The squamous situation: Ancillary testing in pulmonary squamous cell carcinoma and implications for cytology laboratories

For the past few years, pulmonary adenocarcinomas (ADCs) have been in the spotlight as advances in molecular biology have translated into targeted therapies with a tremendous clinical impact. This has affected the triage and workup of our cytopathology specimens in patients with lung cancer, given the growing need to conserve small tissue samples for an increasing number of mutational and fluorescence in situ hybridization (FISH) studies for personalized therapy decisions.1, 2 Pulmonary squamous cell carcinomas (SqCCs) have lagged behind ADCs in terms of molecular testing and targeted therapies, and have largely been excluded from treatment with common targeted therapies because of the rarity of epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements, the risk of severe complications (eg, severe hemoptysis with angiogenesis inhibitors, such as bevacizumab), and the lack of significant improvement with some agents (eg, antifolate agents, such as pemetrexed).3-5 However, there are now increasing developments, particularly in immune-checkpoint therapies, that are impacting the treatment of patients with SqCC. Recently, cytopathology laboratories moved from a simple dichotomous reporting scheme for lung carcinomas (eg, non-small cell lung carcinoma [NSCLC] vs small cell carcinoma) to more specific subtyping of NSCLC (eg, ADC, SqCC, and NSCLC not otherwise specified [NOS]) for triage and treatment decisions.5 Initially, there was a trend for some laboratories to adopt the terminology of “non-squamous NSCLC” to group different NSCLCs that are triaged similarly and may benefit from similar treatment; however, this was discouraged by the recent 2015 World Health Organization (WHO) classification and thus should not be used in the reporting of NSCLCs in small biopsies.5 Subclassification has been possible given the cytomorphologic differences between SqCC and ADC, in combination with the use of reliable immunohistochemical stains (eg, thyroid transcription factor 1 (TTF1) for ADC and p63/p40 for SqCC). In fact, the morphologic subclassification of SqCC is sometimes easier in cytopathology specimens using a Papanicolaou stain to highlight keratinization, and this can decrease the need for immunohistochemical stains.6 In addition, the histopathology of SqCC tends to exhibit less heterogeneity than ADCs, given that only 3 main types (eg, keratinizing, nonkeratinizing, and basaloid) are recognized by the most recent 2015 WHO lung tumor classification.5 Finally, a report indicating a diagnosis of pulmonary SqCC typically indicates that the specimen will not be submitted for EGFR or ALK testing, and the patient is denied treatment with angiogenesis inhibitors and antifolate agents. The guidelines released by the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology support the exclusion of “pure” SqCCs from testing but mention that in cases from young non-smokers, cases that are difficult to subclassify (NSCLC NOS), or in cases with mixed histologies where an ADC component cannot be excluded, then testing for EGFR and ALK should be performed (Table 1).1 This is largely because EGFR mutations have only been reported in up to 5% SqCCs, most of which were observed in small biopsies from patients with advanced disease and are believed to represent adenosquamous carcinomas or poorly differentiated ADCs.4, 7, 8 In addition, because the prevalence of EGFR mutations in adenosquamous carcinomas ranges from about 67% in Asian populations to 13% in non-Asian populations, if we excluded all tumors with partial squamous differentiation from testing, then we potentially could miss this important subset of patients with EGFR-positive adenosquamous carcinoma who could benefit from tyrosine kinase inhibitors.9-12 Given the lack of significant driver mutations and dismal prognosis, SqCCs have largely been treated with platinum-based chemotherapy. Copy number alterations in a few genes, including amplification of SRY-box 2 (SOX2), EGFR, platelet-derived growth factor receptor α (PDGFRA), and fibroblast growth factor receptor 1 (FGFR1) have been reported, which subsequently led to the use of EGFR monoclonal antibodies (eg, necitumumab) and FGFR inhibitors (eg, infigratinib, dovitinib), usually in combination with conventional platinum-based chemotherapy, as potential therapeutic agents with variable success.3, 13-15 A recent notable advance was the approval of EGFR monoclonal therapies (eg, necitumumab) for first-line use in SqCC after the SQUIRE trial, which marks the first major change for SqCC treatment since the start of platinum-based chemotherapy.15 Additional progress came with the comprehensive molecular