Papillary lesions of the breast encompass a broad range of entities with diverse morphologies. There are two main categories: papilloma and papillary carcinoma. Papillomas are benign neoplasms that can show secondary involvement by benign and malignant epithelial proliferations, whereas papillary carcinomas are epithelial malignancies that have an intrinsic papillary architecture. Recognition of the appropriate category helps to frame the diagnostic evaluation. We will examine the histologic distinction between papilloma involved by atypical hyperplasia/in-situ carcinoma and papillary carcinoma, and we will review the diagnostic features of papillary ductal carcinoma in-situ, encapsulated papillary carcinoma, invasive papillary carcinoma, and solid papillary carcinoma. In particular, we will evaluate the unique issues presented by encapsulated papillary carcinoma and solid papillary carcinoma in the assessment for stromal invasion and review current clinical guidelines for those entities.

Dr Alexander Nirenberg¹, Professor Richard Williams<sup>2

1</sup>Dorevitch Pathology ²Dorevitch Pathology, University of Melbourne

Much medical progress is incremental however some current concepts may need major paradigm shifts based on forgotten old or new evidence. Three such concepts are discussed. 

The current grading of solar keratosis based on the number of layers of the epidermis involved is not thought to be the major indicator for risk of developing invasive squamous cell carcinoma. Epidermal basal proliferation and follicular involvement by dysplasia significantly reflect the risk of development of invasive squamous cell carcinoma. This raises the possibility of paying more attention to cytological changes in addition to basal proliferation. (1) 

The current classification of basal cell carcinoma, particularly higher risk subtypes, is not well reproducible, suggesting a need for an updated classification in which high risk subtypes are merged into a single infiltrating subtype. (2) 

Recent evidence on prognostic factors in melanoma questions the utility of sentinel lymph node biopsy in predicting outcome, with the BAUSSS (Breslow depth, Age of patient, Ulceration, Subtype of melanoma, Sex of patient, Site of melanoma) algorithm being put forward as an alternative to current algorithms. Further investigation is needed, especially in view of complications of sentinel lymph node biopsy which are infrequent but not insignificant. (3)

REFERENCES
1. Kandolf L, Peris K, Malvehy J, Mosterd K, Heppt MV, et al. European consensus-based interdisciplinary guideline for diagnosis, treatment and prevention of actinic keratoses, epithelial UV-induced dysplasia and field cancerization on behalf of European Association of Dermato-Oncology, European Dermatology Forum, European Academy of Dermatology and Venereology and Union of Medical Specialists (Union Européenne des Médecins Spécialistes). J Eur Acad Dermatol Venereol. 2024 Jun;38(6):1024-1047. doi: 10.1111/jdv.19897.

2. Fernández-Figueras MT, Malvehi J, Tschandl P, Rutten A, Rongioletti F, et al. Position paper on a simplified histopathological classification of basal cell carcinoma: results of the European Consensus Project. J Eur Acad Dermatol Venereol. 2022 Mar;36(3):351-359.

3. Gebhardt C. Age matters: Rethinking SLNB's reliability in melanoma mortality prediction. J Eur Acad Dermatol Venereol. 2024 Apr;38(4):639-640.

Cancer of unknown primary (CUP) is a primary metastatic malignant epithelial or undifferentiated neoplasm for which a standardized diagnostic workup fails to identify a site of origin.  CUP constitutes approximately 2% of all human cancers, but has a high mortality rate, with median survival less than 1 year.

The most common histology is adenocarcinoma: approximately 50% of CUP cases are well- or moderately differentiated adenocarcinomas. 30% are poorly differentiated adenocarcinomas or undifferentiated carcinoma, 15% are squamous cell carcinomas and the remainder are undifferentiated neoplasms.  Sarcomas, melanomas, germ cell tumours, neuroendocrine tumours and haematological malignancies are not generally included as “CUP” cases, even if the exact site of origin of the tumour is not clear.

Diagnostic challenges include tumours with non-specific morphologic or immunophenotypic features (such as a “biliary-type” adenocarcinoma with CK7+/CK20- immunophenotype), tumours showing aberrant differentiation (such as a SMARCA4-deficient non-small cell lung carcinoma), undifferentiated malignancies (such as undifferentiated melanoma) and rare tumours.

The diagnosis of CUP requires a multidisciplinary approach, with interpretation of histopathological findings in the context of comprehensive clinical history (including history of prior malignancy), clinical examination, evaluation of serum tumour markers, and review of radiology +/- nuclear medicine +/- endoscopic findings.  As diagnostic biopsy often comprises only a small quantity of tumour tissue (e.g. core biopsy), a stepwise approach to immunohistochemistry and, sometimes, molecular testing may be warranted, aiming to provide all necessary diagnostic and prognostic information on limited tissue available.

Lorkowski SW, Dermawan JK and Rubin BP. The practical utility of AI-assisted molecular profiling in the diagnosis and management of cancer of unknown primary:  an updated review.  Virchows Archive 2024;484:369-375. https://doi.org/10.1007/s00428-023-03708-1

Krämer A, Bochtler T, Pauli C, et al.  Cancer of unknown primary:  ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.  Annals of Oncology 2023 34(3):228-246.  https://doi.org/10.1016/j.annonc.2022.11.013.

Beauchamp K, Moran B, O’Brien T, et al. Carcinoma of unknown primary (CUP):  an update for histopathologists.  Cancer and Metastasis Reviews 2023;42:1189-1200. https://doi.org/10.1007/s10555-023-10101-6

Posner A, Prall OWJ, Sivakumaran T, et al. A comparison of DNA sequencing and gene expression profiling to assist tissue of origin diagnosis in cancer of unknown primary. Journal of Pathology 2023;259:81-92. DOI: 10.1002/path.6022

Schipper LJ, Samsom KG, Snaebjornsson P, et al.  Complete genomic characterization in patients with cancer of unknown primary origin in routine diagnostics.  ESMO Open 2022;7(6):1-9. https://doi.org/10.1016/j.esmoop.2022.100611

Pauli C, Bochtler T, Mileshkin L, et al. A Challenging Task: Identifying Patients with Cancer of Unknown Primary (CUP) According to ESMO Guidelines: The CUPISCO Trial Experience. The Oncologist 2021;26:e769–e779.