Subsequent Resection Specimens Research Articles

Admixed foamy cell and signet ring cell change in a cutaneous angiosarcoma – A diagnostic pitfall

Cutaneous epithelioid angiosarcomas are known to exhibit various morphological variations. The present case is first of its own kind describing admixture of foamy cell and signet ring cell morphological patterns in a case of cutaneous angiosarcoma occurring in a 64-year-old female. The initial incisional biopsy revealed predominantly cytoplasmic vacuolations in the tumor cells with only focal presence of typical angiosarcomatous component, while in subsequent resection specimen, these variations were present only focally with predominant classical angiosarcomatous areas. This case highlights the importance of awareness of such morphological variations in angiosarcomas as these can be easily missed or misdiagnosed in small biopsies due to sample selection.

The Impact of Noninvasive Follicular Variant of Papillary Thyroid Carcinoma on Rates of Malignancy for Fine-Needle Aspiration Diagnostic Categories.

Increased recognition of the indolent nature of noninvasive follicular variant of papillary thyroid carcinoma (NFVPTC) along with greater insight into the molecular alterations of these tumors has prompted endocrine pathologists to question whether these tumors warrant a diagnosis of carcinoma. However, a change in terminology would affect the rates of malignancy of fine-needle aspiration (FNA) diagnostic categories. Therefore, the aim of this study was to determine the percentage decrease in associated risk of malignancy for each FNA diagnostic category if NFVPTCs were no longer termed carcinomas. We evaluated a cohort of 655 FNAs with subsequent resection specimens over a 22-month time period. The diagnoses of the preceding FNAs were recorded according to the Bethesda System for Reporting Thyroid Cytopathology. For cases with more than one preceding FNA, the FNA diagnosis associated with the highest risk of malignancy was identified. Slides for all resection specimens with a diagnosis of FVPTC were reviewed to identify noninvasive tumors. By definition, all of these tumors were encapsulated, partially encapsulated, or well circumscribed and lacked any indication of infiltrative growth, capsular penetration, or lymphovascular invasion. Our cohort of 655 FNAs with subsequent resection specimens included 53 (8.1%) nondiagnostic (ND), 167 (25.5%) benign, 97 (14.8%) atypia/follicular lesion of undetermined significance (AUS/FLUS), 88 (13.4%) suspicious for follicular neoplasm (SFN), 94 (14.4%) suspicious for malignancy (SUS), and 156 (23.8%) malignant cases (POS). Surgical resections demonstrated benign findings in 309 (47.2%) and malignant tumors in 346 (52.8%), including 85 NFVPTCs accounting for 24.6% of malignancies. Our rates of malignancy for ND, benign, AUS/FLUS, SFN, SUS, and POS were 18.9%, 13.2%, 39.2%, 45.5%, 87.2%, and 98.7%, respectively. If NFVPTC were no longer termed carcinoma, these rates would drop to 17.0% (10% decrease), 5.4% (59% decrease), 21.6% (45% decrease), 37.5% (18% decrease), 45.7% (48% decrease), and 93.6% (5% decrease), respectively. Our findings demonstrate that if terminology were changed and NFVPTCs were not considered carcinomas, the rates of malignancy for FNA diagnostic categories would be substantially decreased, with the most clinically significant decrease seen in the SUS category, which demonstrated a relative decrease of nearly 50%.

The outcomes of "atypical" and "suspicious" bile duct brushings in the identification of pancreaticobiliary tumors: Follow-up analysis of surgical resection specimens.

Bile duct brushing cytology is frequently used to investigate suspected pancreaticobiliary tumors, but it is associated with low diagnostic sensitivity. As recently proposed by the Papanicolaou Society of Cytopathology in its new classification scheme for pancreaticobiliary cytology, the use of "atypical" and "suspicious (for malignancy)" categories may give a better prediction of malignancy and improve patient management. A series of 65 "atypical" and "suspicious" results initially diagnosed at the University of Washington and Harborview Medical Centers between 2005 and 2012 were analyzed to determine outcomes based on the review of subsequent surgical resection specimens. Seven of 15 (47%) "atypical" cases demonstrated malignant outcomes, whereas 49 of 50 (98%) "suspicious" cases showed documented malignancy within a mean follow-up of 4 months (P < 0.0001 from Pearson's chi-squared test). The analysis of surgical resection specimens demonstrates that 59% of "atypical" and "suspicious" bile duct brushings with malignant outcomes were pancreatic adenocarcinoma (95% confidence interval (CI): 46-71%), 97% of pancreatic adenocarcinomas caused strictures in the head of the pancreas (95% CI: 86-100%), and that 86% of pancreatic adenocarcinomas were moderate to poorly differentiated (95% CI: 73-99%). Fifty-three of the 60 (88%) patients in the presence of prior stenting had a histologically confirmed malignancy. The use of "atypical" and "suspicious" categories may allow more accurate surveillance and/or more rapid surgical exploration of pancreaticobiliary tumors.

