Pulmonary Function in Patients With Multiple Endocrine Neoplasia 2B

Abstract

Context

Multiple endocrine neoplasia type 2B (MEN2B) is a rare cancer predisposition syndrome resulting from an autosomal-dominant germline mutation of the RET proto-oncogene. No prior studies have investigated pulmonary function in patients with MEN2B.

Objective

This study characterized the pulmonary function of patients with MEN2B.

Design

This is a retrospective analysis of pulmonary function tests (PFTs) and chest imaging of patients enrolled in the Natural History Study of Children and Adults with MEN2A or MEN2B at the National Institutes of Health.

Results

Thirty-six patients with MEN2B (18 males, 18 females) were selected based on the availability of PFTs; 27 patients underwent at least 2 PFTs and imaging studies. Diffusion abnormalities were observed in 94% (33/35) of the patients, with 63% (22/35) having moderate to severe defects. A declining trend in diffusion capacity was seen over time, with an estimated slope of −2.9% per year (P = 0.0001). Restrictive and obstructive abnormalities were observed in 57% (20/35) and 39% (14/36), respectively. Computed tomography imaging revealed pulmonary thin-walled cavities (lung cysts) in 28% (9/32) of patients and metastatic lung disease in 34% (11/32) of patients; patients with metastatic lung lesions also tended to have thin-walled cavities (P = 0.035).

Conclusions

This study characterized pulmonary function within a MEN2B cohort. Diffusion, restrictive, and obstructive abnormalities were evident, and lung cysts were present in 28% of patients. Further research is required to determine the mechanism of the atypical pulmonary features observed in this cohort.

Multiple endocrine neoplasia type 2B (MEN2B) is a rare disorder caused by an inherited, autosomal dominant germline mutation of the RET proto-oncogene that occurs with an incidence of approximately 1.4 to 2.6 per million births (1). MEN2B is characterized by the development of medullary thyroid carcinoma (MTC) early in life in 100% of patients, accompanied by ~50% lifetime risk of pheochromocytoma (2,3). MEN2B is further distinguished by phenotypic abnormalities including mucosal neuromas, megacolon with gastrointestinal discomfort, diarrhea, and/or constipation. Skeletal abnormalities are common and include marfanoid habitus, kyphosis, scoliosis, lordosis, joint hypermobility, pes cavus, pectoris excavatum, high-arched palate, and slipped capital femoral epiphysis (4,5).

We characterized the lung function in patients with MEN2B utilizing serial pulmonary function tests (PFTs), and available chest computed tomography (CT) imaging. We investigated the correlation of the functional pulmonary findings with body habitus using body mass index (BMI), scoliosis quantified by lateral spine curvature, tyrosine kinase inhibitor (TKI) exposure, and cancer burden. Each of these variables are prevalent in the MEN2B population and have been previously associated with pulmonary abnormalities (6-9).

Patients and Methods

We performed a retrospective review of all patients enrolled in the Natural History Study of Children and Adults with MEN2A or MEN2B (NCT01660984) at the National Institutes of Health between June 2009 and May 2019. The study was approved by the National Cancer Institute Institutional Review Board, and patient consent or child assent/parental consent was appropriately obtained. A MEN2B diagnosis was confirmed by genetic analysis of the RET proto-oncogene; all patients had the M918T genotype. Of the 45 subjects enrolled with MEN2B, 36 had at least 1 completed PFT and corresponding blood tests. A review of clinically indicated radiographic imaging of the lungs and spine was also considered when available. All subjects had sufficient medical history records regarding oncologic history and body habitus.

