Abstract

COVID-19 pandemic had affected health services around the world, also reducing the diagnosis of lung cancer. On the other hand, examination of surgical specimens in patients with lung cancer and SARS-CoV-2 gave the opportunity to evidence early histologic features related to this emerging pandemic. Different prioritization of health organizations during COVID-19 pandemic resulted in a significant decline of lung cancer screening (up to 56%), delayed diagnosis (up to 30-40%) and higher advanced stage, with some exceptions (i.e., Canada). Increased use of stereotactic radiation treatments in stage I-IIA have been noticed in better-organized health systems. Surgical specimens performed for lung cancer in patients with incipient SARSCoV- 2 permitted to appreciate early histologic findings of COVID-19 with hyperplastic pneumocytes with/without fibrin exudate, alveolar macrophages/myeloid cells, perivascular T-lymphocytic infiltrate and lack of hyaline membrane. While the COVID-19 pandemic has declined the rate of lung cancer diagnosis worldwide, some institutions have significantly limited detrimental effects. Histology related to early SARS-CoV-2 infection in surgical samples for lung cancer revealed specific histologic changes.

Introduction

Coronavirus disease 2019 (COVID-19) pandemic is caused by coronavirus-2 (SARS-CoV-2) and characterized by variable clinical settings, ranging from patients developing mild flu-like symptoms to others rapidly progressing to acute respiratory failure requiring intensive care unit ¹.

The disease significantly disrupted the health systems worldwide and then deeply influenced the management and prognosis of new lung cancer cases. Retrospective studies from various countries resulted in delayed diagnoses, higher advanced stage, lower rate of surgical interventions and higher use of immune-chemotherapy and stereotactic treatments ^2-4. However, the differences between pre-pandemic and pandemic period were not equally distributed worldwide, since some countries did not experience significant changes in lung cancer management through prompt re-organization of treatment modalities.

At the same time, despite intense investigation on COVID-19, its pathogenesis is still poorly understood and the relevance of information has been recently highlighted mainly by laboratory investigations on serum immunologic findings, live biopsies and post-mortem examination of autopsies ^5-12, although prolonged invasive mechanical ventilation and several confounding factors (medications, ventilator-associated pneumonia, oxygen damage, bacterial super-infections, autolytic factors, among others) ¹¹ significantly impaired the recognition of early and/or specific changes due to SARS-CoV-2 infection in autolytic autoptic samples. Indeed, post-mortem analysis generally showed a diffuse alveolar damage, as observed in acute respiratory distress syndrome (ARDS), while a particular emphasis has been given to the occurrence of thrombo-embolic disease, suggesting a potential role of endothelial pathways in the pathogenesis ¹⁰. Nevertheless, the specificity of these findings is questionable, since similar thrombo-embolic disease, excessive pro-coagulant activity, and vascular changes are common in ARDS regardless of its etiology ^13-17, as well-evidenced in old seminal papers and even in other infections.

Considering that only a limited number of cases consisting of live biopsies from patients with COVID-19 permitting to pinpoint the initial phase of the disease are available in the literature ^18-21, examination of surgical specimens from patients with lung cancer incidentally resulting positive for SARS-CoV-2 allowed pathologists to identify the incipient findings characterizing this novel infection without confounding factors.

In this review, we examine the detrimental role of COVID-19 pandemic affecting lung cancer care services in terms of surgery reduction, pathologic upstaging and higher long-term mortality rates, comparing the results from retrospective studies in different countries around the world. At the same time, morphologic and immuno-molecular features of SARS-CoV-2 infection at an earlier stage of the disease described on surgical specimens from patients with lung cancer are reported.