Concordant chromosome 3 results in paired choroidal melanoma biopsies and subsequent tumour resection specimens

Background/aimThe study's aim was to compare chromosome 3 aberrations of choroidal melanoma (CM) as determined by multiplex ligation dependent probe amplification (MLPA) or microsatellite analysis (MSA) in intraocular tumour biopsies...

Use of BRAF v600e immunocytochemistry on FNA direct smears of papillary thyroid carcinoma.

Mutations of v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) are identified in almost half of all papillary thyroid carcinomas (PTCs). These mutations are specific for PTC and may confer a worse prognosis. An immunohistochemical (IHC) stain for BRAF is commercially available and has been validated in surgical specimens. Fine-needle aspiration (FNA) is frequently used as a diagnostic tool for risk stratification of thyroid nodules. Therefore, the authors evaluated the performance of immunostaining with the anti-BRAF antibody VE1 on FNA direct smears. The authors identified 51 FNA specimens that had subsequent surgical resection specimens with a diagnosis of PTC. BRAF VE1 IHC was performed on the surgical specimens to determine their mutation status. The corresponding direct smears were then stained using the same VE1 stain to assess correlation. Twenty-two of the 46 included surgical specimens were positive for BRAF mutations (47.8%) by IHC, consistent with the published rates. The paired cytologic smears from these cases revealed 65.3% concordance. The overall sensitivity of BRAF staining on cytologic smears was 63.6%, and the specificity was 58.3%. Concordance rates were highest in specimens that were diagnosed as malignant or suspicious for malignancy (75% and 85.7%, respectively). The negative predictive value increased to 77.8% when suspicious for follicular neoplasm/suspicious cases were combined. Specimens that were malignant or suspicious on FNA were most likely to be BRAF concordant. Limitations to the interpretation of smears included low cellularity and obscuring blood, macrophages, or colloid. With further refinement, it is possible that BRAF immunocytochemistry can be applied prospectively to thyroid FNAs for risk stratification and to reduce false-negative rates.

Proliferation rate and breast cancer subtype, but not ALDH1 expression, predict pathological response to neoadjuvant chemotherapy in locally advanced breast cancer.

For locally advanced breast cancer, pathological complete response (pCR) following neoadjuvant chemotherapy (NACT) is associated with good disease-free survival. In several studies, response to chemotherapy according to various parameters has shown strong inter-individual variability. We investigated whether different prognostic factors, including ALDH1 expression, might predict response to NACT in female patients with locally advanced breast carcinoma. ER, PR, Her2/neu, Ki-67 and ALDH1 immunohistochemistry were performed on the initial biopsy and subsequent resection specimens. Residual tumour burden was calculated in post NACT resection specimens using residual cancer burden (RCB) protocol. Of our cohort of 66 patients, 24 (36 %) achieved pCR. Triple negative phenotype and high Ki-67 proliferative index (>40 %) were significantly associated with good response to NACT. ALDH1 expression in tumour epithelial (20 %) or stromal (44 %) cells did not correlate with tumour grade, molecular subtype, proliferative index or NACT response. However, epithelial and stromal ALDH1 expression was significantly increased in residual tumour after NACT. In conclusion, triple negative phenotype and high proliferative index, but not ALDH1 expression, are predictive of good pathological response to NACT. Increased ALDH1 expression following NACT might be associated with a higher probability of recurrent disease.

Accuracy of classifying poorly differentiated non-small cell lung carcinoma biopsies with commonly used lung carcinoma markers.

