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Case Presentation

Case Presentation – June 2026 

Metastatic Lung Adenocarcinoma to the Eye 

Written by: Taylor Herring, student, Cleveland Clinic School of Health Professions Cytology Program, Cleveland, OH 

Patient Age: 62-year-old female 

Specimen Type: Left eye, fine needle aspiration. Papanicolaou stained ThinPrep® Non-Gyn slide and Cellient® cell block. The cell block was used for the Hematoxylin and Eosin (H&E) stain as well as the following immunohistochemical (IHC) stains: cytokeratin AE1/3 (+), TTF-1 (+), Napsin A (+), and GATA3 (-). Next generation sequencing revealed a positive KRAS mutation biomarker. IHC stains and molecular results further supported the diagnosis of metastatic lung adenocarcinoma and helped rule out the possibility of a carcinoma of breast origin. 

Patient History: Current smoker of 0.5 packs per day for the past 40 years with no prior diagnosed malignancies. The patient presented with a foreign body sensation in the left eye along with pain, swelling, and blurred vision. Follow-up revealed a rapidly growing ciliary body lesion measuring 5.5 x 8.5 x 9.0 mm. Due to concerns for the possibility of metastatic lung malignancy, the patient was referred for a chest CT where a large left lower lobe mass, concerning for malignancy, was identified. Following the chest CT, the patient underwent an FNA of the eye. 

Cytologic Diagnosis: Positive for malignant cells, Metastatic lung adenocarcinoma. 

Case provided by: Cleveland Clinic, Cleveland, Ohio 

 

Metastatic Lung Adenocarcinoma to the Eye

Etiology: 

Adenocarcinoma is one of the most prevalent non-small cell type of lung cancer and tends to be discovered incidentally or through diagnosed metastasis.1 Genetic mutations in oncoproteins such as KRAS, ALK, and EGFR play a significant role in the pathogenicity and treatment of lung adenocarcinoma. KRAS-mutated cancers are commonly associated with smokers between the ages of 60 and 70 and account for 25% – 30% of mutations in lung adenocarcinoma.2 Lung adenocarcinoma commonly metastasizes to the brain, pleura, and liver while metastasis to the eye is rare due to the absence of lymphatics.3,4 

Clinical Features: 

Approximately 8-10% of metastatic diseases occur intraocularly and mostly arise in the uvea with rare metastasis to the retina.5 Most common symptoms include blurred vision, pain, and vision loss while some patients present no symptoms at all.5,6 An estimated two thirds of patients have a primary cancer diagnosis prior to uveal metastasis, with the most common primary site being breast. The remaining third of patients have no known cancer diagnosis prior to uveal metastasis, and lung was the most frequently found origin.6,7 

Treatment and prognosis: 

The first line of treatments for KRAS-mutated, metastatic non-small cell lung 

cancer (NSCLC) are immunotherapy, chemotherapy, and KRAS-targeted therapy. The treatment outcome is influenced by multiple factors such as PD-L1 expression, resistance to targeted tyrosine kinase inhibitors, and the type of KRAS mutation.8 Advanced or metastatic KRAS-associated NSCLC has a poor prognosis with a median overall survival of 10.7 months.9 A 54% mortality at mean 12-month follow-up was discovered for patients with metastatic lung adenocarcinoma to the eye, with about half of the patients learning of a primary NSCLC after metastasis.7 

In this specific case, the patient passed away three months after this diagnosis was made. 

Cytology: 

Lung adenocarcinoma is found in three-dimensional clusters, papillae, and honeycomb-like sheets. Nuclei are eccentrically placed with prominent nucleoli. Mucin vacuoles may be present in a translucent, foamy cytoplasm.1 Metastatic lung adenocarcinoma to the eye presents as a highly cellular specimen with clusters of cells arranged in glandular formations with high N:C ratios. Positive IHC stains for lung adenocarcinoma include TTF-1, Napsin A and CK7.10 

Differential Diagnosis: 

Malignancies in the eye are sparce and composed of rare primaries and a few metastatic carcinomas. The primaries include melanoma and pediatric retinoblastoma.11 Metastatic carcinomas tend to originate from the lung, breast, kidney, and gastrointestinal tract with the inclusion of cutaneous melanoma.6 

Uveal Melanoma presents as a cellular sample with a mixture of spindled and epithelioid cells. Melanin pigment is also present in a majority of cases.12 A predominantly epithelioid morphology may mimic a uveal metastasis and would likely require ancillary testing to differentiate the two entities. Positive IHC stains for melanoma include HMB45, S100, and melanA.13 Differentiation of uveal melanoma and cutaneous melanomas can be done through molecular testing. Cutaneous melanomas typically have a mutation in BRAF or NRAS while uveal melanomas are characterized by activating mutations in GNAQ or GNA11 with a general lack of BRAF mutations.14 

