Abstract
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare, but increasingly recognized entity that primarily affects middle-aged and elderly women. It is characterized by abnormal proliferation of pulmonary neuroendocrine cells (PNECs) and is considered a preinvasive lesion for carcinoid tumorlets/tumors. Sometimes, DIPNECH is accompanied by constrictive bronchiolitis which usually manifests as chronic cough and/or dyspnea, along with airflow limitation on spirometry. The telltale imaging sign of DIPNECH is the presence of multiple noncalcified pulmonary nodules and mosaic attenuation on CT. However, these clinico-radiologic features of DIPNECH are characteristic but nonspecific; thus, histopathologic confirmation is usually necessary. DIPNECH has an indolent course and only rarely leads to respiratory failure or death; progression to overt neuroendocrine tumor (carcinoid) of the lung occurs in a minority of patients. Of available therapies, somatostatin analogs and mechanistic target of rapamycin inhibitors are the most promising. In this review, we provide an update regarding the diagnosis and management of DIPNECH and describe critical gaps in our understanding of this entity, including the central terms ‘diffuse’ and ‘idiopathic.’ We also summarize the inconsistencies in definitions employed by recent studies and discuss the pitfalls of the DIPNECH definitions proposed by the World Health Organization in 2021. In this context, we propose an objective and reproducible radio-pathologic case definition intended for implementation in the research realm and seeks to enhance homogeneity across cohorts. Furthermore, we discuss aspects of PNECs biology which suggest that PNEC hyperplasia may contribute to the pathogenesis of phenotypes of lung disease aside from constrictive bronchiolitis and carcinoid tumorlets/tumors. Finally, we steer attention to some of the most pressing and impactful research questions awaiting to be unraveled.
Introduction
Pulmonary neuroendocrine cells (PNECs) constitute a minority of airway epithelial cells in the adult human lungs (Boers et al. 1996, Noguchi et al. 2020). PNECs are scattered throughout both lungs; they are mainly located within bronchial walls but can also be situated within bronchioles (i.e. small airways that lack cartilage and have an internal diameter of ≤2 mm) (Samhouri & Ryu 2023a ) and alveolar ducts (Boers et al. 1996, Noguchi et al. 2020).
The existence of PNECs was first described in 1949 (Frohlich 1949). For decades following, the function of PNECs remained unknown, and neuroendocrine cell hyperplasia (NECH) was considered a merely adaptive response to noxious stimuli (e.g. tobacco smoking), physiologic stressors (e.g. high altitude), and chronic lung diseases (Aguayo et al. 1992, Boers et al. 1996, Garg et al. 2019). Recent studies have shown that PNECs serve vital functions (e.g. oxygen sensing, chemo/physical sensing, tissue repair, immunomodulation), sparking interest in their potential etiological role in pulmonary ailments including cancer (Aguayo et al. 1990, Aguayo 1993, Garg et al. 2019, Noguchi et al. 2020, Andersson-Rolf et al. 2021).
In 1992, Aguayo et al. (1992) described six cases with multifocal NECH in conjunction with clinico-radiologic and histopathologic features of airways disease, namely constrictive bronchiolitis (i.e. peribronchiolar fibrosis encroaching on and narrowing bronchiolar lumen) (Fig. 1) (Ryu et al. 2020, Samhouri et al. 2020, Samhouri & Ryu 2023a). Against then-prevailing beliefs, Aguayo et al. (1992) realized that NECH represents the primary process while constrictive bronchiolitis represents the outcome. This entity was initially termed ‘idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells and airways disease’ (Aguayo et al. 1992). Whilst this initial nomenclature implies that ‘airways disease’ is essential to this entity, subsequent studies have proven otherwise insofar as constrictive bronchiolitis was absent in a large proportion of patients (Carr et al. 2015, Marchevsky et al. 2015, Samhouri et al. 2020, Hayes et al. 2022, Tassi et al. 2022).
Chromogranin immunostaining highlights scattered single neuroendocrine cells that can be present in normal airways (A) and neuroendocrine cell hyperplasia with five or more neuroendocrine cells forming nests in an airway (B). Small airways partly obliterated by proliferating neuroendocrine cells and subepithelial fibrosis in a DIPNECH case (C) hematoxylin and eosin staining; (D) MOVAT pentachrome staining; (E) synaptophysin staining; all 3× in original magnification). Carcinoid tumorlet adjacent to a bronchiole in DIPNECH case (F, hematoxylin and eosin staining, 8×).
Citation: Endocrine-Related Cancer 30, 10; 10.1530/ERC-23-0051
Later, in 2001, the World Health Organization (WHO) renamed this entity ‘diffuse idiopathic pulmonary neuroendocrine cell hyperplasia’ (DIPNECH) (Brambilla et al. 2001). The WHO recognizes DIPNECH as a preinvasive lesion for pulmonary carcinoid tumorlets/tumors (i.e. nodular PNEC proliferations invading into and through the airway wall basement membrane) (Fig. 1) (Koo et al. 2010, Rossi et al. 2021). The distinction between carcinoid tumorlets and tumors is purely based on size: tumorlets measure <5 mm, whereas tumors measure ≥5 mm (Mengoli et al. 2018, Rossi et al. 2021).
Respiratory symptoms in DIPNECH, when present, are mainly chronic cough, dyspnea, and/or wheezing. Its telltale imaging sign is the presence of multiple bilateral small noncalcified pulmonary nodules on CT imaging. Because these features are nonspecific (Rossi et al. 2016, Samhouri et al. 2020, 2021, Hayes et al. 2022, Tassi et al. 2022), coupled with the limited awareness of this entity among clinicians (Carr et al. 2015, Samhouri et al. 2020) and radiologists (Little et al. 2020), DIPNECH gets frequently mislabeled as asthma and/or chronic obstructive pulmonary disease (COPD) for many years before its diagnosis (Carr et al. 2015, Little et al. 2020, Samhouri et al. 2020, 2021, Hayes et al. 2022, Hurabielle et al. 2022, Samhouri & Ryu 2023b ). Confirming DIPNECH typically requires surgical lung biopsy (SLB) (Carr et al. 2015, Rossi et al. 2016, Samhouri et al. 2020, 2021, Hayes et al. 2022), which is often avoided given its invasiveness (Samhouri et al. 2022). Also, DIPNECH can be asymptomatic and often discovered incidentally when CT studies are obtained for other purposes (Hayes et al. 2022, Tassi et al. 2022). Accordingly, it is safe to assume that confirmed DIPNECH cases represent the tip of an iceberg of asymptomatic and misdiagnosed cases (Samhouri & Ryu 2023b ).
In the setting of pulmonary neuroendocrine tumors (carcinoid), DIPNECH is prevalent. In three studies that comprised 311 (Hayes et al. 2022), 172 (Prieto et al. 2021), and 105 (Sazonova et al. 2020) consecutive patients with resected pulmonary carcinoids, 61 (20%), 25 (15%), and 22 (21%) had DIPNECH. In the latter study (Sazonova et al. 2020), 16 (15%) additional patients were deemed to have ‘probable’ or ‘possible’ DIPNECH. In another study of 151 consecutive patients with resected pulmonary carcinoids (Mengoli et al. 2018), 72 (48%) met strict histopathologic criteria for DIPNECH (Marchevsky et al. 2015), and 19 (13%) had symptomatic DIPNECH, so-called ‘DIPNECH syndrome.’
Herein, we wish to:
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Increase awareness of DIPNECH by highlighting its key clinico-radiologic features and suggesting a pragmatic approach to its diagnosis and management. Such an approach is based on currently available evidence and may aid clinicians and patients in navigating the uncertainties surrounding DIPNECH.
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Highlight some critical gaps in DIPNECH definitions. We describe the ambiguity surrounding the fundamental term ‘diffuse’ and summarize the resultant inconsistencies in case definitions across recent studies. Moreover, we discuss the pitfalls of the recent DIPNECH definitions posed by the WHO (2021) (Rossi et al. 2021). In this context, we propose an objective and easily reproducible radio-pathologic case definition that is mainly intended for implementation in the research realm and seeks to enhance homogeneity across cohorts, a prerequisite for successful multi-institutional collaborations.
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Put forth the possibility that DIPNECH may give rise to lung diseases other than constrictive bronchiolitis and carcinoids, casting doubt as to how ‘idiopathic’ should be defined. We support our contention by shedding light on pertinent aspects of PNECs biology and many DIPNECH cases from the literature that exhibited notable features/associations.
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Finally, steer attention to some of the most pressing and impactful research questions awaiting to be unraveled.
