Spectrum of atypical ductal hyperplasia (ADH) and ductal carcinoma in-situ (DCIS): Diagnostic challenges.

Breast specimens are some of the more common specimens sent to the pathology laboratory for diagnosis. From a clinical perspective, the diagnoses fall into three broad categories: benign, atypical and malignant with patients then being managed according to established guidelines. However, the pathologic diagnosis can sometimes be challenging, and the distinction between these categories is sometimes far more subtle and subjective than non-pathologist may understand. One recurring diagnostic challenge in breast pathology is the diagnosis of atypical ductal hyperplasia (ADH) versus ductal carcinoma in situ (DCIS). While many cases are straightforward, others are quite borderline and challenging to classify consistently with significant interobserver variation amongst pathologists. The distinction between ADH and DCIS is critical from a clinical management perspective because one is treated as a risk factor, and the other as a malignancy that will be completely surgically excised and may require radiation therapy. This review will address the spectrum of ADH and DCIS with the associated diagnostic challenges in the real-world setting from presentation at core needle biopsy to surgery.

Clinicopathologic and immunohistochemical study of breast angiosarcoma.

Breast angiosarcoma (AS) is a rare malignancy which can be classified into primary or secondary as a result of breast cancer therapy. On histology, breast AS has a wide spectrum of morphologic presentations, and its diagnosis can be challenging based on morphologic evaluation alone. Here, we studied 10 cases of breast AS diagnosed at our institution during a 20-year period, in which 7 cases were radiation-associated AS (RA-AS) and 3 cases were primary AS (P-AS). The average latency between radiotherapy and RA-AS was 8.1 years. RA-AS mostly occurred in breast skin, while all P-AS involved breast parenchyma. All 10 AS cases were high grade, including 4 RA-AS cases demonstrating epithelioid morphology. Histologic morphologies of AS varied from confluent growth of atypical spindle or epithelioid cells to scattered marked pleomorphic cells. Some cases appeared deceptively bland or low grade, but the presence of areas of haemorrhage ('blood lake') or necrosis upgraded them to high grade lesions. Additionally, some epithelioid RA-AS cases with lymphatic differentiation (D2-40 positive) showed pseudopapillary morphology characterized by discohesive cells sloughing off at periphery of vascular cores, resembling papillary breast carcinoma. P-AS did not show prominent vesicular nuclei and/or conspicuous nucleoli, which were features observed in RA-AS. C-MYC immunostain results showed P-AS was completely negative or focal weakly positive in hypercellular areas. In comparison, RA-AS were consistently positive for c-MYC. Epithelioid RA-AS with lymphatic differentiation tended to show stronger and/or more diffuse c-MYC positivity than other AS cases. CD31 and ERG immunostains showed positivity in all cases, while CD34 were negative in some cases with lymphatic differentiation. This study offers a detailed morphologic and immunohistochemical assessment of a rare tumor of the breast that is important to recognize. Common differential diagnosis for breast AS, including post-radiation atypical vascular proliferation (AVP), are also reviewed and discussed.

Tiny but mighty: use of next generation sequencing on discarded cytocentrifuged bile duct brushing specimens to increase sensitivity of cytological diagnosis.

