The Utility of Next-Generation Sequencing in Advanced Breast and Gynecologic Cancers.

OBJECTIVES: Next-generation sequencing (NGS) has the potential to identify genetic alterations that are actionable with targeted therapy. Our objective was to identify the impact of NGS testing on advanced breast and gynecologic malignancies. METHODS: A retrospective review of 108 patients who underwent NGS testing between 2015 and 2019 was performed. The NGS clinical action rate was calculated based on documentation of positive clinical action taken in cases with an actionable NGS result. RESULTS: The 108 specimens tested included 35 breast cancers and 73 gynecologic malignancies, with most of the testing performed at Foundation Medicine (90%). Actionable mutation(s) were identified in 79 (73%) of 108 cases. The overall clinical action rate of NGS testing was 38% (30 of 79 cases). Overall, 47 (44%) of 108 patients died, all succumbing to disease. The average survival was 10.9 months. The survival difference between patients with actionable NGS result and targeted treatment, actionable NGS result but no targeted treatment, and patients with nonactionable NGS result was not significant (log-rank test, P = .5160). CONCLUSIONS: NGS testing for advanced breast and gynecologic cancers at our institution has a 38% clinical action rate. However, the increased clinical action rate over the years did not translate into improved survival.

Immunohistochemical Markers With Potential Diagnostic, Prognostic, and Therapeutic Significance in Uterine Carcinosarcoma: A Clinicopathologic Study of 43 Cases.

Uterine carcinosarcomas (UCS) are rare and highly aggressive tumors. Although it is currently accepted that the majority of UCS are metaplastic carcinomas, their aggressive behavior is unparalleled to that of any other high-grade endometrial neoplasms. Therefore, the search for the distinct immunohistochemical and molecular features that could help in the development of new treatment strategies continues. We evaluated the expression of PDL-1, growth hormone releasing hormone receptor, p53, WT1, PAX-8, estrogen receptor, HNF-1, and mismatch repair proteins in 43 UCS. Tumors were selected from the archives of the Magee-Womens Hospital University of Pittsburgh Medical Center Department of Pathology. Seventeen were stage I, 4 were stage II, 15 were stage III, and 7 were stage IV. The median age was 67 yr and median overall survival was 3.2 yr. Immunostaining for PAX8, HNF-1, and estrogen receptor showed statistically significant difference between epithelial and stromal components. Expression of p53 was significantly associated with clinical high stage, but other markers did not correlate with stage or survival. Immunostaining for programmed death ligand-1 was strongly positive in 30 UCS (70%), including 24 cases with tumor cell positivity, 12 cases with tumor cell and tumor-infiltrating immune cell positivity, and 6 cases with tumor-infiltrating immune cell positivity only. Of 27 tumors tested for mismatch repair expression, 12 (44%) showed loss of expression, 7 of which were PDL-1 positive. Growth hormone releasing hormone receptor was positive in 38 tumors (88%) and predominantly expressed in the epithelial component. The range of positivity for programmed death ligand-1 and growth hormone releasing hormone receptor suggests a possible potential adjuvant treatment that may be considered for UCS.

The histopathology of SPINK1-associated chronic pancreatitis.