DIPNECH: clinico-radiologic presentation, diagnosis, management, and prognosis
Clinical, PFT, and laboratory features
DIPNECH predominantly affects middle-aged and elderly women; 90–100% are female (Carr et al. 2015, Al-Toubah et al. 2020, 2021, Little et al. 2020, Samhouri et al. 2020, 2021, Sun et al. 2022), and median age at diagnosis is 65 years (Samhouri et al. 2020). This tendency seems independent of female hormones; of 23 DIPNECH cases from two studies (Swigris et al. 2005, Mengoli et al. 2018), only one expressed estrogen and/or progesterone receptors. In rats, spontaneous PNEC hyperplasia has a similar tendency to affect older females (Haworth et al. 2007).
In a study of patients with typical pulmonary carcinoids, work-related inhalational exposures and histopathologic DIPNECH were linked (Tassi et al. 2022). Of relevance, exposure to silica is known to cause PNEC hyperplasia in rats and whether the same applies to humans is unknown (Haworth et al. 2007).
The tendency of DIPNECH to affect never-smokers and ex-smokers (Carr et al. 2015, Al-Toubah et al. 2020, 2021, Little et al. 2020, Samhouri et al. 2020, 2021, Sun et al. 2022) is paradoxical since tobacco smoking is a known trigger of NECH (Boers et al. 1996, Garg et al. 2019, Noguchi et al. 2020). This tendency, however, may be partly related to selection bias; parenthetically, respiratory symptoms/impairment may be more readily misattributed to COPD in smokers than nonsmokers, in whom alternative etiologies are more aggressively pursued and identified. Additionally, when NECH and/or carcinoid tumorlets (collectively referred to as pulmonary neuroendocrine lesions (PNELs)) are adjacent to smoking-related histopathologic changes (e.g. chronic bronchitis, emphysema), they are frequently dismissed as ‘secondary’ PNELs (Marchevsky et al. 2015, Rossi et al. 2021, Sun et al. 2022).
Multiple endocrine neoplasia type 1 (MEN1) is a rare genetic disorder that predisposes to various endocrine and neuroendocrine tumors (NETs) including pulmonary carcinoid tumors (van den Broek et al. 2021). Few MEN1 cases developed DIPNECH (Fessler et al. 2004, Davies et al. 2007, Miller 2010). Whether DIPNECH represents an uncommon neuroendocrine manifestation of MEN1 mutations needs clarification (Miller 2010).
Most patients diagnosed to have DIPNECH manifest chronic respiratory symptoms, namely cough, dyspnea, or both (Carr et al. 2015, Samhouri et al. 2020). Others are asymptomatic and the diagnosis is reached while evaluating incidental pulmonary nodules (Carr et al. 2015, Samhouri et al. 2020). Carcinoid syndrome and endocrine syndromes (e.g. acromegaly, Cushing syndrome) are exceptionally unusual (Fessler et al. 2004, Carr et al. 2015, Wirtschafter et al. 2015, Samhouri et al. 2020, Hayes et al. 2022, Tassi et al. 2022). Spirometry is abnormal in most cases and although any pattern can be observed, airflow obstruction is the most common, often in association with air-trapping (Samhouri et al. 2020). Bronchodilator responsiveness was frequently observed (Nassar et al. 2011, Carr et al. 2015, Samhouri et al. 2020, Hurabielle et al. 2022); one study reported its presence in 52% of patients with airflow obstruction (Samhouri et al. 2020).
Routine laboratory tests are ordinarily nonrevealing. Peripheral eosinophil count is usually normal (Hurabielle et al. 2022), which may help distinguish DIPNECH from severe asthma (Hurabielle et al. 2022), which is primarily of the eosinophilic phenotype (Heaney et al. 2021). Chromogranin-A (CG-A) is a commonly used biomarker in patients with NETs (Gut et al. 2016) and may be elevated in DIPNECH (Gorshtein et al. 2012, Carr et al. 2015, Hayes et al. 2022). In the largest cohort to date (Hayes et al. 2022), CG-A was elevated in 45% (n = 22/49) of tested subjects and its concentration was <5× normal in 10, and ≥5× normal in 12. In three other reports (Gorshtein et al. 2012, Carr et al. 2015, Cabezón-Gutiérrez et al. 2019), CG-A was elevated in 6/11 (Gorshtein et al. 2012), 4/7 (Carr et al. 2015), and 0/4 (Cabezón-Gutiérrez et al. 2019) patients tested. The utility of CG-A in the diagnosis, follow-up, and prognostication of DIPNECH has not been studied (Gut et al. 2016).
Importantly, CG-A elevation is nonspecific for NETs (Gut et al. 2016). CG-A elevation secondary to proton pump inhibitors (PPIs) (Gut et al. 2016) is a pertinent limitation since DIPNECH patients may also be taking PPIs, which are commonly prescribed for chronic cough (Carr et al. 2015, Samhouri et al. 2020). However, such elevation is usually mild (Raines et al. 2012) and abates approximately 1 week after PPIs are discontinued (Mosli et al. 2012).
Because CG-A has many limitations, novel biomarkers for NETs are being evaluated. Presently, the most established marker is a transcriptomic multigene blood-based mRNA test (NETest) which has repeatedly been shown to outperform CG-A (Malczewska et al. 2021, Puliani et al. 2022). The NETest has shown promise in monitoring patients with bronchopulmonary NETs, but its use has not been shown to alter management or improve outcomes (Puliani et al. 2022). The potential diagnostic, management, and monitoring role of NETest in DIPNECH deserves exploration.
Imaging
Most studies did not describe chest X-ray findings in DIPNECH (Carr et al. 2015, Little et al. 2020, Samhouri et al. 2020, Hayes et al. 2022), because DIPNECH nodules and bronchiolitis with resultant air-trapping are too subtle to be appreciated on chest radiographs (Ryu et al. 2020, Almquist et al. 2021a ). Therefore, chest CT is the imaging modality of choice whenever DIPNECH is considered (Chassagnon et al. 2015, Little et al. 2020, Samhouri et al. 2020, 2021, Almquist et al. 2021a ).
On CT, DIPNECH invariably manifests bilateral pulmonary nodules that represent PNELs (Carr et al. 2015, Foran et al. 2015, Little et al. 2020, Samhouri et al. 2020, Hurabielle et al. 2022). Typically, DIPNECH nodules are noncalcified, noncavitary (Carr et al. 2015, Little et al. 2020, Samhouri et al. 2020, 2021), of solid attenuation (Sazonova et al. 2020, Almquist et al. 2021a , Samhouri et al. 2021), with round or oval morphology, and have well-defined borders (Fig. 2A) (Carr et al. 2015, Little et al. 2020, Samhouri et al. 2020, 2021, Sazonova et al. 2020). They are dispersed throughout both lungs but apparently favor mid and lower zones (Carr et al. 2015, Little et al. 2020, Sazonova et al. 2020). In the axial plane, data pertaining to their peripheral vs central preference are conflicting (Carr et al. 2015, O’Brien et al. 2018, Little et al. 2020). Multiple studies have noted a peribronchovascular distribution (Carr et al. 2015, O’Brien et al. 2018, Little et al. 2020, Samhouri et al. 2021), and this was the CT feature that best correlated with DIPNECH nodules as opposed to many other causes of pulmonary nodules in women (Samhouri et al. 2021). Little et al. (2020) noted a centrilobular distribution of pulmonary nodules in all cases.
A 63-year-old woman with biopsy proven diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) and carcinoid tumorlets. Computed tomography (CT) showing several well-circumscribed solid noncalcified nodules measuring up to 5 mm in the lingula (A, arrow). CT at end inspiration (B) demonstrated mosaic attenuation of the lung parenchyma which is exaggerated at end expiration (C), compatible with air-trapping due to constrictive bronchiolitis.
Citation: Endocrine-Related Cancer 30, 10; 10.1530/ERC-23-0051
Classically, DIPNECH manifests numerous nodules; however, a relatively small number of nodules is present in some cases. In one study, 24% of patients (n = 10/42) had 3–9 nodules in total (Al-Toubah et al. 2020) while 47% (n = 14/30) had <10 nodules in another study (Little et al. 2020). A third study reported that of ten cases, six had 2–5 pulmonary nodules in total, one had 5–10, and only three had >10 (Hurabielle et al. 2022). Several patients from other cohorts had <10 (Sazonova et al. 2020, Samhouri et al. 2021) and ≤20 nodules (Carr et al. 2015). Accordingly, the minimum number of pulmonary nodules that should prompt suspicion of DIPNECH remains unclear.
