Biopsy Site Changes Research Articles

Mucocele-like Lesion: To Excise or Not to Excise?

Abstract Introduction/Objective Mucocele-like lesions (MLLs) are characterized by cystically dilated, mucin-filled ducts, usually associated with rupture and extravasation of mucin into the stroma. The epithelium lining the ducts may be attenuated or show a spectrum of proliferative changes ranging from hyperplasia to atypical hyperplasia to ductal carcinoma in situ (DCIS). Our study aims to evaluate the necessity of excision of pure MLL without atypia diagnosed on core needle biopsy (CNB). Methods/Case Report We retrospectively identified all subsequent in-house CNBs obtained between January 2017- August 2022 with MLLs. We reviewed all CNB slides with the diagnosis containing a “mucocele-like lesion” and assessed radiologic-pathologic concordance. An upgrade was defined as invasive carcinoma and/or DCIS in the excision. The excision slides of all upgraded cases were re-reviewed. Out of ~16000 consecutive CNBs in the study period, 69 CNBs from 69 patients yielded MLL alone, MLL with atypia, or MLL with carcinoma. We excluded 43 CNBs (7 patients with prior/concurrent carcinoma and 36 without excision). The final cohort consisted of 25 CNBs (14 with pure mucocele-like lesions and 11 MLLs with atypia). The CNB targeted mammographic calcifications in 42 cases, and 4 sonographic mass. Results (if a Case Study enter NA) Subsequent excision or clinical follow-up was available for 14 pure MLLs—of which one was upgraded. Five excisions showed atypia (4 atypical ductal hyperplasias (ADH) and one atypical lobular hyperplasia (ALH)). Excisions of 11 MLL with atypia yielded 1 case upgraded to DCIS (9.09%, 1/11) and seven excisions showed atypia (5 ADH, 1 ALH, and 1 flat epithelial atypia). DCIS in an upgraded case was in an area with biopsy site changes. There was no upgrade to invasive carcinoma in either group. Among the 36 MLLs excluded from the study due to not having excision available for review, twelve were followed up with interval radiology and showed either stable lesions or no residual calcifications. Conclusion There was one case with upgrade of pure MLLs in our series. Clinicoradiological surveillance can be considered in a patient without prior/current carcinoma in pathological-radiological concordant CNB diagnosis of pure MLL.

Histopathologic findings in patients who have undergone blue light cystoscopy and bladder biopsy or transurethral resection: A contemporary clinicopathologic analysis of 100 cases

Blue light cystoscopy is utilized to assist Urologists highlight potentially malignant –bladder lesions that might otherwise be undetected by standard cystoscopic techniques. There is a paucity of published studies in the literature regarding the histopathologic findings in this setting, especially regarding false positive lesions. A search was performed for patients who underwent blue light cystoscopy at our institution from 2017 to 2021. Clinicopathologic data was obtained. One hundred cases were included in the study. The mean patient age was 69 years (range: 33–97 years), with a male predominance (3.5:1). Of these cases, 69 were malignant lesions. Twenty-nine cases were high grade urothelial carcinoma (UCa), including 17/29 (58.6%) that were non-invasive, 7/29 (24.1%) invasive into lamina propria, and 5/29 (17.2%) invasive into muscularis propria (Detrusor muscle). Twenty-seven cases were non-invasive low grade UCa, 12 cases were urothelial carcinoma in situ, and 1 case was prostatic adenocarcinoma. Thirty-one cases were benign lesions, including 11/31 (35%) inflammation, 4/31 (13%) nephrogenic adenoma, 3/31 (10%) each: therapy related changes; cystitis cystica et glandularis; reactive changes/atypia, 2/31 (7%) foreign body reaction, 1/31 (3%) each: urothelial papilloma, urethral polyp, squamous metaplasia, focal atypia, and biopsy site changes. Although most cases were malignant, a significant number of benign entities (false positives) were also identified. Correlation between the histopathologic and blue light cystoscopy findings could play a critical role in further stratification and management of patients undergoing this procedure, including surveillance protocols.