Breast adenocarcinoma is the most common type of metastasis to the uvea.7 These specimens are generally cellular and arranged as single cells or in a single file line pattern. Cells have large, round, and eccentrically placed hyperchromatic nuclei with large cytoplasmic vacuoles (signet 

ring appearance). Positive IHC’s include estrogen receptor, progesterone receptor, and GATA3.15

Pancreatic ductal adenocarcinoma metastasis to the eye is extremely rare16 and presents cytologically with moderate to high cellularity arranged in crowded “drunken honeycomb” appearance and single cells. Nuclei are enlarged with irregular nuclear membranes, chromatin clumping, and parachromatin clearing. Marked anisonucleosis with 4-fold nuclear enlargement and mucinous cytoplasm are helpful features. Positive IHC staining for SMAD4, P53, P16, and MTAP provide further diagnostic value.1 

 

References:

  1. Cibas ES, Ducatman BS. Cibas and Ducatman’s Cytology. 6th ed. Elsevier; 2025:87, 88, 478, 479.
  2. Ding Y. Molecular Markers KRAS. pathologyoutlines.com. Published April 1, 2022. https://www.pathologyoutlines.com/topic/molecularKRAS.html
  3. Cohen VM. Ocular metastases. Eye (Lond). 2013;27(2):137-141. doi:10.1038/eye.2012.252
  4. Tie X, Wang J, Wang Y, et al. The Prognostic Effect of Metastasis Patterns on Overall Survival in Organ Metastatic Lung Adenocarcinoma. Medicine (Baltimore). 2023;102(14):e33297. doi:10.1097/MD.0000000000033297
  5. Konstantinidis L, Damato B. Intraocular Metastases A Review. Asia Pac J Ophthalmol (Phila). 2017; ;6(2):208-214. doi:10.22608/APO.201712
  6. Shields CL,  Shields JA, Gross NE, Schwartz GP, Lally SE. Survey of 520 eyes with uveal metastases. Ophthalmology. 1997;104(8):1265-1276. doi:10.1016/s0161-6420(97)30148-1
  7. Shields CL, Welch RJ, Malik K, et al. Uveal Metastasis: Clinical Features and Survival Outcome of 2214 Tumors in 1111 Patients Based on Primary Tumor Origin. Middle East Afr J Ophthalmol. 2018;25(2):81-90. doi:10.4103/meajo.MEAJO_6_18
  8. Tang Y, Pu X, Yuan X, Pang Z, Li F, Wang X. Targeting KRASG12D mutation in non-small cell lung cancer: molecular mechanisms and therapeutic potential. Cancer Gene Ther. 2024;31(7):961-969. doi:10.1038/s41417-024-00778-4
  9. Bironzo P, Cani M, Jacobs F, et al. Real-world retrospective study of KRAS mutations in advanced non-small cell lung cancer in the era of immunotherapy. Cancer. 2023;129(11):1662-1671. doi:10.1002/cncr.34731
  10. Matsumoto K, Kase S, Namba K, Iwata D, Matsuno Y, Ishida S. A Case of Intraocular Metastasis of Lung Cancer Diagnosed Using Cell Block Preparation of the Vitreous Humor. Cancer Diagn Progn. 2023;3(1):130-134. Published 2023 Jan 3. doi:10.21873/cdp.10190
  11. Eagle RC Jr. The pathology of ocular cancer. Eye (Lond). 2013;27(2):128-136. doi:10.1038/eye.2012.237
  12. Medina CA, Biscotti CV, Singh N, Singh AD. Diagnostic Cytologic Features of Uveal Melanoma. Ophthalmology. 2015;122(8):1580-1584. doi:10.1016/j.ophtha.2015.04.013
  13. Tretter E, Schoenfield L. Melanoma-uvea. www.pathologyoutlines.com. Published August 1, 2018. https://www.pathologyoutlines.com/topic/eyeuveamelanoma.html
  14. Everett L, Damato BE, Bloomer MM, et al. Metastatic Cutaneous Melanoma Presenting with Choroidal Metastasis Simulating Primary Uveal Melanoma. Ocul Oncol Pathol. 2019;5(2):135-138. doi:10.1159/000488708
  15. Li JJX, Tse GM. Classic. www.pathologyoutlines.com. Published November 23, 2021. https://www.pathologyoutlines.com/topic/breastmalignantlobularclassic.html
  16. Singh A, Malik D, Singh S, Vyas VJ. Choroidal metastasis in pancreatic adenocarcinoma. J Cancer Res Ther. 2022;18(1):263-265. doi:10.4103/jcrt.JCRT_45_20

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