BACKGROUND: The identification of genetic risk factors for chronic pancreatitis, such as PRSS1, CFTR and SPINK1, provides the opportunity to define key pathologic hallmarks and etiologic-specific changes. For example, pancreata from PRSS1 and CFTR patients exhibit progressive lipomatous atrophy without significant fibrosis. Considering the pathology of SPINK1-associated pancreatitis is ill-defined, we examined the pancreata of SPINK1 patients with chronic pancreatitis. METHODS: Histologic sections after total pancreatectomy with islet autotransplantation and associated clinicopathologic data were collected from 28 patients with SPINK1 germline alterations. Clinical findings, germline data, anatomic anomalies and pathologic findings were descriptively evaluated. RESULTS: Patients ranged in age from 5 to 48 years (median, 21.6 years) with abdominal pain between 2 and 25 years (median, 5.8 years). Most patients were SPINK1 heterozygous and 14 (50%) had co-occurring CFTR (n = 12) and CTRC (n = 2) mutations. Other pancreatitis risk factors included anatomic anomalies (n = 9) and tobacco use (n = 1). Overall, 24 (86%) patients had additional pancreatitis-associated germline alterations, SPINK1 homozygosity, anatomic anomalies or environmental factors. Examination of pancreata revealed a sequential pattern of exocrine parenchymal loss and replacement by prominent fibrosis, dependent on the duration of abdominal pain. No malignancies were identified, but low-grade pancreatic intraepithelial neoplasia was present for 2 cases. CONCLUSIONS: Within this descriptive study, SPINK1-associated pancreatitis is characterized by parenchymal fibrosis and suggests divergent pathophysiologic mechanisms from PRSS1 and CFTR-associated pancreatitis. Moreover, SPINK1 patients frequently had additional etiologic factors that did not impact the development of pancreatic fibrosis and may implicate SPINK1 as a disease modifier gene.

Educational Case: Orbital B-Cell Lymphoma With Amyloid Deposition.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040.1.

Hematolymphoid neoplasms are common in bone marrow biopsies performed for non-specific, diffuse marrow signal alterations on magnetic resonance imaging.

AIMS: MRI is an imaging modality used for a wide range of clinical indications. Occasionally, non-specific, diffuse T1 marrow signal alterations are identified, which may prompt a bone marrow biopsy (BM). However, there is little data on the clinicopathologic significance of this signal alteration. This study evaluated the frequency and nature of pathologic findings in BM performed to evaluate diffuse MRI T1 marrow signal alterations. METHODS: Records from January 2003 to May 2015 were searched for BM performed to evaluate abnormal MRIs. 179 cases were identified. Patients with nodular/destructive bone lesions on MRI or other imaging studies, or a previous diagnosed metastatic tumor or hematologic malignancy were excluded, resulting in 45 cases. RESULTS: The patients included 22 males and 23 females with a median age of 56 years. The location of the MRI T1 marrow signal alterations included spine, pelvis, knee, skull, femur, and arm. 19/45 patients had neoplasms identified in the BM. The remaining 26 patients had benign BM findings. There was a significant difference in hemoglobin values in patients with neoplastic versus benign BM findings (p = 0.037, unpaired Student's t-test). CONCLUSIONS: Diffuse T1 marrow signal alterations on MRI should warrant a BM evaluation, as 42% of cases showed an underlying hematolymphoid neoplasm or metastatic tumor, even when patients with a known history of malignancy were excluded. When faced with a BM from a patient with a non-specific, diffuse MRI signal alteration, a pathologist should have a high index of suspicion for a malignant neoplasm, most often of hematopoietic/lymphoid type.

Interobserver agreement among pathologists for semiquantitative hormone receptor scoring in breast carcinoma.

The American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines recommend reporting of hormone receptor test results in a semiquantitative manner. This study used 74 resected estrogen receptor (ER)-positive invasive breast cancers to determine reproducibility of semiquantitative scoring of hormone receptors using the H-score method. Four pathologists independently scored each slide. Agreement among observers was analyzed via Fleiss κ statistics on ER and progesterone receptor (PR) categorical scores. Intraclass correlation coefficient (ICC) was used to estimate the interobserver agreement for ER and PR H-scores on a continuous scale (0-300). There was 100% agreement for categorical ER results (κ = 1) and 97% agreement (κ = 0.823, P < .001) for categorical PR results. For quantitative H-scores, ICC agreement was 0.85 (95% confidence interval [CI] = 0.79-0.90) for ER and 0.87 (95% CI = 0.82-0.92) for PR. Because the H-score provides a continuous measure of tumor hormone receptor content, we suggest universal adoption of this method.