• Architecture: Well-formed acini with an inflammatory background
• Cytomorphology:
  ⁃ Polygonal cells with nuclear crowding / overlapping
  ⁃ Nuclei: mildly pleomorphic, eccentric, ovoid, nuclear membrane irregularity / folds, finely textured chromatin
  ⁃ Cytoplasm: abundant, translucent, vacuolated
• No keratinisation

The disordered architecture (overlapping cells) and atypical cytologic features (mild nuclear pleomorphism, nuclear membrane irregularity) should prompt consideration of malignancy. The common primary malignant tumours of the lung include adenocarcinoma, squamous cell carcinoma and small cell carcinoma. Small cell carcinoma is ruled out in this instance because of the low N:C ratio of the cells in this specimen, leaving two main diagnoses:

•  Adenocarcinoma
  • Sheets, acini and papillae with fibrovascular core
  • Finely textured chromatin
  • Eccentric nuclei
  • Abundant, translucent, vacuolated cytoplasm
• Squamous cell carcinoma
  • Sheets with nuclei streaming in parallel fashion
  • Coarsely textured chromatin
  • Dense cytoplasm if keratinised cells are present (Robin blue on DQ, orangeophilic on PAP)
  • Bizarrely shaped individual keratinised cells, if present (tadpole or fibre cells)

It should also be noted that the lung is a frequent site of metastases, in particular carcinoma from the visceral organs. The common sources of malignancy include the colorectum, kidney, breast, female genital tract, prostate, urinary system, upper gastrointestinal tract, pancreatobiliary tract, liver and thyroid.

Clues to metastases:

• Relevant history and imaging findings (e.g. bilateral lung nodules suggests metastases vs solitary lung mass)
• Morphology of some common metastase:
  • Colorectum: columnar cells (picket fence appearance), cigar-shaped nuclei with nuclear palisading, background dirty necrosis
  • Breast (lobular variant): single file arrangement with mucin-containing intracytoplasmic lumina
  • Kidney (clear cell variant): large cells with abundant clear / vacuolated cytoplasm and poorly defined cell membranes
• Immunohistochemistry: some useful markers to suggest possible sites of tumour origin
  • TTF-1: primary lung adenocarcinoma, thyroid and small cell carcinoma of any site
  • PAX8: thyroid, renal, female genital tract
  • ER: breast and female genital tract (a subset of tumours)
  • GATA3: urinary system, breast, some endocrine tumours (e.g. parathyroid, paraganglioma)
  • CDX2: gastrointestinal tract (in general, diffuse for colorectum, patchy for upper tract and pancreatic tumours)

Biopsy of the lesion shows closely packed, infiltrative glands lined by TTF-1 positive epithelium.

IHC panel:

In cases of poorly differentiated carcinoma, positivity for TTF-1 (defined as >10% of cells with positive nuclear staining of any degree (WHO 2015)) confirms the diagnosis of adenocarcinoma, regardless of any staining for the squamous markers (p63, p40, CK5/6).

Lung mass, FNA: Adenocarcinoma

This case features the common morphologic features of adenocarcinoma. The main morphologic differential is squamous cell carcinoma which can be differentiated with features mentioned above. In some instances, especially when the carcinoma is poorly differentiated, judicious use of immunohistochemistry on cell block preparations or concurrent biopsies may be required to tease out the diagnosis, bearing in mind the need to conserve tissue for molecular tests.

It is also important to have relevant clinical and radiological information, as mentioned above, as metastatic adenocarcinoma may have similar cytomorphology to primary lung adenocarcinoma. Moreover, common benign mimics may also be of importance in particular clinical situations.

• Common benign mimics of adenocarcinoma
  • Florid type II pneumocyte hyperplasia
    • May be cytologically identical in a BAL specimen
    • Clinical context of an acutely ill patient with diffuse lung infiltrate
    • Reactive pneumocytes should not be present on a repeat specimen at least 1 month after resolution
  • Reactive bronchial cells, e.g. in BAL / brushing specimens
    • Nucleomegaly / pleomorphism, nuclear hyperchromasia
    • Presence of cilia and terminal bars point to the benign nature of the cells