Immunohistochemical (IHC) staining is an important adjunct to the classification of non-small cell lung carcinoma (NSCLC). Several studies have used tissue microarrays derived from resection specimens to evaluate the accuracy of IHC staining for classifying NSCLC, but few have used actual biopsies of poorly differentiated carcinomas, and the question of how often biopsy IHC in such tumors leads to the correct classification has received little attention. We identified 40 cases of NSCLC that, on biopsy, could not be subclassified by morphology and that had subsequent resection specimens. TTF-1, napsin, p63/p40, and CK5 or a subset thereof were used for IHC classification. Of the 40 cases classified by IHC on biopsy, 33 (82%) had no change in diagnosis after resection. Of the remaining 7 cases, 3 were classified as NSCLC--not otherwise specified on biopsy and subclassified as either adenocarcinoma or squamous cell carcinoma (SCC) on the surgical specimen. One adenocarcinoma biopsy was reclassified as pleomorphic carcinoma. Two SCCs were changed to adenosquamous carcinoma, and 1 SCC was changed to large cell lung carcinoma. Only 1 antibody pair (2%) was discordant between biopsy, and almost all reclassifications were done based on morphologic features rather than change in IHC pattern. We conclude that IHC staining allows accurate subclassification of poorly differentiated NSCLCs on small lung biopsies in most cases, but there is still a substantial "miss" rate (here, 18%). Surgical resection specimens allow further subclassification, mainly due to architectural features not present in the biopsies.

Differences in RRM1 protein expression between diagnostic biopsies and resection specimens, and changes during carboplatin and paclitaxel treatment, in non‐small‐cell lung cancer

It is of interest whether expression of potentially predictive biomarkers changes during chemotherapy, for accurate evaluation after first-line chemotherapy. This study aimed to evaluate changes in RRM1 expression during chemotherapy. RRM1 immunohistochemistry was performed on tumour samples from a total of 118 NSCLC patients with stage T1-4N0-2M0 disease. Samples were included from 65 patients treated with paclitaxel and carboplatin before surgery [neoadjuvant chemotherapy (NAC) group], and 53 patients who had undergone surgery but not chemotherapy [operation (OP) group]. Discordant RRM1 expression (low versus high) was observed in 32% and 43% of paired diagnostic and subsequent resection specimens in the OP group and NAC group, respectively (P = 0.913). Ten (33%) and 12 (23%) tumours in the NAC group and the OP group, respectively, had increased RRM1 expression in the resection specimens (P = 0.289), and 12 (40%) and 19 (36%) tumours had decreased expression (P = 0.707). Eleven (50%) lymph node metastases had higher RRM1 expression following chemotherapy, and two (7%) had decreased expression. The substantial discordance between paired samples emphasizes the need for sufficient tumour tissue in biopsies when RRM1 expression is evaluated. No change in RRM1 expression was observed in primary tumours, but expression seemed to be higher in N2 lymph node metastases following chemotherapy. Tumour heterogeneity and potential post-chemotherapy changes should be considered when RRM1 expression is evaluated.

Histo‐cytological diagnostic accuracy in lung cancer

The majority of patients with lung cancer are treated on the basis of a diagnosis made from the analysis of a small tumour biopsy or a cytological sample and histotype is becoming a critical variable in clinical workup as it has led to the introduction of newer biologically targeted therapies. Consequently, simply classifying cancers as small cell lung cancers or non-small cell lung cancers is no longer sufficient. From 2009 to 2011, a review of the histo-cytological database was conducted to identify all small biopsy and cytology specimens collected for diagnostic purposes in patients with a thoracic lesion. In total, 941 patients were studied by examining exfoliative and/or aspirative cytological samples. To establish the accuracy of these methods, cytological and biopsy diagnoses were compared with each other and with subsequent resection specimens when available. Moreover, during the diagnostic workup, we examined a validated panel of immunohistochemical markers. The diagnostic concordance of pre-operative diagnoses with surgical samples was high in both cytology and biopsy samples [κ=0.71, confidence interval (CI)=0.6-0.81; P<0.0001 and κ=0.61, CI=0.41-0.82; P<0.0001 respectively; good agreement] but concordance between cytology and biopsy was moderate (κ=0.5, CI=0.43-0.54; P<0.0001). Immunohistochemistry-aided diagnoses were definitive for histotype in 92.8% of both cytology (206/222) and biopsy (155/167) specimens. We found that lung cancer diagnosis and subtyping of cytology and biopsy samples are highly feasible and concordant; thus, the diagnostic approach to lung cancer does not require more invasive procedures.

