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September, 2019
Case of the Month

Clinical History: A 73-year-old man was seen in the emergency room for neck and cheek swelling, which turned out to be a blocked salivary duct which eventually resolved. During this visit, it was noted that he had a right upper lobe lung lesion on chest CT imaging. He was a firefighter and continued to smoke a half a pack per day for the last 25-30 years. Later, he underwent wedge resection (Figures 1-3 H&E, 4-7 TTF-1/p40) followed by completion lobectomy of the right upper lobe of lung.

Genomic DNA extracted from this tumor was analyzed to detect somatic variants on 50 genes using next generation sequencing (NGS), which showed only TP53 mutation without any EGFR, KRAS or BRAF mutations. ALK, RET and ROS1 rearrangements were also negative. Later the patient had metastatic disease to several sites including liver, pancreas and chest wall. PD-L1 testing for the clone 22C3 pharmDX showed tumor proportion score of 70%.


Q1. Which of the following is true to this lesion?

  1. Mixed histology of squamous and adenocarcinoma
  2. Less aggressive subtype
  3. Seen in non-smokers
  4. Harbors MAML2 rearrangement

Q2. Immunohistochemical profile of this lesion is best suited to,

  1. Cytokeratins (+), glands p40 (+), solid component p40 (+)
  2. Cytokeratins (+), glands TTF-1 (+), solid component p40 (+)
  3. Cytokeratins (+), glands TTF-1 (+), solid component p40 (-)
  4. Cytokeratins (-), glands TTF-1 (-), solid component p40 (-)

Q3. Which of the following clones of PD-L1 should be utilized in this setting if pembrolizumab (KEYTRUDA) therapy is being considered?

  1. SP142
  2. 28-8
  3. 22C3
  4. SP263

Answers to Quiz

Q1. A
Q2. B
Q3. C


Adenosquamous carcinoma


In the world of precision medicine with advances in immunotherapy, accurate histologic classification of lung cancer is more relevant than before due to the prognostic impact and availability of targeted therapy. Adenosquamous carcinoma is composed of both adenocarcinoma and squamous cell carcinoma, with each component constituting at least 10% of the tumor. It accounts for <4% of all lung cancers, shows a male predominance with median age similar to other lung cancers. It behaves aggressively compared to other non-small cell lung carcinomas. Immunophenotype should support the dual population of tumor cells with distinct components of TTF-1 (&/or Napsin-A) and p40 (&/or p63, CK5/6) positive tumor cells. Entrapped bronchioles with squamous metaplasia and pneumocytes are p40 and TTF-1 positive and may sometimes mimic squamous cell carcinoma and adenocarcinoma respectively. Hence, careful morphologic evaluation to exclude the mimics along with diffuse sheet-like labelling of the immunostains are required for accurate diagnoses. Mucoepidermoid carcinoma, especially the high grade tumors are difficult to distinguish from an adenosquamous carcinoma. Proximal endobronchial location, admixture of squamoid and mucinous cells, lack of squamous cell carcinoma in-situ and negative TTF-1/Napsin-A stains are helpful pointers towards a diagnosis of mucoepidermoid carcinoma. A MAML2 rearrangement is characteristic of low-grade mucoepidermoid carcinoma while inconsistently present in high-grade tumors.

Genetic analyses of adenosquamous carcinoma have shown mutations of EGFR and KRAS more commonly than others. ALK and ROS1 rearrangements and HER2 mutations are seen in a few cases. Molecular testing is of paramount importance to guide the need for targeted therapies.

Several PD-L1 immunohistochemistry (IHC) tests are commercially available to detect the PD-L1 protein. United States (US) Food and Drug Administration (FDA) recommends 22C3-IHC testing for treatment selection for administration of pembrolizumab therapy. The other IHC antibody clones such as 28-8, SP142 and SP263 are used for nivolumab, atezolizumab and durvalumab treatment selections respectively.

Take home message

Positivity for TTF-1 in malignant glands and p40 in the solid component supports the diagnosis of adenosquamous carcinoma.


1. Borczuk AC. Uncommon types of lung carcinoma with mixed histology: sarcomatoid carcinoma, adenosquamous carcinoma, and mucoepidermoid carcinoma. Arch Pathol Lab Med 2018;142(8):914-21.

2. Travis WD, et al. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. WHO Classification of Tumours, 4th Edition, Volume 7, 2015.

3. Udall et al. PD-L1 diagnostic tests: a systematic literature review of scoring algorithms and test-validation metrics. Diagnostic Pathology 2018;13(1):12.


Raghavendra Pillappa, M.D
Assistant Professor of Pathology
Pulmonary Pathologist
Director, Immunohistochemistry
Department of Pathology
Virginia Commonwealth University
Richmond, VA
2019 PPS Lifetime Achievement Award
Professor Elisabeth Brambilla
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