Lung cancer epidemiology and management during the COVID-19 pandemic

Globally, coronavirus disease 2019 (COVID-19) significantly declined clinical activities, including cancer care, in order to follow national health systems directives. A cross-sectional study conducted in 356 centers across 54 countries found that 88% of oncologic centers had a hard time delivering care to patients, due to the large burden on the health care system, lack of protective equipment, decline in number of healthcare personnel working, and low access to medications ^1-3. Another recent study by Patt et al. ³ reported that screening of cancers declined drastically due to the COVID-19 pandemic, including 56% for lung cancer. All these data potentially lead to a delayed diagnosis and more advanced stage patients. On the other hand, Garassino et al. ⁴ reported increased mortality in patients with thoracic malignancy who were infected with COVID-19.

In a retrospective chart review study from Canada comparing lung cancer management before and during the COVID-19 pandemic, Kasymjanova et al. ²² found that referral to a lung cancer specialist and subsequent diagnosis of lung cancer declined by 34.7% during the pandemic, a figure further supported by the study conducted by Dr. Reyes and colleagues reporting a 38% decrease in new lung cancer cases in 2020 compared to the pre-COVID-19 era ²³.

Kasymjanova et al. ²² also reported a significant increase in the utilization of radiosurgery as the first definitive treatment, and a decrease in both systemic treatment as well as surgery compared to the pre-COVID-19 era. No significant differences were observed in starting chemotherapy and radiation treatment, but a delay in lung cancer surgery during the pandemic time was noted. Oncologists relies on an increase in newly diagnosed lung cancer patients in the coming year.

Conversely, in another Canadian experience, Blais at el. ²⁴ found no difference in wait time to obtain a lung cancer diagnosis before and during the pandemic. To obviate to surgical interventions, the Quebec Lung Cancer Network recommended stereotactic radiation for stage I-IIa lung cancers.

As a result of prioritization of available treatments, a 14% (21% in 2020 vs. 7% in 2019) increase in radiosurgery given with the curative intent to early-stage disease and a 13% (25% in 2020 vs. 38% in 2019) decrease in surgical resections during the pandemic was observed ²⁴. This decline in surgery was partially due to reduced operating room hours, the lack of medical staff, and long waiting list.

In a multicentric, observational, retrospective study from 25 Oncology Department from Italy, the authors observed a slight statistically non-significant reduction (-6.9%) in newly diagnosed lung cancer in 2020 when compared with 2019 (p = 0.09) ²⁵. However, diagnoses of lung cancer during the pandemic were more likely in advanced stage (72% vs. 67%) and current smokers (p < 0.01). Of note, no significant differences were noted concerning the interval between symptoms onset and radiological diagnosis, symptoms onset and pathologic confirmation, or treatment start.

Another paper from northern Italy evidenced a decline of new lung cancer diagnosis in 2020 (-21 cases) when compared with 2019, particularly in men ²⁶. There was also a significant reduction of lung cancer stage I passing from 19.8% to 12.9% (p < 0.05) and conversely an increase of stage III (12.7% vs. 19.1%; p < 0.05). Curiously, there was a significant increase in cytology (12% vs. 20.8%; p < 0.01) over biopsy (70.1% vs. 60.1%; p < 0.05) in pathologic diagnosis of lung cancer. Surgery declined (28.7% vs. 21.5%; p < 0.05) but increased in stage III (19.5% vs. 25.9%; p of = 0.46), while chemotherapy increased (17.6% vs. 34.3%; p < 0.01) for all stages ²⁶.

The reorganization of health services has ensured a decrease in surgical interventions (due to the unavailability of operating rooms) counterbalanced by an increase in chemotherapy.

Tomos et al. ²⁷ evaluated 61 patients with early-stage lung cancer during (28) and before (33) pandemic, demonstrating a significantly longer delay of treatment and an increase in tumor size during the pandemic (p < 0.001), although no significant differences were detected in the increase of the stage of lung cancer between the subgroups. The authors stated that COVID-19 pandemic had a significant impact in lung cancer management.

Concerning recommendations on surgical treatment of early-stage lung cancer during the pandemic, data are contradictory. It has been generally proposed that elective surgeries should be rescheduled; however, contrarily, the European Association of Medical Oncology recommends keeping all surgeries as a priority in the management of early NSCLC and that surgical delays should not exceed six to eight weeks ^28-32.