Needle tract seeding in renal tumor biopsies: experience from a single institution

BackgroundPercutaneous needle biopsy of renal masses has been increasingly utilized to aid the diagnosis and guide management. It is generally considered as a safe procedure. However, tumor seeding along the needle tract, one of the complications, theoretically poses potential risk of tumor spread by seeded malignant cells. Prior studies on the frequency of needle tract seeding in renal tumor biopsies are limited and clinical significance of biopsy-associated tumor seeding remains largely controversial.MethodsHere we investigated the frequencies of biopsy needle tract tumor seeding at our institution by reviewing the histology of renal cell carcinoma nephrectomy specimens with a prior biopsy within the last seventeen years. Biopsy site changes were recognized as a combination of foreign body reaction, hemosiderin deposition, fibrosis and fat necrosis. The histologic evidence of needle tract tumor seeding was identified as clusters of tumor cells embedded in perinephric tissue spatially associated with the biopsy site. In addition, association between parameters of biopsy techniques and tumor seeding were investigated.ResultsWe observed needle tract tumor seeding to perinephric tissue in six out of ninety-eight (6 %) renal cell carcinoma cases including clear cell renal cell carcinoma, papillary renal cell carcinoma, chromophobe, and clear cell papillary renal cell carcinoma. The needle tract tumor seeding was exclusively observed in papillary renal cell carcinomas (6/28, 21 %) that were unifocal, small-sized (≤ 4 cm), confined to the kidney and had type 1 features. No recurrence or metastasis was observed in the papillary renal cell carcinoma cases with tumor seeding or the stage-matched cases without tumor seeding.ConclusionsOur study demonstrated a higher than reported frequency of needle tract tumor seeding. Effective communication between pathologists and clinicians as well as documentation of tumor seeding is recommended. Further studies with a larger patient cohort and longer follow up to evaluate the impact of needle tract tumor seeding on long term prognosis are needed. This may also help reach a consensus on appropriate pathologic staging of renal cell carcinoma when the only site of perinephric fat invasion is within a biopsy needle tract.

#EBUSTwitter: Novel Use of Social Media for Conception, Coordination, and Completion of an International, Multicenter Pathology Study.

Social media sites are increasingly used for education, networking, and rapid dissemination of medical information, but their utility for facilitating research has remained largely untapped. To describe in detail our experience using a social media platform (Twitter) for the successful initiation, coordination, and completion of an international, multi-institution pathology research study. Following a tweet describing a hitherto-unreported biopsy-related histologic finding in a mediastinal lymph node following endobronchial ultrasound-guided transbronchial needle aspiration, a tweet was posted to invite pathologists to participate in a validation study. Twitter's direct messaging feature was used to create a group to facilitate communication among participating pathologists. Contributing pathologists reviewed consecutive cases of mediastinal lymph node resection following endobronchial ultrasound-guided transbronchial needle aspiration and examined them specifically for biopsy site changes. Data spreadsheets containing deidentified data and digital photomicrographs of suspected biopsy site changes were submitted via an online file hosting service for central review by 5 pathologists from different institutions. A total of 24 pathologists from 14 institutions in 5 countries participated in the study within 143 days of study conception, and a total of 297 cases were collected and analyzed. The time interval between study conception and acceptance of the manuscript for publication was 346 days. To our knowledge, this is the first time that a social media platform has been used to generate a research idea based on a tweet, recruit coinvestigators publicly, communicate with collaborating pathologists, and successfully complete a pathology study.

Flat Epithelial Atypia in Breast Core Needle Biopsies With Radiologic-Pathologic Concordance: Is Excision Necessary?