DIPNECH nodules are nonmigratory and may or may not grow, in size and number, slowly over time (Little et al. 2020, Sun et al. 2022). In 30 patients with a median follow-up of 3.4 years (Little et al. 2020), nodules number and size of the largest nodule remained unchanged in 14 (47%) and 10 (33%) cases, respectively. In the remaining 20 subjects (67%), growth was minimal; the median increase in the largest nodule diameter was 3.6 mm over 3.4 years (Little et al. 2020). Another study reported a comparably indolent course, with an average growth rate of 0.8 mm/year (Sun et al. 2022).
Besides pulmonary nodules, mosaic attenuation (i.e. patchwork regions of differing CT densities) (Hansell et al. 2008) is another key radiologic feature of DIPNECH (Figs. 2B and C) (Chassagnon et al. 2015, Samhouri et al. 2020, 2021, Hurabielle et al. 2022). Mosaic attenuation on inspiratory CT scans often represents air-trapping (as confirmed by exaggeration of regional density differences on expiratory images) and is an indirect feature of bronchiolitis (Stern et al. 1995, Kligerman et al. 2015, Samhouri et al. 2021, Samhouri & Ryu 2023a ). For its higher sensitivity and specificity, expiratory CT imaging is essential whenever air-trapping is a concern (Stern & Frank 1994, Kligerman et al. 2015).
The prevalence of mosaic attenuation and expiratory air-trapping has varied widely across DIPNECH cohorts, an observation that is likely related to the subjective nature of these CT features, as well as selection bias since some studies required the presence of airways disease in their case definition while others did not. Some studies reported that mosaic attenuation was appreciable on nearly 80% of inspiratory scans (Carr et al. 2015, Samhouri et al. 2020) and air-trapping was present in all patients with expiratory imaging (Carr et al. 2015, Little et al. 2020). In contrast, Mengoli et al. (2018) identified air-trapping in 9/19 (47%) patients with symptomatic DIPNECH, and only 9/72 (13%) patients with histopathologic DIPNECH (Mengoli et al. 2018). Hurabielle et al. (2022) detected air-trapping in 54% of their patients with symptomatic DIPNECH. Sun et al. (2022) identified mosaic attenuation in 50% and air-trapping in 27%. In a literature review (Wirtschafter et al. 2015), 39/159 (25%) cases had mosaic attenuation and 42/159 (26%) had air-trapping. Importantly, CT studies may depict other indirect features of bronchiolitis, such as subsegmental atelectasis (Carr et al. 2015).
Large airways abnormalities (e.g. bronchial wall thickening, beaded appearance of airways, bronchiectasis) were observed with varying frequencies across cohorts (Carr et al. 2015, Little et al. 2020). In a matched case-control study using quantitative CT (O’Brien et al. 2022), airway wall thickness and airway-to-artery ratio were higher in DIPNECH cases than controls. A multivariable model incorporating these parameters and nodule number could identify DIPNECH cases with high accuracy (O’Brien et al. 2022).
Regarding somatostatin receptor (SSTR)-based imaging modalities (i.e. Octreoscan and 68Ga-DOTATATE), low-grade uptake was seen in 33/41 (80%) DIPNECH patients (Hayes et al. 2022), and uptake was limited to the dominant lesion in all 10 patients from another cohort (Gorshtein et al. 2012). Though shown to express SSTRs (Mengoli et al. 2018), DIPNECH lesions may not demonstrate uptake due to their small size which diminishes the sensitivity of SSTR-based imaging modalities (Maxwell et al. 2014, Maxwell & Howe 2015).
Diagnostic approach
The CT pattern of bilateral pulmonary nodules together with mosaic attenuation is the telltale sign of DIPNECH (Chassagnon et al. 2015, Samhouri et al. 2020, 2021, Hurabielle et al. 2022). Nonetheless, this pattern is nonspecific (Samhouri et al. 2021, Tassi et al. 2022) and may be encountered in other respiratory and systemic disorders (Samhouri et al. 2021). Based on their review of 51 cases exhibiting this CT pattern, Samhouri et al. (2021) proposed a diagnostic algorithm that entails a thorough clinical, laboratory, and radiologic evaluation and may, in highly selected cases, render DIPNECH the most likely diagnosis (Samhouri et al. 2021). Notwithstanding, we and others (Samhouri et al. 2021, Tassi et al. 2022) believe that histopathologic confirmation is required to make a definitive diagnosis of DIPNECH.
Per current definitions, a histopathologic diagnosis of DIPNECH necessitates that NECH be multifocal (Marchevsky et al. 2015, Samhouri et al. 2020, Rossi et al. 2021). Because NECH is patchy, fulfilling stringent histopathologic criteria requires tissue specimens larger than those obtained via transbronchial or transthoracic needle biopsies (Carr et al. 2015, Samhouri et al. 2020, 2021). Larger specimens can be obtained using transbronchial cryobiopsy, a technique that showed encouraging results in diagnosing bronchiolitis (Sirol Aflah Syazatul et al. 2020), but only anecdotal success in DIPNECH (Sauer et al. 2017, Sirol Aflah Syazatul et al. 2020). Until more data concerning its yield and safety in DIPNECH accumulates, transbronchial cryobiopsy cannot be routinely recommended, and SLB remains the gold-standard diagnostic procedure.
That said, suspected cases should not be routinely referred to undergo lung biopsy. Instead, clinicians should inform patients about the risks of various biopsy procedures (Samhouri et al. 2022), including the possibility of nondiagnostic results. These downsides should be weighed against the benefits of achieving diagnostic certainty: i) exclusion of alternative etiologies (e.g. fungal infection, metastatic cancer); ii) determining eligibility for certain DIPNECH therapies, carcinoid tumor surveillance, and participation in future clinical trials; and iii) abandoning unnecessary and ineffective lifestyle modifications and therapies (e.g. avoidance of pets, use of systemic steroids and biologic agents) imposed by an erroneous diagnosis (e.g. asthma) (Hurabielle et al. 2022). Patients should also be informed that, if pursued, SLB offers a therapeutic (i.e. resecting the dominant lesion) and not only diagnostic role. Ultimately, well-informed patients should make these decisions.
Management
General principles
Once DIPNECH is diagnosed, formulating an effective management plan poses another challenge. Data pertaining to DIPNECH management are derived from case reports/series and small retrospective studies. In most reports, patients received multiple therapies simultaneously (inhaled bronchodilators, inhaled and/or systemic corticosteroids, somatostatin analogs (SSAs), mechanistic target of rapamycin (mTOR) inhibitors) which precludes reaching definitive conclusions regarding the efficacy of any particular intervention.
There are substantial regional differences in the approach to patients with NETs (Singh et al. 2020), and, likely, DIPNECH. In the United States, patients with DIPNECH may receive care from either medical oncologists or pulmonologists. Given its often prominent and potentially disabling pulmonary manifestations, involving a pulmonologist in the care of patients with DIPNECH is desirable. In circumstances where SSAs are being administered by pulmonologists for respiratory symptom management, involvement of medical oncology may not be needed unless there is overt progression to a pulmonary carcinoid tumor. Multidisciplinary care, including the utilization of tumor boards, may be preferred in cases where decisions regarding both symptomatic and tumor growth management are needed.
Clinicians may consider some general principles when approaching DIPNECH patients: i) investigate and treat prevalent comorbid conditions that may be contributing to presenting symptoms (e.g. postnasal drip and gastroesophageal reflux disease in patients with chronic cough); ii) provide supportive management (e.g. smoking cessation, vaccination, oxygen supplementation, pulmonary rehabilitation, referral to lung transplantation as indicated); iii) it is advisable that medications targeted at alleviating respiratory symptoms be introduced sequentially, enabling patients and clinicians to determine the efficacy, or lack thereof, of each therapeutic class; and iv) when evidence prioritizing one management strategy over another is lacking, clinicians should educate and empower patients to make health-related decisions that align with their priorities and preferences.
Pathobiologic aspects pertinent to DIPNECH management
The genetic and/or environmental factors underlying DIPNECH remain elusive. However, DIPNECH cells have aberrant activation of mTOR pathway (Rossi et al. 2012, Mengoli et al. 2018), which may be the driver of their relentless growth and survival. Hyperplastic PNECs can form nodular growths within the mucosa of small airways, narrowing airway lumens and obstructing airflow. Also, hyperplastic PNECs secrete supraphysiologic quantities of bioactive substances capable of inducing airway fibrosis (i.e. constrictive bronchiolitis), airway inflammation, and/or bronchospasm (Andersson-Rolf et al. 2021). The latter may explain the unexpectedly high prevalence of bronchodilator responsiveness in DIPNECH (Nassar et al. 2011, Carr et al. 2015, Samhouri et al. 2020, Hurabielle et al. 2022).
