Breast conservation in ductal carcinoma in situ (DCIS): what defines optimal margins?

The introduction of mammographic screening has resulted in a rise in the detection rate of ductal carcinoma in situ (DCIS), currently accounting for one‐fifth of screen‐detected breast cancers. Although 60–70% of DCIS are treated with breast‐conserving surgery (BCS) with or without radiotherapy, the frequency of subsequent surgery to re‐excise positive margins in order to reduce the probability of recurrences remains high. DCIS recurrence is associated not only with financial, health and psychological implications; approximately half these recurrences are invasive disease. An appropriate margin width for patients undergoing BCS for invasive breast cancer has been largely agreed. Although there is a perception that such recommendations may be applicable to DCIS, major differences exist which may affect this application. Importantly, DCIS patients often do not receive systemic adjuvant (endocrine) therapy and not all receive radiotherapy in routine practice. There is evidence that wide margins (i.e. >10 mm) confer better protection against recurrence than positive (i.e. 0 mm) margins; however, there remains a debate concerning the optimum margin width between 0 and 10 mm. Previous studies have demonstrated that radiation therapy may not compensate for lack of re‐excision in those patients with positive or close margins, while wide margins will inevitably compromise cosmesis and patients’ body image perception. This review aims to address the clinical question of the minimal margin width in DCIS treated with BCS that is associated with the lowest recurrence rate and when, therefore, further surgical intervention for re‐excision can be safely avoided. A range of clinical circumstances that might affect this are considered.     

Nodular fasciitis of the vulva: a challenging histopathologic diagnosis supported by the detection of USP6 gene rearrangement

Nodular fasciitis involving the vulva on physical examination can mimic a Bartholin gland lesion, and histologically can have overlapping features with more ominous mesenchymal pathologies. We describe a case in which a 52‐year‐old perimenopausal woman presents with a vulvar mass. After an initial biopsy and later excision, the myofibroblastic lesion was noted to have areas of differing cellularity, with compact nodule formations at the periphery. Immunohistochemical staining showed lesional cells to be positive for desmin, estrogen receptor, progesterone receptor, and smooth muscle actin, and negative for CD34, ALK‐1, myogenin, caldesmon, S100, and wide spectrum (Oscar) cytokeratin. Desmin is generally negative in this lesion type, but the positivity in this case was considered to be secondary to the origin of the myofibroblastic cells of the vulva. The morphologic pattern and immunophenotype favored a diagnosis of nodular fasciitis, however, the degree of hypercellularity and desmin positivity warranted further analysis. The diagnosis was supported with fluorescence in situ hybridization that demonstrated USP6 gene rearrangement. This highlights the necessity in certain challenging cases for ancillary molecular and/or cytogenetic analysis.     

Epithelial–mesenchymal transition in carcinomas of the female genital tract

Invasion is a defining feature of malignancy, but the mechanisms of invasion in many common cancers, including gynaecological malignancies, remain unclear. However, it has been proposed that malignant cells may usurp a normal embryological process, epithelial–mesenchymal transition (EMT), as a means of acquiring migratory capacity. The synergistic role of the tumour microenvironment in EMT induction has also been explored and helps to explain the spatially restricted distribution of EMT at the deep tumour margin (invasive front). Furthermore, tumour cells undergoing EMT may acquire cancer stem cell characteristics, and this may be relevant to the entire metastatic process and to tumour recurrence and treatment failure. Nevertheless, doubts persist regarding the role of EMT in malignant progression in vivo, partly because few studies have correlated molecular and histological alterations in clinical pathology specimens. In the current review we summarize the evidence for EMT in the common gynaecological epithelial malignancies, and discuss the morphological and immunohistochemical changes occurring at the invasive tumour front that may represent EMT‐like processes. The possibility that carcinosarcomas represent a variant type of EMT with ‘fixed’ mesenchymal differentiation is also considered. Diagnostic histopathologists are ideally placed to critically evaluate the role of EMT in gynaecological and other types of malignancy.     

Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer

BACKGROUND: Short-term preoperative radiotherapy and total mesorectal excision have each been shown to improve local control of disease in patients with resectable rectal cancer. We conducted a multicenter, randomized trial to determine whether the addition of preoperative radiotherapy increases the benefit of total mesorectal excision. METHODS: We randomly assigned 1861 patients with resectable rectal cancer either to preoperative radiotherapy (5 Gy on each of five days) followed by total mesorectal excision (924 patients) or to total mesorectal excision alone (937 patients). The trial was conducted with the use of standardization and quality-control measures to ensure the consistency of the radiotherapy, surgery, and pathological techniques. RESULTS: Of the 1861 patients randomly assigned to one of the two treatment groups, 1805 were eligible to participate. The overall rate of survival at two years among the eligible patients was 82.0 percent in the group assigned to both radiotherapy and surgery and 81.8 percent in the group assigned to surgery alone (P=0.84). Among the 1748 patients who underwent a macroscopically complete local resection, the rate of local recurrence at two years was 5.3 percent. The rate of local recurrence at two years was 2.4 percent in the radiotherapy-plus-surgery group and 8.2 percent in the surgery-only group (P<0.001). CONCLUSIONS: Short-term preoperative radiotherapy reduces the risk of local recurrence in patients with rectal cancer who undergo a standardized total mesorectal excision.     

KRAS and BRAF mutations in anal carcinoma

The EGF receptor (EGFR) is expressed in most cases of anal carcinomas. Anecdotal benefit from EGFR‐targeted therapy has been reported in anal cancer and a negative correlation with Kirsten Ras (KRAS) mutation status has been proposed. The purpose of this retrospective study was to investigate the frequency and the prognostic value of KRAS and BRAF mutations in a large cohort of patients with anal cancer. One hundred and ninety‐three patients with T1‐4N0‐3M0‐1 anal carcinoma were included in the study . Patients were treated with curative (92%) or palliative intent (8%) between January 2000 and January 2010. KRAS mutations were detected using Therascreen^®KRAS real‐time PCR assay (Qiagen) and V600E or V600D/K BRAF mutations were uncovered using Pyrosequencing. The frequency of KRAS and BRAF mutations was low; KRAS mutations were detected in 1.6% and BRAF mutations in 4.7% of the biopsies. No impact of KRAS or BRAF status on survival was found. In conclusion, both KRAS and BRAF mutations are rare in anal cancer. The low frequency of KRAS mutations support protocols exploring EGFR‐targeted therapy in patients with metastatic anal cancer, while treatment with BRAF inhibitors might be relevant for only a very few patients.     

Should endometriomas be treated before IVF-ICSI cycles?

The laparoscopic excision of ovarian endometriomas appears to increase the chances of spontaneous conception, but the value of this treatment in women selected for IVF-ICSI cycles is debated. Studies recruiting women with unilateral disease and comparing ovarian responsiveness in the affected and contralateral intact gonads indicate that excision of endometriomas is associated with a quantitative damage to ovarian reserve. There are no randomized trials comparing laparoscopic excision to expectant management before IVF-ICSI cycles. The idea that surgery increases IVF pregnancy rates is not supported by the available evidence. However, the chance of conception is not the only issue that has to be considered. Some potential drawbacks are associated with both therapeutical strategies. Specifically, costs and hazard of surgical complications support expectant management whereas oocyte retrieval risks, the possibility of missing occult malignancy and endometriosis progression due to ovarian stimulation would favour surgical treatment. Alternative therapeutical options include medical treatment and ultrasound-guided aspiration. Whereas prolonged GnRH agonist down-regulation may be beneficial, data on ultrasound aspiration are more controversial.     