characterization of pulmonary SqCCs by The Cancer Genome Atlas, which identified 44% with alterations in markers of squamous differentiation (eg, amplification of SOX2 and/or tumor protein 63 [TP63]); 47% with alterations in the phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) pathway; 72% with inactivation of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene, which encodes p16; and almost universal mutations of TP53.3 Another notable finding is that pulmonary SqCCs tend to exhibit a mutational overlap with head and neck SqCCs that are not human papillomavirus (HPV)-related, in that both tumors have an increased frequency of mutations in PIK3CA, phosphatase and tensin homolog (PTEN), TP53, CDKN2A, notch homolog 1 (NOTCH1), and HRAS (Harvey rat sarcoma virus oncogene homolog).3 In practice, the PIK3CA mutations have been less prevalent in some clinical studies (about 5%), but they do appear to be more prominent in SqCC than in ADC.4, 16 In the near future, newly available therapies targeting the PI3K/AKT/mTOR pathway may be potentially advantageous to patients with SqCCs, given the frequent activation of this pathway in a subset of SqCCs, and mutations in this pathway could be detected with next-generation sequencing panels applied to cytologic material. Immune-checkpoint inhibitor therapies are now changing lung cancer treatment, particularly those inhibitors targeting the interaction of programmed death receptor 1 (PD-1) and programmed death-ligand 1 (PD-L1), given their ability to help reestablish the antitumor immune response that is hindered by the interaction of PD-L1 on tumor cells binding to PD-1 on T cells.17-19 The US Food and Drug Administration (FDA) first approved an anti–PD-1 monoclonal antibody (nivolumab) for SqCC of the lung in March 2015, and the CHECKMATE-017 trial demonstrated that PD-L1 expression in the tumor cells was not predictive of a response in SqCC and thus, PD-L1 testing was not necessary for treatment.18 This is in contrast to another anti–PD-1 agent (pembrolizumab) that was FDA approved in October 2015, in which improved survival was more closely linked to those with tumors that expressed PD-L1 (companion diagnostic).19 The recent study in The New England Journal of Medicine, which demonstrated improved survival for patients with EGFR-negative and ALK-negative NSCLC when treated with pembrolizumab as a first-line agent over platinum-based conventional chemotherapy, will likely increase demands for testing in all laboratories.17 Additional studies and newer trials investigating different immune-checkpoint inhibitors and different combinations of immunologic therapies as first-line and second-line agents are under way. Furthermore, the immune checkpoint inhibitors have shown favorable responses in other tumor types as well, such as melanoma, renal cell carcinoma, bladder carcinoma, and others; thus, the requests for testing will be increasing on tumor types beyond just lung cancer and laboratories will have to make important decisions about how they will perform testing. In summary, pulmonary SqCCs of the lung have a more dismal prognosis than pulmonary ADCs and, in the past few years, have been overshadowed by the significant developments and targeted therapy success in pulmonary ADCs. However, precise subtyping of NSCLCs and appropriate triage of tumors without pure squamous morphology for molecular testing has been important for cytopathology laboratories. In addition, rendering a cytologic diagnosis of SqCC has aided oncologists in avoiding therapies that would be less effective (eg, pemetrexed) or potentially damaging (eg, bevacizumab). Moving forward, demands for next-generation sequencing and PD-L1 evaluation will likely increase for NSCLCs, including SqCC, as more targeted molecular and immunologic therapies arise. Given the already implemented protocols to maximize tissue for pulmonary ADCs, incorporating more testing for pulmonary SqCCs should be seamless for cytopathology laboratories as SqCCs start to share the spotlight. No specific funding was disclosed. The author made no disclosures. Dr. Monaco is an Associate Professor at the University of Pittsburgh Medical Center (UPMC) in the Department of Pathology. She is currently the Cytopathology Fellowship Program Director at UPMC and is also Director of the Fine-Needle Aspiration Biopsy Services at Children's Hospital of Pittsburgh of UPMC and UPMC-Shadyside Hospital. Dr. Monaco has presented several educational courses at national meetings, including the United States and Canadian Academy of Pathology, the American Society of Cytopathology, and the American Society for Clinical Pathology (ASCP). She is currently a co-chair for the ASCP Case Reports in Cytopathology.

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