Flat epithelial atypia (FEA) is an alteration of terminal duct lobular units by a proliferation of ductal epithelium with low-grade atypia. No consensus exists on whether the diagnosis of FEA in core needle biopsy (CNB) requires excision (EXC). We retrospectively identified all in-house CNBs obtained between January 2012 and July 2018 with FEA. We reviewed all CNB slides and assessed radiologic-pathologic concordance. An upgrade was defined as invasive carcinoma (IC) and/or ductal carcinoma in situ in the EXC. The EXC slides of all upgraded cases were rereviewed. Out of ∼15,700 consecutive CNBs in the study period, 106 CNBs from 106 patients yielded FEA alone or with classic lobular neoplasia (LN). We excluded 52 CNBs (40 patients with prior/concurrent carcinoma and 12 without EXC). After rereview, we reclassified 14 cases (2 marked nuclear atypia, 10 focal atypical ductal hyperplasia, 2 benign). The final FEA study cohort consisted of 40 CNBs from 40 women. The CNB targeted mammographic calcifications in 36 (90%) cases, magnetic resonance imaging nonmass enhancement in 3 (8%), and 1 (2%) sonographic mass. All CNBs were deemed radiologic-pathologic concordant. FEA was present alone in 34 CNBs and with LN in 6. EXC yielded 2 low-grade IC, each spanning <2 mm, identified in tissue sections without biopsy site changes. The remaining 38 cases had no upgrade. Classic LN did not affect the upgrade. The upgrade rate of FEA was 5%; both minute, low-grade "incidental" IC. We conclude that nonsurgical management may be considered in patients without prior/concurrent carcinoma and radiologic-pathologic concordant CNB diagnosis of FEA.

Frozen Sections of Sentinel Lymph Nodes From Breast Cancer Patients Who Undergo Neoadjuvant Therapy Are Accurately Diagnosed Using Telepathology

Abstract Objectives Telepathology enables histologic diagnosis to be made from a scanned slide visualized on a computer. Frozen sections (FSs) can be performed at remote locations and read by a pathologist at a central site. At our institution, qualifying breast cancer patients are enrolled in clinical trials that require FS on sentinel lymph nodes (SLNs) after neoadjuvant therapy (NAT), including chemotherapy or endocrine therapy. In this setting, histology is complicated by treatment effect and biopsy site changes. Others have reported good accuracy of FSs on SLNs after NAT. We investigated whether pathologists are accurate in diagnosing SLN FSs for such cases while using telepathology. To our knowledge, this has not been reported previously. Methods SLNs were entirely submitted and serially sectioned (2-mm thickness). At least two levels were cut. All FSs were submitted for formalin-fixed, paraffin-embedded permanent sections. A pathology assistant at the remote location prepared the FSs and scanned slides using the VisionTek M6 digital microscope ecosystem (East Dundee, IL). Cases were interpreted by board-certified pathologists who completed training on the VisionTek system. For this study, diagnoses from FSs and permanents were compared. Results Forty-five SLNs from 19 breast neoadjuvant cases were read by VisionTek from March 2017 to January 2019. Forty-three cases (96%) called negative by FSs were confirmed negative (on permanents). One hundred percent called positive by FSs were positive. Four SLN called atypical on FSs were positive. Three of these were neoadjuvant endocrine cases for invasive lobular carcinoma. Two cases called atypical were negative. One of these, called atypical/suspicious, resulted in axillary dissection. This case was reviewed by three pathologists at the time of surgery. It had abundant treatment effect, mimicking carcinoma. Conclusion While pitfalls exist, overall, the diagnostic accuracy of frozen section analysis by telepathology of SLNs from breast cases after neoadjuvant therapy is high.

Displaced Cartilage Within Lymph Node Parenchyma Is a Novel Biopsy Site Change in Resected Mediastinal Lymph Nodes Following EBUS-TBNA.