In Japan, Terashima et al. ³³ reported a decreased number of lung cancer diagnoses during pandemic period, from 82 to 75 and a higher rate of advanced-stage cancer (65.9% vs. 46.7%) when compared to pre-pandemic times. There was a lower percentage of patients treated with surgery and consequently higher number of cases undergoing chemotherapy (24.4% vs. 41.3% and 57.3% vs. 40.0%), respectively. A delay in pre-diagnosis (28.2 vs 11.4 days) and time for surgery was noted (67.3 vs. 45.6 days) during the pandemic.

A retrospective case-control study from 2 regions in Germany including all patients receiving their first diagnosis of NSCLC between January 2019 and March 2021 revealed that the number of patients diagnosed with NSCLC dropped substantially during the COVID-19 period ³⁴. Patients experienced an increase of tumor stage, N3-status (p = 0.022) due to a delay in the diagnosis of NSCLC, although no increase in inoperable stages was demonstrated and no robust data on overall prognosis in this cohorts of patients are available ³⁴.

Olesen et al. ³⁵ used the Danish Lung Cancer Registry and a generalized linear model to estimate the prevalence of lung cancer between the pre-pandemic and pandemic periods, demonstrating a decline in NSCLC cases during the first lockdown in 2020, but no difference in distribution of income or educational level was observed, neither in the quality of treatment – as measured by curative intent, proportion of patients resected or who died within 90 days of diagnosis.

In a study by the Greater Paris University Hospital (French), the authors noted during the first lockdown a decreased rate of new diagnoses of lung cancer by 32% compared with that recorded in 2018-2019 ³⁶. Initial tumor stage, repartition of patients among treatment categories, and multidisciplinary tumor board-related delays remained unchanged. Similarly, the 6-month overall survival rates of patients undergoing tumor surgery were 98% vs. 97% and the percentage of patients receiving systemic therapy were 78% vs. 79%. Poorer overall survival rate was noted in patients with COVID-19 receiving systemic treatment ³⁶.

In a recent brief report from Brazil, the authors reported an overall decline of 22% of lung cancer surgery during the first pandemic wave, with a doubled rate perceived in the poorer regions of the country ³⁷.

In UK, a retrospective observational study on the incidence rates for lung cancer calculated from The National Lung Cancer Audit Rapid Cancer Registration Datasets for 2019 and 2020 evidenced a 26% reduction in lung cancer incidence during the first national lockdown, including a 23% reduction in NSCLC and a 45% reduction in SCLC incidence ³⁸.

A retrospective study of the Queensland Cardiac Outcomes Registry (Australia) comparing the data with and without the introduction of COVID-restrictions demonstrated a significant delay from time of diagnosis to surgery from 80 to 96 days (p < 0.0005) during COVID restrictions ³⁹. Restrictions were associated with surgery reduction and a significant increase in pathological upstaging after the introduction of COVID-restrictions.

The meta-analysis by Wang et al. ⁴⁰ on 20 studies reported that overall 2.4% of cancer patients were infected with SARS-CoV-2. Of note, the mortality rate in patients with lung cancer was notably higher than that in other solid malignancies (p < 0.001). Among lung cancer patients, a higher mortality rate was possibly associated with SARS-CoV-2 infection (p < 0.001). Nevertheless, the study showed that after the outbreak of COVID-19, the proportion of patients diagnosed with advanced lung cancer did not significantly increase (p = 0.854).

Since early stage is the most promising finding when curative intent is considered in lung cancer, a major reason for the high mortality rate in lung cancer patients is that patients are diagnosed at a later stage during COVID-19 pandemic.

Since stereotactic radiation (SBRT) is considered an effective alternative to surgery for early-stage NSCLC care, there was an increase of this procedure during the COVID-19 pandemic. However, delayed surgery (over 90 days) was associated with poorer survival among patients receiving surgery at different delays, but better overall survival when compared to early SBRT (5-year survival 76.9% versus 32.3%; p < 0.001), then resulting the standard of care to treat operable early-stage lung cancer despite delays imposed by the COVID-19 pandemic ⁴¹.