Bile duct brushing (BDB) is used to evaluate pancreatobiliary lesions as it widely samples lesions with a low complication rate. Cytological evaluation of BDB is a specific but insensitive test. There is limited literature on the use of post-cytocentrifuged (PCC) samples, which are usually discarded, for next-generation sequencing (NGS) as an adjunct to cytological diagnosis of BDB. In this study we investigate whether molecular analysis by NGS of PCC specimens improves the sensitivity of diagnosis. PCC samples from 100 consecutive BDB specimens spanning 93 unique patients were retained. DNA was extracted and mutational analysis was performed agnostic of morphologic or clinical findings. Each BDB specimen was characterized as negative, atypical or positive based on morphological analysis by trained cytopathologists. Performance characteristics for mutational profiling and morphological analysis were calculated on the basis of clinicopathologic follow-up. There was sufficient clinicopathologic follow-up to classify 94 of 100 cases as either malignant (n = 43) or benign (n = 51). Based on morphologic analysis of cytology, these 94 cases were classified as either benign (n = 55), atypical (n = 18), or as at least suspicious or positive for malignancy (n = 21). Morphologic analysis of cytology showed a sensitivity of 49% and a specificity of 100% if atypical cases were considered negative. NGS revealed oncogenic alterations in 40/43 (93%) of malignant cases based on clinicopathologic follow-up. The most common alterations were in KRAS and TP53, observed in 77% and 49% of malignant cases respectively. No alterations were observed in the 51 benign cases classified based on clinicopathologic follow-up. Supplementing cytomorphologic analysis with molecular profiling of PCC by targeted NGS analysis increased the sensitivity to 93% and maintained specificity at 100%. This study provides evidence for the utility of NGS molecular profiling of PCC specimens to increase the sensitivity of BDB cytology samples, although studies with larger cohorts are needed to verify these findings.

Cat Scratch Disease of the Breast/Axilla: Recognition of a Rare Disease and Approaches for Differential Diagnosis.

Cat scratch disease rarely presents as a breast or axillary mass mimicking carcinoma both clinically and radiologically. Diagnosing breast/axillary cat scratch disease is challenging due to its rarity and nonspecific findings. Here, we reported 2 patients with breast cat scratch disease and reviewed 14 patients with cat scratch disease involving breast/axilla from the past 30 years. It mainly affects women (median age: 48), consistently presenting as axillary lymphadenopathy, and demonstrates ipsilateral breast mass in half of patients (50%, 8/16). The breast mass was most commonly located in the upper outer quadrant (88%, 7/8), indicating the possibility of disease extension from axillary adenopathy. Around half of patients (56%, 9/16) reported cat exposure. Histologically, most patients (93%, 14/15) presented as necrotizing granulomas, with characteristic stellate-shaped necrosis in 5 patients. Although pathologic differential diagnoses between cat scratch disease and cancer are straightforward, distinguishing cat scratch disease from other granulomatous mastitis poses diagnostic challenges. Silver stains should be included in the diagnostic workup panel when highly suspecting cat scratch disease clinically. However, they were only able to highlight the causative microorganism in 54% (7/18) patients, and the gram stain was negative in all 12 tested patients. In contrast, polymerase chain reaction (PCR) for the causative microorganism was consistently positive in all 3 tested patients, while serologic test confirmed diagnosis in 85% (11/13) patients; 1 patient with negative serology showed a positive PCR result. Therefore, upfront PCR tests with or without serologic study should be considered to confirm the diagnosis of cat scratch disease in a timely manner.

Breast MALT Lymphoma: A Clinical, Histomorphologic, and Immunophenotypic Evaluation.

Introduction. Primary breast extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is rare and understudied. Embryonically, mammary glands are developed as specialized skin appendages. It is possible that overlapping features exist between breast MALT lymphoma and primary cutaneous marginal zone lymphoma. Methods. We studied 5 primary and 6 secondary breast MALT lymphomas diagnosed in our institution during a 20-year period. Clinical and pathologic features of these lymphomas were analyzed and compared. Results. Most primary and secondary breast MALT lymphomas had similar clinical presentations as unilateral breast lesions without axillary lymphadenopathy. However, primary lymphomas tended to be diagnosed in older patients (median: 77 years old) than secondary lymphomas (median: 60 years old). Thyroid abnormality was a common finding in both primary (3/5) and secondary (5/6) lymphomas. Hashimoto's thyroiditis was diagnosed in one primary lymphoma. No distinct histopathologic findings were found in primary lymphomas. Features for primary cutaneous marginal zone lymphoma, including overexpression of IgG and IgG4 and high IgG4/IgG ratio, were absent in all primary but present in one secondary lymphoma with cutaneous origin. This secondary lymphoma also had expansion of CD30-positive cells. Conclusion. Primary breast MALT lymphoma does not share the distinctive features of primary cutaneous marginal zone lymphoma that set it apart from other extranodal marginal zone lymphomas. Having increased IgG- and IgG4-positive cells with a high IgG/IgG4 ratio in breast MALT lymphoma may indicate cutaneous origin. CD30 overexpression may be a feature seen in marginal zone lymphoma of cutaneous origin, which needs further studies to prove.

