; none had either an invasive or intraepithelial carcinoma. Based on our findings, we consider flat DIN 1 a marker of slightly increased risk for subsequent development of invasive breast carcinoma. When flat DIN 1 is found on CNB as the most advanced lesion after mammographic correlation, an excisional biopsy is not mandatory; however, close follow-up is advised with repeat mammograms for early detection of any clinically occult carcinoma in the vicinity of flat DIN 1 that may have been missed by the CNB.     

Significance of HPV 16 and 18 viral load quantitation in women referred for colposcopy

The clinical utility of HPV 16 and 18 viral loads remains debated. The aim of this study was to assess the clinical significance of HPV 16 and 18 viral load and to determine a cut‐off for optimal prediction of grade 2 or higher cervical intraepithelial neoplasia among patients referred to colposcopy. A total of 186 cervico‐vaginal specimens harboring HPV 16 and/or 18 obtained at the time of colposcopy from patients without previous cervical neoplasia were tested for HPV 16 and 18 detection and quantitation using quantitative duplex real‐time PCR method. Grade 2 or higher cervical intraepithelial neoplasia was diagnosed in 87 (46.8%) cases. Only HPV 16 median viral load increased significantly with the lesion grade: 9.1 × 10⁴ in normal cervix or grade 1 cervical intraepithelial lesion versus 4.0 × 10⁶ copies per million cells in grade 2 or higher cervical intraepithelial lesion (P < 0.001). The highest predictive value for grade 2 or higher cervical intraepithelial lesion was observed with a HPV 16 viral load cut‐off of 3.0 × 10⁶ copies per million cells (91% specificity, 58.2% sensitivity). Using this cut‐off, the highest predictive value of HPV 16 viral load was observed among those referred for previous low‐grade abnormal cervical cytology (96.4% specificity, 88% sensitivity). HPV 18 quantitation showed very poor predictive value. Specific attention should be given when performing colposcopic examination of women with an HPV 16 viral load higher than 3.0 × 10⁶ copies per million cells, especially among those referred after a low‐grade abnormal cytology. J. Med. Virol. 84:306–313, 2012. © 2011 Wiley Periodicals, Inc.     

Genome wide array comparative genomic hybridisation analysis of premalignant lesions of the stomach.

BACKGROUND: Gastric cancer is one of the most frequent malignancies in the world, ranking fifth in the Netherlands as a cause of cancer death. Surgery is the only curative treatment for advanced cases, but results of gastrectomy largely depend on the stage of the disease. A better understanding of the mechanisms of progression from a preneoplastic condition through intraepithelial neoplasia to invasive cancer may provide information relevant to designing focused prevention strategies. METHODS: Because the pattern of chromosomal aberrations in precursors of gastric cancer is unclear, 11 gastric polyps with intraepithelial neoplasia (three hyperplastic polyps and eight adenomas) were analysed by microarray comparative genomic hybridisation to study chromosomal instability in precursors of gastric cancer. RESULTS: Chromosomal aberrations were detected in all specimens. Adenomas showed no more chromosomal aberrations than did the hyperplastic polyps. The most frequent aberrations were gain of 7q36 and 20q12, and loss of 5q14-q21 in the adenomas, and loss of 15q11-14, 1p21-31, and 21q11-21.2 in the hyperplastic polyps. The most frequent chromosomal aberration in common to both types was loss of 9p21.3. CONCLUSION: Hyperplastic polyps showed many chromosomal aberrations, confirming that neoplastic transformation can occur in these lesions. These observations are consistent with the existence of two morphologically and genetically distinct pathways to gastric cancer-the hyperplastic polyp pathway and the (intestinal type) adenoma pathway. The relative contribution of each to gastric carcinogenesis in general, and how they compare to patterns of chromosomal aberrations in the more prevalent flat foci of intraepithelial neoplasia remain to be determined.     

How should we grade CIN?

How should we grade CIN? The grading of cervical intraepithelial neoplasia (CIN) is problematic. CIN represents a morphological continuum, but biopsies displaying this lesion are classified into two (e.g. Bethesda) or three grade categories, sometimes with poor reproducibility. There are also difficulties in reliably distinguishing low‐grade CIN from its reactive simulants. Because of problems with inter‐ and intra‐observer disagreement in the grading of CIN and the diagnosis of low‐grade lesions, three expert contributions were commissioned to address the question `how should we grade CIN?'.     

