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; S. Emily Bachert, MD, associate pathologist, Brigham and Women’s Hospital, Boston; Amarpreet Bhalla, MD, assistant professor of pathology, Albert Einstein College of Medicine, Montefiore Medical Center; Divya Sharma, MD, associate professor, Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center; and Paula Toro, MD, gastrointestinal and hepatobiliary fellow, Cleveland Clinic.
Survival outcomes with poorly differentiated colorectal carcinoma variants
August 2025—Certain subtypes of colorectal carcinoma pose diagnostic challenges in daily practice due to sometimes overlapping morphologic and immunohistochemical features and are associated with worse prognoses than poorly differentiated adenocarcinoma not otherwise specified (PDA-NOS). Other variants of poorly differentiated colon cancers with solid growth patterns that have, anecdotally, been recognized as posing diagnostic challenges include large cell neuroendocrine carcinoma (LCNEC), medullary carcinoma (MC), undifferentiated carcinoma (UC), and lymphoepithelioma-like carcinoma (LELC). The authors conducted a study to determine survival outcomes between patients with poorly differentiated adenocarcinoma and those with a variant carcinoma morphology that may affect prognosis. They also analyzed interobserver agreement among gastrointestinal pathologists at their institution in subclassifying poorly differentiated colorectal carcinoma. All consecutive patients with diagnoses of PDA-NOS, MC, LCNEC, UC, and LELC between July 2018 and July 2023 were included. A Cox proportional regression test was used for multivariate analysis, and log-rank and Kaplan-Meier tests were used for univariate and survival analyses. In the same cohort of patients, 58 samples were identified and reviewed by three GI subspecialty-trained pathologists who were asked to identify the cases as PDA-NOS, LCNEC, MC, UC, or LELC. Interobserver agreement was analyzed using Fleiss’ kappa. Of the 77 patients, 63 had PDA-NOS, three had LCNEC, six had MC, four had UC, and one had LELC. Multivariate analysis using Cox proportional regression showed that tumor size (P = .001; hazard ratio [HR], 1.22; 95 percent confidence interval [CI], 1.08–1.38), patient age (P = .001; HR, 1.73; 95 percent CI, 1.24–2.40), and M stage (P = .02; HR, 2.22; 95 percent CI, 1.14–4.32) were significantly associated with worse overall survival. The three GI pathologists agreed on 42 (72 percent) of the 58 cases analyzed. The most common diagnosis was PDA-NOS, and agreement was unanimous for 33 (57 percent). Moderate agreement (κ = 0.41–0.60) between all three GI pathologists was noted. This study evaluated the challenges associated with histological evaluation of colon cancers with poorly differentiated morphologies. It found that MC and LCNEC had different prognostic implications than PDA-NOS and UC. Additionally, the GI pathologists in the study showed moderate interobserver agreement, indicating that some variability in diagnosing poorly differentiated CRC subtypes may be inevitable.
Xu Z, Theisen BK, Chang Q, et al. Survival outcomes of poorly differentiated colorectal carcinoma variants: Insights from a single teaching institute. Hum Pathol. doi.org/10.1016/j.humpath.2024.105710
Correspondence: Dr. Beena U. Ahsan at bahsan1@hfhs.org
Ability of small circulating tumor cells to predict worse prognosis in NSCLC patients
Most patients with non-small cell lung cancers are diagnosed at advanced stages. The five-year survival rate for patients with advanced lung cancer is less than 20 percent, making lung cancer the leading cause of cancer-related deaths worldwide. The authors conducted a study to identify indicators that can predict the prognosis of lung cancer patients. To determine the correlation between circulating tumor cells (CTCs) and circulating tumor-derived endothelial cells (CTECs) and their subtypes and the prognosis of patients with non-small cell lung cancer (NSCLC), the authors enrolled 48 NSCLC patients who had not undergone treatment in their study. Peripheral blood was collected from the patients before any treatment and analyzed by the subtraction enrichment and immunostaining fluorescence in situ hybridization technique. This was done to determine the correlation between CTCs and CTECs and lung cancer disease progression and identify prognostic indicators. The authors found that the positivity rate of CTCs was 100 percent and the positivity rate of CTECs was 81.3 percent. The positivity rate of small-size CTCs was higher in patients with advanced-stage lymph node metastases than in those with early or no lymph node metastases. CTCs and CTECs had diverse cell subtypes and differed in their distribution in the blood. The size of CTCs and CTECs in peripheral blood also differed. Therefore, CTCs and CTECs were classified based on the size of leukocytes. Cells larger than 5 μm were deemed large size, and cells smaller than 5 μm were considered to be small size. The positivity rate for large-size CTECs was higher for patients with advanced NSCLC than for early stage disease patients (P = .03). Patients with one or more small-size CTCs had shorter progression-free survival, and small-size CTCs were an independent prognostic factor. The authors concluded that small-size CTCs are a reliable prognostic indicator and a probable predictor of severity of disease in NSCLC patients.
Sun Q, Li W, Yang D, et al. The presence of small-size circulating tumor cells predicts worse prognosis in non–small cell lung cancer patients. Arch Pathol Lab Med. 2025;149:39–49.