Biopsy site changes in mediastinal lymph nodes (LNs) attributable to prior endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) have not been studied in a systematic manner. Twenty-four contributors from 14 institutions in 5 countries collaborated via social media (Twitter) to retrospectively review consecutive cases of resected mediastinal LNs from patients with prior EBUS-TBNA. Resected LNs were reexamined by submitting pathologists for changes attributable to EBUS-TBNA. Patients who received neoadjuvant therapy were excluded. Cases with suspected biopsy site changes underwent central review by 5 pathologists. A total of 297 mediastinal LN resection specimens from 297 patients (183 male/114 female, mean age: 65 y, range: 23 to 87) were reviewed. Biopsy site changes were most common in station 7 (10 cases) followed by 11R, 4R, and 10R, and were found in 34/297 (11.4%) cases, including displacement of tiny cartilage fragments into LN parenchyma in 26, intranodal or perinodal scars in 7, and hemosiderin in 1. Cartilage fragments ranged from 0.26 to 1.03 mm in length and 0.18 to 0.62 mm in width. The mean interval between EBUS-TBNA and LN resection was 38 days (range: 10 to 112) in cases with biopsy site changes. A control group of 40 cases without prior EBUS-TBNA, including 193 mediastinal LN stations, showed no evidence of biopsy site changes. Biopsy site changes are identified in a subset of resected mediastinal LNs previously sampled by EBUS-TBNA. The location of the abnormalities, temporal association with prior EBUS-TBNA, and the absence of such findings in cases without prior EBUS-TBNA support the contention that they are caused by EBUS-TBNA.

Biopsy Site Changes in Resected Mediastinal Lymph Nodes with Prior Endobronchial Ultrasound-Guided Transbronchial Fine Needle Aspiration (EBUS-TBNA)

Biopsy Site Changes in Resected Mediastinal Lymph Nodes with Prior Endobronchial Ultrasound-Guided Transbronchial Fine Needle Aspiration (EBUS-TBNA)

The 21-gene recurrence score in special histologic subtypes of breast cancer with favorable prognosis.

The 21-gene recurrence score (RS) assay predicts the likelihood of distant recurrence and chemotherapy benefit in early-stage, estrogen receptor (ER)-positive, HER2-negative breast cancer. Data on the RS of special histologic subtypes of invasive breast carcinoma with favorable prognosis are limited. We reviewed our institutional database to identify patients with special histologic subtypes of breast cancer associated with favorable prognosis and available RS results. Our cohort consists of fifty-seven women: thirty-three patients with pure mucinous carcinoma (MC), ten with tubular carcinoma (TC), nine with encapsulated papillary carcinoma (EPC), and five with solid papillary carcinoma (SPC). Most (44/57, 77.2%) carcinomas had low RS (≤17), and none had high RS (≥31). All EPCs had low RS, but other subtypes had RS 18-30. Higher RS was associated with lower progesterone receptor (PR) expression by immunohistochemistry and lower PR mRNA scores (P≤0.007). No morphologic feature (tumor grade, biopsy site changes, cellular stroma, inflammatory cells) was associated with RS≥18. At a median follow-up of 40months, the distant recurrence-free survival was 100%. One patient with SPC developed locoregional recurrence at 22months. As the largest series to date, our study raises the question of whether the RS assay is necessary for breast cancers with favorable histology. Reflex testing of node-negative, ER+/HER2- breast cancers may be deferred for these special histologic subtypes, emphasizing the need for multidisciplinary discussions between breast pathologists and other members of the breast cancer team.

Abstract CT076: Women's triple-negative, first-line treatment: Improving outcomes in triple-negative breast cancer using molecular triaging and diagnostic imaging to guide neoadjuvant therapy

