First-Line Therapy for Non-Small Cell Lung Cancer Including Targeted Therapy: A Brief Review

Richard A. Robbins, MD*

Thomas D. Kummet, MD**

*Phoenix Pulmonary and Critical Care Research and Education Foundation

Gilbert, AZ USA

**Sequim, WA USA 

Abstract

Operative removal of non-small cell lung cancer remains the mainstay of therapy. When this is not possible, cytotoxic chemotherapy and/or radiotherapy can be given but are marginally effective in prolonging overall survival. However, with a better understanding of the pathobiology of the lung cancer cells, new targeted therapies have been developed which may produce dramatic responses in selected patients. This brief review will emphasize these newer therapies in this rapidly evolving field.

Introduction

Lung cancer is extremely common and remains by far the most frequent cause of cancer-related death with approximately 154,050 deaths estimated to occur during 2018 (1). Although lung cancer deaths have declined in men, the deaths have risen in women and now account for nearly half of all women’s cancer deaths (1). Unfortunately, the vast majority are diagnosed with advanced, unresectable disease that remains incurable (1). Overall the five-year survival rate is <1% for advanced (stage IVB) disease, while the five-year survival rate for all stages is approximately 15 % (1).

Data linking cigarette smoking to human lung cancer is incontrovertible (2). The risk increases with both the amount of smoking and the duration of smoking (2). Passive or second-hand smoke is also associated with an increase in the risk of lung cancer, although this increase is far lower than that observed with active smoking (2). Smoking cessation clearly decreases the risk of lung cancer (2).

Primary lung cancers can be divided into two main types based on their histology, small cell lung cancer and non-small cell lung cancer (NSCLC) (3). NSCLC constitute about 85% of lung cancers with the rest consisting of small cell and some rarer cancers (3). A basic understanding of the pathobiology of NSCLC has shown that the tumor cells depend on the formation of new blood vessels (angiogenesis), transfer of a phosphate group from ATP to tyrosine on proteins (tyrosine kinase), and regulation of programmed death ligands (checkpoint proteins) (4). Targeted therapy against these pathobiologic processes have shown dramatic effects in some NSCLC patients (4).

NSCLC is divided into 4 stages designated by roman numerals (5). The stages are based on the size of the tumor; whether it has metastasized locally or distally; and use the TNM classification where T designates tumor size; N regional lymph node metastasis; and M distant metastasis. Stages I and II are limited to the chest but stage III has metastasized to the pleura and/or regional lung lymph nodes. Stage IIIA means the cancer has metastasized to lymph nodes that are on the same side of the chest as the cancer (ipsilateral) while stage IIIB signifies metastasis to lymph nodes on the opposite side of the chest (contralateral). Stage IV denotes there are distant metastasis outside the chest. The above is admittedly an oversimplification and there are subtle nuances that define the stages which can be found at the National Cancer Institute website (5).

An overall summary of standard preferred by the National Cancer Institute for NSCLC by stage is shown in Table 1 (6).

Table 1. Standard preferred therapy for NSCLC by stage (6).

Surgery

Operative removal of the lung cancer is the cornerstone of management for patients with early-stage (stages I–II) NSCLC and selected patients with stage IIIA disease (7). Lobectomy is the operation of choice for localized NSCLC based on a randomized trial of lobectomy versus more limited resection (8). Operative intervention should be offered to all patients with stage I and II NSCLC who clinically are medically fit for surgical resection. However, patients may be unable to undergo a lobectomy for a variety of reasons such as: 1. severely compromised pulmonary function; 2. multisystem disease making lobectomy excessively hazardous; 3. advanced age; or 4. refusal of the operation. Some patients who cannot tolerate a full lobectomy but may be able to tolerate a more limited sublobar operation (6). For patients in whom complete tumor resection cannot be achieved with lobectomy, sleeve lobectomy is recommended over pneumonectomy because it preserves pulmonary function (6). In addition, the question of whether video-assisted thorascopic surgery (VATS) is equivalent to thoracotomy for patients with lung cancer comes up often, particularly in patients that are less than ideal surgical candidates. In a series of 741 patients with stage IA NSCLC, 5-year survival was similar but VATS was associated with fewer complications and a shorter length of hospital stay (9).  Therefore, VATS is an optional surgical approach particularly in poorer risk patients.