Mechanisms of change: Effects of repetitive exposure to feared stimuli on the brain's fear network

Repetitive exposure to feared stimuli is considered as the essential element in therapy with phobic patients. However, the mechanisms mediating symptom reduction and their underlying neurobiological processes are poorly understood. Therefore, we presented the same fear‐relevant and neutral stimuli repeatedly to individuals with high and low fear of animals during fMRI scanning. High‐, but not low‐fearful individuals showed an initial fear‐stimulus‐related potentiation of amygdala and insula activity. Potentiation of the amygdala in the high‐fearful group habituated quickly, but insula activity was still potentiated during later repetition trials. Both groups showed an initial potentiation of the dorsomedial prefrontal cortex (dmPFC) that continuously decreased in low‐, but not in high‐fearful participants. Thus, within‐session habituation may occur on an automatic processing level (amygdala), but does not cause lasting neural changes on a higher order cortical level (dmPFC).     

An update on anal neoplasia

Although anal cancer remains a relatively uncommon tumour its frequency is rising, especially in high‐risk groups. It is now well recognized that anal squamous cell carcinoma, the largely predominant tumour type, shares many similarities with cancer of the uterine cervix, with a major role for oncogenic human papilloma viruses in both tumours. Anal squamous precancerous lesions have now to be classified with the same criteria and terminology as their cervical counterparts, by using the Lower Anogenital Squamous Terminology (LAST) proposal. Only p16 protein is a useful marker in this setting at the present time. As most cases of anal cancer are treated by non‐surgical procedures, pathology has a limited role in the staging of the disease, except for early lesions treated by local excision, and when the sentinel lymph node procedure is undertaken that is still under evaluation. A variety of other tumour types can occur more rarely, with difficult diagnostic issues, solved in most cases by immunohistochemistry.     

Recent advances in the pathology of heritable gastric cancer syndromes

Despite the relative rarity of hereditary gastric cancer syndromes, the prompt recognition of their specific clinical features and histopathological characteristics is pivotal in offering patients the most appropriate treatment. In this article, we address the three major inherited syndromes that primarily affect the stomach: hereditary diffuse gastric cancer (HDGC), caused by germline variants in CDH1 and CTNNA1; gastric adenocarcinoma and proximal polyposis of the stomach, caused by germline mutations in promoter 1B of APC; and familial intestinal gastric cancer, which has a poorly defined genetic cause. The main focus will be on HDGC, in light of the recent publication of updated clinical practice guidelines and emerging concepts regarding HDGC histopathology. In particular, we describe the broad morphological spectrum of HDGC lesions, stressing the importance of recognising indolent and aggressive phenotypes. Moreover, we discuss the increased risk of gastric (pre)malignancies developing in patients with other well‐defined hereditary cancer syndromes, such as familial adenomatous polyposis, Lynch syndrome, Peutz–Jeghers syndrome, juvenile polyposis, Li–Fraumeni syndrome, and hereditary breast and ovarian cancer syndrome.     

Staging of prostate cancer

Prostatic carcinoma (PCa) is a significant cause of cancer morbidity and mortality worldwide. Accurate staging is critical for prognosis assessment and treatment planning for PCa. Despite the large volume of clinical activity and research, the challenge to define the most appropriate and clinically relevant staging system remains. The pathologically complex and uncertain clinical course of prostate cancer further complicates the design of staging classification and a substaging system suitable for individualized care. This review will focus on recent progress and controversial issues related to prostate cancer staging. The 2010 revision of the American Joint Committee on Cancer/Union Internationale Contre le Cancer (AJCC/UICC) tumour, node and metastasis (TNM) system is the most widely used staging system at this time. Despite general acceptance of the system as a whole, there is controversy and uncertainty about its application, particularly for T2 subclassification. The three-tiered T2 classification system for organ-confined prostate cancer is superfluous, considering the biology and anatomy of PCa. A tumour size-based substaging system may be considered in the future TNM subclassification of pT2 cancer. Lymph node status is one of the most important prognostic factors for prostate cancer. Nevertheless, clinical outcomes in patients with positive lymph nodes are variable. Identification of patients at the greatest risk of systemic progression helps in the selection of appropriate therapy. The data suggest that the inherent aggressiveness of metastatic prostate cancer is closely linked to the tumour volume of lymph node metastasis. We recommend that a future TNM staging system should consider subclassification of node-positive cancer on the basis of nodal cancer volume, using the diameter of the largest nodal metastasis and/or the number of positive nodes.     