Crucially, DIPNECH cells express SSTRs (Mengoli et al. 2018) which exert antisecretory and antitumor (antiproliferative and proapoptotic) effects upon stimulation with somatostatin (Susini & Buscail 2006). Conceivably, SSAs and mTOR inhibitors may slow or reverse the primary disease process in DIPNECH and not only ameliorate its symptoms (Russier et al. 2018, Al-Toubah et al. 2020). Further details concerning PNEC biology are discussed later.
Suggested approach to managing respiratory symptoms/airways disease in DIPNECH
When symptomatology warrants pharmacotherapy, medications with a favorable cost and safety profile (e.g. inhaled β2-agonists, inhaled corticosteroids, and antitussive agents) are to be commenced first. The sequence in which to introduce them depends on the individual clinical context and patients’ preferences. Due to inefficacy and profound toxicity (Nassar et al. 2011, Carr et al. 2015, Samhouri et al. 2020), systemic corticosteroids are discouraged.
If symptoms persist despite these therapies, a trial of SSAs could be considered as they seem well-tolerated and have strong pathobiologic rationale, albeit data supporting clinical efficacy is sparse and inconclusive. In one study of 42 patients who received SSAs, 32 improved (Al-Toubah et al. 2020). This observation was confounded by the fact that 31/42 patients concurrently received other therapies (‘inhalers, benzonatate, and oral steroids’), and 37/42 underwent resection of the dominant carcinoid lesion (Al-Toubah et al. 2020). In two other cohorts (Carr et al. 2015, Samhouri et al. 2020), only 4/14 (Samhouri et al. 2020) and 3/11(Carr et al. 2015) patients who received SSAs reported symptomatic improvement, and 1/8 (Samhouri et al. 2020) and 0/9(Carr et al. 2015) patients with follow-up PFTs demonstrated improvement. In another cohort (Hayes et al. 2022), ten patients with respiratory symptoms received SSAs; cough improved in three, and dyspnea improved in none.
Given their substantial toxicity, including pulmonary toxicity, it is our opinion that mTOR inhibitors should not be instituted for the sole purpose of ameliorating respiratory symptoms, and their use is preferably reserved for DIPNECH patients with progressive respiratory failure (Mourad & Hamblin 2015, Russier et al. 2018), and/or metastatic carcinoids (per carcinoid tumor management guidelines) (Yao et al. 2016, Singh et al. 2020).
Carcinoid tumors: management and surveillance
Carcinoid tumors arise in a subset (11–27%) (Almquist et al. 2021b , Hayes et al. 2022, Sun et al. 2022) of patients with DIPNECH (referred to as DIPNECH-carcinoids hereafter). In fact, it is common to see a spectrum of pathology ranging from NECH to tumorlets to carcinoid tumor within the same specimen (Sun et al. 2022). DIPNECH-carcinoids and sporadic carcinoids have fundamental differences in clinical presentation (number of lesions (Sazonova et al. 2020), location (central vs peripheral)) (Mengoli et al. 2018, Papaxoinis et al. 2018, Tassi et al. 2022) and immunohistochemical staining patterns (TTF-1 and OTP) (Nonaka et al. 2016, Mengoli et al. 2018, Papaxoinis et al. 2018). Multiple studies have directly compared DIPNECH-carcinoids vs sporadic carcinoids in terms of invasiveness, yielding opposing conclusions (Papaxoinis et al. 2018, Prieto et al. 2021, van den Broek et al. 2021, Tassi et al. 2022). Despite these differences, the management of DIPNECH-carcinoids has been extrapolated from that of sporadic carcinoids where considerably more data exist (Al-Toubah et al. 2020, Samhouri et al. 2020, Almquist et al. 2021a ).
Because a comprehensive discussion regarding carcinoid tumor management is beyond the scope of this review (Detterbeck 2010, Singh et al. 2020, Baudin et al. 2021), we will underscore some differences that render the risk–benefit analyses of surgical resection more nuanced in DIPNECH-carcinoids than sporadic carcinoids. First, patients with DIPNECH-carcinoids are older (Sazonova et al. 2020, Prieto et al. 2021, van den Broek et al. 2021, Tassi et al. 2022), with worse baseline respiratory function (Mengoli et al. 2018, Sazonova et al. 2020) and more comorbidities (Prieto et al. 2021). Second, unlike sporadic carcinoids, DIPNECH-carcinoids do not typically arise in or obstruct central airways (Mengoli et al. 2018, Papaxoinis et al. 2018, Tassi et al. 2022); consequently, they seldom present with severe complications such as post-obstructive pneumonia or hemoptysis (Carr et al. 2015, Mengoli et al. 2018, Samhouri et al. 2020). Given their peripheral location, DIPNECH-carcinoids require less extensive surgical resections than sporadic carcinoids (van den Broek et al. 2021, Tassi et al. 2022) (lobectomy in 15 vs 57%; and wedge resection in 48 vs 10%, respectively) (van den Broek et al. 2021). Third, the multiplicity and multifocality of DIPNECH-carcinoids pose unique challenges (choosing which lesion(s) to resect; size threshold at which resection becomes necessary; safety of repeated lung resections).
Uncertainties about when to intervene on DIPNECH-carcinoids cast doubt on the utility of surveillance CT scans in DIPNECH. There is no evidence showing that early detection and resection of DIPNECH-carcinoids positively impact outcomes, especially considering the relatively indolent course and low metastatic potential of these tumors (Carr et al. 2015, Papaxoinis et al. 2018, Samhouri et al. 2020, Prieto et al. 2021, van den Broek et al. 2021, Hayes et al. 2022, Tassi et al. 2022) as well as the older age and comorbidities which may limit the life expectancy of affected individuals. In fact, some patients with DIPNECH may suffer complications related to overdiagnosis and overtreatment of DIPNECH-carcinoids. Other disadvantages of carcinoid surveillance include radiation exposure, detection of incidental findings, added costs, and anxiety. Considering its unproven benefits and potential harms, clinicians should not firmly recommend carcinoid tumor surveillance to DIPNECH patients. Instead, we advocate for shared decision-making between clinicians and patients who are well-informed of the risks and not only the benefits of screening – similar to other cancer screening programs (Tanner & Silvestri 2019).
If carcinoid tumor surveillance is pursued, we recommend performing a low-dose chest CT scan without intravenous contrast (Table 1). However, in the minority of patients exhibiting hilar and/or mediastinal lymphadenopathy, intravenous contrast administration becomes necessary. Nevertheless, the optimal screening interval remains unknown. Although annual or biennial surveillance seems appropriate (Almquist et al. 2021a, Sun et al. 2022), extending this interval further is reasonable since DIPNECH-carcinoids grow slowly (Little et al. 2020, Sun et al. 2022) and harm may result from greater cumulative ionizing radiation exposure. Currently, available data do not support using any tumor markers for DIPNECH-carcinoid surveillance.
DIPNECH: summary of the clinico-radiologic features and approach to diagnosis and management.