Correspondence: Dr. Huiqin Guo at guohuiqin@mail.ccmu.edu.cn
Validation of metallothionein IHC as a screening test for Wilson disease
Wilson disease is a rare autosomal recessive condition with protean clinical manifestations that result from biallelic ATP7B mutations. Nondestructive tissue tests that can be applied clinically to tissue specimens are not widely available to assess patients for the disease. The authors previously showed that metallothionein (MTH) immunohistochemistry has a high sensitivity and specificity for diagnosing Wilson disease and, therefore, is a potentially powerful diagnostic tool that can be used in routine histologic sections. The authors conducted a study to validate their findings in a large cohort of patients with Wilson disease and correlate MTH expression with other histologic features. They identified 91 cases of the disease, which included 28 needle biopsies and 63 resections, from 14 centers worldwide. Histologic features were evaluated, and a histopathological pattern was assigned to each case. All cases were evaluated with Masson trichrome and MTH IHC (clone UC1MT, Abcam) using a published technique. Liver tissue from chronic cholestatic diseases (n = 42) was used as a control. The median age of the patient cohort was 28.5 years. Of the 91 cases, 83 were positive for MTH immunostain (more than 50 percent of hepatocytes with at least moderate staining). All 42 control cases were negative for MTH immunostain. The sensitivity and specificity of MTH immunostain for Wilson disease were 91.20 and 100 percent, respectively. The authors also compared MTH IHC to the simple copper stains Timm, orcein, and rhodanine, and to quantitative tissue copper. The sensitivity of special stains was less than 60 percent, which was attributed to these stains highlighting copper-binding proteins and lysosomal copper-bound proteins as compared to free copper deposition in Wilson disease. The quantitative tissue copper assessment requires approximately 2 mg of tissue (1 cm of an 18-gauge needle biopsy) as compared to one unstained slide for IHC. MTH IHC is a sensitive, specific, cost-effective screening tool for Wilson disease. It can be used for patients across age groups, histologic patterns, and fibrosis stages. The authors propose a practical algorithmic approach for evaluating potential Wilson disease patients that includes MTH IHC on liver biopsies.
Stokes NL, Patil A, Adeyi O, et al. Validation of metallothionein immunohistochemistry as a highly sensitive screening test for Wilson disease. Mod Pathol. 2025. doi.org/10.1016/j.modpat.2024.100628
Correspondence: Dr. Rondell P. Graham at graham.rondell@mayo.edu
Impact of a grossing tumor-margin distance threshold for frozen section in lung surgery
Intraoperative frozen section examination of oncologic surgical specimens is frequently performed to ensure complete surgical resection. Data on the gross evaluation of surgical margins are limited. The authors published a study suggesting the use of a macroscopic 2-cm tumor-margin cutoff during intraoperative evaluation to decrease the number of unnecessary frozen sections. They validated the safety and clinical impact of implementing a 2-cm tumor-margin threshold for frozen section diagnosis in evaluating surgical margins during oncologic lung surgery at the Institut Universitaire de Cardiologie et de Pneumologie de Québec. This retrospective analysis included patients who underwent lung resection for primary or metastatic neoplasms between 2018 and 2022. Clinicopathological data were retrieved from the medical files. Univariate and multivariate analyses were used to identify the variables associated with positive margins. This study included 1,575 tumors from 1,299 patients. Frozen section evaluations were performed in 24.4 percent of patients. No positive margins were observed when the tumor-margin distance was more than 2 cm. The incidence rate of positive margins was 2.95 percent, with parenchymal margins being the most affected. Multivariate analysis identified tumor-margin distance as a significant predictor of positive margin status. This practice led to a 79.9 percent reduction in frozen section evaluations without compromising the accuracy of margin assessment or patient safety. The authors concluded that a 2-cm tumor-margin distance threshold for intraoperative frozen section evaluation in oncologic lung surgery is safe and effective at reducing unnecessary frozen section evaluations while maintaining accurate margin assessments.
Kordahi M, Gagné A, Abolfathi H, et al. Impact of implementing a grossing tumor-margin distance threshold for frozen section in oncologic lung surgery. Am J Surg Pathol. 2025;49:169–175.
Correspondence: Dr. Philippe Joubert at philippe.joubert.1@ulaval.ca
Localized urinary bladder amyloidosis as a urothelial cancer mimicker
Localized amyloidosis of the bladder is rare and often mimics bladder malignancy. It is typically associated with the extracellular deposition of lambda or kappa monoclonal light chains. Its cause is unknown, but it is thought to be due to chronic inflammation or cystitis. The authors conducted a study to highlight the importance of localized urinary bladder amyloidosis as a rare mimicker of urothelial malignancy and elucidate its clinical, histopathologic, and cytopathologic manifestations. Cases of urinary bladder amyloidosis diagnosed between 2000 and 2023 were retrieved retrospectively from pathology archives. Electronic medical records, including cystoscopy findings and pathology slides with Congo red stain, were reviewed. The authors presented six cases with localized urinary bladder amyloidosis. Four of the six patients were women and ranged in age from 46 to 69 years (mean age, 58 years). Five of six patients presented with hematuria, and bladder amyloidosis was discovered incidentally in one patient. Cystoscopy findings invariably were concerning for malignancy, with raised erythema in five patients and fungating mass protruding into the bladder lumen in one patient. Bladder biopsies and urine cytology were negative for malignancy in all cases. Congo red–positive amyloid deposits involved the lamina propria with sparing of the detrusor muscle. The deposits were typed as derived from the kappa light chain in five patients, and no information was available for one patient. Subsequent clinical workup ruled out systemic amyloidosis. These cases of urinary bladder amyloidosis highlight the importance of considering amyloidosis in the differential diagnosis of hematuria and in assessing cystoscopy findings for lesions mimicking malignancy.
Regmi A, Mehta M, Farooq AV, et al. Localized urinary bladder amyloidosis as urothelial cancer mimicker: A case series examining cystoscopic, histologic, and cytologic findings. Arch Pathol Lab Med. 2025;149:191–194.
Correspondence: Dr. Aayushma Regmi at aayushma.regmi@luhs.org