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Collision tumors, characterized by the coexistence of two unique neoplasms in close approximation, are rare and pose diagnostic challenges. This is particularly true when the unique neoplasms are of the same histologic type. Here we report such a case where comprehensive tumor profiling by next generation sequencing (NGS) as well as immunohistochemistry revealed two independent adenocarcinomas comprising what was initially diagnosed as a single adenocarcinoma of the gastroesophageal (GEJ) junction. Biopsy of the esophageal portion of the GEJ mass showed a mismatch repair deficient tumor with loss of immunoreactivity for MLH1 and PMS2, while the biopsy taken from the gastric portion of the mass revealed a separate tumor with a discordant, non-overlapping, set of molecular alterations, including an EML4::ALK fusion, as well as intact MMR. This case illustrates one way in which NGS can reveal diagnoses such as collision tumor that are wholly unexpected based on clinical and histological grounds. Such diagnoses can have important implications for patient care, particularly in cases where there is discordance for targetable molecular alterations., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Shridar Ganesan reports a relationship with Merck that includes: employment and equity or stocks. Shridar Ganesan reports a relationship with Ibris Inc that includes: equity or stocks. Shridar Ganesan reports a relationship with Inspirata Inc that includes: consulting or advisory and equity or stocks. Shridar Ganesan reports a relationship with Silagene that includes: consulting or advisory and equity or stocks. Shridar Ganesan reports a relationship with Novartis that includes: consulting or advisory. Shridar Ganesan reports a relationship with Roche that includes: consulting or advisory. Shridar Ganesan reports a relationship with Foghorn Therapeutics that includes: consulting or advisory. Shridar Ganesan reports a relationship with Foundation Medicine Inc that includes: consulting or advisory. Shridar Ganesan reports a relationship with Merck Sharp & Dohme that includes: consulting or advisory. Shridar Ganesan reports a relationship with EQRx that includes: consulting or advisory. Shridar Ganesan reports a relationship with EMD Serono Inc that includes: consulting or advisory. Shridar Ganesan reports a relationship with KayoThera that includes: consulting or advisory. Shridar Ganesan reports a relationship with Ipsen that includes: consulting or advisory. Shridar Ganesan reports a relationship with M2Gen that includes: funding grants. Shridar Ganesan reports a relationship with Gandeeva that includes: funding grants. Gregory M. Riedlinger reports a relationship with AstraZeneca that includes: consulting or advisory. Gregory M. Riedlinger reports a relationship with Pfizer that includes: consulting or advisory. Shridar Ganesan has patent licensed to Ibris, Inc. Shridar Ganesan has patent licensed to Inspirata, Inc. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier Inc.)

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are biliary tract pathologies with increased risk of HCC, although HCC is more commonly associated with viral hepatitis and steatohepatitis. HCC risk stratification in PBC/PSC populations may help select patients for surveillance. We hypothesized that metabolic syndrome associated diagnoses and co-morbid nonalcoholic fatty liver disease (NAFLD) may be risk factors for HCC in patients with PBC and PSC. We undertook a multi-institutional case control study of PSC (19 cases, 38 controls) and PBC (39 cases and controls) patients with advanced fibrosis, matched for known HCC risk factors of age and sex, who had native liver explant or resection specimens. In the PSC population, HCC risk was significantly associated with multiple metabolic syndrome associated diagnoses (OR 13, p = 0.02), hyperlipidemia (OR 29, p = 0.03), and obesity (OR 6.8, p = 0.01). In the PBC cohort, only type 2 diabetes was a risk factor for HCC (OR 4.7, p = 0.03). In the PSC cohort, thick fibrous septae were associated with HCC risk (OR 3.4, p = 0.04). No other pathologic features of the nonneoplastic liver were significantly associated with HCC, including features of NAFLD such as macrovesicular steatosis, pericellular fibrosis, and steatohepatitis. Metabolic syndrome associated diagnoses, specifically type 2 diabetes among PBC patients, is associated with HCC risk in patients