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Esophageal squamous cell carcinoma with pagetoid spread: a clinicopathologic study

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Abstract

Pagetoid spread in esophageal squamous epithelium associated with underlying esophageal adenocarcinoma (EAC) has been well studied. Case reports describing pagetoid spread of esophageal squamous cell carcinomas (ESCC) also exist in the literature. The latter, however, has not been systematically studied. In this study, we report seven cases of pagetoid spread associated with ESCC. The clinical, morphologic, and immunophenotypic profiles of pagetoid spread in the context of ESCC and EAC are compared. Cases of pagetoid spread of ESCC were identified through computerized search of pathology archives at five institutions. Additional cases were identified through manual review of surgical resection cases of treatment naive ESCC in Mass General Brigham (MGB) pathology archive. Clinical history was collected via chart review. Immunohistochemistry for CK7, CK20, CDX2, p53, p63, and p40 was performed on selected cases. A computerized search of pathology archives of five institutions revealed only two cases. A manual review of 76 resected untreated ESCC revealed five additional cases with unequivocal pagetoid spread of ESCC, indicating the condition was not uncommon but rarely reported. Patient age ranged from 54 to 78 years (median, 65). There were six women and one man. One case had in situ disease, five had pT1 (1 pT1a and 4 pT1b), and one had pT3 disease. One of the patients with pT1 tumor had a positive lymph node, while the remaining six patients were all N0. Four tumors were in the proximal to mid esophagus, and three in the distal esophagus. Patient survival ranged from 25 months to more than 288 months. The pagetoid tumor cells demonstrated enlarged, hyperchromatic nuclei with variable amounts of eosinophilic cytoplasm. The cytoplasm was often condensed to the perinuclear area, creating peripheral clearing. By immunohistochemistry, the pagetoid cells were positive for p40 (6/6) and p63 (7/7) and negative for CDX2 (7/7). The tumor cells showed mutant-type staining for p53 in five of seven cases. One of the patients had pagetoid tumor cells at the resection margin and subsequently had recurrent disease 2 years later. All other patients had negative resection margins and did not have local recurrence. Four cases of pagetoid spread in the context of EAC were used as a comparison group. Previously published studies were also analyzed. These tumors were all located in the distal esophagus or gastroesophageal junction. All cases were associated with underlying invasive EAC. Pagetoid spread associated with EAC often had cytoplasmic vacuoles or mucin. They were more frequently positive for CK7 than pagetoid ESCC (p = 0.01). Both ESCC and EAC may give rise to pagetoid spread of tumor cells within surface squamous epithelium. Pagetoid spread from ESCC and EAC have overlapping morphologic features. P40 and p63 immunostains can facilitate the distinction between ESCC and EAC. P53 immunostain can aid in confirmation of malignancy. Understanding their overlapping pathologic features will help pathologists avoid pitfalls and diagnose these lesions correctly on biopsy specimens.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Authors and Affiliations

  1. Department of Pathology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA, USA

    Tiffany R. Miller, Jason L. Hornick, Mark S. Redston & Lei Zhao

  2. Department of Dermatology, Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, USA

    Tiffany R. Miller

  3. Harvard Medical School, Boston, USA

    Tiffany R. Miller, Vikram Deshpande, Jason L. Hornick, Mark S. Redston & Lei Zhao

  4. Department of Pathology, Yale University School of Medicine, New Haven, USA

    Xuchen Zhang

  5. Department of Pathology, Columbia University, New York, NY, USA

    Huaibin M. Ko & Stephen M. Lagana

  6. Department of Pathology, University of Chicago, Chicago, USA

    Namrata Setia & Lindsay Yassan

  7. Department of Pathology, University of Michigan, Ann Arbor, USA

    Maria Westerhoff

  8. Department of Pathology, Beth Israel Deaconess Medical Center, Boston, USA

    Vikram Deshpande

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Contributions

TRM and LZ designed the study. TRM, XZ, HMK, SL, NS, LY, MW, VD, JLH, MSR, and LZ collected the data. TRM and LZ analyzed the data. TRM and LZ drafted the manuscript. TRM, XZ, HMK, NS, MW, JLH, and LZ revised the manuscript.

Corresponding author

Correspondence to Lei Zhao.

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Conflict of interest

TRM, XZ, HMK, SL, NS, LY, MW, MSR, and LZ have no relevant disclosures. VD serves on the Scientific advisory boards of Incyte and Viela and receives research support from Advanced Cell Diagnostic and Agios. JLH is a consultant to Aadi Bioscience, TRACON Pharmaceuticals, Adaptimmune, and Leica Biosystems.

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Miller, T.R., Zhang, X., Ko, H.M. et al. Esophageal squamous cell carcinoma with pagetoid spread: a clinicopathologic study. Virchows Arch (2024). https://doi.org/10.1007/s00428-024-03788-7

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