CARLo‐7—A plausible biomarker for bladder cancer

Cancer is defined as undifferentiated and unchecked growth of cells damaging the surrounding tissue. Cancers manifest altered gene expression. Gene expression is regulated by a diverse array of non‐protein‐coding RNA. Aberrant expression of long non‐coding RNAs (lncRNAs) has been recently found to have functional consequences in cancers. In the current study, we report CARLo‐7 as the only bladder cancer–specific lncRNA from the CARLos cluster. The expression of this lncRNA correlates with bladder cancer grade. We propose that CARLo‐7 has an oncogenic potential and might be regulator of cell proliferation. Furthermore, by comparison the expression of proto‐oncogene MYC, which is the only well‐annotated gene close to the cancer ‐ associated linkage disequilibrium blocks of this region, does not show a pronounced change in expression between the low‐ and high‐grade tumours. Our results indicate that CARlo‐7 can act as a prognostic marker for bladder cancer.     

Mutation screening and transmission disequilibrium study of ATP10C in autism

Autism is a complex genetic disorder. Chromosome 15 is of particular interest in this disorder, because of previous reports of individuals with autism with chromosomal abnormalities in the 15q11‐q13 region. Transmission disequilibrium between polymorphisms in this region and autism has been also been reported in some, but not all studies. Recently, a novel maternally expressed gene, ATP10C, was characterized and mapped to the chromosome 15q11‐q13 region, 200 kb distal to UBE3A. It encodes a putative aminophospholipid translocase likely to be involved in the asymmetric distribution of proteins in the cell membrane. Preferential maternal expression has been demonstrated in fibroblasts and brain. Because of its physical location and imprinting pattern, ATP10C was considered to be a candidate gene for chromosome 15‐associated autism. In an effort to find the genes responsible for autism in this chromosomal region, 1.5 kb of the 5′ flanking region, as well as the coding and splicing regions of ATP10C, were screened for sequence variants. Several polymorphic markers including five nonsynonymous SNPs were identified. To investigate transmission disequilibrium between ATP10C and autism, a family‐based association study was conducted for 14 markers in 115 autism trios. No significant transmission disequilibrium was found, suggesting ATP10C is unlikely to contribute strongly to susceptibility to autism in these families. However, due to limited power to detect genes of modest effect, the possible functional role of the nonsynonymous SNPs and the functional implications of the SNPs identified from 5′ flanking region and intron 2 splicing region may be evaluated in further studies. © 2002 Wiley‐Liss, Inc.     

A 15‐year‐long Southern blotting analysis of FMR1 to detect female carriers and for prenatal diagnosis of fragile X syndrome in Taiwan

Here, we review the results of Southern blotting analyses of the FMR1 gene performed in our reference laboratory in Taiwan over a 15‐year period. In total, 725 high‐risk women with a family history of fragile X syndrome (FXS) or idiopathic intellectual disability, 3911 low‐risk pregnant women without such family history, and prenatal diagnosis data for 32 foetuses from 24 carrier mothers were included. Only 2 carriers were in the low‐risk group, which indicated a prevalence of 1 of 1955 women (95% confidence interval: 1/7156‐1/539). A total of 100 carriers were found to be in the high‐risk group, thus revealing a significantly higher frequency than the low‐risk group (100/725 vs 2/3911, P<0.0001). Eight of the 14 foetuses that inherited the maternal mutant allele were verified to have a full mutation, with the smallest maternal pre‐mutation allele carrying 56 CGG repeats. The overall findings confirmed that the carrier prevalence among low‐risk women in Taiwan is significantly lower than that reported in western countries. Therefore, the most important step for preventing FXS in Taiwan would be to focus on high‐risk women by promoting general awareness of this disease and spreading knowledge regarding the benefits of carrier screening and prenatal testing.     

