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.
Cutaneous crystal-storing histiocytosis: a case series with literature review
October 2025—Crystal-storing histiocytosis is a rare disorder in which crystals accumulate in the cytoplasm of histiocytes. It is usually associated with a lymphoplasmacytic neoplasm. Cutaneous crystal-storing histiocytosis (CSH) is extraordinarily rare and limited to case reports in the literature. The authors reported on two cases of CSH with cutaneous involvement. Case one was a 65-year-old male with a four-month history of a pruritic eruption that started as a solitary pink to skin-colored indurated plaque on the anterior neck before progressing to involve the whole neck, chest wall, and face. Case two was a 54-year-old woman with a history of unspecified lymphoma who presented with a soft nodule on the forearm. Biopsies from both patients had similar findings and showed a proliferation of epithelioid cells with pink cytoplasm and intracellular crystalline structures infiltrating the dermis and subcutaneous fat. In the first case, the cells were positive for CD43, CD45, CD68, and IgG kappa. In the second case, the crystals were positive for IgG lambda. The patients were diagnosed with cutaneous CSH based on these findings. The authors concluded that a diagnosis of CSH, whether cutaneous or not, should prompt clinical evaluation for an underlying lymphoproliferative or plasma cell disorder.
Homsi HA, Knapp C, Agrawal S, et al. Cutaneous crystal storing histiocytosis: A case series with review of literature. J Cutan Pathol. 2024;51(7):506–512.
Correspondence: Dr. Shira Ronen at [email protected]
Insights into stratified mucin-producing lesions of the anus
Primary anal cancers are rare and typically driven by high-risk human papillomavirus infection. Though squamous cell carcinoma is most common, a spectrum of HPV-related nonsquamous anogenital neoplasms with similarities to cervical-stratified mucin-producing carcinoma has been reported. The authors conducted a study in which they mined their institutional archives to characterize the clinicopathologic features of this emerging entity. They identified six cases (four women and two men; mean age, 70 years) from the files at two institutions. The study included four cases of invasive stratified mucin-producing carcinoma and two cases of stratified mucin-producing intraepithelial lesions (SMILE). Clinical presentation included a rectal/anal mass or polyp, rectal bleeding, pain, weight loss, or presentation at the time of screening colonoscopy. Tumors displayed histologic features analogous to those seen in the gynecologic tract. Cases of invasive stratified mucinous carcinoma showed infiltrative tumor nests with variable intracytoplasmic mucin, peripheral palisading, prominent apoptosis, and neutrophilic infiltrate. One invasive stratified mucinous carcinoma was associated with high-grade glandular dysplasia, and one SMILE showed adjoining conventional low-grade squamous intraepithelial lesions. All lesions stained with p16 showed block-like p16 expression. HPV in situ hybridization was performed in five cases, four of which were positive. One was interpreted as equivocal. Follow-up information, available for four patients, revealed one local recurrence followed by death due to unrelated causes in a patient who had invasive stratified mucin-producing carcinoma. The authors concluded that their study reports the first series of HPV-associated primary anal stratified mucin-producing neoplasms analogous to those seen in the gynecologic tract, further broadening the spectrum of HPV-related anal neoplasia.
Sappenfield R, Camacho-Cordovez F, Larman T, et al. Stratified mucin-producing lesions of the anus: Insights into an emerging histologic type of HPV-driven anal neoplasia. Am J Surg Pathol. 2025;49(2):121–129.