PFTs

All PFTs were performed in the Pulmonary Function Laboratory of the National Heart, Lung, and Blood Institute at the National Institutes of Health, using the VMAX™ Encore PFT system, software v. 21.1A (CareFusion Corporation, San Diego, CA, US) as part of an annual evaluation of participants in the above protocol. American Thoracic Society/European Respiratory Society guidelines were followed (10-12). Data were obtained from spirometry, including forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC); lung volume, total lung capacity (TLC), and carbon monoxide diffusion capacity (DLCO) were also analyzed. PFT abnormalities were classified as restrictive (normal FEV1/FVC and low TLC), obstructive (low FEV1/FVC and normal TLC) or mixed (low FEV1/FVC and reduced TLC) according to the American Thoracic Society Task Force guidelines. A low value was defined as below the lower limits of normal. The percentage reference values were derived from adjustments for age, sex, race, and height. The severity of spirometry abnormality based on the FEV1 percent reference was characterized as normal (FEV1% ref >80), mild (FEV1% ref >70), moderate (FEV1% ref 60-69), moderately severe (FEV1% ref 50-59), severe (FEV1% ref 35-49 ,or very severe (FEV1% ref <35). Diffusion abnormalities were graded as follows: normal (DLCO percentage [DLCO%] ref >70), mild (DLCO% >60 and <70), moderate (DLCO% ref 40–59), and severe (DLCO% ref <40) (13). The DLCO was adjusted for hemoglobin; diffusing capacity of the lung (DL) adjusted percentage (DLadjusted%) reference and DLCO% reference were also used in correlation analysis.

Normal spirometric values were based on the third National Health and Nutrition Examination Survey (NHANES III) population study, which sampled African Americans, Mexican Americans, and Caucasians, aged 8 to 80 (14). Using age, height, gender, and race/ethnicity, Hankinson et al derived reference equations for the NHANES III data set. For children under 8 years, the National Heart, Lung, and Blood Institute pulmonary function laboratory used the reference equations by Wang et al for spirometry (15). If the subject’s measured value was above the lower limits of normal, the measurement was considered normal (13).

Diffusion levels were measured via a single breath technique in accordance with the American Thoracic Society and European Respiratory Society Task Force (13). During the period of data collection for this study, the diffusion reference set published by Crapo and Morris was applied to individuals ≥18 years of age (16). This reference set had been included in 2005 American Thoracic Society/European Respiratory Society Interpretation Guidelines (13). While for children less than 18 years old, the lab used a reference set derived from Montreal Children’s Hospital. If the reference set did not provide a lower limit of normal, measurements ≥80% of predicted were considered normal.

Radiology

Seven patients without adequate imaging were excluded from evaluation of scoliosis; of these, 3 were also excluded from pulmonary radiographic evaluation because CT chest images were not indicated for their care. For the spine curvature studies, the most recent axial CT chest, abdomen, and pelvic images were selected, and extent of spine malformation was estimated by using Cobb angle calculations. In cases where scoliosis was surgically corrected, the scan immediately preceding the intervention was evaluated. The PACS Cobb angle measurement tool (Carestream Health, Rochester, NY, US) was utilized on coronal reformations by selecting the endplate of the most tilted vertebrae above and below the apex of the spinal curvature, ensuring approximation to the superior and inferior aspects of the vertebral body, respectively. Each investigator independently selected the end vertebrae of the curve, and lateral convexity deviation was noted. While plain radiographs are typically used in the diagnosis of scoliosis, CT images provide the same information, while adding 3-dimensional structure details; therefore, the image modality used here is not considered a major limitation in this study (17).

For the lung-specific review, all available CT images were reviewed, and cases that were suspicious for pulmonary abnormalities were noted. Subsequently, the cases were classified by thin wall cavities (lung cysts) as few (ranging from 1 to 6) or too numerous to count; the pulmonary abnormalities were further classified as thin- (<2 mm) or thick-walled cavities and compared qualitatively over time when sequential imaging was available. Metastatic MTC to the lung was denoted as present or absent.

Statistical analyses

Mixed modeling regression was used to determine the relationship of DLCO% reference and DL percentage reference as compared to BMI, log of calcitonin levels, presence of radiographically evident lung abnormalities, and patient age at time of evaluation. Length of time on study was added to this model to adjust for the strong decreasing trend in DLCO over time. To further study this decrease in DLCO over time, a broader analysis was conducted that included TLC.