Longitudinal assessment of TUBB3 expression in non-small cell lung cancer patients

Class-III-beta-tubulin (TUBB3) expression may be a potential predictive factor for treatment with microtubule interfering cytotoxic drugs in non-small cell lung cancer (NSCLC). Potential changes in TUBB3 expression during chemotherapy may be of interest if future choice of chemotherapy is to be based on TUBB3 expression. If the biomarker expression changes during chemotherapy, biopsies before initiation of chemotherapy beyond first line may be needed if treatment decision is to be based on TUBB3 expression. Thus, the aim was to explore TUBB3 expression heterogeneity and changes during chemotherapy. TUBB3 expression was investigated by immunohistochemistry performed on diagnostic biopsies and on available subsequent resection specimens in 65 NSCLC patients stage T1-3N0-2 who received neoadjuvant carboplatin and paclitaxel (NAC-group). Another group of 53 NSCLC patients stage T1-4N0-1 was treated with surgery alone without preceding chemotherapy (OP-group). Paired repeated samples were compared in order to evaluate for changes in TUBB3 expression. No statistically significant change in TUBB3 expression was observed between initial diagnostic biopsies and subsequent surgical resections of primary tumors in either the OP-group (p = 0.124) or the NAC-group (p = 0.414). When dichotomized into high and low TUBB3 expression, discordance between diagnostic biopsies and resection specimens of the primary tumors occurred in 22 % and 40 % in the OP-group and NAC-group, respectively (p = 0.169). Significantly more patients having low TUBB3 expression experienced down-staging during neoadjuvant chemotherapy compared to patients having high TUBB3 expression (p = 0.022). A high degree of discordance of TUBB3 expression between paired repeated tumor samples was observed, which likely reflects intratumoral heterogeneity. This emphasizes a need for optimal tumor tissue samples in order to stratify patients based on TUBB3 expression. No significant changes in TUBB3 expression after neoadjuvant carboplatin and paclitaxel chemotherapy occurred, suggesting no need for rebiopsy in case second-line chemotherapy with microtubule interfering cytotoxic treatments is necessary.

PWE-041 Histopathological Uncertainties in the Management of Early Colorectal Cancers Resected through Endoscopic Therapy

IntroductionStandards for Colorectal cancer (CRC) resection specimen histology reporting consider factors thought to have apparent significance for prognosis and further therapy. Whilst well validated for surgical resection, the increasing use...

Tumor Regression Grading of Gastrointestinal Carcinomas after Neoadjuvant Treatment

Multimodal therapy concepts have been successfully implemented in the treatment of locally advanced gastrointestinal malignancies. The effects of neoadjuvant chemo- or radiochemotherapy such as scarry fibrosis or resorptive changes and inflammation can be determined by histopathological investigation of the subsequent resection specimen. Tumor regression grading (TRG) systems which aim to categorize the amount of regressive changes after cytotoxic treatment mostly refer onto the amount of therapy induced fibrosis in relation to residual tumor or the estimated percentage of residual tumor in relation to the previous tumor site. Commonly used TRGs for upper gastrointestinal carcinomas are the Mandard grading and the Becker grading system, e.g., and for rectal cancer the Dworak or the Rödel grading system, or other systems which follow similar definitions. Namely for gastro-esophageal carcinomas these TRGs provide important prognostic information since complete or subtotal tumor regression has shown to be associated with better patient’s outcome. The prognostic value of TRG may even exceed those of currently used staging systems (e.g., TNM staging) for tumors treated by neoadjuvant therapy. There have been some limitations described regarding interobserver variability especially in borderline cases, which may be improved by standardization of work up of resection specimen and better training of histopathologic determination of regressive changes. It is highly recommended that TRG should be implemented in every histopathological report of neoadjuvant treated gastrointestinal carcinomas. The aim of this review is to disclose the relevance of histomorphological TRG to accomplish an optimal therapy for patients with gastrointestinal carcinomas.