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| Clinical, PFT, and laboratory features | ||
| Demographics | Middle-aged and elderly nonsmoking women | This striking gender predominance remains unexplained |
| Potentially related to occupational inhalational exposures | ||
| Clinical presentation | Longstanding respiratory symptoms (namely cough and/or dyspnea) in most patients | Many had been diagnosed with asthma and/or COPD |
| Carcinoid syndrome and endocrine disorders (e.g. Cushing syndrome, acromegaly) are exceptionally unusual | ||
| Incidentally noted pulmonary nodules in an otherwise asymptomatic individual | ||
| PFT features | PFT is abnormal in most. Airflow obstruction is the most common pattern, often with air-trapping, and sometimes with BDR | Interestingly, the airflow obstruction was independent of constrictive bronchiolitis on histopathology |
| Laboratory findings | CG-A is elevated in some | Utility of serum CG-A in DIPNECH is important to study |
| Urinary 5-HIAA elevation was seldom reported | Possible utility of CG-A in BAL fluid deserves exploration | |
| Radiologic features | ||
| Chest X-ray | Usually normal | DIPNECH nodules are too small to be appreciable on X-ray |
| Chest CT scan | Bilateral noncalcified pulmonary nodules in all | DIPNECH nodules are small, favor mid and lower lung zones, have a peribronchovascular and centrilobular distribution, and grow slowly. Although classically numerous, <10 nodules were present in many DIPNECH cases |
| Mosaic attenuation (inspiratory scans) and air-trapping (expiratory scans): prevalence varied across studies | ||
| This combination is the CT hallmark of DIPNECH | ||
| SSTR-based imaging | Uptake may be seen in some patients, and is usually demonstrated by the dominant lesion | 68Ga-DOTATATE is more sensitive than Octreoscan |
| Their sensitivity is diminished in smaller lesions (<2 cm) | ||
| Scenarios in which DIPNECH is to be suspected | Woman with no or minimal smoking history and fixed airflow obstruction or previous diagnosis of COPD | |
| Woman with ‘asthma’ who does not improve with usual asthma therapies, especially those with non-eosinophilic asthma phenotype | ||
| Woman with chronic cough and pulmonary nodules on chest CT | ||
| Woman with carcinoid tumor (especially peripheral) and >10 other noncalcified nodules | ||
| Diagnostic approach | When suspected, high-resolution chest CT scans with expiratory images, and MIP images (which are known to enhance the detection of nodules) should be performed | Herein, we propose a definition that requires the presence of (i) PNELs on histopathology and (ii) CT evidence of diffuse disease (i.e. >10 noncalcified pulmonary nodules) |
| Definitive diagnosis cannot be established without histopathologic confirmation. Strict histopathologic criteria (e.g. Marchevsky criteria) render SLB, a highly invasive procedure, necessary | Our proposed definition allows obtaining histopathologic confirmation using less invasive lung biopsy procedures (e.g. transthoracic and transbronchial needle biopsy) | |
| Clinicians must always discuss the risks and benefits of lung biopsy procedures with patients, who should ultimately decide if such undertaking aligns with their wishes | ||
| Management | ||
| Respiratory symptoms/impairment (i.e. airways diseases) | Investigate and treat comorbid conditions. Provide supportive management (vaccination, oxygen supplementation, etc.) | |
| Introduce medications sequentially and start with those that have a favorable cost and safety profile | ||
| For patients who do not respond to above therapies, consider a therapeutic trial with SSAs | ||
| For patients with progressive respiratory failure, consider SSAs and/or mTOR inhibitorsa. | ||
| Carcinoid tumor management | Until more data becomes available, management of DIPNECH-carcinoids can be extrapolated from that of sporadic carcinoids | |
| When formulating management plans, clinicians may consider some key differences in patient and disease characteristics in DIPNECH-carcinoids vs sporadic carcinoids (patients with DIPNECH-carcinoids are older with worse respiratory status and more comorbidities; DIPNECH-carcinoids can be multifocal) | ||
| In patients with multifocal DIPNECH-carcinoids, it may be wise to pursue systemic therapies with antitumor effects (i.e. SSAs and/or mTOR inhibitors) rather than multifocal and repeated lung resection procedures | ||
| Carcinoid tumor surveillance | There is no evidence that carcinoid tumor surveillance improves outcomes in DIPNECH | |
| Clinicians should inform patients about the potential risks of pursuing carcinoid tumor surveillance (overdiagnosis and overtreatment of DIPNECH-carcinoids; extra cost; detection of incidental findings; radiation exposure; anxiety) | ||
| Considering unproven benefits and potential harm, clinicians should not firmly recommend carcinoid surveillance to all patients. Instead, shared decision-making between clinicians and well-informed patients is preferred | ||
| If well-informed patients desire to pursue carcinoid tumor surveillance, we generally recommend performing low-dose chest CT scan without IV contrast. In the minority of patients manifesting hilar/mediastinal lymphadenopathy, low-dose chest CT scan with IV contrast is indicated. No specific screening interval is recommended; however, 1-year or 2-year screening intervals seem appropriate | ||
aRecommending these medications is based on their pathobiologic merit and supportive data derived from small case reports/series as well as expert opinions. Considering their potential toxicity and cost, careful patient selection and monitoring are necessary. Drug level monitoring is required for mTOR inhibitors.
CT, computed tomography; DIPNECH, diffuse idiopathic pulmonary neuroendocrine cell hyperplasia; HRCT, high-resolution CT; MNEP, multifocal neuroendocrine proliferation; mTOR, mechanistic target of rapamycin; NECH, neuroendocrine cell hyperplasia; NE, neuroendocrine; NEP, neuroendocrine proliferations; PFT, pulmonary function testing; PNEC, pulmonary neuroendocrine cells; PNEL, pulmonary neuroendocrine lesion.
Prognosis
DIPNECH has an indolent clinical course and respiratory decline may or may not ensue over time (Carr et al. 2015, Samhouri et al. 2020). Expectedly, the pace of respiratory function decline varies, with slow deterioration in most patients and more rapid deterioration in some (Carr et al. 2015). Rarely, DIPNECH leads to respiratory failure requiring lung transplantation or causing death (Carr et al. 2015, Samhouri et al. 2020, Almquist et al. 2021a , Hayes et al. 2022). In a single-center retrospective cohort study of 61 patients with DIPNECH-carcinoids, no deaths attributable to respiratory failure occurred during a median follow-up of 46 months (Hayes et al. 2022). In another retrospective study of 30 DIPNECH patients, only 1 succumbed to respiratory failure from progressive constrictive bronchiolitis (Carr et al. 2015). In another cohort (Samhouri et al. 2020), of 35 DIPNECH patients with a median follow-up of 30 months, 1 required lung transplantation for multifactorial respiratory failure.
From a cancer viewpoint, DIPNECH-carcinoids have a favorable prognosis. Most DIPNECH-carcinoids are typical (Papaxoinis et al. 2018, Prieto et al. 2021, van den Broek et al. 2021, Hayes et al. 2022), and stage IA or IB at diagnosis (Prieto et al. 2021, van den Broek et al. 2021, Tassi et al. 2022). Following resection, most (75%) DIPNECH-carcinoids do not relapse in ≥10 years (Hayes et al. 2022). In a retrospective study of 41 patients with resected typical DIPNECH-carcinoids, 81% had no relapse during follow-up (mean 9.6 years) (Tassi et al. 2022). In another retrospective study of 61 patients with DIPNECH-carcinoids, only 4 (7%) had carcinoid-related death, and 15-year survival was 86% (Hayes et al. 2022). Of 41 patients with typical DIPNECH-carcinoids, only 4 (10%) had carcinoid-related death, and 10-year survival was 72% (Tassi et al. 2022). In a cohort of 25 DIPNECH-carcinoid cases, 7-year survival was 93.3% (Prieto et al. 2021). In another cohort of 27 DIPNECH-carcinoid cases, no deaths occurred during a median follow-up of 2.9 years, and disease-specific survival was not estimable (van den Broek et al. 2021).
DIPNECH: unresolved issues
Definition of DIPNECH
Multifocal NECH is frequently observed in the vicinity of carcinoid tumors (particularly peripheral carcinoids) (Mengoli et al. 2018, Papaxoinis et al. 2018) and may not always be representative of DIPNECH (Tassi et al. 2023). Similarly, and as discussed previously, NECH may represent an adaptive response to various exposures or insults (Aguayo et al. 1992, Boers et al. 1996). The extent of this abnormality can help distinguish so-called ‘reactive’ or ‘secondary’ NECH from ‘diffuse’ NECH (DIPNECH). However, the central term ‘diffuse’ remains poorly defined.
Before 2021, DIPNECH diagnosis had remained strictly histopathologic. In its initial inclusion (2001) (Brambilla et al. 2001), the WHO did not specify how ‘diffuse’ should be defined. Later, Marchevsky et al. (Marchevsky et al. 2015) proposed histopathologic criteria that mandate the presence of NECH (i.e. presence of ≥5 PNECs within the basement membrane of ≥3 bronchioles) and ≥3 carcinoid tumorlets. These criteria were acknowledged, but not adopted by the 2021 WHO Classification of Tumors which stated ‘… this [set of criteria] requires further validation’ and no alternative definition was proposed (Rossi et al. 2021).
Because no consensus exists, investigators have employed varying definitions when classifying cases as DIPNECH vs non-DIPNECH (Table 2), with some studies utilizing ‘expert/multidisciplinary panels’ to make this fundamental assertion (Sazonova et al. 2020, Sun et al. 2022). Essentially, the lack of studies assessing the diagnostic accuracy as well as the intrarater and interrater reliability of such panels/teams threatens the validity of studies relying on such methodology and renders the generalizability and reproducibility of their conclusions questionable.