Abstract BACKGROUND: Triple negative breast cancer (TNBC) is a heterogeneous disease with identified biologically diverse subtypes. There are known differences in response to neoadjuvant chemotherapy (NACT) in TNBC patients with 50% having excellent response to treatment (pCR/Residual cancer burden [RCB]-I) and good survival prognosis, while 50% demonstrate marked residual disease (RCB-II-III) with significantly worse prognosis. Lack of response early into NACT indicates a low chance (5%) of achieving pCR. Thus, it is important to develop diagnostic platforms predictive of pCR, in order to direct patients with responsive disease toward standard NACT and non-responsive disease toward experimental therapies within clinical trials. METHODS: All patients will undergo biopsy of the primary tumor for molecular analyses, but will then be randomized 2:1 to know these results versus not (control). An algorithm that incorporates pre-defined genomic signatures will determine predicted sensitivity to NACT, which contains anthracyclines and taxanes. All patients will begin standard of care anthracycline based NACT with diagnostic imaging to assess response after 4 cycles. Patients who fit molecular/imaging criteria for non-responsive disease will undergo a second biopsy to confirm tumor cellularity and be offered a clinical trial based upon the initial molecular profiling (if known) or based upon physician/patient choice if randomized to the control arm. Patients who fit criteria for responsive disease in either arm will be recommended to continue with taxane-based NACT. Rates of excellent therapy response (pCR/RCB-I) will be compared between the randomized arms. One additional core and two FNAs will be obtained at the time of each planned biopsy and used to generate cell lines and PDX models for study of therapy resistance. Inclusion criteria include: Tumor size ?1.5 cm diameter; TNBC by standard assays; ?18 years of age; LVEF ?50%; adequate organ and bone marrow function. Exclusion criteria include: Stage IV disease; history of invasive cancer within 5 years; excisional biopsy of the primary tumor; biopsy site changes that limit response assessment; medically unfit for chemotherapy; prior anthracycline; &amp;gt;grade II neuropathy; Zubrod performance status of &amp;gt;2; history of serious cardiac event. The study was activated on 11/09/2015. To date, 10 patients have been enrolled. PRIMARY AIM: Prospectively determine the impact of a molecular diagnostic/imaging platform to guide neoadjuvant therapy in patients with localized invasive TNBC. SECONDARY AIMS: -Determine the impact of targeted therapy to improve pathological response in chemotherapy resistant disease in patients who are selected for clinical trials based upon molecular features of their tumors. -Generate a translational research platform to facilitate molecular diagnostic development, study mechanisms of acquired resistance, and inform the next generation of clinical trials. STATISTICAL METHODS: A maximum of 360 patients will be randomized (2:1)using a group sequential design with one-sided O’Brien-Fleming boundaries, with two equally spaced binding interim tests for futility and superiority and one final test, having an overall Type I error .05 and power .80 to detect an improvement in pCR/RCB-I from 50% to 64%. Citation Format: Zahi Mitri, Naoto T. Ueno, Wei Yang, Vicente Valero, Jennifer K. Litton, Rashmi Murthy, Bora Lim, Nuhad K. Ibrahim, Banu K. Arun, Elizabeth A. Mittendorf, Kelly K. Hunt, Funda Meric-Bernstam, Alastair Thompson, Michael Gilcrease, Helen Piwnica-Worms, Debasish Tripathy, William Fraser Symmans, Stacy Moulder-Thompson. Women's triple-negative, first-line treatment: Improving outcomes in triple-negative breast cancer using molecular triaging and diagnostic imaging to guide neoadjuvant therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT076.

Biopsy-site Changes in Lung Adenocarcinoma With Prior Core Needle Biopsy

Although biopsy-site changes are known to cause diagnostic difficulties in thyroid and breast specimens, especially when assessing invasion, such changes have not been described in the lung. Assessment of invasion is important in lung cancers to distinguish bronchioloalveolar carcinoma [adenocarcinoma in situ (AIS)] from invasive adenocarcinoma. The aim of this study was to determine whether biopsy-site changes occur in the lung and whether they may impact this differential diagnosis. Lobectomy specimens were examined from patients whose previous core needle biopsies showed well-differentiated adenocarcinoma with a lepidic pattern. There were 26 adenocarcinomas, including 14 minimally invasive adenocarcinomas, 2 invasive well-differentiated adenocarcinomas, and 10 AISs. Biopsy-site changes were identified in 9 of 26 (35%), including 4 minimally invasive adenocarcinomas, 3 AISs, and 2 well-differentiated adenocarcinomas. The interval between biopsy and resection ranged from 12 to 45 days (mean, 26.1 d). The biopsy sites consisted of a linear scar composed of collagen and plump fibroblasts, ranging from 2.0 to 13.1 mm in length and 0.5 to 1.6 mm in width. Scattered lymphocytes and plasma cells were present in 8 cases, pigment-laden macrophages in 4, and foreign body giant cells in 3. Benign entrapped lung epithelium was present within the scar in all 9 and entrapped malignant epithelium in 4. Biopsy-site changes can be identified in a significant proportion of lung tumors after core needle biopsy. They need to be distinguished from tumor-related stromal reactions that are considered an indication of invasion and are important in the differentiation of AIS and invasive adenocarcinoma.

