Differences in pathological diagnoses between bronchoscopic tissue and resected specimens of non-small cell lung cancer: A retrospective single center study

doi:10.21203/rs.3.rs-4721952/v1

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Differences in pathological diagnoses between bronchoscopic tissue and resected specimens of non-small cell lung cancer: A retrospective single center study

https://doi.org/10.21203/rs.3.rs-4721952/v1

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Background

Immune checkpoint inhibitor (ICI) combination chemotherapy has been used as preoperative and postoperative treatment for resectable non-small cell lung cancer. Programmed cell death protein-1 (PD-L1) is a biomarker that predicts the therapeutic effect of ICIs. In lung cancer, it is evaluated using the Tumor Proportion Score. Tumors are heterogeneous, and if the amount of collected tissue is small, the location of the tissue may affect the diagnosis. We evaluated the revision rate of the resected specimens and considered its impact on PD-L1 measurement.

Methods

Over 5 years, 237 cases of non-small cell lung cancer underwent surgery. Of these, 126 cases underwent preoperative bronchoscopy. Bronchoscopy included forceps biopsy, brushing, and bronchoalveolar lavage. Endoscopic ultrasound was used for peripheral lesions. Cases in which cancer was diagnosed from bronchoscopic specimens were considered to have a definitive diagnosis. Simultaneous multiple small cell and non-small cell lung cancer were identified. Cases of small cell lung cancer were excluded from analyses.

Results

Bronchoscopy diagnosed cancer in 45.2% of cases. The revision rate of pathological diagnosis in resected specimens was 10.5%. Cases diagnosed as adenosquamous carcinoma, large cell neuroendocrine carcinoma, large cell carcinoma, spindle cell carcinoma, or pleomorphic carcinoma in resected specimens may have been revised from the diagnosis based on preoperative bronchoscopic specimens. In this study, 19.8% of cases were pathological stage 0-IA2 with T factors 2 cm or less, and the diagnostic rate by bronchoscopic examination was low at 16%. PD-L1 testing was measured in 11 cases using bronchoscopic specimens, one of which could not be measured because there was no evaluable tumor.

Conclusions

In this study, the pathological revision rate was 10.5% when comparing preoperative bronchoscopic specimens with resected specimens, which may have had an impact on PD-L1 evaluation.

Bronchoscopy

Surgery

Non-small cell lung cancer

Programmed death-ligand 1

Immune checkpoint inhibitors (ICIs) have been used as neoadjuvant and adjuvant treatments for resectable lung cancer (1, 2). The CheckMate 816 Clinical Trials showed that nivolumab combined chemotherapy improved the long-term clinical outcomes of patients with resectable stage IB to IIIA non-small cell lung cancer (NSCLC) compared with chemotherapy alone (hazard ratio for disease recurrence or death = 0.63), and the pathological complete response rate was 24.0% (95% confidence interval 18.0–31.0) regardless of resection [1].

The IMpower010 study showed a disease-free survival benefit with atezolizumab as supportive therapy after adjuvant chemotherapy in patients with resected stage II-IIIA NSCLC, with a notable benefit in the subgroup of tumors expressing programmed cell death protein-1 (PD-L1) and with a Tumor Proportion Score (TPS) ≥ 1% [2]. Because ICI therapy is now incorporated into preoperative treatment, the importance of preoperative pathological diagnosis is gradually increasing. Furthermore, as the indications for ICI therapy expand, the importance of PD-L1 evaluation is also increasing.

The diagnostic yield of transbronchial lung biopsy (TBLB) for malignant diagnoses is 25.16% with a diagnostic accuracy of 87.74% [3]. Radial endobronchial ultrasound (R-EBUS) has a high diagnostic yield in peripheral lung lesions, particularly in those with malignant lesions > 2 cm that are associated with computed tomography (CT) endobronchial signs and in those where the R-EBUS probe is inserted within the lesion (as opposed to being adjacent to the lesion) [3]. However, the amount of tumor that can be extracted by bronchoscopy is smaller than that obtained by surgery.

The assessment of PD-L1 is essential when administering ICIs. At least 100 tumor cells are required to assess PD-L1 expression [4, 5], and PD-L1 expression may be underestimated in specimens older than 3 years [5, 6]. Therefore, it is important to perform the test at the appropriate time and with the appropriate tissue.

