Editors: Rouzan Karabakhtsian, MD, PhD, professor of pathology and director of the Women’s Health Pathology Fellowship, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY; Shaomin Hu, MD, PhD, staff pathologist, Cleveland Clinic; S. Emily Bachert, MD, breast pathology fellow, Brigham and Women’s Hospital, Boston; and Amarpreet Bhalla, MD, assistant professor of pathology, Albert Einstein College of Medicine, Montefiore Medical Center.
Characteristics and clinical significance of atypical mitosis in breast cancer
February 2023—Atypical mitosis is considered a feature of malignancy, but its significance in breast cancer remains elusive. The authors conducted a study to assess the clinical value of atypical mitoses in breast cancer and explore their underlying molecular features. They quantified and correlated atypical and typical mitotic figures with clinicopathological variables in a large cohort of primary breast cancer tissue sections (n=846) using digitalized H&E whole slide images. They also used RNA sequencing data from The Cancer Genome Atlas (TCGA) breast cancer data set (n=1,032) to link atypical mitoses to the underlying genetic alterations and pathways. In the study, the median of typical mitoses was 17 per 3 mm2 (range, 0–120 mitoses), while the median of atypical mitoses was four (range, 0–103 mitoses). High atypical mitoses were significantly associated with parameters characteristic of aggressive tumor behavior. Total number of mitoses and a high atypical-to-typical mitoses ratio (greater than 0.27) were associated with poor breast cancer-specific survival (p = 0.04 and 0.01, respectively). The atypical-to-typical mitoses ratio dichotomized triple-negative breast cancer patients into two distinct groups in terms of association with outcome, while the overall number of mitoses did not. Moreover, triple-negative breast cancer patients who had a high atypical-to-typical mitoses ratio and were treated with adjuvant chemotherapy were associated with shorter survival (p = 0.003). Transcriptomic analysis of the TCGA-BRCA cohort dichotomized based on atypical mitoses identified 2,494 differentially expressed genes. These included genes linked to pathways involved in chromosomal localization and segregation, centrosome assembly, spindle and microtubule formation, regulation of cell cycle, and DNA repair. The authors concluded that the atypical-to-typical mitoses ratio has prognostic value independent of the overall mitotic count in breast cancer patients and could predict response to chemotherapy in triple-negative breast cancer.
Lashen A, Toss MS, Alsaleem M, et al. The characteristics and clinical significance of atypical mitosis in breast cancer. Mod Pathol. 2022;35(10):1341–1348.
Correspondence: Dr. Emad Rakha at emad.rakha@nottingham.ac.uk
Histological features of Clostridioides difficile colitis in patients with IBD
People with inflammatory bowel disease are at increased risk for Clostridioides difficile infection, although it can be difficult to recognize this clinically important infection. C. difficile infection does not produce pseudomembranes when it occurs in people with inflammatory bowel disease (IBD). Those who have IBD may also be colonized by the organism, in which case diarrheal symptoms are not necessarily attributed to C. difficile. The authors performed a study to determine whether any features distinguish C. difficile-associated colitis from an IBD flare. They reviewed the clinical, endoscopic, and biopsy findings from 50 patients with established IBD and worsening diarrhea—22 with concurrent positive C. difficile stool toxin PCR assays and 28 with negative C. difficile assay results. They found that patients infected with C. difficile had symptoms and endoscopic findings that were indistinguishable from those with active IBD. Although most biopsy samples from patients with C. difficile infection showed chronic active colitis indistinguishable from IBD, some displayed neutrophilic infiltrates unaccompanied by plasma cell-rich inflammation involving superficial (41 percent) and crypt (18 percent) epithelium and neutrophilic infiltrates within lamina propria distant from foci of cryptitis (32 percent). All three of these features were significantly more common among infected than uninfected patients (four percent [P=0.002], zero [P=0.03], and four percent [P=0.02], respectively). Although colonic biopsies from IBD patients with C. difficile infection usually lack features that help distinguish it from colitic flares, some cases show an acute colitis pattern not seen in IBD alone. When identified in biopsies from symptomatic IBD patients, these changes should alert pathologists to the possibility of this clinically important infection.
Sweeney JR, Crawford CV, Yantiss RK. Histological features of Clostridioides difficile colitis in patients with inflammatory bowel disease. Histopathology. 2022;81:312–318.
Correspondence: Dr. Jacob R. Sweeney at sweenej4@ccf.org
Variability in tumor grade at radical prostatectomy based on grading approach
Multifocal prostate cancer at radical prostatectomy may be graded by assessing each tumor nodule or by global grading of all tumor nodules in aggregate. The authors conducted a study to assess case-level grade variability between the two grading approaches. They reviewed 776 radical prostatectomies (RPs) exhibiting multifocal prostate cancer with different tumor nodule grade groups (GGs). Two grading approaches were assigned to each RP: one based on the tumor nodule with the highest grade being designated the overall grade and one based on a global grade generated by combining the Gleason pattern volumes for all tumor nodules within an RP specimen. The authors compared the results of the methods. The case-level grade changed by one or more GGs between the two grading methods in 35 percent (132 of 374) of GG3 through GG5 cases. In 12 percent (37 of 309) of GG2 cases with a Gleason pattern four of more than five percent based on individual tumor nodule grading, the Gleason pattern four decreased to less than five percent based on the global approach. Minor tertiary pattern five (Gleason pattern five of less than five percent) was observed in 6.8 percent (11 of 161) of GG4 (Gleason score 3 + 5 = 8 and 5 + 3 = 8) and GG5 cases with global grading. The risk of grade discrepancy between the two methods was associated with the highest grade tumor nodule volume (inverse relationship), patient age, and number of tumor nodules (P<0.001, P=0.003, and P<0.001, respectively). The authors concluded that the global-grading approach resulted in a lower grade in 35 percent of GG3 through GG5 cases compared with grading based on the highest grade tumor nodule. Significant risk factors for this discrepancy with the global-grading approach occur when the highest grade tumor nodule has a relatively small tumor volume and with a higher number of tumor nodules per RP. The variability observed between the two grading approaches may limit the interchangeability of post-RP multi-institutional databases if the institutions use different grading methods.