Lateral spine curvature was measured at 1 time point; therefore, tests were run twice against the Cobb angle using PFT data at the earliest and latest test date. The Cochran-Armitage test was used to evaluate diffusion abnormality in those with a Cobb angle ≥10° compared to patients with a Cobb angle <10°, while the Fisher’s exact test and Cochran-Armitage test were used to test restrictive and obstructive differences between these 2 groups.

Results

There were 18 males and 18 females included on this study, the average age was 17.7 years old (range 5-35) at time of first PFT evaluation (Table 1). Nine patients had a history of pheochromocytoma. Thirty-two patients had metastatic MTC with 31 patients having involvement of the lymph nodes/neck, 7 patients with bone lesions, 11 with pulmonary lesions, and 11 patients with liver metastasis. Median calcitonin was 1020 pg/mL with a range of <5 pg/mL to 57 839 pg/mL. Treatment history included 22 TKI naïve patients, and 14 patients with TKI exposure either prior or currently; 10 patients were treated only with vandetanib, 1 was treated only with cabozantinib, and 3 patients had a treatment history that included both drugs. Most patients had no pulmonary symptoms, and all patients maintained normal oxygen saturation (≥95%) levels at the time of PFT evaluation. One patient (patient #13; see Table 2) had a history of childhood asthma but had not required any treatment in the 4 years prior to this study.

Table 1.

Selected characteristics for 36 patients with MEN2B

Sex	18 F, 18 M
Age (years)	17.6 (5 to 35)
BMI	17.1 (10.4 to 33.5)
Calcitonin (pg/mL)	1020* (<5 to 57 839)
Hemoglobin (g/dL)	14.3 ± 1.6
CEA (ug/L)	15.8a (0.4 to 867)
TKI exposed vs TKI unexposed	14 vs 22
Pulmonary function parameters		Percentage predicted normal
FVC (L)	3.36	80 ± 17
FEV1 (L)	2.69	76 ± 18
FEV1/FVC (%)	—	82 ± 12
TLC (L)	4.51	84 ± 13
RV (L)	1.10	81 ± 33
RV/TLC (L)	23.94	105 ± 46
DLCO (mL/min/mmHg)	21.02	62 ± 12
DL	20.71	61 ± 12
DLCO/VA	5.42	83 ± 14
DL/VA (mL/min/mm Hg/L)	5.00	81 ± 13

Abbreviations: BMI, body mass index; CEA, carcinoembryonic antigen; DL, diffusing capacity; DLCO, diffusing capacity for carbon monoxide; DLCO/VA, diffusing capacity for carbon monoxide divided by alveolar volume; DL/VA, diffusing capacity/alveolar volume; FEV1, forced expiratory volume in 1 sec; FVC, forced vital capacity; MEN2B, multiple endocrine neoplasia type 2B; RV, residual volume; TKI, tyrosine kinase inhibitor; TLC, total lung capacity.

^aMedian.

Table 2.

Characteristics and pulmonary function test results in patients with multiple endocrine neoplasia type 2B