In the north American SABR-BRIDGE study on the use of stereotactic ablative radiotherapy (SABR) as a bridge to surgery during COVID-19, 72 patients underwent SABR. After SABR, 26 patients underwent resection and the median time-to-surgery was 4.5 months post-SABR although with more difficulty secondary to radiation in 38% ⁴². The SABR-BRIDGE approach allowed for delivery of treatment during a period of operating room closure and was well-tolerated, although in the exploratory best-case scenario analysis pathologic complete response did not exceed 82%.

A single-cancer care center retrospective analysis in Ontario (Canada) aimed to assess whether the COVID-19 pandemic affected patients with NSCLC between a pre-pandemic period (January 2019 to February 2020) and pandemic (March 2020 to February 2021) included 695 patients, of whom 650 underwent surgery ⁴³. The mean number of patients referred per month during the pre-COVID-19 period was 55.9 compared to 50.5 (p = 0.3) and there was no significant difference between the 2 periods in tumor size, number of lymph nodes involved or the resultant pathologic stage. There was no significant difference between the 2 study periods in the minimally invasive surgery categorization, surgery, length of hospital stay, or mortality (p = 0.9). The study did not find any significant difference in outcomes between patients treated before (n = 330) and during (n = 320) the pandemic. Potential detrimental effects on prognosis and survival of lung cancer patients during COVID-19 pandemic have not been seen in the health organization described by Keogh et al. ⁴⁴, suggesting that the effects of pandemic can be blunted by using proactive preservative strategies and surgeon advocacy.

This is of relevance, as it was noted in a study in the UK that there was a reduction of 37% in cancer treatment for cases deemed nonurgent, and that suboptimal treatment or changes to treatment should be considered in tandem with diagnostic delays when considering the impact of the COVID-19 pandemic on cancer care. These delays in diagnosis and perturbations to cancer treatment in other nations will likely lead to exponential increases in excess deaths owing to pathologic upstaging, and overall worsened morbidity and mortality.

In conformance with health system directives and national proactive advocacy by thoracic surgeons, this institution has prioritized cancer operations throughout the pandemic while pausing all other elective operations and offering promising early view of maintained lung cancer patient outcomes.

Finally, Mayne et al. ⁴⁴ performed a Cox regression analysis using the National Lung Screening Trial (NLST) (n = 392) and National Cancer Data Base (NCDB) (n = 275,198) data aimed at examining the association between treatment delay and all-cause mortality for stage III-IV lung NSCLC. No significant differences in survival were found between early and delayed treatment for patients with stage IIIA-to-IV NSCLC (all log-rank P > . 05). The national analysis demonstrated that an extended treatment delay by 3 to 4 months was not associated with significantly decreased overall survival compared to prompt treatment, reassuring patients with stage III-IV disease and guiding decision-making for administrators and public health officials during pandemic waves.

A brief summary of the main detrimental findings derived from COVID-19 pandemic in patients with lung cancer is reported in Table I.

Considering the type of procedure used during the COVID-19 pandemic to diagnose lung cancer, Zhao et al. ⁴⁵ decided to discontinue rapid-on-site evaluation (ROSE), adopting a direct-to-cell block approach. The diagnostic yield comparison was performed on a series of 734 patients (1097 cases with ROSE for 452 patients; 806 cases without ROSE but with direct-to-cell block for 282 patients). The inadequacy rate of EBUS-TBNA was 6.4% higher on average for cases with ROSE compared with a direct-to-cell block approach without statistical significance. The direct-to-cell block approach had no negative effects on cytopathology quality, then permitting to have diagnostic samples during the COVID-19 pandemic when shortage of staff and supplies have resulted in challenging re-organization of bronchoscopic procedures.

Stella et al. ⁴⁶ reported on a consecutive series of 229 patients presenting a peripheral lung mass suspected to be neoplastic undergoing CT scan-guided transthoracic fine needle aspiration biopsy (109 patients in the pre-COVID 19 pandemic, 120 patients during COVID-19). Quite unexpectedly, the authors did not observe significant differences in terms of diagnostic and complication rates.