Correspondence: Dr. Lysandra Voltaggio at [email protected]
Stromal tumor-infiltrating lymphocytes in breast cancer that is hormone receptor positive/HER-2 negative
The immune landscape of hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer (HR+/HER2− mBC), the most common subtype of breast cancer, remains understudied. This is primarily due to fewer sample-acquisition opportunities with metastases than with primary tumors. The authors conducted a study in which they explored stromal tumor-infiltrating lymphocytes (sTIL) in samples of metastatic tissue collected through their post-mortem tissue donation program, UZ/KU Leuven Post-mortem Tissue Donation Program to Enhance Research (NCT04531696), in Belgium. The sTILs were scored according to the World Health Organization classification of breast tumors. The levels of sTILs, as a percentage, were evaluated on 427 metastases and 38 primary untreated tumors acquired from 20 patients with HR+/HER2− mBC. Estrogen receptor status was evaluated on 362 metastases with a cutoff value for positivity set at one percent, according to American Society of Clinical Oncology/College of American Pathologists guidelines. The authors’ analyses show that 54 percent and 15 percent of metastases had sTIL levels of one percent or greater and five percent or greater, respectively. These levels tended to be lower in metastases than in their respective primary tumors (estimate, −2.83; 95 percent confidence interval [CI], −5.77 to 0.11; P = .07). The sTIL levels were lower in metastases from invasive lobular carcinoma than in metastases from invasive breast carcinoma of no special type (estimate, −1.67; 95 percent CI, −2.35 to −0.98; P < .001). A loss of estrogen receptor expression was observed in 14 percent of metastases, yet negative estrogen receptor status was not significantly associated with increased sTIL levels. Furthermore, sTIL levels were significantly higher in lung and axillary lymph node metastases than in all other metastases. Although these analyses were conducted on multiple metastases obtained at the end of life and after several lines of treatment, the authors concluded that the data provide novel and valuable insights into the state of immune infiltration in patients with HR+/HER2− mBC.
Pabba A, Zels G, De Schepper M, et al. Stromal tumor-infiltrating lymphocytes in hormone receptor-positive/HER2 negative metastatic breast cancer. Mod Pathol. 2025. doi.org/10.1016/j.modpat.2024.100650
Correspondence: Dr. Christine Desmedt at [email protected]
Analysis of medullary carcinomas of the nonampullary small intestine
Gastrointestinal medullary carcinoma is a rare histologic subtype of adenocarcinoma. Because nonampullary small bowel medullary carcinomas (SB-MCs) are poorly characterized, the authors analyzed their clinicopathologic and immunohistochemical features and compared them with nonmedullary small bowel adenocarcinomas (NM-SBAs). Surgically resected SBAs collected through the Small Bowel Cancer Italian Consortium were classified as SB-MCs (carcinomas with 50 percent or more of tumor fulfilling the typical histologic criteria of MC) or NM-SBAs. Immunohistochemistry for cytokeratin 7 (CK7), CK20, CDX2, programmed death-ligand 1 (PD-L1), and mismatch repair proteins was performed in SB-MCs and NM-SBAs. SB-MCs were also tested for CK8/18, synaptophysin, SMARCB1, SMARCA2, SMARCA4, and ARID1A, as well as for Epstein-Barr virus–encoded RNAs by in situ hybridization. MLH1 promoter methylation status was evaluated in MLH1-deficient cases. Eleven SB-MCs and 149 NM-SBAs were identified. One (nine percent) SB-MC was Epstein-Barr virus positive, while 10 (91 percent) harbored mismatch repair deficiency (dMMR). MLH1 promoter hypermethylation was found in all eight dMMR SB-MCs tested. Switch/sucrose nonfermentable deficiency was seen in two (18 percent) SB-MCs, both with isolated loss of ARID1A. Compared with NM-SBAs, SB-MCs exhibited an association with celiac disease (P< .001) and higher rates of dMMR (P< .001) and PD-L1 positivity by tumor proportion score or combined positive score (P< .001 for both), as well as a lower rate of CK20 expression (P = .024). Survival analysis revealed a better prognosis for SB-MC patients than for NM-SBA patients (P = .02). The authors concluded that SB-MCs represent a distinct histologic subtype with peculiar features compared with NM-SBAs, including association with celiac disease, dMMR, PD-L1 expression, and better prognosis.
Vanoli A, Grillo F, De Lisi G, et al. Medullary carcinomas of the nonampullary small intestine: association with coeliac disease, mismatch repair deficiency, PD-L1 expression, and favorable prognosis. Histopathology. 2025;86:236–246.
Correspondence: Dr. Alessandro Vanoli at [email protected]