Rapid On-site Evaluation Practice Variability Appraisal (ROSE PETAL) survey.

BACKGROUND: Rapid on-site evaluation (ROSE) is frequently used during diagnostic procedures in patients with or suspected to have lung cancer. There is variation in ROSE use among bronchoscopists, and discussion of ROSE results can have significant consequences for patients. This study was performed to define ROSE practice and result disclosure patterns among bronchoscopists. METHODS: This cross-sectional study was performed using an electronic survey disseminated to the members of the American Association for Bronchology and Interventional Pulmonology and the Society for Advanced Bronchoscopy. The questions centered around ROSE availability, utilization, barriers, and discussion of results with patients. RESULTS: There were 137 respondents. Most identified themselves as interventional pulmonologists (109, 80%); most respondents worked in an academic setting (71, 52%). Availability of ROSE was reported by 121 (88%) respondents. Time constraints (28%), availability of cytology (22%), and scheduling conflicts (20%) were the most reported barriers to ROSE use. Endobronchial ultrasound transbronchial needle aspiration (85%) and nonrobotic peripheral bronchoscopy (65%) were the most reported procedures that used ROSE. There was heterogeneity regarding discussion of ROSE results with the patient or their caregiver in the immediate postprocedure setting: yes - always (40, 33%), yes - sometimes (32, 26%), yes - rarely (18, 15%), or no (31, 26%). Thirty-eight respondents reported they believed ROSE was ≥90% concordant with final cytology results. CONCLUSIONS: The results confirmed the heterogeneity of practice patterns. Estimates of ROSE-final cytology concordance were lower than previously published concordance results. Notably, the discussion of ROSE results varied significantly.

Upgrade rates of intraductal papilloma with and without atypia diagnosed on core needle biopsy and clinicopathologic predictors.

Surgical excision of breast intraductal papilloma (IDP) without atypia diagnosed on core needle biopsy (CNB) is controversial as the risk of upgrade to malignant lesions is not well established. This study investigates upgrade rates of benign and atypical IDP to ductal carcinoma in situ (DCIS) and invasive carcinoma (IC) and clinicopathologic predictors. We identified 556 cases of IDP diagnosed on CNB at a single institution from 2010 to 2020 after excluding patients with a history of breast carcinoma, ipsilateral high-risk lesion, radiologic/pathologic discordance, or less than 2 years of follow-up if no excision within 1 year. Of these, 97 biopsies were consistent with atypical IDP and 459 were benign IDP. Surgical excision was performed for 318 (57.2%), and the remaining 238 (42.8%) underwent active monitoring. The upgrade rate for IDP without atypia was 2/225 (0.9%; 1 DCIS and 1 IC). Of 93 surgically excised atypical IDPs, 19 (20.4%) upgraded (14 DCIS and 5 IC). Of 238 nonexcised IDPs followed clinically (range, 24-140 months, mean 60 months), there was no subsequent breast cancer diagnosed at the IDP site on follow-up. Mean age of patients was 56 yr ± 12.6 SD without upgrade, 63 yr ± 10.6 SD (P = .027) with DCIS, and 61 yr ± 10.8 SD (P = .35) with IC. Atypical IDP was more likely to upgrade if biopsied by stereotactic guidance (8/19, 42.1% P = .035). At our institution, we had an exceedingly low upgrade rate for benign IDP. Overall, patients with upgrade to DCIS were older. For atypical IDP, upgrade was seen in higher proportions of stereotactic biopsies.

