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January, 2022
Case of the Month

Clinical History: A PET-positive 1.5-cm solitary central pulmonary nodule was resected in a 67 year-old woman (non-smoker). The clinical suspicion was malignancy. Macroscopically, the nodule was tan-white and well demarcated. As depicted in Figure 1 (H&E) and Figure 2 (EvG), histologically the nodule was predominantly endobronchial with minimal alveolar extension and consisted of a papillary tumor. There was an acute inflammatory infiltrate between the fibrovascular cores. The surrounding lung parenchyma showed mucostasis and lympho-follicular inflammation, which could be attributed to a post-obstructive complication. The fibrovascular cores were lined by glandular epithelium with pseudostratified ciliated and non-ciliated cuboidal to columnar mucin-filled cells (Figure 3) and interspersed areas of acanthotic squamous epithelium (Figure 4, H&E; Figure 5, p40). There was no atypia, karyorrhexis or necrosis.

Q1. Is this lesion benign or malignant?

  1. Benign
  2. Uncertain clinical behavior
  3. Malignant - low grade
  4. Malignant - high grade

Q2. The lesion is associated with which of the following viral infections

  1. HPV
  2. HIV
  3. EBV
  4. None of the above

Q3. Which mutations are often found in this lesion?

  1. KRAS
  2. BRAF
  3. EGFR
  4. AKT1

Answers to Quiz

Q1. A
Q2. D
Q3. B and D


Mixed squamous cell and glandular papilloma


Benign neoplasms of the lung are overall rare; the most common are hamartomas. Papillomas are very rare lesions. Most frequently bronchial papillomas are of squamous cell type. Mixed squamous and glandular papilloma is a papillary tumor with mixed glandular and squamous epithelium, where each epithelial component constitutes at least one third of the lesion (essential diagnostic criterion according to WHO 2021). Similar tumors with only a glandular component are diagnosed as glandular papilloma. Papillomas occur in an endobronchial location (desirable diagnostic criterion according to WHO 2021). Complete tumor resection is needed for a definitive diagnosis, and carcinoma - in particular mucoepidermoid carcinoma - needs to be excluded (desirable diagnostic criterion according to WHO 2021).

Recently, AKT1 and concurrent BRAF V600E or HRAS mutations were described in peripheral glandular papillomas and mixed squamous cell and glandular papillomas but not in bronchiolar adenoma/CMPT (see PPS case of the month January 2019), which are believed to be different tumors. Corroborating these results, we were able to demonstrate concurrent BRAF and AKT1 mutations in the current case.

Surgical resection is curative for mixed squamous and glandular papillomas. Contrary to pure squamous papillomas, HPV has not been identified in mixed squamous and glandular papillomas. Only one squamous cell carcinoma arising in a mixed squamous and glandular papilloma has been reported, but this was a peripheral lesion.

Take home message for trainees: Mixed squamous cell and glandular papilloma is a rare benign tumor of the lung, without association to HPV, and with frequent co-occurring AKT1 and BRAF or HRAS mutations.


Lagana SM, Hanna RF, Borczuk AC. Pleomorphic (spindle and squamous cell) carcinoma arising in a peripheral mixed squamous and glandular papilloma in a 70-year-old man. Arch Pathol Lab Med 2011;135:1353-6.

Sasaki E, Masago K, Fujita S, et al. AKT1 mutations in peripheral bronchiolar papilloma: glandular papilloma and mixed squamous cell and glandular papilloma is distinct from bronchiolar adenoma. Am J Surg Pathol 2021;45:119-26.


Sabina Berezowska, MD
Associate Professor
Institute of Pathology
Lausanne University Hospital and University of Lausanne
Lausanne, Switzerland
2019 PPS Lifetime Achievement Award
Professor Elisabeth Brambilla
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