Constitutional LZTR1 mutation presenting with a unilateral vestibular schwannoma in a teenager

Schwannomatosis is a rare neurofibromatosis clinically diagnosed by age‐dependent criteria, with bilateral vestibular schwannoma and/or a constitutional NF2 mutation representing exclusion criteria. Following SMARCB1 germline mutations, constitutional mutations in LZTR1 were discovered. We report on the molecular investigation in a patient presenting at 14 years with a unilateral vestibular schwannoma, ultimately causing blindness and unilateral hearing loss, in the absence of other schwannomas or a positive family history. In DNA derived from frozen tumor tissue, a comprehensive NF2, SMARCB1 and LZTR1 analysis showed an NF2 truncating mutation c.1006_1021delins16; an LZTR1 mutation c.791+1G>A; and a partial 22q deletion including NF2, SMARCB1 and LZTR1. Sequence analysis on peripheral blood derived DNA showed the LZTR1 mutation to be constitutional, but the NF2 mutation and partial 22q deletion were not found, indicating them to be somatic events. RNA‐based targeted analysis confirmed missplicing of LZTR1 intron 8, predicted to result in a premature stop codon. This LZTR1 mutation was paternally inherited. While isolated vestibular schwannoma or NF2 may be considered in a young individual with a unilateral vestibular schwannoma, this report suggests that LZTR1 ‐related schwannomatosis be added to this differential diagnosis.     

Is laparoscopic technique oncologically appropriate for colorectal cancer surgery?

The role of laparoscopy for curative colorectal cancer surgery remains a topic of much debate. Even though, two oncologic issues, abdominal wall cancer recurrence and adequacy of intraperitoneal staging, are still of major concern, we believe that abdominal wall cancer recurrence may be largely avoidable using the appropriate surgical oncologic principles. In addition, laparoscopy appears to be quite valuable for accurate staging if used in combination with laparoscopic ultrasonography. The question, "Is laparoscopic technique oncologically appropriate for colorectal cancer surgery?", cannot be answered clearly until long-term recurrence and survival rates have been determined in a large number of patients undergoing curative laparoscopic cancer surgery. We, however, have still not had a single port-site recurrence at the Cleveland Clinic to date, having performed over eighty curative colectomies for cancer (performed only in a prospective randomized study) with a median follow-up of approximately two and half years.     

Polymorphisms in the CLDN1 and CLDN7 genes are related to differentiation and tumor stage in colon carcinoma

Tight junction is composed of transmembrane proteins important for maintaining cell polarity and regulating ion flow. Among these proteins are the tissue‐specific claudins, proteins that have recently been suggested as tumor markers for several different types of cancer. An altered claudin expression has been observed in colon, prostatic, ovarian, and breast carcinoma. The aim of this study was to analyze the allele frequencies of three common single nucleotide polymorphisms (SNPs) in the genes for claudin 1 and claudin 7 in colon cancer (CC) patients and in a control population of healthy blood donors. Pyrosequencing was used to genotype the CLDN1 SNP rs9869263 (c.369C>T), and the CLDN7 SNPs rs4562 (c.590C>T) and rs374400 (c.606T>G) in DNA from 102 formalin fixed paraffin embedded (FFPE) colon cancer tissue, and 111 blood leukocyte DNA from blood/plasma donors. These results were correlated with clinical parameters such as TNM stage, tumor localization, tumor differentiation, complexity index, sex, and age. We found that there was a significant association between the CLDN1 genotype CC in tumor samples and a higher risk of colon cancer development (OR 3.0, p < 0.001). We also found that the CLDN7 rs4562 (c.590C>T) genotype CT had a higher risk of lymph node involvement (p = 0.031) and a lower degree of tumor differentiation (p = 0.028). In the control population, the allele frequencies were very similar to those in the HapMap cohort for CLDN7. The CLDN1 rs9869263 genotype (c.369C>T) was related to increased risk of colon cancer, and the CLDN7 rs4562 genotype (c.590C>T) was related to tumor differentiation and lymph node involvement in colon carcinoma. Further studies are warranted to ascertain their potential uses as biomarkers predicting tumor development, proliferation, and outcome in this disease.     