Prognostic/Predictive Immunohistochemistry Assays for Estrogen Receptor–Positive Breast Cancer: Back to the Future?

Given its identity as the first common malignancy with a molecular target, it is not surprising that breast cancer is the battleground for the many controversies that surround the use of multiparametric biomarker assays to guide cancer therapy. Historically, one of the most important classifications for breast cancer is its division into estrogen receptor (ER) –positive and ER-negative disease, because this division has important prognostic and predictive implications for the use of endocrine therapy. During the last 10 years, breast cancer classification has been refined and extended through transcriptional profiling, whole genome and exome sequencing, as well as other sophisticated molecular assays with the hope that such knowledge will facilitate determination of the exact prognosis and correct treatment plan for an individual patient. No fewer than a dozen such assays are in various phases of development or application for early breast cancer. Their credentialing raises a number of critical questions. In the article that accompanies this editorial, Bartlett et al describe the performance of a multiprotein immunohistochemical (IHC) assay called Mammostrat in tumors from patients who were enrolled on the Tamoxifen versus Exemestane Adjuvant Multicenter (TEAM) trial. First reported by Ring et al, this five-marker panel (p53, NDRG1, CEACAM5, SLC7A5, and HTF9C) was developed to assess prognosis in patients with early-stage, ER-positive breast cancer and was tested further in several additional cohorts, largely in the setting of adjuvant tamoxifen. The markers used in the panel were purposely selected to be distinct from conventional breast cancer markers such as ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), or Ki-67. They represent components of DNA damage and cell cycle (p53, HTF9C), stress response (NDRG1), nutritional (SLC7A5), and differentiation (CEACAM5) pathways that are linked to cell growth and differentiation. Their expression is qualitatively assessed and then combined into a quantitative risk index for recurrence using a defined mathematical algorithm to identify individuals with low (score 0), moderate (score 0 and 7), or high (score 7) risk of recurrence. This algorithm is similar to the more commonly used 21-gene test (Oncotype DX assay; Genomic Health, Redwood City, CA), and the less well-known sevengene test (bioTheranostics Breast Cancer Index; bioTheranostics, San Diego, CA). The study by Bartlett et al is the largest evaluation of the Mammostrat (Clarient, Aliso Viejo, CA) prognostic panel to date. Tissue microarrays with triplicate cores derived from 4,598 patients who were enrolled onto the TEAM trial (which randomly assigned postmenopausal patients with early-stage, hormone receptor–positive breast cancer to 5 years of exemestane or a sequence of tamoxifen followed by exemestane) were assessed in a central laboratory. In multivariate regression analyses that were corrected for conventional clinicopathologic parameters, the Mammostrat assay provided significant additional information on distant recurrence-free survival after endocrine therapy in patients with ER-positive, node-negative disease, as well as all patients not exposed to chemotherapy, and in the entire patient cohort (n 3,837). Disappointingly, but not surprisingly, no differences were seen between the two endocrine regimens. No markers that can reliably differentiate between the benefit of tamoxifen or the aromatase inhibitor have been identified to date. The utility of the assay to predict for response to chemotherapy, which is arguably the most important question for management of early-stage, hormoneresponsive breast cancer, could not be assessed. The strengths of this study include the use of tissues from a well-designed, well-conducted clinical trial of substantial size with clear outcomes and the performance of the assay in a central laboratory using predefined guidelines. Because Mammostrat is an IHC assay, it has a distinct advantage over nonmorphologic molecular assays in that it evaluates protein expression at the in situ level. The results are therefore not confounded by the admixture of normal or proliferative breast tissue, the presence of inflammatory cells, or biopsy site changes that are commonly present within the tumor tissue block and can complicate interpretation of assays such as Oncotype DX that use mRNA isolated from tissue sections. Like many such analyses, the study does suffer from the common problem of the vanishing denominator. A total of 9,778 patients were enrolled onto the TEAM trial and blocks were recovered from 4,598 patients to construct the tissue microarrays; Mammostrat JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 36 DECEMBER 2