Practical problems in breast screening. Columnar cell lesions including flat epithelial atypia and lobular neoplasia

Columnar cell lesions (CCL) and lobular neoplasia (LN) are encountered with increasing frequency in breast screening biopsies. CCLs are frequently associated with microcalcifications, whereas LN is an incidental finding in most cases. Flat epithelia atypia (FEA) the atypical variant of CLL, LN and atypical ductal hyperplasia (ADH) are frequently associated lesions. Molecular genetic studies of CCL, ductal carcinoma in situ (DCIS) and low grade invasive carcinomas revealed similar chromosomal alterations supporting the assumption that CCLs are neoplastic proliferations. The frequent association of FEA together with well differentiated invasive carcinomas provides further evidence of this concept. There is no internationally accepted classification of CCLs at present. CDH1-gene mutations are the cardinal feature of LN and invasive lobular carcinoma. In immunohistochemically CDH1-positive cases, alternative genetic alterations of the CDH1 pathway can lead to functional loss of CDH1. In our opinion morphologically and immunohistochemically hybrid lesions may represent this group of lobular lesions. Recent follow-up data suggest a higher rate of ipsilateral carcinomas in patients with previously diagnosed LN. It is currently an open question whether FEA and LN are members of a common family of intralobular proliferations, which are non-obligatory precursors of a low nuclear grade breast neoplasia family.     

Frequency of clinically occult intraepithelial and invasive neoplasia in reduction mammoplasty specimens: a study of 516 cases

Reduction mammoplasty is a frequently performed procedure for the treatment of macromastia and for the achievement of symmetry in breast cancer patients following lumpectomy. Slides from 516 consecutive bilateral reduction mammoplasties performed for macromastia over 15 years were reviewed. Among these, 92 (18%) low-risk ductal intraepithelial neoplasia/intraductal hyperplasia, 28 (5%) ductal intraepithelial neoplasia 1 (1 low-grade ductal carcinoma in situ, 11 atypical intraductal hyperplasia, and 16 flat type), 17 (3%) lobular intraepithelial neoplasia, and 1 (0.2%) tubular carcinoma were identified. The patients were categorized into 3 age groups: <40 (n=352), 40 to 50 (n=107), and over 50 years (n=57); the frequency of the lesions increased with age. These data confirm the low frequency of clinically occult malignancies identified in reduction mammoplasty specimens and provide substantial information about the frequency of a variety of intraepithelial proliferations. Preoperative mammography, specimen orientation, and inking of margins with 1 color are advised when reduction mammoplasty is scheduled for women>or=40 years of age.     

Expression of urocortin in pancreatic ductal adenocarcinoma and pancreatic intraepithelial neoplasia

Urocortin (UCN) is a 40‐aminoacid neuropeptide that regulates angiogenesis and inhibits cell proliferation. Our aim was to examine the relationship of UCN expression to the clinicopathological parameters of pancreatic ductal adenocarcinoma (PDAC) and histological grade of pancreatic intraepithelial neoplasia (PanIN). Tissue microarray was used to analyze UCN protein expression in 89 surgical specimens including 21 PanIN, 3 PDAC arising from PanIN, and 65 PDAC without PanIN. UCN immunoscores ranging from 0 to 12 were obtained by multiplying intensity (scored on a 3‐point scale) by the percentage of stained cells (scored on a 4‐point scale). Strong expression of UCN was detected in 5 specimens of non‐neoplastic pancreatic ductal epithelia. UCN immunoscore was significantly higher in PanIN‐1 than in PanIN‐2 and PanIN‐3 (p = 0.038) and significantly higher in well‐differentiated PDAC or early American Joint Committee on Cancer (AJCC) stage PDAC than in poorly differentiated or advanced stage PDAC (p = 0.025, p = 0.018). Higher expression of UCN correlates with PDAC tumor grade and AJCC pathologic stage as well as PanIN grade. Immunohistochemical assessment of UCN may help clinicians predict tumor recurrence rate and help pathologists make a proper diagnosis.     

Human papillomavirus (HPV) E6/E7 mRNA as a triage test after detection of HPV 16 and HPV 18 DNA