Summary of the case definitions used in recent DIPNECH studies.
| Study | Sample size | Study population and accepted case definitions | Comments |
|---|---|---|---|
| Carr et al. (2015) | n = 30 | DIPNECH on pathology report (n = 21) | Unclear which criteria were used to establish ‘clinical diagnosis’ and ‘high clinical suspicion’ |
| Typical carcinoid on needle biopsy of a pulmonary nodule with ‘high clinical suspicion’ for DIPNECH (e.g. obstructive physiology, typical HRCT scan findings) (n = ‘several’) | |||
| Clinical diagnosis (n = 2) | |||
| Hayes et al. (2022) | n = 61 | n = 43 had histopathologic DIPNECH | Histopathologic DIPNECH defined as: NECH and ≥3 carcinoid tumorlets |
| n = 18 had DIPNECH classified by ‘high suspicion based on combination of histology, clinical data, and CT’ | |||
| Little et al. (2020) | n = 32 | DIPNECH on pathology report (n = unspecified) | Exact CT features considered suggestive of DIPNECH were not specified |
| Evidence of carcinoid tumor on biopsy of lung or liver (in case of metastatic carcinoid of presumed pulmonary origin) with ‘CT features that suggest DIPNECH’ (n = unspecified) | |||
| Marchevsky et al. (2015) | n = 29 | 70 consecutive patients with multifocal neuroendocrine proliferations were divided into 4 groups (NECH only; ≥2 carcinoid tumorlets without NECH; NECH and 2 carcinoid tumorlets; and NECH with ≥3 carcinoid tumorlets) | Gender, clinical data, PFT features, and CT findings were not considered when the authors made the distinction between DIPNECH and ‘secondary’ multifocal neuroendocrine proliferations |
| The diagnostic criteria proposed by this study were predicated on two assumptions: (i) DIPNECH cannot cause or co-exist with lung disease other than constrictive bronchiolitis or carcinoid tumorlets/tumors; and (ii) multifocal neuroendocrine proliferations are less likely to represent DIPNECH if not associated with carcinoid tumors | |||
| NECH was defined as ‘the presence of five or more NE cells, singly or in clusters located within the basement membrane of the bronchiolar epithelium of at least three bronchioles | |||
| In this cohort, 61 (87%) were female. Although the presence of multifocal PNEC proliferation in a middle-aged or elderly female is rather suspicious of DIPNECH, only 29 were considered to have DIPNECH and the remainder (n = 41) were considered ‘secondary’ | |||
| Counterarguments to these assumptions are discussed in detail within the manuscript | |||
| Prieto et al. (2021) | n = 25 | Of 172 patients with pulmonary carcinoid tumors, 25 had DIPNECH based on diagnostic histopathologic features | Surprisingly, there was no significant difference in the prevalence of respiratory symptoms or preoperative FEV1 between those with and without DIPNECH |
| Clinico-radiologic features were not taken into account to define DIPNECH vs non-DIPNECH cases | CT features in DIPNECH vs non-DIPNECH were not reported | ||
| Samhouri et al. (2020) | n = 44 | Histopathological diagnosis in all (n = 44) | Clinico-radiologic features were not taken into account to define cases |
| Histopathological diagnosis was established by finding multifocal proliferation of PNECs involving the bronchial or bronchiolar epithelium | |||
| Sazonova et al. (2020) | n = 22 | Presence/absence of DIPNECH among 105 patients with resected pulmonary carcinoids was determined by an ‘expert panel’ that reviewed clinical, PFT, CT, and histological data | A novel approach to histopathologic assessment was adopted. Number of PNELs was adjusted for the number of bronchioles |
| 77/105 patients had CT scans (23 DIPNECH vs 54 non-DIPNECH); none had expiratory imaging | |||
| n = 22 had ‘definitive DIPNECH’, N = 5 had ‘probable DIPNECH’, and n = 11 had ‘possible DIPNECH’. In the remainder (n = 67), DIPNECH was deemed absent | Interestingly, of 54 patients labeled as ‘non-DIPNECH’, many had CT features suggestive of DIPNECH: 18 had bilateral nodules (>10 nodules in 12 cases), all of which were round or oval and predominantly solid in attenuation; 16 had mosaic attenuation | ||
| Sun et al. (2022) | n = 33 | Of 78 patients with PNELs on histopathology, 33 were classified as DIPNECH, and 45 as non-DIPNECH. This distinction was based on multidisciplinary review | Of the 45 patients labeled as non-DIPNECH: 40 had carcinoid tumorlets; 3 had carcinoid tumorlet and carcinoid tumor; 1 had NECH and carcinoid tumorlet; and 1 had NECH, carcinoid tumorlet and carcinoid tumor |
| Of 33 patients labeled as DIPNECH: | |||
| PNELs were classified as ‘non-DIPNECH’ or ‘secondary NECH’ simply because a lung disease other than constrictive bronchiolitis or carcinoid turmorlet/tumors was present in the vicinity | |||
| n = 24 had histopathologic DIPNECH (unclear which criteria) | |||
| n = 9 had clinical DIPNECH based on multidisciplinary review using ‘characteristic radiographic and clinical features’. These included ‘symptoms related to airway obstruction, mosaic attenuation on CT and/or bilateral pulmonary nodules’ | Surprisingly, prevalence of respiratory symptoms, PFT abnormalities, and bilateral pulmonary nodules on CT was similar between DIPNECH and ‘secondary NECH/tumorlet’ | ||
| Tassi et al. (2022) | n = 41 | Of 234 with resected typical carcinoid tumors, 41 (18%) had multifocal NECH and/or carcinoid tumorlets | Although these histopathologic findings are usually referred to as DIPNECH, the authors reserved this term to those with clinical, PFT, and histopathologic features of airways disease |
| Wirtschafter et al. (2015) | n = 30 | The authors summarized 169 DIPNECH cases reported in the literature and added 30 cases in whom DIPNECH was defined by the presence of NECH and ≥3 carcinoid tumorlets (Marchevsky et al. (2015) | Most key clinico-radiologic features were not separately reported for those 30 patients added by Wirtschafter et al. Wirtschafter et al. (2015). Instead, these cases were blended in the larger literature review that included a total of 199 cases |
CT, computed tomography; DIPNECH, diffuse idiopathic pulmonary neuroendocrine cell hyperplasia; HRCT, high-resolution CT; MNEP, multifocal neuroendocrine proliferation; NE, neuroendocrine; NECH, neuroendocrine cell hyperplasia; NEP, neuroendocrine proliferations; PFT, pulmonary function testing; PNEC, pulmonary neuroendocrine cells; PNEL, pulmonary neuroendocrine lesion.
To complicate matters further, in 2021, the WHO introduced the term ‘Clinical DIPNECH’ (Rossi et al. 2021), wherein a diagnosis can be established based on clinical (’symptoms related to airway obstruction such as cough, breathlessness, and wheezing’) (Rossi et al. 2021) and radiologic (’CT findings of mosaic attenuation with or without bilateral pulmonary nodules’) (Rossi et al. 2021) features that are highly nonspecific (Samhouri et al. 2021) while leaving histopathologic confirmation optional (Rossi et al. 2021). Since mosaic attenuation is less sensitive than pulmonary nodules (Mengoli et al. 2018, Hurabielle et al. 2022, Sun et al. 2022) and its identification is more prone to subjectivity, it is surprising that the WHO mandated the presence of mosaic attenuation but not pulmonary nodules (Rossi et al. 2021). Importantly, the combined presence of bilateral pulmonary nodules and mosaic attenuation is still nonspecific; of 40 women with demographic and clinico-radiologic features reminiscent of DIPNECH, only 5 (13%) had DIPNECH (Samhouri et al. 2021). Upon comparing DIPNECH vs non-DIPNECH diagnoses, none of the CT characteristics (size, number, morphology, attenuation, distribution) of DIPNECH nodules was sufficiently specific (Samhouri et al. 2021).
Evidently, an improved definition that can be widely accepted is needed (Fournel 2023). In our opinion, such a definition is one that merges the two WHO definitions (i.e. ‘Pathological’ and ‘Clinical’ DIPNECH) and mandates the two features described in all DIPNECH cases (Carr et al. 2015, Little et al. 2020, Samhouri et al. 2020, Hurabielle et al. 2022): i) histopathologic evidence of PNELs, and irrespective of their extent because PNELs are patchy and fulfilling stringent criteria (e.g. Marchevsky criteria) (Marchevsky et al. 2015) may not be possible, particularly when limited sampling procedures are performed; and ii) radiologic affirmation of the diffuse nature of these PNELs which, on CT, appear as noncalcified nodules with well-defined borders (Carr et al. 2015, Little et al. 2020, Samhouri et al. 2020, 2021). Because mosaic attenuation is less sensitive than pulmonary nodules (Carr et al. 2015, Mengoli et al. 2018, Samhouri et al. 2020, Hurabielle et al. 2022, Sun et al. 2022), its presence, though supportive, should not be mandated.