Endogenous Versus Tumor-Specific Host Response to Breast Carcinoma: A Study of Stromal Response in Synchronous Breast Primaries and Biopsy Site Changes

We recently described two types of stromal response in breast cancer derived from gene expression studies of tenosynovial giant cell tumors and fibromatosis. The purpose of this study is to elucidate the basis of this stromal response--whether they are elicited by individual tumors or whether they represent an endogenous host reaction produced by the patient. Stromal signatures from patients with synchronous dual primaries were analyzed by immunohistochemistry on a tissue microarray (n = 26 pairs) to evaluate the similarity of stromal responses in different tumors within the same patient. We also characterized the extent to which the stromal signatures were conserved between stromal response to injury compared to the stromal response to carcinoma using gene expression profiling and tissue microarray immunohistochemistry. The two stromal response signatures showed divergent associations in synchronous primaries: the DTF fibroblast response is more likely to be similar in a patient with multiple breast primaries (permutation analysis P = 0.0027), whereas CSF1 macrophage response shows no significant concordance in separate tumors within a given patient. The DTF fibroblast signature showed more concordance across normal, cancer, and biopsy site samples from within a patient, than across normal, cancer, and biopsy site samples from a random group of patients, whereas the CSF1 macrophage response did not. The results suggest that the DTF fibroblast response is host-specific, whereas the CSF1 response may be tumor-elicited. Our findings provide further insight into stromal response and may facilitate the development of therapeutic strategies to target particular stromal subtypes.

Excision is indicated for intraductal papilloma of the breast diagnosed on core needle biopsy

Although it has been accepted that intraductal papillomas with atypia or malignancy diagnosed on core needle biopsy require surgical excision, the management of pure intraductal papillomas has been controversial. Because some series reported a small but definite incidence of atypia or malignancy, whereas others claimed that radiologic follow-up was adequate, this study evaluated results of excision of all pure intraductal papillomas diagnosed on core needle biopsy at this institution. By using computerized pathology files from January of 2000 to December of 2004, 200 cases of intraductal papillomas on core needle biopsy were identified. Information regarding excision was available in 104 cases. All specimens were reviewed to confirm both the diagnoses as well as the presence of biopsy site changes in excision specimens, and the findings were correlated with radiologic data. The age of the patients ranged from 25 to 82 years (mean, 55.5). The diagnoses on excision were as follows: intraductal papillomas = 71 cases (68.3%), no residual intraductal papillomas = 16 (15.3%), atypical duct hyperplasia = 8 (7.7%), ductal carcinoma in situ = 6 (5.8%), and invasive carcinoma = 3 (2.9%). In cases with atypia or malignancy, these findings were adjacent to but not in the biopsy site. In cases with atypical duct hyperplasia or ductal carcinoma in situ, a spectrum of histologic changes ranging from florid to atypical duct hyperplasia (14 cases), to ductal carcinoma in situ (6 cases) were present, all involving intraductal papillomas. The upstage rate of pure intraductal papillomas on core needle biopsy to atypia or malignancy on excision was 16.4%. Because of sampling error and the close proximity of atypia or malignancy to the intraductal papillomas (suggesting precancerous potential), excision was recommended of these lesions diagnosed on core needle biopsy. Close radiologic-pathologic correlation was important in the evaluation of these lesions.