Succinate dehydrogenase-deficient gastrointestinal stromal tumor of stomach diagnosed by endoscopic ultrasound-guided fine-needle biopsy: Report of a distinct subtype in cytology.

Succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (GISTs) are characterized by the lack of mutations in KIT receptor tyrosine kinase complex and platelet derived growth factor receptor-alpha (PDGFRA) that are commonly found in the majority of GISTs. SDH-deficient GISTs comprise approximately 5%-10% of all GISTs. This subset may be associated with Carney Triad and Carney-Stratakis syndrome. SDH-deficient GISTs show unique demographic, radiologic, morphologic findings, clinical behavior, and treatment response. To our knowledge, the identification and characterization of this subset of GISTs have not yet been described in the cytopathology literature. By understanding the clinical as well as the other unique features of this tumor, in addition to the rapidly evolving identification of specific molecular alterations and targeted therapies, cytopathologists may play an important role in the diagnosis and work-up of these patients to allow clinicians to better manage and treat them. We present a young female with gastric SDH-deficient GIST diagnosed by fine-needle biopsy with supporting surgical pathology follow-up and molecular confirmation. This report suggests that the diagnosis of SDH-deficient GIST can be made on cytology in the appropriate clinical setting by using cytomorphologic features and demonstrating SDH loss by IHC on the cell block. In addition, molecular testing may be possible on the cytology cell block or supernatant to confirm the diagnosis.

Concordance of breast cancer biomarker status between routine immunohistochemistry/in situ hybridization and Oncotype DX qRT-PCR with investigation of discordance, a study of 591 cases.

Patients with estrogen receptor (ER)+/human epidermal growth factor receptor (HER)2-, lymph node- breast cancer with high recurrence risk benefit from adjuvant chemotherapy in addition to hormonal therapy. This study compares ER, progesterone receptor (PR), and HER2 status between routine immunohistochemistry (IHC)/in situ hybridization (ISH) and Oncotype DX (ODX) in 591 cases. ODX recurrence score (RS) and clinicopathologic features were compared between ER/PR-concordant and discordant cases. Hematoxylin and eosin (H&E) slides from ER discordant cases were reexamined. Concordance was high between ODX and IHC for ER status (580/591, 98.1%) and moderate for PR status (512/591, 86.6%). All 11 ER discordant cases were ER+ by IHC but ER- by ODX and high risk by ODX. Histologically, all of these cases were grade III invasive ductal carcinoma (IDC), except one case diagnosed as IDC with apocrine features. Although this case was grade I and ER/PR+ by IHC, this patient received chemotherapy because of high RS. Of 79 PR discordant cases, 60 were PR+ by IHC but PR- by ODX. Five hundred eighty-four cases had available HER2 data, with high negative agreement (580/582, 99.7%). However, both HER2+ cases by ISH were HER2- by ODX. Mean RS was higher for ER discordant than concordant cases (48.0 versus 17.1, P < 0.0001) and for PR discordant (IHC+/ODX-) than concordant cases (27.2 versus 16.7, P < 0.0001) with no significant differences in recurrence or metastasis. Overall, detection was more sensitive by IHC, and high RS of discordant cases suggests possible risk overestimation. Therapeutic decisions for discordant cases should continue to be based on clinicopathologic correlation and not oncotype alone.

Use of cytology centrifuged supernatants improves cost and turnaround time for targeted next generation sequencing.

BACKGROUND: Molecular testing is an essential step in providing patients with advanced non-small-cell lung cancer (NSCLC), the most appropriate front-line targeted therapies. We recently implemented targeted NGS on previously discarded cytology centrifuged supernatant (CCS). METHODS: In this study, we reviewed our implementation process to evaluate its performance. Performance and turnaround time (TAT) of molecular testing on all cytology NSCLC cases submitted for targeted NGS from June 2018 to September 2019 were evaluated, which included 46 and 62 cytology cases before and after implementation of CCS, respectively. Associated cost savings using CCS was also analyzed. RESULTS: The mean TAT defined as the time of collection to time of reporting was 8.5 ± 1.8 days in CCS cohort (range 5-13) as compared with 12.2 ± 5.3 days in the (FFPE) cell block (CB) cohort (range: 6-27). The success rate of sequencing was similar for both cohorts (100% in CCS and 96% in FFPE CB). CONCLUSION: Our results demonstrate that NGS using CCS improves TAT, preserves FFPE CB for other testing, and results in cost savings of $50 per case.