ID	Sex	Age	Metastatic Disease	TKI Exposed	PHEO	Cobb Angle	Lung Imaging	PFT
								Diffusiona	Spirometric abnormalityb
1	M	25	Bone; LN/neck; liver	Yes	Yes	11°	TWC	2	2
2	F	16	LN/neck; bone	Yes	No	<10°	Normal	2	3
3	F	24	LN/neck	Yes	Left	42.1°	TWC	1	0
4	M	17	Prostate	No	No	<10°	Normal	1	0
5	F	18	LN/neck; brain; lung	Yes	No	<10°	Metastatic lesions	2	4
6	F	21	LN/neck; lung	Yes	No	<10°	TWC, Metastatic lesions	3	4
7	F	16	Bone; liver, LN/neck	Yes	No	<10°	Normal	2	0
8	F	16	LN/neck	No	No	<10°	Normal	2	0
9	M	20	LN/neck	No	Bilateral	31.1°	Normal	2	0
10	F	21	LN/neck; mediastinum lung	Yes	No	<10°	TWC, Metastatic lesions	2	0
11	F	20	Lungs; liver; bone; LN/neck	No	Bilateral	<10°	TWC, Metastatic lesions	2	3
12	F	15	LN/neck, liver	No	No	Excluded	Normal	0	0
13	M	16	Prostate; brain; liver; bone; LN/neck	Yes	No	<10°	Normal	2	3
14	M	17	LN/neck	No	No	Excluded	Excluded	2	0
15	F	15	LN/neck	No	No	12.6°	Normal	1	0
16	F	17	LN/neck; lung	No	Left	<10°	TWC, Metastatic lesions	0	0
17	F	14	LN/neck	No	No	Excluded	Excluded	0	0
18	M	17	No	No	No		Normal	2	0
19	M	31	LN/neck	No	No	<10°	Normal	1	2
20	M	17	LN/neck	No	Left	11.4°	Normal	1	0
21	M	15	Lungs; LN/neck; mediastinum	Yes	No	<10°	Metastatic lesions	1	0
22	M	15	Liver; bone; LN/neck	Yes	No	<10°	Normal	2	0
23	F	11	Lungs; LN/neck; liver; pancreas/mediastinumbone	No	No	11.3°	Metastatic lesions, TWC	2	3
24	M	17	Liver; LN/neck	No	No	Excluded	TWC	0	0
25	F	9	LN/neck	No	No	<10°	Normal	2	0
26	M	11	LN/neck	No	No	<10°	Normal	1	0
27	M	18	LN/neck	No	No	<10°	Normal	1	0
28	M	19	LN/neck; lung	Yes	No	14.6°	Metastatic lesions	2	0
29	F	15	LN/neck	No	Right	Excluded	Normal	2	3
30	M	21	Lung, LN/neck, bone	Yes	No	<10°	Metastatic lesions, TWC	2	0
31	F	16	LN/neck; lung; liver	Yes	No	15.3°	Metastatic lesions	2	4
32	M	5	No	No	No	Excluded	Excluded	0	0
33	F	12	Retro-peritoneum liver, axillae; LN/neck	Yes	No	13.7°	Normal	Ex	3
34	M	9	No	No	No	Excluded	Excluded	1	0
35	F	35	No	No	Bilateral	<10°	Normal	2	0
36	M	32	LN/neck; lung; liver	No	Left	<10°	Metastatic lesions	1	0

Age is at first PFT evaluation. Normal spine = lateral spine curvature ≤10 degrees.

Abbreviations: F, female; LN, lymph node; M, male; MTC, medullary thyroid carcinoma; Pheo, pheochromocytoma; TKI, tyrosine kinase inhibitor; TWC (lung cysts), thin-walled cavity.a

^aFor diffusion defect: 0 = no defect; 1 = mild defect; 2 = moderate defect; 3 = severe defect; 4 = severe defect.

^bFor FEV1 (spirometry): 0 = normal; 1 = mild; 2 = moderate; 3 = moderately severe; 4 = severe; 5 = very severe defect.

PFTs and diffusion tests

Thirty-six patients were selected based on the availability of PFTs (Table 2); 27 patients (75%) underwent at least 2 PFTs and imaging studies. One subject declined participation to the lung volume measurements. The median interval between consecutive studies was 12 months, 49% of patients had their follow up study at 10 to 14 months, with a range of 1 to 70 months (N = 59). Pulmonary function is shown by the mean of all data points: FVC of 80% ± 17, FEV1 of 76% ± 18, FEV1/FVC of 82% ± 12, TLC of 84% ± 13, RV of 81% ± 33, and RV/TLC of 105% ± 46. Diffusion abnormalities were observed at some point in 94% (33/35) of the patients, with 63% (22/35) having moderate to severe defects; at most recent testing, 83% (29/35) had some impairment. Restrictive and obstructive abnormalities were observed in 57% (20/35) and 39% (14/36) of this cohort, respectively. Computed tomography imaging revealed pulmonary thin-walled cavities in 28% (9/32) of patients and metastatic disease in 34% (11/32); patients with metastatic lung lesions tended to have concurrent lung cysts (P = 0.035).