In our hospital, we have encountered cases in which the pathological diagnosis of the bronchoscopic specimen obtained preoperatively was revised in the resected specimen after surgery for NSCLC. We evaluated the revision rate of the resected specimens and considered its impact on PD-L1 measurement with a literature review.

Of 237 surgical cases diagnosed with NSCLC at our hospital between January 1, 2019 and December 31, 2023, 126 cases in which bronchoscopy was performed before surgery were included. Two cases in which bronchoscopy was performed at other hospitals were also included. Information was collected retrospectively from electronic medical records.

Two cases of simultaneous multiple lung cancer, small cell lung cancer and NSCLC, were identified. One of the cases was diagnosed with small cell lung cancer by preoperative bronchoscopic examination. In this case, a diagnosis of NSCLC was not obtained, so the preoperative diagnosis was deemed to be inconclusive because it was determined that only the components of small cell lung cancer were collected by bronchoscopy.

A flowchart of the cases is shown in Fig. 1. Cases diagnosed as cancer, regardless of histology, were considered diagnosed. Although the histological type of NSCLC was unknown, cases with a diagnosis of carcinoma were included in the group with a definite diagnosis. Suspected cases, and cases with an unclear diagnosis of benign or malignant cancer were classified as undiagnosed.

[Figure 1 near here]

Bronchoscopic equipment and specimen handling

The bronchoscope equipment used were an Olympus CV-290, Evis X1 CV-1500, BF-P290, and BF-1TQ290 manufactured by Olympus Corporation (Tokyo, Japan). Specimens collected with the use of a bronchoscope were immediately fixed in 10% neutral buffered formalin and used for pathological analysis. The pathology staff injected 10% neutral buffered formalin into specimens after we removed specimens, immediately.

Bronchoscopic biopsies were performed using different instruments and sampling methods: transbronchial biopsy forceps, transbronchial brush, and radial probe endobronchial ultrasound-guided transbronchial lung biopsy (EBUS-TBLB). Cases with a definite diagnosis were considered cancer based on cytology or histology.

PD-L1 evaluation method

PD-L1 testing was outsourced to an LSI Medience Corporation(Tokyo, Japan), and the antibody used was PD-L1 22C3 pharmDx.

The backgrounds of the patients in this study are shown in Table 1. Thoracoscopic surgery was performed in 88.9% (112/126) of cases, and 75% (9/12) of open chest surgery cases were treated before surgery. There were two other cases, one of which underwent bronchoscopic laser ablation, and the other underwent left cervical lymph node biopsy.

Table 1

Background of patients in this study.
Patient background	n = 126
Age, years	(Median)	73 (	49–90)
Sex	Male	73
	Female	53
Procedure	Lobectomy	110
	Segmentectomy	4
	Partial resection	8
	Others	4
Approach	VATS	112
	Thoracotomy	12
	Others	2
Complete resection	R0	100
	R1	10
	R2	14
	others	2
Pathological stage	0	8
8th Edition of the UICC	IA	24
	IB	20
	IIA	8
	IIB	29
	IIIA	14
	IIIB	8
	IIIC	1
	IVA	9
	IVB	3
Tissue type (surgical specimen)	Sq	28
	Ad	87
	AdSq	2
	Pleo	3
	LCNEC	2
	Large cell carcinoma	1
	Spindle cell carcinoma	1
	other	2
Recurrence	Yes	27
	No	84
Outcome	Survival	98
	Death from other illnesses	13
	Death from underlying disease	15
Observation period	(Median) Month	27	(0–59)
UICC: Union for International Cancer Control; AdSq: Adenosquamous carcinoma; LCNEC: Large cell neuroendocrine carcinoma; Ad: Adenocarcinoma; Sq: Squamoous cell carcinoma; Pleo: Pleomorphic carcinoma

Bronchoscopic examination provided a definitive diagnosis for 57 of 126 cases (45.2%). Bronchoscopic examination included three cases where it was difficult to determine whether the tumor was benign or malignant, one case where atypical cells were found, and one case where small cell lung cancer was diagnosed. Other details of resected pathology included two cases where no tumor cells were found because of preoperative treatment.