with biliary type cirrhosis. However, we found no evidence that HCC risk is related to co-morbid NAFLD, indicating a likely distinct mechanism of metabolic syndrome-associated carcinogenesis in these populations., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: The Ki-67 proliferation index is integral to gastroenteropancreatic neuroendocrine tumor (GEP-NET) assessment. Automated Ki-67 measurement would aid clinical workflows, but adoption has lagged owing to concerns of nonequivalency. We sought to address this concern by comparing 2 digital image analysis (DIA) platforms to manual counting with same-case/different-hotspot and same-hotspot/different-methodology concordance assessment., Methods: We assembled a cohort of GEP-NETs (n = 20) from 16 patients. Two sets of Ki-67 hotspots were manually counted by three observers and by two DIA platforms, QuantCenter and HALO. Concordance between methods and observers was assessed using intraclass correlation coefficient (ICC) measures. For each comparison pair, the number of cases within ±0.2xKi-67 of its comparator was assessed., Results: DIA Ki-67 showed excellent correlation with manual counting, and ICC was excellent in both within-hotspot and case-level assessments. In expert-vs-DIA, DIA-vs-DIA, or expert-vs-expert comparisons, the best-performing was DIA Ki-67 by QuantCenter, which showed 65% cases within ±0.2xKi-67 of manual counting., Conclusions: Ki-67 measurement by DIA is highly correlated with expert-assessed values. However, close concordance by strict criteria (>80% within ±0.2xKi-67) is not seen with DIA-vs-expert or expert-vs-expert comparisons. The results show analytic noninferiority and support widespread adoption of carefully optimized and validated DIA Ki-67., (© American Society for Clinical Pathology, 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: The ongoing global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic necessitates adaptations in the practice of surgical pathology at scale. Primary diagnosis by whole-slide imaging (WSI) is a key component that would aid departments in providing uninterrupted histopathology diagnosis and maintaining revenue streams from disruption. We sought to perform rapid validation of the use of WSI in primary diagnosis meeting recommendations of the College of American Pathologists guidelines., Methods: Glass slides from clinically reported cases from 5 participating pathologists with a preset washout period were digitally scanned and reviewed in settings identical to typical reporting. Cases were classified as concordant or with minor or major disagreement with the original diagnosis. Randomized subsampling was performed, and mean concordance rates were calculated., Results: In total, 171 cases were included and distributed equally among participants. For the group as a whole, the mean concordance rate in sampled cases (n = 90) was 83.6% counting all discrepancies and 94.6% counting only major disagreements. The mean pathologist concordance rate in sampled cases (n = 18) ranged from 90.49% to 97%., Conclusions: We describe a novel double-blinded method for rapid validation of WSI for primary diagnosis. Our findings highlight the occurrence of a range of diagnostic reproducibility when deploying digital methods., (© American Society for Clinical Pathology, 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: We recently encountered a patient with unexplained hyperleukocytosis (105.4 K/μL at presentation), subsequently found to have colon cancer with a marked tumor-associated neutrophilic infiltrate; the leukocytosis abruptly improved after tumor removal. Paraneoplastic leukemoid reaction (PLR) is a rare entity, occurring due to tumor cytokine secretion (typically granulocyte-colony stimulating factor [G-CSF]). We describe a case and aggregate results of previously published cases., Methods: We reviewed the English-language literature for all prior reports of PLR, recording age, gender, histologic diagnosis, WBC count, G-CSF level, and overall survival. We analyzed clinicopathologic variables' impact on survival., Results: We identified 179 cases (mean age 64; 72 % M). Adeno-, squamous cell, sarcomatoid, and undifferentiated carcinomas accounted for >70 %. Esophagus, gallbladder, lung, liver, and pancreas were the most common primaries. At time of publication 81 % of patients had died, with mean overall survival of 4 months. There was no correlation between WBC count and G-CSF level. On univariate