Patients 18, 32, 34, and 35 had thyroidectomies at birth and had no evidence of metastatic disease at the time of our study. Patients 18 and 35 were included in the lung radiographic evaluation and did not have evidence of lung abnormalities. Patients 32 and 34 were excluded from lung radiographic imaging because it was not relevant to their care. Patients 18 and 35 (17 and 35 years old, respectively) had diffusion defects that fell in the moderate category (DLCO 40%-60%). Patient 34 (9 years old) had a mild diffusion defect. Patient 32 (5 years old) had normal diffusion. All of these patients had normal FEV1 spirometry results (FEV1% ref >80).

Diffusion abnormalities were evident in 94% (33/35) over the course of the study. At the time of most recent testing, 10 patients (29%) had mild defects, 19 (54%) had moderate defects, and 1 patient (3%) had a severe diffusion abnormality (Table 3). Overall diffusion impairment was demonstrated by DLCO% reference of 62 ± 12, DLadjusted% reference of 61% ± 12, DLCO adjusted for volume percentage (DLCO/VA%) reference of 83% ± 14, and DL/alveolar volume (VA) adjusted percentage reference of 81% ± 13. Length of time on study was associated with a strong decreasing trend in DLCO % reference, with an estimated slope of -2.9% per year (P = 0.0001). This change over time showed a negative slope in most patients, but a fraction had improvement in DLCO. The DL adjusted percent reference was strongly correlated with the DLCO percent reference (Pearson and Spearman correlation = 0.97, unadjusted for correlated values from the same patients). Consequently, DL adjusted % reference also showed a decreasing trend of -2.8% per year (P = 0.0003).

Table 3.

Diffusion abnormalities by DLCO and FEV1

Scale	Patients (n)
	TKI+	TKI−
DLCO
Normal	0	5
Mild (DLCO >60%)	2	8
Moderate (DLCO 40-60%)	10	9
Severe (DLCO <40%)	1	0
FEV1 % ref
Normal (FEV1 >80)	7	18
Mild (FEV1 >70)	0	0
Moderate (FEV1 60-69)	1	1
Moderately severe (50-59)	3	3
Severe (35-49)	3	0
Very severe (<35)	0	0

For diffusion defect: 0 = no defect; 1 = mild defect; 2 = moderate defect; 3 = severe defect; 4 = very severe defect.

For FEV1 (spirometry): 0 = Normal; 1 = Mild; 2 = Moderate; 3 = Moderately severe; 4 = Severe; 5=Very severe.

Abbreviations: DLCO, diffusing capacity for carbon monoxide; FEV1, forced expiratory volume in 1 sec.

A broader analysis was conducted to investigate possible contributing factors in the dataset that might account for this trend in DLCO percent reference. Patients with greater TLC % reference were less likely to show large negative slopes. The TLC % reference was strongly correlated with the DLCO percent reference (linear regression slope 0.45 ± 0.12, P = 0.0002). No noteworthy trends were observed between DLCO and FEV1/FVC ratio or as a function of age of subject during the PFT.

The TLC percent reference also correlated strongly with the FVC pre percent reference and the FEV1 pre percent reference values (unadjusted correlation coefficients close to 0.75) and all three of these factors were strongly associated with DL adjusted percent reference (p<0.0001 for each). All three factors, FEV1 pre percent reference, the FVC pre percent reference and TLC percent reference were tested in one linear regression model for association with DL adjusted percent, and it was found that FVC pre % reference had a strong association (slope 0.27 ± 0.13, P = 0.038), TLC ref had a weaker association (P = 0.14) and FEV1 pre % ref had very little independent association (P = 0.97).