Radiotherapy

Although lobectomy is the treatment of choice for NSCLC patients with early-stage disease, some are unable to undergo an operation due to reasons listed above. For those patients, radiotherapy can be administered with curative intent, albeit with lower overall survival rates when compared to surgery (10,11).

The radiation oncology community is excited about the potential of stereotactic body radiation therapy (SBRT) (12,13). SBRT is a type of external radiation therapy that uses special equipment to position a patient and precisely deliver radiation to tumors in the body (except the brain). Although there is no data yet, trials are ongoing comparing SBRT with surgery in early stage NSCLC.

Adjuvant Therapy

Adjuvant chemotherapy. Adjuvant chemotherapy is chemotherapy that is given in addition to either surgical and/or radiation therapy. Data from recent randomized adjuvant clinical trials and a meta-analysis support the use of adjuvant chemotherapy in NSCLC (14). A 5.4% five-year survival benefit was observed in a meta-analysis of five randomized trials compared to observation. Not surprisingly, the survival benefit varied according to stage but the benefit was most pronounced for patients with stage II and IIIA disease. Survival benefit in patients with stage IB disease did not reach statistical significance. Importantly, patients with stage IA disease appeared to do worse with adjuvant chemotherapy, and therefore, is not currently recommended.

Adjuvant radiotherapy. The PORT meta-analysis of 2,128 patients demonstrated that the use of post-operative radiotherapy was associated with a detrimental effect on survival (15,16). The decrease in survival was more pronounced for patients with lower nodal status. The PORT meta-analysis has been criticized for its long enrolment period and use of different types of machines, techniques and radiation doses. Despite these criticisms, three randomized phase III trials support the PORT meta-analysis’ conclusion that the use of post-operative radiotherapy provides no survival benefit (17-19). For patients with N2-positive disease, however, a retrospective analysis demonstrated higher survival for those patients who had received post-operative radiotherapy (20). On the basis of the above studies, most do not recommend routine post-operative radiotherapy with the possible exception of those with N2 disease.

Locally Advanced Disease

About a third of patients with NSCLC present with disease that remains localized to the thorax but may be too extensive for surgical treatment (stage III) (21). Concurrent chemotherapy and radiation therapy is considered the standard therapy for this situation but results in only a modest, although statistically significant, survival benefit compared with sequential administration (21). However, significant toxicity results from this approach and so it is usually offered only to those with good performance status.

Surgery after chemotherapy in patients with N2 disease was tested in two randomized trials. A European trial used three cycles of cisplatin-based chemotherapy, then randomized the patients to surgery or sequential thoracic radiotherapy (22). There was no significant difference in overall survival or progression-free survival. An American trial used a slightly different protocol (23). Patients with N2 disease were given two cycles with concurrent radiotherapy and then randomized to further radiation or surgery. This trial showed a better progression free survival with surgery but no difference in overall survival.

Metastatic Disease

About 40% of patients with NSCLC present with advanced stage IV disease. Until recently, cytotoxic chemotherapy was the cornerstone of treatment for stage IV disease but is now recommended as first line therapy alone only for patients with low or no expression of markers for targeted therapy (24). Unfortunately, in stage IV NSCLC standard cytotoxic chemotherapy alone is minimally effective. A meta-analysis that included 16 randomized trials with 2,714 patients demonstrated that cytotoxic chemotherapy offers an overall survival advantage of only 9% at 12 months compared with supportive care (25). Two-drug chemotherapy (doublets) appears to be superior to either a single agent or three-drug combinations (26). Cisplatin-based doublets are associated with a marginal one-year survival benefit compared with platinum-free regimens (27). Platinum-free regimens can be given as an alternative especially in patients who cannot tolerate platinum-based treatment (24). Although gemcitabine, vinorelbine, paclitaxel or pemetrexed are often added to either cisplatin or carboplatin, the choice of the second drug does not appear to matter in increasing survival (28).