Abstracts and Case Studies From the College of American Pathologists 2012 Annual Meeting (CAP '12)

Abstracts and Case Studies From the College of American Pathologists 2012 Annual Meeting (CAP '12)

The utility of diagnostic biopsy specimens for predictive molecular testing in colorectal cancer

If stratified medicine is to be applied in the neoadjuvant setting, predictive testing will have to be undertaken on preoperative diagnostic biopsy specimens. The aim of this study was to evaluate whether a diagnostic biopsy was adequately representative of the main tumour in colorectal cancer. Thirty cases of paired biopsy and subsequent resection specimens were randomly selected. Samples were screened for mutation in KRAS (codons 12/13, 61, and 146), BRAF (codon 600 and exon 11), PIK3CA (exons 1, 9, and 20), TP53 (exons 5-8), and microsatellite instability, using the quick multiplex consensus or standard polymerase chain reaction (PCR) protocols followed by high-resolution melting analysis. A total of 570 paired PCR tests were performed for mutation detection, and identical results were obtained in both biopsy and resection specimens in 569 tests (>99% concordance). Four cases (13%) showed microsatellite instability, and, in all four cases, instability was seen at identical mononucleotide markers in both biopsy and matched resection specimens. This is the first study to show that diagnostic biopsy specimens, even though they are a tiny sample of the tumour, are sufficiently representative for use in predictive testing for early driver mutations in colorectal cancer.

Immunohistochemical Expression of HBME-1, E-cadherin, and CD56 in the Differential Diagnosis of Thyroid Nodules

Distinction between benign and malignant thyroid tumors is essential for proper clinical management. The aim of this study was to evaluate the diagnostic potential of a set of 3 molecular markers in the differential diagnosis of thyroid tumors. Immunohistochemistry for HBME-1, E-cadherin (E-CAD), and CD56 was carried out in 36 follicular adenomas, 77 colloid goiters, 36 papillary thyroid carcinomas, and 14 follicular carcinomas. Sixty-eight thyroid fine needle aspiration (FNA) cases confirmed by subsequent surgical resection specimens were selected. Immunocytochemistry for HBME-1, E-CAD, and CD56 was performed in these cases, including 25 papillary thyroid carcinomas, 1 follicular carcinoma, 22 follicular adenomas, and 20 colloid goiters. PTC was characterized by a decreased expression of E-CAD and CD56 contrary to the surrounding benign thyroid tissues. There was no HBME-1 expression in benign thyroid tissues, but it was high in papillary thyroid carcinomas and weak in follicular adenomas. The expression of E-CAD and CD56 was significantly higher in follicular adenomas than in the surrounding thyroid tissues. Analyzing the FNA material, HBME-1 expression was documented in 96% of papillary thyroid carcinomas, but there was no expression in the benign lesions. E-CAD and CD56 expression was significantly weakened in papillary thyroid carcinomas, but enhanced in follicular adenomas. HBME-1 was found only in malignant lesions and can be considered the most sensitive, specific single marker in papillary thyroid carcinomas. CD56 and E-CAD can assist in the decision-making on the benign and malignant nature of the nodule. Immunocytochemistry is of value as an ancillary test to enhance the diagnostic accuracy of thyroid FNA samples.

KRAS mutational status of endoscopic biopsies matches resection specimens

AimsThis study was performed to determine systematically whether KRAS mutational analysis in biopsy tissue is a reliable indicator of KRAS status in subsequent corresponding resection specimens.Methods30 colorectal cancer (CRC) patients...

Unicentric plasma cell variant of castleman disease in the mesenteric lymph node: a rare and unusual case

Castleman disease, also known as angiofollicular lymph node hyperplasia is a rare lymphoproliferative disorder of unknown aetiology that was first desribed by Castleman in 1954. It is clinically classified into unicentric or multicentric variants according to its localisation and is histologically classified into hyaline vascular, plasma cell or mixed type. We present a rare and unusual case of unicentric plasma cell variant of Castleman disease involving a mesenteric mass of an 18-year-old previously well woman who presented with a 1 year history of constitutional symptoms. The core biopsy in conjunction with a fine needle aspiration biopsy showed no diagnostic evidence of malignancy. Subsequent exci-sional resection specimen confirmed the diagnosis, which was HHV-8 negative. We discuss the cytological and histological features of this rare lesion and its pathogenesis and differential diagnosis. Exact sub-classification of Castleman disease is vital as it has significant implication in terms of management and clinical behaviour.