analysis, WBC count was the only variable associated with survival (P = 0.03). Patients with WBC counts >100 K/μL were twice as likely to die as those with counts from 11 K to 40 K/μL., Conclusions: PLR, typically carcinoma-associated, is characterized by dismal prognosis. The WBC count is inversely related to survival. Knowledge of this phenomenon militates against protracted, expensive work ups. In malignant neoplasms with prominent neutrophilic stroma, the pathologist should correlate with the WBC count and, if markedly elevated (>40 K/μL), raise consideration for PLR., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Background: This is the first case-control study investigating an association between gallbladder hyperkinesia and symptomatic acalculous chronic cholecystitis., Methods: This retrospective study in a single academic center compared resolution of biliary pain in adults with gallbladder hyperkinesia, defined as a hepatobiliary iminodiacetic acid scan ejection fraction ≥80%, undergoing cholecystectomy (study group) with those treated medically without cholecystectomy (control group). Of 1,477 hepatobiliary iminodiacetic acid scans done between 2013 and 2018, a total of 296 adults without gallstones had an ejection fraction ≥80%, of whom 46 patients met predetermined eligibility criteria. Demographic data, hepatobiliary iminodiacetic acid scan ejection fraction, chronicity of pain, and resolution of pain were compared between groups., Results: Demographics (mean ± standard deviation) in the control group (n = 25) and in the study group (n = 21) were, respectively, age 40 y ± 16 y and 39 y ± 14 y, body mass index 28.9 ± 5.2 and 29.1 ± 7.1 kg/m 2 , with 15 (60%) and 18 (86%) females in each. Resolution of pain after cholecystectomy occurred in 18 of 21 patients (86%); however, pain persisted in 20 of 25 patients (80%) treated medically after mean follow-up of 36 ± 28 months (range 10-120 months) (P < .01). Pain resolution with cholecystectomy was independent of demographic variables, hepatobiliary iminodiacetic acid scan ejection fraction, and chronicity of pain. The odds of pain resolution was 19.7 times greater with cholecystectomy than without (odds ratio, 19.7; 95% confidence interval, 4.34, 89.43; P < .01), and remained robust even with the odds adjusted for each covariate. Gallbladder histopathology confirmed chronic cholecystitis in all 21 cholecystectomy specimens., Conclusion: Symptomatic gallbladder hyperkinesia could be a new indication for cholecystectomy in adults., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Dermatofibrosarcoma protuberans is a rare soft tissue malignancy that, if left untreated, can be locally destructive and life-threatening. Dermatofibrosarcoma protuberans is uncommon in the breast, and the similarity of its morphologic features with other spindle cell malignancies can make correct identification difficult. Immunohistochemistry and molecular testing can aid in the correct diagnosis when there is diagnostic uncertainty. Imatinib, a selective tyrosine kinase inhibitor, has been used for adjuvant treatment of dermatofibrosarcoma protuberans following surgical resection. When used as a neoadjuvant treatment, imatinib offers the opportunity to decrease tumor size prior to surgery to lessen the chance for disfigurement., Case Presentation: We present the case of a Caucasian woman who was 46-year-old when she first noted a mass in her right breast in 2015; she was initially diagnosed as having metaplastic breast carcinoma. Mastectomy and systemic chemotherapy were planned; however, after review of pathology at a referral center, the diagnosis was changed to dermatofibrosarcoma protuberans. She was treated with 4 months of neoadjuvant imatinib with adequate tumor shrinkage to perform breast conservation., Conclusion: This patient's case stresses the importance of correctly diagnosing this rare breast tumor through the histopathologic appearance of dermatofibrosarcoma protuberans, molecular pathogenesis, and immunohistochemistry. These techniques can help differentiate dermatofibrosarcoma protuberans from metaplastic breast carcinoma and other spindle cell lesions of the breast. This is critical, as the treatment options for metaplastic breast carcinoma significantly differ from treatment options for dermatofibrosarcoma protuberans. This case describes the use of imatinib as a neoadjuvant option to reduce preoperative tumor size and improve surgical outcomes.