Histology of SARS-CoV-2 infection in lung cancer specimens

A few cases of patients undergoing surgical resection to remove early-stage lung cancer showed ground glass opacities at CT scan and positivity for SARS-CoV-2 RT-PCR testing ^18-21. A brief summary of the main histologic changes reported in cases of lung cancer resection with SARS-COV-2 infection is presented in Table II. The most important issue in these cases relies on the possibility to observe early pathologic changes in live biopsies without confounding features related to therapies (i.e., ventilation, drugs), concurrent infections or autolytic phenomenon characterizing autopsies ¹¹.

Specimens from this specific setting of patients had no or limited clinical symptoms related to COVID-19 and developed respiratory failure later and finally die. These pre-symptomatic patients allow pathologists to observe histologic changes of pulmonary parenchyma (the most damaged organ in SARS-CoV-2 infection) at the earliest stages possibly permitting to understand the pathogenetic sequence of the disease.

In particular, Tian et al. ¹⁹ presented 2 patients (84-year-old woman and 73-year-old man with lung adenocarcinoma) undergoing surgery for lung cancer and incidentally discovered to have COVID-19 in which the non-neoplastic tissue showed alveolar edema with proteinaceous exudates, patchy fibrin plugs mixed with alveolar macrophages and lymphocytic inflammatory infiltrate. The alveolar walls or septa were expanded by proliferating fibroblasts with parallel type II pneumocyte hyperplasia. Of note, no neutrophilic infiltration or hyaline membrane was present at this early stage.

Zeng et al. ¹⁸ reported a case of meningothelial-like nodule surgically-resected in a 55-year-old non-smoking woman rapidly developing lymphopenia with fever and positive PCR for SARS-CoV-2. In the lung parenchyma there were histologic features consistent with COVID-19 in its early phases, predominantly characterized by exudative inflammation. The visceral pleura, there was severe exudation of monocytes and lymphocytes. The inflammatory cells were discovered around small blood vessels, surrounding alveolar septa with widened alveolar septa, hyperemia and dilation of capillaries. In the alveolar spaces, there were many monocytes, a few lymphocytes, and few multinucleated giant cells. Of note, neither fibrinous exudate nor hyaline membrane formation were present, while patchy focal hyperplasia of type II pneumocytes was present.

Cai et al. ²⁰ focused their attention to the impact of coronavirus disease 2019 (COVID-19) on lung cancer resections, since 7 among 139 patients they operated at the beginning of pandemic were positive for COVID-19. Lymphopenia often occurred immediately after lung surgery and was considered a sign of SARS-CoV-2 infection. Besides that, the main histologic features in non-neoplastic parenchyma consisted of alveolar macrophages no obvious hyaline membrane and very limited inflammatory infiltrate and/or pneumocytic hyperplasia, basically demonstrating a significant different histologic background if compared to what reported in autoptic specimens.

The authors reported 3 deaths (42.8%) related to COVID-19 infection, leading them to conclude that “lung resection surgery might be a risk factor for death in patients with COVID-19”, possibly related to the immunosuppressive state, but little was detailed on pathologic changes In addition, some cases overtly showed confounding histologic features related to obstructive pneumonia secondary to lung cancer, common interstitial diseases as smoker-related interstitial fibrosis and other co-morbidities (e.g., vascular hypertension, metabolic systemic diseases) that obviously obscured appreciation of specific histologic changes due to SARS-CoV-2 infection.

Supporting this assumption, Tien et al. ¹⁹ and Zeng et al. ¹⁸ reported as specific findings of SARS-CoV-2 the presence of “alveolar large protein globules” that instead are very common and non-specific findings known as “corpora amylacea”.