Regarding what defines ‘diffuse’ or ‘multiple’ nodules on chest CT, we suggest using >10 nodules, a cut-off previously shown to correlate with histopathologic DIPNECH (Sazonova et al. 2020). Our proposed cut-off is even more conservative than that of ≥5 nodules which, according to one study (O’Brien et al. 2022), has a sensitivity of 81% and a specificity of 87%. To add perspective, identifying >10 noncalcified pulmonary nodules is an uncommon occurrence in the general population. In a prospective trial from the United States, each of 1520 heavy-smokers (48% female) underwent five annual CT scans, revealing 3356 noncalcified nodules in total (average of 2.2 per individual over 5 years) (Swensen et al. 2005). In a South Korean study, only 835 (4.6%) of 17,968 never-smokers (69% female) had more than one nodule on CT (Kim et al. 2020). Taken together, identifying >10 noncalcified pulmonary nodules in the context of biopsy-proven PNELs is likely to prove highly specific for DIPNECH, especially when no other explanation for these nodules (e.g. sarcoidosis, rheumatoid arthritis) exists (Samhouri et al. 2021).
Similar uncertainty surrounds the term ‘idiopathic’ (Marchevsky et al. 2015, Almquist et al. 2021a , Rossi et al. 2021) and stems from numerous studies (Aguayo et al. 1990, Aguayo 1993, 1994, Zhou et al. 2013, Tighe et al. 2019, Kayalar et al. 2020, Noguchi et al. 2020, Kayalar & Oztay 2022, Zhang et al. 2022) suggesting that NECH can play causal roles in various lung diseases (detailed later). Also, many cases in the literature link DIPNECH to pulmonary fibrosis, non-carcinoid lung cancer, and some cancer syndromes (Tables 3 and 4). Considering the rarity of DIPNECH and those conditions in Tables 3 and 4, their co-existence is difficult to explain by chance alone and may indicate a causal relationship or shared etiology. These associations, though uncommon, deserve exploration as they may provide invaluable mechanistic insights. However, these intriguing associations will remain unexplored unless we adopt a new definition that, unlike current definitions (Marchevsky et al. 2015, Rossi et al. 2021, Sun et al. 2022), does not actively exclude the conceivable possibilities that DIPNECH may i) cause lung diseases other than constrictive bronchiolitis and carcinoid tumorlets/tumors; ii) be a manifestation of a broader neoplastic syndrome; and/or iii) co-exist with another disease that has similar etiologic factors. As such, we advocate for DIPNECH to remain a consideration whenever both our proposed criteria (earlier) are met and to not rule it out simply because a histopathologic abnormality, that is traditionally considered unrelated to DIPNECH, is co-identified with PNELs (Marchevsky et al. 2015, Rossi et al. 2021, Sun et al. 2022).
Summary of some notable DIPNECH cases reported in the literature, with focus on associations between DIPNECH and other neoplasms.
| Study | Brief case description | Comments |
|---|---|---|
| DIPNECH and lung adenocarcinoma (LAC)
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| Al-Ayoubi et al. (2014) |
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| Gorospe et al. (2017) |
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| Mireskandari et al. (2013) |
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| Warth et al. (2008) |
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| Jin et al. (2018) |
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| Baniak et al. (2016) |
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| Samhouri et al. (2020) |
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| Marchevsky et al. (2015) |
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| Inomata et al. (2022) |
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| Trisolini et al. (2016) |
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| Hayes et al. (2022) |
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| Sun et al. (2022) |
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| DIPNECH in association with multiple non-carcinoid tumors, or another rare neoplastic lesion
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| Pedro et al. (2020) |
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| Hayes et al. (2022) |
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| Hassan et al. (2015) |
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| Samhouri et al. (2020) |
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| Sun et al. (2022) |
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| Davies et al. (2007) |
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| Han et al. (2020) |
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| Wang et al. (2014) |
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CT, computed tomography; DIPNECH, diffuse idiopathic pulmonary neuroendocrine cell hyperplasia; LAC, lung adenocarcinoma; MEN, multiple endocrine neoplasia; PNEL, pulmonary neuroendocrine lesion; RLL, right lower lobe; RML, right middle lobe; RUL, right upper lobe; SLB, surgical lung biopsy; VATS, video-assisted thoracoscopic surgery.
Summary of some notable DIPNECH cases reported in the literature, with focus on associations between DIPNECH and ILD.
| First author | Brief description | Comments |
|---|---|---|
| Carr et al. (2015) |
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| Samhouri et al. (2020) |
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| Shyu et al. (2018) |
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| Sun et al. (2022) |
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| Reyes et al. (2007) |
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| Chatterjee et al. (2016) |
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| Marchevsky et al. (2015) |
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| Tassi et al. (2022) |
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| Pietrangeli et al. (2015) |
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| Myint et al. (2018) |
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CB, constrictive bronchiolitis; CT, computed tomography; ILD, interstitial lung disease; MNEP, multifocal neuroendocrine proliferations; NECH, neuroendocrine cell hyperplasia; PFT, pulmonary function test; PNEC, pulmonary neuroendocrine cell; SLB, surgical lung biopsy; UIP, usual interstitial pneumonia.
Furthermore, we do not favor including features of airways disease (i.e. respiratory symptoms, PFT abnormalities, or constrictive bronchiolitis on histopathology) in DIPNECH definition as these were absent in many cases (Carr et al. 2015, Mengoli et al. 2018, Samhouri et al. 2020). On the other hand, we favor using clear terms (’symptomatic vs asymptomatic’ DIPNECH) over others that may create confusion (e.g. ‘DIPNECH syndrome vs DIPNECH’ (Rossi et al. 2016, Mengoli et al. 2018) or ‘Clinical vs Pathological’ DIPNECH (Rossi et al. 2021, Sun et al. 2022).
The major advantages of our proposed definition (Table 5) are its easy reproducibility and reliance on objective data. Moreover, our definition is likely to prove highly specific for DIPNECH (Sazonova et al. 2020, Samhouri et al. 2021, O’Brien et al. 2022, Tassi et al. 2022). Because it accepts radiologic evidence of diffuse disease, our proposed definition requires less elaborate histopathologic findings and thus, biopsy procedures less invasive than SLB (i.e. transbronchial and transthoracic needle biopsies; transbronchial cryobiopsy) may suffice; this parallels other authors’ sentiment (Carr et al. 2015, Rossi et al. 2016, Tassi et al. 2022). By abandoning some arbitrary assumptions concerning the term ‘idiopathic,’ our proposed definition allows investigators to approach DIPNECH with the curiosity needed in such an early phase of discovery, improving our chances of elucidating the full spectrum of this relatively new and peculiar entity.
Summary of DIPNECH definitions.
| World Health Organization Classification of Tumors (2021) | Marchevsky criteria | Our proposed definition |
|---|---|---|
| 1. Clinical DIPNECH | Neuroendocrine cell hyperplasia (i.e. presence of ≥5 PNECs within the basement membrane of ≥3 bronchioles) Plus ≥3 carcinoid tumorlets |
Any abnormal PNEC proliferation (i.e. neuroendocrine cell hyperplasia, tumorlet(s), carcinoid tumor) Plus >10 noncalcified pulmonary nodules, particularly when no other explanation for these pulmonary nodules exists Irrespective of the presence/absence of Respiratory symptoms Clinical, histopathologic, or CT evidence of constrictive bronchiolitis Histopathologic findings traditionally considered unrelated to DIPNECH in the vicinity of PNELs |
| Essential Symptoms related to airway obstruction such as cough, breathlessness, and wheezing, often misdiagnosed as asthma CT findings of mosaic attenuation with or without bilateral pulmonary nodules <5 mm (i.e. probable tumorlets), or ≥5 mm (probable carcinoid tumors) Desirable Middle-aged women with dyspnea Pathological confirmation of multifocal neuroendocrine cell hyperplasia and/or tumorlet(s) |
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| 2. Pathological DIPNECH | ||
| Essential | ||
| Neuroendocrine cell hyperplasia and/or tumorlets, both usually multifocal | ||
| Desirable | ||
| Constrictive bronchiolitis is frequent, particularly in clinical DIPNECH | ||
| Carcinoid tumors, single or multiple, may be present | ||
| Multidisciplinary exclusion of reactive neuroendocrine cell hyperplasia and tumorlets either in association with lung neoplasms other than carcinoids or due to non-neoplastic lung disorders such as interstitial fibrosis or small airway disease other than constrictive bronchiolitis |
CT, computed tomography; DIPNECH, diffuse idiopathic pulmonary neuroendocrine cell hyperplasia; PNEC, pulmonary neuroendocrine cell; PNEL, pulmonary neuroendocrine lesion.