Metastatic Clear Cell Adenocarcinoma of the Urethra in a Male Patient: Report of a Case

A 39-year-old white male presented with urinary hesitancy 2.5 years ago. He was referred to a urologist who performed cystoscopic evaluation and discovered a urethral mass with no abnormalities in the bladder. A staging positron emission tomography (PET) scan revealed fluorine-18 (F) fluorodeoxyglucose (FDG) uptake in a soft tissue prominence in the urethra and bilateral inguinal and iliac FDG-avid lymphadenopathy. Computed tomography (CT) of the hest also demonstrated several bilateral lung nodules. Needle biopsy f a left pelvic lymph node showed adenocarcinoma with micropapllary architecture (Figure 1A). Immunohistochemical analysis howed the carcinoma was positive for CK7 and CAM 5.2 and negtive for CK20, -fetoprotein, CDX-2, and prostate-specific antigen the immunostains are not shown). Sections from the subsequent ransurethral resection specimen of the urethral tumor showed an denocarcinoma with a tubulocystic, micropapillary, and solid archiecture (Figure 1B-D). The tumor had hobnail cells, clear and amhophilic cytoplasm, and high-grade nuclear atypia (Figure 1E). An

‘Difficult to diagnose’ desmoid tumours: a potential role for CTNNB1 mutational analysis

The utility of CTNNB1 (encoding β-catenin) genotyping for diagnosing sporadic desmoid tumours (DT) when traditional clinicopathological parameters were inconclusive was evaluated. Cases included were: (i) new primary lesions where initial DT diagnosis was inconclusive; and (ii) possible recurrent DT versus scar. Formalin-fixed paraffin-embedded (FFPE) tissues were obtained via needle biopsy or a surgical excision (57 specimens) as part of initial assessment. DNA extraction, CTNNB1 exon 3 amplification and sequencing were conducted in a Clinical Laboratory Improvement Amendments of 1988 (CLIA)-approved molecular diagnostics laboratory. For patients with no previous DT history (n = 47) sequencing identified mutations in 30 (64%), substantiating DT diagnosis. In biopsies with non-mutated (NM) CTNNB1 (n = 17) the test was inconclusive; in seven of these, a diagnosis of DT was strongly favoured in the subsequent surgical resection specimen. Ten patients with previously resected DT were evaluated; mutation was identified in six cases (60%), indicating DT over scar. In two (20%) with primary tumours harbouring CTNNB1 mutation no mutation was found, favouring scar over DT; the other two NM-CTNNB1 cases (20%) were inconclusive. CTNNB1 genotyping can be very useful in 'difficult to diagnose' lesions when the differential diagnosis includes DT. Recognizing inherent test limitations, the presence of CTNNB1 mutation can inform the therapeutic approach.

Subclassification of atypical cells of undetermined significance in direct smears of fine-needle aspirations of the thyroid

Atypical cells of undetermined significance (AUS) in thyroid fine-needle aspirates (FNAs) may have poor interobserver agreement. Some authors have suggested that "atrophic" microfollicles should be diagnosed as benign. This laboratory sought to determine whether criteria for this diagnosis could be improved by subcategorizing cases into specific patterns, including the atrophic pattern, and determining their risk of malignancy. A series of 7089 FNAs were reviewed and correlated with subsequent resection specimens. Cases of AUS were reviewed and subclassified. Cases could be subcategorized into the following categories: 1) atypical, papillary carcinoma cannot be ruled out, 2) atypical, Hürthle cell neoplasm can not be ruled out, 3) cellular atrophic pattern, 4) scant atrophic pattern, and 5) cytologic atypia alone. Cytologic atypia alone (50%) and both atrophic patterns (21% and 34%) had a significant risk of malignancy. The majority of AUS cases in thyroid FNA can be subcategorized into 5 different patterns, all with associated significant risk of malignancy. "Atrophic" microfollicles are a significant risk factor for malignancy and should not be diagnosed as benign on the basis of lack of cytologic atypia.