Iakymenko OA, Briski LM, Punnen S, et al. Variance of tumor grade at radical prostatectomy with assessment of each tumor nodule versus global grading. Arch Pathol Lab Med. 2022;146(8):1032–1036.
Correspondence: Dr. Oleksandr Kryvenko at o.kryvenko@med.miami.edu
Analysis and long-term follow-up of patients with nodal blue nevi
Blue nevi are benign melanocytic neoplasms that show a range of clinical and morphologic patterns and include common/dendritic, cellular, and atypical cellular subtypes. Like other nevi, they most commonly occur in skin but occasionally can involve lymph nodes, where they may be misinterpreted as metastatic melanoma. The question of whether benign blue nevi can metastasize to lymph nodes and their natural history and prognostic significance have generated controversy. Few cases of nodal blue nevi have been reported in the literature, and those cases have had limited clinical follow-up and supporting molecular data. The authors conducted a study to determine the clinical, pathologic, and molecular features of blue nevi involving lymph nodes and to clarify their clinical significance, provide evidence to further understanding of their pathogenesis, and highlight potential pitfalls in interpreting lymph nodes. Thirteen cases of blue nevi involving lymph nodes, accessioned from 1984 to 2018, were identified in the archives of Royal Prince Alfred Hospital, Sydney, Australia. A detailed assessment of the clinical and pathologic features of each case was performed, including an evaluation of all available IHC stains. Extended clinical follow-up was available for nine patients. Droplet digital polymerase chain reaction for GNAQQ209L, GNACQ209P, and GNA11Q209L mutations was performed on seven cases of blue nevi within lymph nodes and on two cases of matching cutaneous (presumed primary) blue nevi. All cases showed typical histologic features of blue nevi. BAP1 was retained in all cases tested (n=7). Neither recurrence nor metastasis of a blue nevus was found in long-term clinical follow-up for any case (n=9; median follow-up, 12 years). The majority of cases (five of seven evaluated) had GNAQ and GNA11 driver mutations. The two patients with a matched primary cutaneous blue nevus and regionally associated nodal blue nevus each had the same GNAQQ209L mutation in both sites. The authors concluded that blue nevi can involve lymph nodes and are associated with benign clinical behavior, and they probably represent “benign” metastasis. It is important to be aware of these lesions when evaluating lymph nodes to avoid misdiagnosing them as metastatic melanoma.
Colebatch AJ, Adhikari C, Diefenbach RJ, et al. Comprehensive clinical, histopathologic, and molecular analysis and long-term follow-up of patients with nodal blue nevi. Am J Surg Pathol. 2022;46(8):1048–1059.
Correspondence: Dr. Richard A. Scolyer at richard.scolyer@health.nsw.gov.au
Assessment of atypical thymomas with squamoid and spindle cell features
Thymomas are rare tumors characterized by a broad range of morphologic appearances that can sometimes hinder tumor classification. The authors studied 120 thymoma patients in whom tumors were characterized by sheets of atypical epithelial cells with squamoid or spindle cell features, or both. The tumors occurred in 63 men and 57 women and presented as a discrete mass in the anterior mediastinum measuring 2 to 23 cm (mean, 8.2 cm). Patients ranged from 14 to 86 years old (mean, 57.8 years old) and most had symptoms referable to a mass lesion. Twenty of the study patients had myasthenia gravis or another autoimmune disorder. Seventy-six cases were characterized by a predominant population of round to polygonal tumor cells, and 32 cases were characterized by atypical oval or spindle cells. Twelve cases showed mixed features, and 16 cases showed the development of thymic carcinoma arising from thymoma. All cases were positive for p40 and p63 and cytokeratin AE1/AE3. CD5 was positive in the epithelial tumor cells in 23 of 92 (25 percent) cases of atypical thymomas, and CD117 was positive in 13 of 92 (14 percent) cases. MIB1 showed a significant increase in proliferative activity (mean, 11.6 percent). Next-generation sequencing in 47 cases did not disclose any variants amenable to targeted therapies. Clinical follow-up ranging from two to 29 years showed a progressive increase in aggressive behavior and fatality rate with advancing stage. Overall survival was 87 percent at five years, 67 percent at 10 years, and 23 percent at 20 years. Completeness of resection and staging were the most significant parameters for survival. The more aggressive tumors followed a protracted clinical course with multiple recurrences and metastases over a long time period (mean, 19.8 years from time of initial relapse to death). In summary, atypical thymomas are a distinct category of thymic epithelial neoplasm characterized by a slow, progressive clinical course with increased potential for metastases, transformation to a higher grade malignancy, and fatal outcome in some cases.
Suster DI, Mackinnon AC, DiStasio M, et al. Atypical thymomas with squamoid and spindle cell features: clinicopathologic, immunohistochemical and molecular genetic study of 120 cases with long-term follow-up. Mod Pathol. 2022;35(7):875–894.
Correspondence: Dr. Saul Suster at ssuster@mcw.edu