Clinical, imaging, and intervention factors associated with the upgrade of isolated flat epithelial atypia.

PURPOSE: This study aims to determine clinical, imaging, and intervention factors associated with the upgrade of flat epithelial atypia (FEA) diagnosed on vacuum-assisted biopsy (VAB) in order to formulate criteria for excision and better assist in management. METHODS: Between 2012 and 2015, 254 patients had a form of atypia diagnosed on ultrasound, MRI or stereotactic VAB and met eligibility for this study. Demographic, imaging, biopsy and pathology characteristics were analyzed for association with upgrade. We compared isolated FEA to all of the atypias grouped together. RESULTS: Of the 254 atypia lesions, 72 (28%) were isolated FEA, and the upgrade rate was 2.8% (2/72). Statistically significant factors present with upgrade of isolated FEA include personal history of breast cancer and cancer diagnosis on a concurrent separate core biopsy. Other factors associated with upgrade include first degree family history of breast cancer, segmental calcification distribution, extent of calcifications >2 cm, and <25% of calcifications removed on biopsy. CONCLUSION: In patients with biopsy results of isolated FEA, in the absence of personal or first degree family history of breast cancer, cancer on a concurrent biopsy, segmental calcification distribution, extent of calcifications >2 cm, and only 0-24% calcifications removed on biopsy, patients may be safely followed with imaging, avoiding unnecessary excision.

Comparison of Oncotype DX Recurrence Score by Histologic Types of Breast Carcinoma.

CONTEXT: Oncotype DX (ODX) is a widely used commercial assay that estimates the risk of distant recurrence and may predict the benefit of chemotherapy in a subset of breast cancers. Some studies have shown the ability to predict Oncotype DX recurrence score (ODXRS), based on routinely reported pathologic features; however, there are limited data correlating specific histologic type of breast cancer to ODXRS. OBJECTIVE: To compare ODXRS to specific histologic types of breast cancer. DESIGN: One hundred eighty-four cases were sent for ODXRS testing and the results were compared with histologic type and grade. RESULTS: The highest average ODXRS was seen in invasive ductal carcinoma with micropapillary features (29) followed by invasive ductal carcinoma not otherwise specified (mean = 19.4, SD = 11.6), invasive mucinous carcinoma (mean = 17.2, SD = 5.9), invasive lobular carcinoma (mean = 15.7, SD = 7.2), mixed ductal and lobular carcinoma (mean = 14.1, SD = 7.7), tubular carcinoma (10.0), and mixed ductal and mucinous carcinoma (mean = 8.0, SD = 4.2). Most tumors that had a high ODXRS were grade 3 invasive ductal carcinoma, representing 13 of a total of 20 cases (65%). Interestingly, 3 of the 4 cases of pure invasive mucinous carcinoma had an intermediate ODXRS. CONCLUSIONS: Although the numbers are small, our findings raise further awareness of the significance between histologic type and grade, and RS in breast cancer. In some special histologic types of breast cancer, particularly those considered to follow either an excellent or poor clinical course by histology alone, it is unclear whether the ODXRS results are as meaningful as in carcinomas of no special type. Further investigation with higher numbers and outcome data is needed.

Does total manual rescreening of negative pap tests screened by the ThinPrep imaging system add any value?