DLCO % reference correlated poorly with BMI (P = 0.28) [Fig. 1A], while decreasing DLCO % and DL % references correlated with calcitonin levels (P = 0.034 and P = 0.1, respectively) [Fig. 1C]. Adjusting for the length of time on study in this model weakens the correlation of DLCO% and DL % to calcitonin levels (P = 0.18 and P = 0.41, respectively).

Figure 1.

Correlative tests and variance over time, which demonstrate (A) DLCO% reference as compared to BMI (B) change in BMI over time per patient, (C) DLCO% reference as compared to calcitonin levels (pg/mL) (P = 0.034) and (D) the DLCO% reference change over time per patient; broader analysis showed that patients with higher TLC were less likely to have negative slopes.

Males were found to have slightly higher FVC than females at baseline (medians 87 and 81, respectively, P = 0.036) and slightly higher FEV1 (84 vs. 72.5, P = 0.056). However, there is less difference in the FEV1/FVC (83.5 vs. 86, P = 0.15). There is no apparent difference between males and females in the severity of diffusion abnormalities. The trend in DLCO % reference of -2.9% per year is more negative in females than in males however the standard error is large, so this is consistent with random variation. There is no evidence that sex affects the DLCO % reference vs BMI relationship.

Prior or current use of TKI affected the DLCO % reference (estimated mean 66% without TKI use vs. 58% with TKI use, P = 0.032) when tested as a single factor; however, adjustment for the general downward trend over length of time on study resulted in a nonsignificant association (P = 0.21).

Radiology

Of the 36 patients reviewed for this study, 32 patients had adequate imaging for evaluation of the lungs and 29 patients had adequate imaging for scoliosis evaluation. Available chest CT images were reviewed for evidence of lung metastasis and/or thin walled cavities/lung cysts (Fig. 2). Lung lesions were noted in 34% of patients (11/32), and thin walled cavities were seen in 28% of patients (9/32). Six of the 11 patients (55%) with lung metastasis also had thin walled cavities; conversely, 3 of the 21 patients (14%) without lung metastasis had thin walled cavities (P = 0.035 by Fisher’s exact test). While we can’t completely exclude the possibility that the blebs are metastases, after extensive review of the sequential imaging extensively we feel that the blebs/cysts are less likely to be metastatic disease.

Figure 2.

(A) Axial CT image of pulmonary thin-walled cavities. (B) Coronal maximum intensity projection reformation showing lateral spine curvature.

Of the 29 patients included for spinal analysis, 10 (34%) had Cobb angles ≥10° and were included for the spine curvature sub-analysis. This sub-cohort resembled the patients with Cobb angles <10° in all characteristics except for tending toward lower BMIs. This group had a slightly steeper estimated decline in DLCO % reference over the study time length (-3.7% per year, P = 0.0035). The presence of moderate to severe diffusion abnormalities showed no association with Cobb angle variation (P = 1.0 by the Cochran-Armitage test for trend).

Patients with scoliosis tend to have slightly higher levels of the most severe DL/VA percentage reference values with an estimated median difference of 7, but not conclusively so (P = 0.18). One patient eligible for scoliosis evaluation (Table 2; patient #33) declined to participate in the diffusion testing.

Discussion

Various phenotypic features of MEN2B have been reported including early-onset MTC, mucosal neuromas, and asthenic “marfanoid” body habitus (18). However, there is no description of the pulmonary system in patients with MEN2B. This study evaluated lung function and anatomy using PFTs and available CT images. Restrictive and obstructive abnormalities were observed in 57% (20/35) and 39% (14/36) patients, respectively. Diffusion capacity declined over time in most patients. While we can tentatively rule out some potential underlying etiologies for these abnormalities in pulmonary function, a singular mechanism is not apparent. Marfanoid body habitus, TKI exposure, and cancer burden were identified as 3 prevalent variables in patients with MEN2B that have been independently linked to diminished lung function in prior studies (9). Within this cohort, body habitus and spine curvature appeared to correlate with PFTs while TKI exposure and cancer burden as measured by calcitonin levels had questionable correlation with diffusion and no correlation with restrictive or obstructive findings.