[Table 1 near here]

Of the 57 cases in which a pathological diagnosis was made by bronchoscopy, the diagnosis was revised in six cases (10.5%) based on the resection specimen (Table 2). There were two cases of squamous cell carcinoma to adenosquamous carcinoma (AdSq), one case of NSCLC to large cell neuroendocrine carcinoma (LCNEC), one case of adenocarcinoma to large cell carcinoma, one case of NSCLC to spindle cell carcinoma, and one case of squamous cell carcinoma (Sq) to pleomorphic carcinoma. Of the six cases in which the diagnosis was revised after surgery, two had PD-L1 assayed using bronchoscopic specimens, one of which ended in death from the underlying disease.

Table 2

A list of cases in which the diagnosis differed before and after surgery
Cases	Sex	Age (years)	Pathology (bronchoscopic)	Procedure	Postoperative pathology	TNM	Pathological stage	PD-L1(%) BF / Ope	R	Outcome
①	M	61	Non-small cell lung carcinoma	VATS LLL	Large cell neuroendocrine carcinoma	pT2aN0M0	IB	N / N	0	Alive
②	M	52	Non-small cell lung carcinoma	oRUL	Spindle cell carcinoma	ypT2bN0M0	IIA	100 / N	0	Alive
③	M	70	Squamous cell carcinoma	oRUL + Br plasty	Pleomorphic carcinoma	pT2bN1M0	IIB	N / N	0	Alive
④	F	67	Squamous cell carcinoma	VATS RLL	Adenosquamous carcinoma	pT4N0M0	IIIA	N / 1 ~ 24	0	Alive
⑤	M	71	Adenocarcinoma	VATS LUL	Large cell carcinoma	pT4N2M0	IIIB	N / 95	0	Alive
⑥	M	74	Squamous cell carcinoma	VATS RLL	Adenosquamous carcinoma	pT4N0M0	IIIA	1 ~ 24 / N	1	Death
TNM: Tumor, Nodes, Metastasis; VATS: Video-assisted thoracic surgery; LLL: Left lower lobectomy; oRUL: Open right upper lobectomy; Br plasty: Bronchoplasty; RLL: Right lower lobectomy; LUL: Left upper lobectomy; N: Not measured; BF: Bronchoscopy; Ope; Operation

[Table 2 near here]

The diagnostic yield by pathological stage using bronchoscopy is shown in Table 3. Of the 57 cases in which a diagnosis was obtained, cervical lymph node metastasis and LN#4R lymph node metastasis were classified as "other" because of postoperative recurrence or metastasis after treatment.

Table 3

Bronchoscopy diagnostic rate by pathological stage
Pathological stage	BF (%) n = 126
0	25 (2/8)
IA	16.7 (4/24)
IB	40 (8/20)
IIA	37.5 (3/8)
IIB	62.1 (18/29)
IIIA	71.4 (10/14)
IIIB	50 (4/8)
IIIC	0 (0/1)
IVA	55.6 (5/9)
IVB	33.3 (1/3)
0-IA2	16.0 (4/25)
IA3-IVB	51.5 (51/99)
Others^a	100 (2/2)
Total	45.2 (57/126)
^aTwo cases of recurrence and metastasis.
BF: Bronchoscopy

In our hospital, early lung cancer (p-Stage 0-IA2, with a tumor diameter 2 cm or less) accounted for 19.8% (25/126) of all cases, with a diagnosis rate of 16%. The diagnosis rate for cases of p-Stage IA3 or higher was 51.5%.

[Table 3 near here]

PD-L1 was measured in 60 cases overall: 11 from bronchoscopic specimens and 49 from resection specimens. The PD-L1 expression in bronchoscopic and surgical specimens is summarized in Table 4. PD-L1 could not be assessed by bronchoscopy in 9.1% (1/11) of cases because of the absence of assessable tumor cells. PD-L1 was assessable in all cases with surgical specimens.