Pernazza et al. ²¹ described a 61-year-old male, smoker, with lung adenocarcinoma and a previously treated MALT-type lymphoma, developing lymphopenia and fever after surgery and testing positive for SARS-CoV-2 at pharyngeal swab PCR. Histologic examination of lung non-neoplastic lung parenchyma showed diffuse alveolar hemorrhage and alveolar macrophages with scattered giant cells. Alveolar damage with pneumocyte hyperplasia and scanty fibrin deposition in absence of hyaline membrane were noted. The interalveolar interstitial spaces were characterized by edema and mild inflammatory infiltrate with predominance of CD8 + cytotoxic T lymphocytes, while perivascular neutrophil margination around small arterioles and scattered fibrous plugs were also observed.

Based on these few examples of early COVID-19 observed in asymptomatic patients undergoing lung surgery for cancer or benign lesions, the pathophysiology of SARS is related to dysfunction of the immune system, including hyperinduction of chemokines and cytokines, an abnormal cellular immune response. A dysfunctional immune system with consequent hyperactivation of chemokines, cytokines, an exaggerated storm-like cellular immune response characterizes the pathogenesis of COVID-19, as previously observed in SARS. SARS-CoV-2 seem to directly attack epithelial cells, leading to hyperplasia of type II pneumocytes as well as endothelial cells. The inflammatory cells are mainly T lymphocytes and monocytes/macrophages causing abnormal release of cytokines with a redistribution of CD4+ lymphocytes (reduction in peripheral blood). In a previous series of transbronchial biopsies from paucisymptomatic patients with SARS-CoV-2 infection, Doglioni et al. ⁸ showed “patchy” distribution of alveolar epithelial type II cells hyperplasia, ranging from cases with isolated small clusters of hyperplastic pneumocytes to wide proliferation of micro-nodular and/or pseudo-papillary sprouts, interposed to variable proportions of normally looking type-I pneumocytes in early phases of the disease. No hyaline membranes were present, while alveolar epithelial changes were associated with congestion of interstitial capillaries leading to colander-like arrangement, dilatation and tortuosity of post-capillary venules showing thickened, edematous walls, without overt vasculitis or endothelialitis. Peri-vascular CD3 + lymphocyte infiltrates and irregular clusters of “unusual” CD14 + mononuclear myeloid cells were demonstrated within alveolar spaces, characterized by small size and heterogeneous nuclear shape.

Conclusion

During COVID-19 pandemic, most national health systems recommended cancellation of elective surgery aimed at increasing the bed capacity, permitting to have supplies of personal protective equipment, protecting and dedicating health-care workers in intensive care units. This approach necessarily resulted in delayed diagnoses, higher advanced stage, lower rate of surgical interventions and higher use of immune-chemotherapy and stereotactic treatments. However, these differences between pre-pandemic and pandemic periods were not equally distributed worldwide, since some national health systems had no detrimental impact or limitations in advanced lung cancer management. Since respiratory failure is the leading cause of death in patients with COVID-19 and little is known on the interaction between viral damage and host response at the lung tissue level, surgical resection of limited-stage NSCLC or benign neoplasm in patients incidentally discovered to have SARS-CoV-2 gave the pathologist an opportunity to examine the early phases of COVID-19. Indeed, early phase of SARS-CoV-2 infection does not match entirely with typical diffuse alveolar damage, as evidenced in post-mortem analysis.

In addition, this “unique” and not-autolytic tissue permitted to investigate by in-situ molecular analyses (immunohistochemistry, in situ hybridization) the site of lung alterations and the immune characteristics of various cells involved in this complex scenario driven by derangement of the cross-talk between innate and adaptive immune mechanisms triggered by viral infection, including infected pneumocytes, endothelial cells and specialized monocytes (CD14 +, CD16 +, IL-6 +).

ACKNOWLEDGEMENTS

None.

CONFLICTS OF INTEREST

All authors declare no competing interests in connection with this article.

FUNDING

No funding source were applied with this article.

AUTHORS’ CONTRIBUTIONS

All authors contributed equally to the conception, drafting, and editing of the manuscript.

ETHICAL CONSIDERATION

Ethical approval was not sought due to the non-experimental nature of the present work.

Figures and tables

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