Skeletal abnormalities: spinal deformities and marfanoid habitus

Carney et al reported 26% of 21 patients with MEN2B had either kyphoscoliosis or lordosis, while ~75% of patients had marfanoid habitus as well as proximal muscle wasting and weakness (19,20). Spinal anatomy can impact lung function and cause restriction that manifests as decreased TLC (21). Severe scoliosis can distort the thoracic space, which limits lung development and/or mechanically compromises lung tissue expansion (22,23).

Given the physical similarities between MEN2B and other connective tissue disorders such as Marfan syndrome, a genetic connective tissue component cannot be ruled out. For example, the thin-walled cavities seen on CT imaging have been observed in the Marfan population, described as bullae. Scoliosis is also commonly seen in both Marfan syndrome and MEN2B (24-26). Therefore, our study investigated the impact of spine curvature or body habitus on lung function in patients with MEN2B. It was noted that the DLCO percent reference declined over time in most patients; this was particularly pronounced in those with scoliosis (spine curvature ≥10°). The sub-cohort of patients with lateral spine curvature also tended to have worse restrictive disease. However, patients without spine abnormalities were also seen to have diffusion and restrictive abnormalities, which indicates that body habitus is not a sole determinant of lung function.

Tyrosine kinase inhibitor exposure

The American Thyroid Association guidelines recommend a total thyroidectomy within the first year of life, or as soon as possible following MEN2B diagnosis (18). When systemic therapies are indicated, TKIs are the treatment of choice. Approved TKIs include vandetanib, which selectively targets RET (proto-oncogene tyrosine-protein kinase receptor Ret), VEGFR-2 (vascular endothelial growth factor receptor), and EGFR (epidermal growth factor receptor), and cabozantinib, which targets RET (proto-oncogene tyrosine-protein kinase receptor Ret); MET (tyrosine-protein kinase Met or hepatocyte growth factor receptor [HGFR]); VEGFR-1, -2, and -3 (vascular endothelial growth factor receptor); KIT (KIT receptor tyrosine kinase); TrKB (Tropomyosin receptor kinase B); FLT-3 (fms-like tyrosine kinase 3); AXL (AXL receptor tyrosine kinase); and TIE-2 (TIE receptor tyrosine kinase) (27,28). Previous studies showed a correlation between vandetanib or cabozantinib exposure and pulmonary toxicity, including interstitial lung disease, dyspnea, and hypoxia (29,30). Bronte et al noted dyspnea in patients receiving cabozantanib during the treatment of MTC; of 219, 29 (13.6%) had dyspnea with 5 (2.3%) experiencing more severe grade 3 to 4 adverse events (31).

We investigated a possible correlation between TKI exposure and lung abnormalities within our patient cohort. The majority of patients did not endorse respiratory symptoms, irrespective of PFT result. Of the 2 symptomatic patients, one had a pre-existing history of asthma, and the other patient had metastatic lung disease. There were no adverse pulmonary events related to TKI use in our cohort of patients. Furthermore, our results showed no significant association of TKI exposure with the presence of radiographically evident pulmonary thin-walled cavities. Prior or current use of TKI was negatively correlated with the DLCO% reference when tested as a single factor; however, correction for the general downward trend over length of time on study resulted in a nonsignificant association. It is difficult to draw conclusions about the effect of TKI from our small analysis. No patient was initiated on TKIs during the period of PFT evaluations. A longitudinal pulmonary assessment that includes measurements with and without systemic therapy may lend further insight into affects TKIs may have on patients with MEN2B (Fig. 3).