Detection of Residual Tumor Cells in Bladder Biopsy Specimens: Pitfalls in the Interpretation of Cytokeratin Stains

Some patients who have had prior bladder biopsies or transurethral resections undergo a repeat resection within several months for various reasons. The detection of a few residual tumor cells in bladder specimens with prior biopsy site changes can be challenging based on histology alone. Immunohistochemistry for cytokeratins may be used as an adjunct in this situation. We have noted several cases in which keratin stains were performed and positive cells were noted, raising the issue as to whether the cytokeratin positive cells were residual tumor cells or stromal cells. Immunohistochemistry for a panel of antibodies [AE1/AE3, CAM 5.2, high molecular weight cytokeratin, smooth muscle actin (SMA), desmin, and anaplastic lymphoma kinase (ALK)] was performed on 29 cases of bladder biopsies with prior biopsy site changes. Of 29 patients, 25 had a prior history of bladder tumor: 17 had invasive high-grade urothelial carcinoma (T1, 5 cases; T2, 11 cases; T3,1 case); 7 had noninvasive high-grade papillary urothelial carcinoma; 1 had noninvasive low-grade papillary urothelial carcinoma). One of the patients with noninvasive high-grade papillary urothelial carcinoma and one of the patents with invasive high-grade urothelial carcinoma had associated carcinoma in-situ. Four patients had prior benign bladder diagnoses: cystitis cystica et glandularis; polypoid cystitis; follicular cystitis; and neurogenic bladder with benign prostate hyperplasia. Of the 29 cases, 6 (21%) had cells with staining for at least 2 of the cytokeratin markers. Cytokeratin (CK) AE1/ AE3 was positive for cells in 8/29 cases (28%). In 6 of these cases, cells displayed a spindle cell and 2 cases a more epithelioid morphology. CAM 5.2 was positive in cells in 5/29 cases (17%); 3 of the cases had spindle cell and 2 cases epithelioid morphology. High molecular weight cytokeratin was expressed in cells in 2/29 cases (7%) with 1 case having spindle cell and 1 epithelioid morphology. SMA was positive in cells with a spindle cell morphology and negative in the more epitheloid cytokeratin positive cells. Desmin was positive in 3/6 keratin positive spindle cells and negative in keratin positive epithelioid cells. ALK was negative in all the cases. Three cases with spindle cell morphology and positivity for at least 1 of the keratins and SMA stains were interpreted as aberrant keratin expression in myofibroblastic cells based on the staining and the morphology of the spindle cells. Another 3 cases with concurrent staining for at least 1 of the keratins, SMA and desmin were consistent with smooth muscle cells on the basis of their cellular morphology. Another 2 cases had cells, which expressed at least 2 CK markers but did not express SMA, desmin, or ALK and a more epithelioid morphology. These cells were interpreted as residual tumors cells. When interpreting CK stains for the detection of residual tumor cells, one should pay attention to the nature of the cells and not assume all CK staining cells are residual tumor cells.

Spectrum and Diagnosis of Myocardial Rejection

Right ventricular endomyocardial biopsy has become the mainstay for the diagnosis of acute cardiac rejection. The intelligent inerpretation of endomyocardial biopsy specimens requires knowledge of the artifacts inherent to the procedure as well as specific rejection and nonrejection pathology. Myocardial contraction bands, artifactual tissue spreading, and prior biopsy site changes should not be misinterpreted as evidence of myocyte damage, interstitial edema, or rejection, respectively. The Billingham criteria for acute cardiac rejection (mild, moderate, and severe) are still the most widely utilized, although other schemes for rejection have also shown clinical usefulness. Additionally, there is increasing evidence that some patients may develop a vascular or humoral rejection that may be more difficult to diagnose by endomyocardial biopsy without utilization of special techniques--for example, immunofluorescence. Nonrejection pathology frequently seen post-transplantation includes ischemia or catecholamine effect, interstitial fibrosis, myocardial calcification, cyclosporine-associated endocardial infiltrates (Quilty effect), myocyte hypertrophy, and infections (CMV, toxoplasmosis). Coronary artery disease continues to be the most significant threat to long-term survival. The spectrum of pathologic changes in the vessels range from mild intimal thickening to severe concentric intimal fibrosis involving extramural, as well as intramural, coronaries to lesions virtually identical to native atherosclerosis. Patients with diffuse narrowing involving large and small intramyocardial vessels appear to be at greater risk for myocardial infarction, death, or retransplantation than patients with other types of coronary pathology. Although important, these large vessel changes are rarely identified by endomyocardial biopsy.