Table 4

PD-L1 expression in bronchoscopic and surgical specimens.
PD-L1; TPS	BF (%) n = 11	Ope (%) n = 49
< 1%	0 (0/11)	20.4 (10/49)
1–49%	54.5 (6/11)	46.9 (23/49)
≥ 50%	36.4 (4/11)	32.6 (16/49)
No assessable tumor cells	9.1 (1/11)	0 (0/49)
TPS: Tumor Proportion Score; BF: Bronchoscopy; Ope: Operation
Among the 126 cases, there was no overlap in PD-L1 testing between bronchoscopic and surgical specimens. PD-L1 was measured in 11 bronchoscopic specimens and 49 surgical specimens.

[Table 4 near here]

The most common diagnostic methods for NSCLC are bronchoscopy, CT-guided needle biopsy, and surgery. Bronchoscopy, which is less invasive, is generally the first choice. CT-guided needle biopsy was associated with symptomatic air embolism in 0.08% of cases, and 32.7% of symptomatic patients with air embolism suffered from sequelae or died [7]. In addition, CT-guided needle biopsy for malignant lung tumors in contact with the pleura resulted in pleural dissemination in 11% of cases [8]. CT-guided needle biopsy for early-stage lung cancer is not generally chosen because of the risk of cancer dissemination, where complete surgical resection is impossible. Diagnosis by surgery requires general anesthesia, which has a mortality rate of 0.5% and frequency of complications of 9.6% [9]. The mortality rate of bronchoscopy is 0.003%[10], and that of CT-guided biopsy is 0.07% [11]. Surgical diagnosis is more invasive than bronchoscopy or CT-guided biopsy. Other complications specific to surgery include postoperative pain, pneumonia, pulmonary fistula, bronchial fistula, and lymphatic fistula.

Therefore, the indications for surgical biopsy are limited. Surgical biopsy is selected for patients in good general condition in cases where a diagnosis is difficult to achieve using bronchoscopy, CT-guided biopsy, and other minimally invasive tests such as sputum cytology and pleural effusion cytology. However, even if cancer is diagnosed by cytology, it may be difficult to assess PD-L1 expression or related genes because the amount of tumor cells is small. Although some diagnostic items can be tested using cell blocks from pleural effusion, they do not encompass the entire tumor, so they are not suitable for the accurate evaluation of the TPS. The diagnostic accuracy of TBLB and CT-guided biopsy for malignant tumors was reported to be 70.6–87.74% [6, 8] and 91.61% [6], respectively, whereas the diagnostic rate of surgery was reported to be 100% [9].

Bronchoscopy is less invasive than surgery and has a lower risk of cancer seeding and air embolism than CT-guided biopsy, but its diagnostic rate is lower. However, the diagnostic rate has been improved by ultrasound bronchoscopy, but it is difficult to diagnose cases in which the tumor is not exposed in the bronchus or small peripheral lesions.

In this study, the diagnostic rate of bronchoscopy was 45.2%. One of the reasons for the low diagnostic rate might be that, because surgical cases were the focus, many cases of early lung cancer and small peripheral lesions were included. The diagnostic sensitivity of peripheral lung cancer with a tumor diameter less than 2 cm was reported to be 34% [12]. In our hospital, early-stage lung cancer (p-Stage 0-IA2) accounted for 19.8% of all cases. All p-Stage 0-IA2 cases had tumors less than 2 cm in diameter, and the bronchoscopic diagnostic rate at our hospital was 16%. This rate is lower than the diagnostic rate of general bronchoscopic procedures.

In this study, the difference in diagnosis between bronchoscopic specimens and surgical biopsies was 10.5%. Adenosquamous carcinoma, large cell neuroendocrine carcinoma, large cell carcinoma, spindle cell carcinoma, and pleomorphic carcinoma exhibited heterogeneous histological images, which makes their accurate evaluation difficult by preoperative bronchoscopic examination.

Cancer is heterogeneous, and bronchoscopic specimens can only evaluate a small portion of the tumor; therefore, an accurate diagnosis cannot be made. Test items evaluated by TPS, such as PD-L1, cannot be evaluated correctly because only a portion of the tumor is reflected in tissues collected by bronchoscopic examination.