Expandable and rigid endorectal coils for prostate MRI: impact on prostate distortion and rigid image registration

Endorectal coils (ERCs) are used for acquiring high spatial resolution magnetic resonance (MR) images of the human prostate. The goal of this study is to determine the impact of an expandable versus a rigid ERC on changes in the location and deformation of the prostate gland and subsequently on registering prostate images acquired with and without an ERC. Sagittal and axial T2 weighted MR images were acquired from 25 patients receiving a combined MR imaging/MR spectroscopic imaging staging exam for prostate cancer. Within the same exam, images were acquired using an external pelvic phased array coil both alone and in combination with either an expandable ERC (MedRad, Pittsburgh, PA) or a rigid ERC (USA Instruments, Aurora, OH). Rotations, translations and deformations caused by the ERC were measured and compared. The ability to register images acquired with and without the ERC using a manual rigid-body registration was assessed using a similarity index (SI). Both ERCs caused the prostate to tilt anteriorly with an average tilt of 18.5 degrees (17.4 +/- 9.9 and 19.5 +/- 11.3 degrees, mean +/- standard deviation, for expandable and rigid ERC, respectively). However, the expandable coil caused a significantly larger distortion of the prostate as compared to the rigid coil; compressing the prostate in the anterior/posterior direction by 4.1 +/- 3.0 mm vs 1.2 +/- 2.2 mm (14.5% vs 4.8%) (p < 0.0001), and widening the prostate in the right/left direction by 3.8 +/- 3.7 mm vs 1.5 +/- 3.1 mm (8.3% vs 3.4%) (p = 0.004). Additionally, the ability to manually align prostate images acquired with and without ERC was significantly (p < 0.0001) better for the rigid coil (SI = 0.941 +/- 0.008 vs 0.899 +/- 0.033, for the rigid and expandable coils, respectively). In conclusion, the manual rigid-body alignment of prostate MR images acquired with and without the ERC can be improved through the use of a rigid ERC.     

Histopathological screening for prostate carcinoma: is a benign biopsy a negative biopsy?

In case of clinical suspicion of a prostate malignancy, a prostate biopsy is the most widely used approach to confirm prostate cancer. Unfortunately, exclusion of prostate cancer is not feasible by means of biopsy and also the negative rate remains consistently high. Here, we review the information the surgical pathologist can still gain from a prostate biopsy in absence of overt carcinoma.     

Results of conservative management of epithelial malignant and borderline ovarian tumours

Conservative management of at least part of both the ovary and uterus can be proposed in patients with borderline ovarian tumour, in order to preserve fertility potential. This conservative management could be carried out even in patients with borderline ovarian tumour associated with non-invasive peritoneal implants (if complete resection of peritoneal disease has been performed). When facing persistent infertility after this conservative surgery, ovarian induction or an in-vitro procedure could be proposed in patients with an early-stage disease, though the number of attempts must be limited. Removal of the preserved ovary after completion of pregnancy(ies) is unnecessary if patients agree to careful follow-up. In patients with epithelial ovarian cancer, conservative management could safely be performed in young patients who wish to preserve fertility function and who fulfil the following criteria: unilateral tumour (stage IA), grade 1 (and 2?), adequate staging surgery and careful follow-up. Removal of the preserved ovary should be carried out after completion of pregnancy(ies) in order to reduce the risk of ovarian tumour recurrence.