Figure 3.

(A) Diffusion capacity of 35 patients (Patient #33 declined participation), measured by DLCO% reference, with distinction indicated between patients with TKI exposure vs naïve. (B) Restrictive capacity of 36 patients, measured by FEV1% reference.

Burden of MTC

Calcitonin is often used as a surrogate measurement of MTC disease burden, as the dedifferentiated cancerous parafollicular cells (C-cells) continue to produce calcitonin with growth of the disease. Patients with more advanced cancers can have ancillary symptoms including muscle wasting and weight loss, which can greatly impact the pulmonary function by affecting the muscularity of breathing. Our study investigated the relationship between calcitonin levels and PFT results to evaluate the possible correlation between cancer burden and pulmonary function. Decreasing DLCO% was correlated with increasing log (calcitonin levels) (P = 0.034), which is used as a surrogate to measure cancer burden. Future studies should investigate the impact of low muscle tone in patients with MEN2B on respiration capacities using the maximal inspiratory pressure, maximal expiratory pressure, and maximum voluntary ventilation.

Molecular mechanism: future studies

It is possible that there is an unidentified molecular mechanism arising from a germline RET mutation. RET is an important gene for the normal development of the kidney, enteric nervous system development, and spermiogenesis, with less clear implications in lung development (32,33). Avian models have demonstrated that RET staining becomes more prominent throughout development in the lung buds, in addition to the enteric nervous system (34-36). RET knockout mice have aganglionic gastrointestinal tracts, indicating a critical role in the establishment of the enteric neuronal lineage; however, they show no innervation abnormalities in the lung or rostral foregut (37-39). Burns et al used chimeric grafting to follow the development of the lung ganglia from the vagal neural crest cell and found expression of the transcription factor Sox10 and the receptors EDNRB and RET, as well as the RET co-receptor GFRα1. The authors suggested that at low levels of RET expression, the GFRα1 co-receptor may help to potentiate RET signaling, which would account for the appropriate innervation of the lung as compared to that in the aganglionic gut (40). It is possible that an aberration in this pathway is causing a subclinical yet atypical innervation pattern in the lung. Further study is warranted to explore the mechanism of pulmonary abnormalities seen in patients.

Clinical implications and conclusions

The clinical implications, if any, of these findings are unclear. Currently, it appears reasonable to obtain PFTs prior to initiating TKI therapy due to the previously reported potential negative impact on pulmonary function. From our sample, it appears that the thin-walled cavities are not qualitatively progressive; however, patients with this finding should be monitored for changes as clinically indicated.

Most prior literature related to pulmonary effects in patients with MTC cite case studies that explore respiratory difficulties on primary presentation or descriptions of cardiotoxic effects of TKI treatment studies for MTC, without a specific focus on the MEN2B subgroup. This study investigated pulmonary function in our cohort of young adult and pediatric patients with MEN2B. Our findings have potential implications on routine monitoring and pre-TKI treatment evaluation of patients with MEN2B.

Our study is limited in several ways. First, the longitudinal results do not include data regarding change in PFTs before as compared to after starting TKI treatment. Second, our data are limited to a small number of patients, many of whom are quite young. A small sample size is difficult to extrapolate to the larger MEN2B population. Furthermore, the younger patients may not produce reliable respiratory data due to the attention and physical force required to generate a quality PFT. Finally, there may be a time-dependent factor that accounts for these changes that was not assessed in our analysis. This is supported by our observation that seemingly correlating factors lose significance when adjusted for time, which may suggest that the original correlation was indirect.

Future study of the pulmonary changes in this cohort should include more functional assessments such as walk tests, sitting and supine spirometry, and respiratory muscle strength testing. Our study was not designed to determine the cause of diffusion capacity degeneration over time, and further investigation is warranted.

Additional Information

Disclosure Summary: The authors have nothing to disclose.

Data Availability: All data generated or analyzed during this study are included in this published article or in the data repositories listed in References.