Previous studies reported no difference in the expression rate of PD-L1 before and after surgery [13–15]. The concordance rate of TPS between biopsy and surgical materials was reported to be 86.7% [16]. With heterogeneous tumor cell populations, it is difficult to evaluate the overall tumor picture by preoperative testing. In cases where preoperative and postoperative diagnoses differ, as in this study, the evaluation of PD-L1 may also change.

Depending on the histological type of tumor in which PD-L1 is measured, the entire tumor cannot be evaluated, so bronchoscopy may not be able to accurately evaluate the TPS. In addition, PD-L1 may not be evaluated if the amount of specimen collected is small. In this study, PD-L1 could not be measured in one case of bronchoscopic specimen. For resectable NSCLC, the most accurate method to accurately evaluate the TPS is the measurement of PD-L1 immediately after surgery in surgical specimens with a large tumor burden. Furthermore, even in cases where PD-L1 was measured preoperatively, cases with histological types such as AdSq, LCNEC, large cell carcinoma, spindle cell carcinoma, and pleomorphic carcinoma, the diagnoses may differ before and after surgery, and we think that PD-L1 should be reevaluated after surgery. In Case 6, if PD-L1 had been remeasured in the resected specimen, it might have influenced the outcome (Table 2).

Study limitations

Because this was a retrospective study, the suitability of bronchoscopy was left to the discretion of each attending physician, which may have resulted in bias. Because of the limitations in health insurance coverage in Japan, PD-L1 could only be measured once at our facility. Therefore, the change in PD-L1 before and after surgery could not be evaluated in this study. In addition, our hospital tended to have a higher proportion of early-stage lung cancer that was operable. Early-stage lung cancer includes peripheral lesions with a small tumor size, which may be involved in the reduced diagnostic yield of bronchoscopy. In addition, there were no cases diagnosed by endobronchial ultrasonography guided transbronchial needle aspiration, which may have affected the diagnostic yield.

Study advantages

Because the study was performed at a single facility, the equipment and personnel used were consistent, and it was possible to consistently follow the patients from bronchoscopy to surgery and throughout the postoperative course.

To date, there have been no reports on the appropriate timing for measuring PD-L1, with reference to the difference between diagnosis by preoperative bronchoscopy and postoperative surgical pathology. Testing at the appropriate time with the appropriate specimen is extremely important for the increasingly complex treatment of lung cancer, and will contribute to the personalized treatment of NSCLC.

In this study, 10.5% of cases with a diagnosis made by bronchoscopy had a different outcome when the diagnosis was made after resection. Tumor cells are heterogeneous, and it is difficult to accurately evaluate the overall tumor profile by bronchoscopic examination. This may have had a negative impact on the evaluation of PD-L1. Further investigation is needed.

ICIs

Immune checkpoint inhibitors

NSCLC

Non-small cell lung cancer

PD-L1

Programmed cell death protein-1

TPS

Tumor Proportion Score

TBLB

Transbronchial lung biopsy

R-EBUS

Radial endobronchial ultrasound

Computed tomography

AdSq

Adenosquamous carcinoma

LCNEC

Large cell neuroendocrine carcinoma

Reporting Checklist: The authors have completed the STROBE reporting checklist.

Ethics approval and consent to participate: The authors are accountable for all aspects of the work and ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the ethics committee of the Shimonoseki City Hospital (Japan; No.:2024SCHEC-017), and individual consent for this retrospective analysis was waived.

Consent for publication: Individual consent for this retrospective analysis was waived.

Availability of data and materials: Not applicable.

Competing interests: JY served as the principal investigator for Insmed Inc. and Janssen Pharmaceuticals. YN declare that they have no competing interests. YH declare that they have no competing interests. HM declare that they have no competing interests. MI declare that they have no competing interests.

Funding: None

Authors’ Contributions: MI conceptualized and designed the study. JY provided administrative support. MI provided study materials and patients. YH and HM collected and assembled the data. YN performed data analysis and interpretation. All authors contributed to manuscript writing. All authors read and approved the final manuscript.

Acknowledgements

We thank J. Ludovic Croxford, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

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No competing interests reported.

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Differences in pathological diagnoses between bronchoscopic tissue and resected specimens of non-small cell lung cancer: A retrospective single center study

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Background

Methods

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Background

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