High‐risk human papillomavirus (HPV) DNA detection provides high sensitivity but low specificity for moderate‐grade cervical intraepithelial neoplasia or worse histological identification. A prospective study evaluated mRNA testing efficacy for predicting this histological diagnosis in case of HPV 16 and/or 18 DNA detection. A total of 165 endocervical samples harboring HPV 16 and/or 18 DNA were tested with NucliSENS‐EasyQ® HPV E6/E7‐mRNA‐assay (Biomerieux, Marcy l´Etoile, France). Women with cytological alterations were referred to colposcopy (n = 111). Moderate‐grade cervical intraepithelial neoplasia or worse was diagnosed in 25.8% of women presenting atypical squamous cells of undetermined significance or low‐grade squamous intraepithelial lesions and in 89.8% of women with high‐grade squamous intraepithelial lesions. mRNA sensitivity was 81.3% and 84.1%, respectively. Specificity was 52.2%, and 80.0%, respectively. Negative predictive value (NPV) was 88.9% in undetermined or low‐grade squamous lesions. Positive predictive value (PPV) was 97.4% in high‐grade squamous lesions. mRNA reduced colposcopies by 44.3% in undetermined or low‐grade squamous lesions. Direct treatment of mRNA‐positive cases reduced 77.5% of colposcopies in high‐grade squamous lesions. Women without cytological alterations were followed for 18 months (n = 35), and moderate‐grade cervical intraepithelial neoplasia or worse was diagnosed in 34.3%; mRNA sensitivity and specificity were 83.3% and 86.9%, respectively. PPV and NPV were 76.9% and 90.9%, respectively for predicting moderate‐grade cervical intraepithelial neoplasia or worse in 18 months. mRNA reduced the number of visits for follow‐up in 62.2%. In conclusion, NucliSENS‐EasyQ® HPV E6/E7‐mRNA‐assay (Biomerieux) can serve as a triage test in case of HPV 16 and/or 18 DNA detection. J. Med. Virol. 85: 1063–1068, 2013. © 2013 Wiley Periodicals, Inc.     

The role of E-cadherin in low-grade ductal breast tumourigenesis

Grade I invasive ductal breast carcinomas have a specific pattern of genetic aberrations, namely gain of 1q and loss of 16q. This pattern is very similar to the changes seen in invasive lobular breast carcinomas (ILCs). The gene on 16q involved in ILC is known to be E-cadherin (CDH1). This study has investigated whether the same gene is responsible for grade I invasive ductal carcinoma (IDC), using allele imbalance analysis, mutation screening, and immunohistochemistry (IHC). The data suggest that despite the shared pattern of genetic aberrations seen in grade I IDC and ILC, CDH1 is not the target gene in low-grade ductal tumourigenesis.     

Anal cytology as a predictor of anal intraepithelial neoplasia in HIV‐positive men and women

Human immunodeficiency virus (HIV)‐infected individuals have increased risk of anal intraepithelial neoplasia (AIN) and squamous cell carcinoma (SCC). Cytologic screening is invaluable in the detection of cervical neoplasia, therefore many clinicians have adopted anal cytology as part of anal cancer screening in patients at high‐risk for anal neoplasia. The purpose of this study is to determine whether anal cytology is a valuable screening test for identifying AIN in HIV+ patients. The cohort included 228 HIV+ patients who underwent anal cancer screening with collection of 318 anal cytology specimens between January 2006 and December 2009. Of this group, 74 (32.5%) patients had associated anal biopsies within a 6‐month period, with a total of 89 comparison cases. The anal cytology samples were classified using the 2001 Bethesda System terminology. The sensitivity of anal cytology in detecting ASC‐US, AIN 1‐3 or SCC was 93%. Cytology was 88% sensitive for detecting low‐grade AIN (AIN 1), but only 20% sensitive for detecting high‐grade AIN (AIN 2–3) or SCC. Atypical squamous cells of undetermined significance cases were distributed evenly between low‐ and high‐grade AIN, with two cases having normal histology. Only six cases had negative cytology, all of which were associated with AIN on biopsy, for a false negative rate of 7%. Anal cytology is a good predictor of AIN, as confirmed by the high degree of sensitivity. However, there is poor correlation between the cytological and histological grade of AIN. Cytology underestimates the grade of dysplasia compared to the corresponding biopsy. Diagn. Cytopathol. 2013;41:697–702. © 2013 Wiley Periodicals, Inc.     

Intraductal papillary neoplasm of the bile duct associated with Clonorchis sinensis infection

Columnar cell lesions (CCLs) are one of the most common abnormalities in the adult female human breast, characterized by the presence of columnar-shaped epithelial cells lining enlarged terminal-duct lobular units. CCLs are being seen increasingly in core biopsies taken for the non-palpable calcifications. The increased incidence may reflect improved delineation and recognition of CCLs by pathologists or a true increase in incidence related to biological and/or environmental factors. Columnar cell-like lesions have been described under a variety of names such as blunt duct adenosis, flat epithelial atypia, and ductal intraepithelial neoplasia type DIN1a. The current histologic classification used by some pathologists divides them into simple columnar cell change and columnar cell hyperplasia, both of which can occur with or without atypia. Columnar cells lack mature luminal or basal/myoepithelial phenotype markers, but they are usually positive for estrogen receptor-alpha. The cellular origin of CCLs and their possible relationship to either expansion or metaplasia of a preexisting normal cell phenotype remains unclear. CCLs are frequently associated with lobular and ductal in situ tumors and invasive lobular and tubular carcinomas. The relationship and natural history of CCLs to invasive ductal carcinoma is enigmatic, but they may prove of clinical relevance when detected by screening mammography.