Context.—: Conflicting data about the clinical significance of microscopic Crohn disease (CD) activity at resection margins have led to varying practice patterns for routine reporting by pathologists., Objective.—: To characterize the association between active disease at resection margins with postoperative CD recurrence and time-to-recurrence in the era of anti-tumor necrosis factor therapy., Design.—: We performed a multicenter retrospective cohort study of 101 consecutive CD bowel resections during 10 years. Margin slides were reviewed, and CD activity at the margins was graded as none, mild, moderate, or severe. The association between microscopic CD activity at the margin with postoperative recurrence and time-to-recurrence were evaluated with logistic regression and Cox regression analyses, respectively., Results.—: Crohn disease activity at resection margins was reported in 43% of pathology reports. Resection margins had CD involvement in 39.6% of cases, 20 of which were classified as mild, 6 as moderate, and 12 with severe CD activity. Although patients with mild (odds ratio, 1.14; 95% CI, 0.40-3.20) and moderate to severe (odds ratio, 1.97; 95% CI, 0.62-6.35) activity were at increased risk of disease recurrence, the differences were not statistically significant. Patients with mild (hazard ratio, 0.97; 95% CI, 0.50-1.91) and moderate to severe (hazard ratio, 1.29; 95% CI, 0.65-2.55) disease activity at margins did not have significantly different time-to-recurrence compared with those without disease activity., Conclusions.—: Our study suggests CD activity at resection margins is not significantly associated with postoperative CD recurrence.

Endometrial cancer is the most common gynecologic malignancy in the United States. However, bony metastasis is infrequent and exceptionally rare as the initial presentation. We report a case of a 77-year-old female with a clinically silent endometrial carcinoma who presented with a left tibial metastasis as the first manifestation of her disease. Ours is only the third case diagnosed by fine-needle aspiration (FNA) cytology, and the first to detail the cytomorphologic features of metastatic endometrial cancer to bone. These microscopic findings, including three-dimensional cohesive clusters with cellular overlapping and cuboidal to columnar cells exhibiting low nuclear: cytoplasmic ratios and partially vacuolated cytoplasm, differ significantly from those of endometrial carcinoma on a Papanicolaou test. The tumor bore similarity to the more commonly encountered metastatic colon cancer, but immunohistochemical staining enabled reliable distinction between these entities. A review of osseous metastases of endometrial cancer demonstrates a predilection for bones of the lower extremity and pelvis with a predominance of the endometrioid histologic subtype. In about a quarter of the cases, the bony metastasis was the first manifestation of the cancer. FNA was an effective diagnostic modality for this unusual presentation of a common malignancy. Awareness of this entity and its differential diagnosis is essential for accurate and timely diagnosis.

Medullary carcinoma is a recently recognized rare subtype of colorectal cancer resembling both poorly differentiated adenocarcinoma and neuroendocrine tumors. Medullary carcinoma most commonly presents in the proximal colon and can be differentiated from other right-sided malignant lesions by histology and immunochemical markers. We present here a rare case of an adult patient with rectal bleeding who was found to have an intussusception due to underlying medullary carcinoma of the splenic flexure. A 72-year-old woman presented to our GI clinic with rectal bleeding. Colonoscopy revealed a necrotic mass of the sigmoid colon, later determined by CT to be a colo-colonic intussusception at the level of the splenic flexure. Patient underwent diagnostic laparoscopy with findings of a large splenic flexure mass, which was resected and found to be medullary carcinoma of the colon. The tumor was poorly differentiated and exhibited microsatellite instability but was discovered at an early stage and thus did not require any adjuvant chemotherapy. Unlike most previously reported cases of medullary carcinoma, our patient presented with a left sided tumor. To our knowledge, this is the first report of a medullary colon cancer presenting with intussusception.