Research Paper Review: Subareolar Tissue Biopsy and Occult Nipple Involvement in Nipple-Sparing Mastectomies

Here I am again with a second journal article for this rotation!

It’s my last week in Frozen Sections/Intraoperative Consultations (IOC). I have seen a good variety of specimens, especially after spending days at the Montreal General Hospital. However, it was during my stay at the Royal Victoria Hospital, particularly my first two weeks, that I encountered breast specimens from mastectomies. Hence why I chose this article.

As previously, because this is a learning exercise for me, I will list notes per section of the article.

Article details

Ma, Lucy X et al. “Subareolar Tissue Biopsy Predicts Occult Nipple Involvement in Nipple-Sparing Mastectomies”. American Journal of Clinical Pathology, 2021. Oxford University Press (OUP), Accessed 18 Nov 2021.


Nipple-sparing mastectomy (NSM)

  • Preferred for increased patient satisfaction and better cosmetic results.
  • Associated with complications, such as skin flap and nipple necrosis and an increased recurrence and risk of residual malignancy
  • Used for early-stage and peripherally located tumors
  • Pathologic evaluation of the nipple margin is necessary; if positive, the nipple-areolar complex (NAC) or nipple is excised

Reported risk factors on predicting NAC involvement are varied and include:

  • Tumor distance to the nipple
  • Presence of nodal involvement
  • Multi-centricity
  • Tumor size and grade

Statistics so far show that:

  • Overall rates of positive subareolar tissue biopsy are from 2.7% to 34.2%
  • Rates of residual malignancy in NAC are from 0% to 42.3%
  • There is good concordance between IOC/frozen sections of the NAC and final reports as seen on permanent sections.


  • Retrospective chart review of 1,026 consecutive NSMs with separately submitted subareolar tissue biopsies
  • Outcome measures included concordance rate and disease features associated with a positive subareolar biopsy


  • Rate of positive subareolar tissue is 7.2%
  • Factors that were significantly associated with a positive subareolar biopsy
  • Multifocal/multicentric disease
  • Presence of lymphovascular invasion
  • Nodal involvement
  • 51% of positive nipple biopsies showed residual carcinoma
  • There was a 3.3% discrepancy between IOC results and permanent diagnoses, mostly because of false negatives


  • There is lack of standardization on evaluating patient selection for NSM, sample techniques, and evaluating a positive margin
  • Findings show that tumor size and distance of tumor from the nipple are not predictive of occult nipple involvement nor are contraindications to NSM
  • The main confounder of a positive subareolar tissue biopsy is LCIS, and studies that consider LCIS as a malignant finding report higher rates of positive biopsies.
  • False negatives are more common due to sampling or interpretative errors.
  • In this study, one false-positive case was due to the misreading of a histiocytic infiltrate, a response from surgery.
  • There is also the question of whether the subareolar tissue biopsy is representative of occult nipple involvement.


  • Intraoperative frozen sections of the subareolar tissue in NSM are reliable.
  • Nipple/NAC resection should be seriously considered in cases of a positive subareolar tissue biopsy.


Image of an empty cryostat taken by Chris Stock (source).

Dr. Jade Marie Tomaszewski is a pathologist-in-training at McGill University, where she also did her degree in MSc Pathology. She obtained her medical degree (MD) from the University of the Philippines, after completing a BSc in Molecular Biology and Biotechnology. In her (little) spare time, she enjoys spending time with family, curling up with a book and a large mug of tea, and trying out new recipes in the kitchen. You can follow her on LinkedIn and Twitter.

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