A 64-year-old female, a lifelong non-smoker, had been under observation for an incidentally discovered pulmonary nodule in her left lower lobe for the past seven years. The nodule was first noted during an evaluation for upper abdominal pain, accompanied by recurring nausea, vomiting, and loose stools. A CT of the abdomen revealed a 9mm nodule in the left lower lobe, which, at the time, was considered an incidental finding. One year later, the nodule was re-assessed and noted to have slightly increased in size to 10mm. Throughout this period, the patient remained entirely asymptomatic from a respiratory perspective, with no evidence of unexplained weight loss or other concerning systemic symptoms. She denies any significant occupational exposures.

Most recently, the nodule was re-evaluated on a CT of the chest, where it was found to have grown slightly, now measuring 1.2 x 1.1 cm. The nodule showed mild FDG avidity on PET scan, though there are still no overt signs of respiratory illness. Although the nodule was stable, a primary lung malignancy could not be categorically excluded, and she underwent an endoscopic ultrasound evaluation, during which fine needle aspiration and concurrent biopsy was performed on the nodule.

 

Authors

• Harpreet Virk, Shannon Rodgers. Department of Pathology. University Hospitals Cleveland Medical Centre. Case Western Reserve University, Cleveland, OH

click on image for larger version

Figure 1	Figure 2	Figure 3
Figure 4	Figure 5	Figure 6
Figure 7	Figure 8

Images 1-8:

• Figure 1: EBUS FNA of lung nodule, aspirate smear, Diff-Quik stained, 400x magnification
• Figure 2: EBUS FNA of lung nodule, aspirate smear, Diff-Quik stained, 400x magnification.
• Figure 3: Cell block, Hematoxylin and Eosin (H&E) stain, 400x magnification.
• Figure 4: Transbronchial lung biopsy from the nodule, Hematoxylin and Eosin (H&E) stain, 400x magnification.
• Figure 5: Transbronchial lung biopsy, BRAF immunohistochemical stain, 400x magnification.
• Figure 6: Transbronchial lung biopsy, CK7 immunohistochemical stain, 400x magnification.
• Figure 7: Transbronchial lung biopsy, TTF1 immunohistochemical stain, 400x magnification.
• Figure 8: Transbronchial lung biopsy, p40 immunohistochemical stain, 400x magnification.

Questions:

1. What is the best diagnosis based on cytomorphology and immunocytochemical stains? (Figure 1 to 6).
   
   
1. Lung mucinous adenocarcinoma
2. Ciliated muconodular papillary tumor
3. Low grade mucoepidermoid carcinoma
4. Bronchogenic cyst
5. Metastatic carcinoma



2. Which of the following is the characteristic finding on cytology smears of this lesion?
   
   
   1. Marked nuclear atypia
   2. Inflammatory background
   3. Abundant ciliated columnar epithelial cells
   4. Frequent mitosis
   5. Squamous metaplasia
      1. 
         
         
3. Which of the following immunohistochemical stain would be NEGATIVE in this lesion?
   
   
   1. CK7
   2. BRAF
   3. TTF-1
   4. P40
   5. Synaptophysin

Answers:

Question 1: Correct Answer is B

The FNA aspirate smears and cell block section (Figure1-3) show sheets of ciliated columnar epithelial cells, few mucous cells, and basal cells, the cells show no significant nuclear atypia or mitotic activity Focal areas (Figure 3) show extracellular mucin. The section from the concurrent transbronchial lung biopsy (Figure 4) shows proliferation of cells with papillary architecture, composed of bilayered cellular elements, columnar epithelial cells and underlying basal cells.  The columnar cells are composed of mucous cells and ciliated cells. The columnar cells show weak cytoplasmic positivity for BRAF. BRAF also highlights cilia in the columnar cells (Figure 5). All neoplastic cells are diffusely positive for CK7 (Figure 6) and occasional cells are also positive for TTF-1 (Figure 7). The intact basal layer is highlighted with p40 (Figure 8). Overall, the findings favor a diagnosis of bronchiolar adenoma/ciliated muconodular papillary tumor (CMPT).

Similar to adenocarcinoma, CMPTs can display growth patterns including glandular, papillary, and micropapillary structures however, marked nuclear atypia, pleomorphism and mitosis are not seen. The intact basal layer (highlighted by p40 IHC) and presence of intact cilia favor against an overtly malignant neoplasm. Mucoepidermoid carcinomas (MEC) can be also confused with CMPTs owing to the presence of mucinous cells, basal cells, and papillary architecture. However, unlike CMPTs, MEC show discriminable, albeit mild, nuclear atypia and admixed squamous epithelial cells and intermediate cells are also seen. Bronchogenic cysts are characterized by an abundance of ciliated respiratory epithelial cells lining the cyst cavity. The cyst wall typically demonstrates varying amounts of seromucinous glands, along with a prominent cartilage and smooth muscle. In cytology, a differential diagnosis of benign bronchial epithelium with mucus cell hyperplasia might be considered. However, the presence of a distinct mass on radiological imaging, coupled with the aspiration of abundant ciliated bronchial epithelial cells arranged in a complex architectural pattern, rules out a benign aspirate.
Although CMPTs are rare, their recognition is increasing as more cases are being documented. Most CMPT cases involve middle-aged or elderly patients and are often incidentally discovered. They are most often interpreted clinically and radiologically as primary lung cancers because of their peripheral location, irregular borders, and occasional gradual enlargement. CPMTs follow an indolent clinical course without recurrence or metastasis even after limited resection.

Question 2: Correct Answer is C

The characteristic histologically feature of CPMT is the presence of tripartite elements
(ciliated columnar cells, mucous cells, and basal cells) surrounded by an intra-alveolar mucin pool. The cells lack nuclear atypia and pleomorphism. No increase in mitoses (Ki67 <1 %) and necrosis are seen. Background can show scattered inflammatory cells composed of lymphocytes and histiocytes, however this is not a characteristic finding. Squamous metaplasia is also not a feature of this lesion.  
The cytological characteristics of CMPTs closely resemble those of normal proximal airway epithelium. Therefore, for accurate diagnosis, it is crucial to confirm that the samples are unequivocally derived from the tumor itself.

Question 3: Correct Answer is E

Immunohistochemistry (IHC) in CPMT is crucial to exclude an invasive tumour and other differential diagnosis. The ciliated columnar epithelial cells show positive staining for thyroid transcription factor 1 (TTF-1), cytokeratin 7, and Napsin A. The basal cells are frequently positive for p40, CK5/6, and p63. The cells are negative for neuroendocrine markers (synaptophysin and chromogranin). Ki67 index is low (usually less than 1%). CPMTs frequently contain driver oncogenes (EGFR, BRAF, ALK, and KRAS), favoring a neoplastic rather than reactive process. Hence, these BRAF mutated lesions often show anywhere from weak to strong cytoplasmic positivity for BRAF V600E IHC.

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