We compared the performance of utilizing the ThinPrep® Imaging System (TIS) according to the manufacturer's directions to screening with the TIS plus total manual rescreening in Pap tests that were initially diagnosed as NIL to determine whether manual rescreening decreases the false-negative rate for epithelial lesions. Three thousand three hundred forty cases were diagnosed as NIL on the 22 fields of view selected by the TIS and subsequently manually rescreened by the same cytotechnologist. Six hundred seventy-four cases were sent to a cytopathologist for final diagnosis based on review criteria. Biopsy follow-up and Human Papilloma Virus (HPV) test results were noted if available for cases with a diagnosis of ASCUS or above. Three thousand one hundred fifty-nine (94.6%) were confirmed NIL and 181 cases were diagnosed as abnormal on manual rescreen. There were 147 ASCUS, 6 ASCH, 9 AGC, 19 LSIL, and 0 HSIL cases. The overall false-negative rate of screening for atypia/SIL with the TIS was 5.4%. Of the 147 cases with HPV results, 43 (29%) were positive. Only 1 cervical intraepithelial neoplasia 2 was found on biopsy follow-up, in a case of ASCUS with a positive HPV. Based on our data, the TIS for screening of Pap tests is reliable in NIL cases as compared to total manual rescreening. The majority of the false-negative cases were diagnosed as ASCUS on subsequent review, with 0 HSIL cases. Our results confirm that the TIS is highly accurate in excluding HSIL, negating the need for total manual rescreening of NIL Pap tests.

Glandular cells in vaginal cytology Papanicolaou tests in patients with hysterectomy for endometrial adenocarcinoma.

The vaginal apex is the most common site of recurrence in patients with endometrial cancer. Although studies demonstrate that <1% of asymptomatic vaginal recurrences are detected by routine vaginal cytology alone, many practitioners still include it as part of the routine surveillance in these patients after hysterectomy. To further evaluate the effectiveness of vaginal cytology as a surveillance tool, we assessed the subsequent findings in patients reported to have benign and atypical glandular cells on vaginal cytology after hysterectomy performed for endometrial cancer.

Interinstitutional consultation in fine-needle aspiration cytopathology: a study of 742 cases.

BACKGROUND: The importance of interinstitutional consultation (IC) has been documented across a variety of surgical pathology organ systems. However, to the authors' knowledge, few studies exist regarding this practice within cytopathology and specifically within fine-needle aspiration cytology (FNAC). METHODS: All FNAC cases between September 2002 and January 2007 were reviewed. Original diagnoses and second opinion diagnoses (SODs) were categorized as either no diagnostic disagreement, or minor diagnostic disagreement, or major diagnostic disagreement, and the latter was defined as either a 2-step deviation on a scale of "unsatisfactory, benign, atypical, suspicious, and malignant" or a change in treatment and/or prognosis. Outcome was determined by a review of the electronic medical record. RESULTS: Among 742 FNAC cases from outside laboratories, there were minor disagreements in 132 cases (17.8%) and major disagreements in 69 cases (9.3%) compared with the SODs from the authors' laboratory. Follow-up was available for 60 of 69 major discrepancies. The SOD was supported on follow-up in 65% of major discrepancies, and the initial diagnosis was supported better in 33% of major discrepancies. In 55% of cases in which the original institution diagnosis was supported better, either no case slides were received for examination or the slides contained material that was considered nondiagnostic by the authors. An SOD prompted a change in clinical management in 32 of 742 patients (4.3%). Aspirates that were most prone to change in management or therapy were from the thyroid (13 cases), neck (soft tissue and lymph nodes; 9 cases), salivary gland (2 cases), and liver (2 cases). Of 60 major diagnostic disagreements, board-certified cytopathologists rendered an SOD in 44 cases, and 75% of the diagnoses were supported better by follow-up, whereas pathologists who were not board certified in cytopathology had only 38% of SODs supported. CONCLUSIONS: Of 742 FNAC cases, 9.3% had major diagnostic disagreements; and, in 4.3%, patient management and therapy were altered. These results were similar to studies in surgical pathology emphasizing the importance of IC in FNAC. The authors concluded that FNAC IC benefits patient care.