Our proposed definition may need refinement as data accumulate. We acknowledge that histopathologic confirmation is not always feasible in the clinical setting. In the research realm, however, we encourage our fellow investigators to limit their reports to histologically confirmed cases, at least until specific and validated clinico-radiologic criteria become available (Samhouri et al. 2020, Tassi et al. 2022). Also, we urge our fellow researchers to refrain from using case definitions that rely on ‘expert opinions,’ since this approach will only consolidate what we already know, or think we know about DIPNECH.
PNEC biology and pathophysiology
PNECs are situated within airway walls, can be solitary or in clusters (neuroepithelial bodies (NEBs)) (Boers et al. 1996, Noguchi et al. 2020), serve various functions, and their role in disease and health has been increasingly recognized (Noguchi et al. 2020, Andersson-Rolf et al. 2021). PNECs secrete numerous substances, some of which are fibrogenic (Zhou et al. 2013, Tighe et al. 2019, Kayalar et al. 2020, Noguchi et al. 2020, Kayalar & Oztay 2022), and were implicated in the pathogenesis of tissue fibrosis (including pulmonary and pleural fibrosis) occurring in carcinoid syndrome secondary to extrapulmonary NETs (Modlin et al. 2004, Blažević et al. 2018).
In DIPNECH, these substances are secreted in supraphysiologic quantities by hyperplastic PNECs and are thought to underlie the peribronchiolar fibrosis and constrictive bronchiolitis associated with this entity (Rossi et al. 2016, Samhouri et al. 2020). Plausibly, these substances may reach beyond adjacent airways to affect neighboring alveoli and pulmonary parenchyma, potentially causing interstitial fibrosis (He et al. 2012). Gastrin-releasing peptide (GRP), which is highly expressed by DIPNECH cells (Mengoli et al. 2018), deserves special mention in this context since it was found to stimulate the proliferation of pulmonary fibroblasts and their transdifferentiation into myofibroblasts, two instrumental steps in tissue fibrosis (Kayalar et al. 2020, Kayalar & Oztay 2022). GRP also orchestrates radiation-induced pulmonary fibrosis (Zhou et al. 2013, Tighe et al. 2019). Pertinently, Carr et al. (Carr et al. 2015) reported that 73% of their DIPNECH cohort had foci of subsegmental scarring or atelectasis on CT, while Samhouri et al. (Samhouri et al. 2020) reported that 9% of their DIPNECH cohort exhibited interstitial fibrosis on CT. Table 4 includes additional cases linking DIPNECH to interstitial lung disease.
PNECs express receptors that belong to the olfactory receptor family, which enables them to sense and react to inhaled chemicals, including nicotine (Noguchi et al. 2020). Data suggest that the peptides secreted by hyperplastic PNECs may mediate tobacco-related lung damage (Aguayo et al. 1990, Aguayo 1993, 1994, Noguchi et al. 2020). NECH developed more frequently in smokers than nonsmokers, and its development may precede the onset of COPD (Noguchi et al. 2020). Smokers with NECH were more likely to develop smoking-related lung diseases than smokers without NECH (Aguayo et al. 1990, Aguayo 1993). Further, Tassi et al. (Tassi et al. 2022) reported that histopathologic DIPNECH was connected to the presence of emphysema, noting that patients were matched according to age and smoking history, among other variables. Alshehri et al. (Alshehri et al. 1997) implicated diffuse PNEC hyperplasia in the development of presumably bombesin-mediated panacinar emphysema in a 6-year-old child.
NEBs serve as stem cell niche inasmuch they secrete peptides that act in a paracrine fashion to promote the proliferation and regeneration of surrounding epithelial cells;(Noguchi et al. 2020) in a murine model of acute lung injury, epithelial recovery occurred preferentially around NEBs (Giangreco et al. 2009). Once again, GRP can function as a growth factor, and its role in carcinogenesis is well-studied (Patel et al. 2006). Among smokers, those with higher GRP concentrations in bronchoalveolar fluid had higher risk of developing lung cancer (Quinn et al. 1991, Baniak et al. 2016). Of essence, PNEC-derived peptides promote dysregulated growth of non-PNEC lung epithelial cells, which ultimately leads to the development of lung cancers aside from carcinoid tumors (Sunday et al. 1994).
Future directions
Despite recent advances, DIPNECH remains elusive and its research is hindered by its rarity, which discourages pharmaceutical companies and research agencies from allocating funds to its study. This hurdle may be overcome by i) spreading awareness of DIPNECH among clinicians and radiologists, increasing its detection and ii) establishing collaborations across centers and creating a disease registry. For such collaborative efforts to succeed, a uniform and specific case definition is required. Unfortunately, current definitions are neither uniform nor specific, introducing detrimental biases to studies and inevitably leading to erroneous and conflicting conclusions. Thus, constructing a refined definition is urgently needed.
Researchers should focus on identifying specific and minimally invasive approaches to diagnosing DIPNECH. The value of existing biomarkers such as CG-A, GRP, and the NETest (whether in the serum or bronchoalveolar fluid) deserves studying, and novel biomarkers need to be identified. Diagnostic yield and safety of less invasive biopsy procedures, particularly transbronchial cryobiopsy deserve evaluation. As data mount, researchers may succeed in devising and validating diagnostic clinico-radiologic criteria that are highly sensitive and specific.
Clinical researchers should invest in conducting multicenter, placebo-controlled clinical trials that evaluate important short-term (respiratory symptoms control and health-related quality of life; respiratory system performance measured by serial PFTs and six-minute walk tests) and long-term outcomes (progression to carcinoid tumors and metastasis; need for oxygen supplementation and/or lung transplantation; disease-specific and all-cause mortality) in response to available therapies, of which SSAs and mTOR inhibitors seem most promising. At the time of writing this article, no clinical trials studying DIPNECH were underway (www.clinicaltrials.gov).
Basic science studies probing into DIPNECH pathobiology are desperately needed. Understanding its pathobiology will lay the foundation for identifying effective therapies and novel biomarkers. Its intriguing tendency to affect women and the extraordinarily unusual instances in which men were affected deserve exploration as these may provide priceless etiopathogenic insights (Samhouri et al. 2020). Similarly, the seldom familial cases (Cabezón-Gutiérrez et al. 2019) represent invaluable opportunities whereby potential genetic and/or environmental inciting factors could be discerned. Finally, the connection (if any exists) between DIPNECH and its putatively pediatric counterpart, neuroendocrine hyperplasia of infancy (Nevel et al. 2016, Mengoli et al. 2018), is another avenue worthy of exploration.
Conclusion
DIPNECH is an underrecognized entity characterized by PNEC hyperplasia, which may give rise to carcinoid tumorlets/tumors (Rossi et al. 2021). In some, constrictive bronchiolitis is present and manifests longstanding respiratory symptoms. In a middle-aged or elderly woman, identifying multiple noncalcified pulmonary nodules on CT warrants consideration of DIPNECH, particularly if mosaic attenuation and/or expiratory air-trapping are present (Samhouri et al. 2020, 2021). DIPNECH causes difficult-to-control respiratory symptoms but rarely leads to death from respiratory failure or metastatic cancer (Carr et al. 2015, Samhouri et al. 2020, Almquist et al. 2021a, Hayes et al. 2022, Tassi et al. 2022). Its diagnosis and management are challenging, and available data are sparse and of poor quality. Numerous basic science studies indicate that PNEC hyperplasia may contribute to the pathogenesis of lung diseases besides constrictive bronchiolitis and carcinoid tumors/tumorlets (Aguayo 1993, Noguchi et al. 2020). Currently employed DIPNECH definitions (Marchevsky et al. 2015, Rossi et al. 2021, Sun et al. 2022) actively exclude such possibilities despite strong pathobiologic merit and supportive clinical evidence (Carr et al. 2015, Samhouri et al. 2020). There is a desperate need for a unified and improved definition which accepts that DIPNECH, wherein numerous substances with biologically diverse effects are present in excess (Noguchi et al. 2020, Andersson-Rolf et al. 2021), is a disease spectrum rather than one predictable entity.
Declaration of interest
B F S has provided consultation (unpaid) to AI Therapeutics, that is unrelated to the present work. T R H received research support from Thermo Fisher Scientific, Advanced Accelerator Applications (a Novartis company), Camurus, Crinetics, and ITM Isotopen Technologien Muenchen, and is on the consultancy/advisory board for Ipsen, TerSera, Advanced Accelerator Applications, ITM isotopen technologien Muenchen, Crinetics, Viewpoint Molecular Targeting, and Camurus; none of these is related to the present work. C W K, C M, E S Y, C F T, and J H R have no conflicts to disclose.
Funding
This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.
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