Targeted Therapies

Starting in the early 2000s, NSCLC subtypes have evolved from being histologically described to molecularly defined. The use of targeted therapies in lung cancer based on molecular markers is a very rapidly changing field. At the time this article was being written (February 2018) the information was current but recommended therapies are likely to change with development of new therapies and research. It is important to point out that despite these advances, there remains no cure for stable IV NSCLC. Table 2 represents a summary of targets and targeted therapy along with the American Society of Clinical Oncology (ASCO) recommendations for stage IV NSCLC as of February 2018 (24).

Table 2. Targets and targeted therapies for NSCLC (24).

*Currently not recommended for clinical use by ASCO.

The need for adequate tissue to perform molecular studies creates challenges for pulmonologists doing bronchoscopic procedures. Whereas it was previously adequate to obtain diagnostic material. However, it is now important to obtain adequate tissue to perform additional molecular testing to allow determination of whether targeted therapies are appropriate. Sometimes tissue is inadequate which might necessitate a second procedure if clinically warranted.  

Vascular Growth Factors

Epidermal Growth Factor Receptor (EGFR). The EGFR pathway represents the pioneer of personalized medicine in lung cancer. EGFR is a transmembrane receptor that is highly expressed by some NSCLCs. Binding of ligands (epidermal growth factor, tumor growth factor-alpha, betacellulin, epiregulin or amphiregullin) to the extracellular EGFR domain results in autophosphorylation through tyrosine kinase activity (29). This initiates an intracellular signal transduction cascade that affects cell proliferation, motility and survival (29). Inhibition of ligand and EGFR binding or the activation of tyrosine kinases inhibit the downstream pathways resulting in inhibition of cancer cell growth (29).

Initial studies showed that most patients with NSCLC had no response to the tyrosine kinase inhibitor (TKI), gefitinib, which targets phosphorylation of EGFR (30). However, about 10 percent of patients had a rapid and often dramatic clinical response (30). An explanation for these results occurred with the identification of mutations of the tyrosine kinase coding domain (exons 18–21) of the EGFR gene. Subsequent research linked these mutations to the clinical response to gefitinib (31,32). Although about 10% of Caucasian NSCLC have these mutations, the mutations were observed more commonly in Asian patients, particularly non-smoking women (33). There is now overwhelming and consistent evidence from multiple trials that all the approved EGFR-TKIs (gefitinib, erlotinib, or afatinib) have greater activity than platinum-based chemotherapy as the first-line treatment of patients with advanced NSCLC with activating EGFR mutations (24).  These agents have more favorable toxicity profiles than platinum-based chemotherapy and have demonstrated improvements in quality of life. The choice of which EGFR-TKI to recommend to patients should be based on the availability and toxicity of the individual therapy. Randomized clinical trials are ongoing comparing EGFR-TKIs. The results of these trials may help refine this in the future.

Despite high tumor response rates with first-line EGFR-TKIs, NSCLC progresses in a majority of patients after 9 to 13 months of treatment. At the time of progression, approximately 60% of patients (regardless of race or ethnic background) are found to have a Thr790Met point mutation (T790M) in the gene encoding EGFR (34). The presence of the T790M variant reduces binding of first-generation EGFR-TKIs to the leading to disease progression (34). Osimertinib is an irreversible EGFR-TKI that can bind to EGFR despite the T790M resistance mutations and has recently become clinically available (35). Currently it is recommended for T790M mutations that occur after the first-line EGFR-TKIs have failed (24).

Cetuximab is a monoclonal antibody directed against EGFR itself. In the past, addition of cetuximab to cisplatin doublet chemotherapy in EGFR positive tumors was usual. However, cetuximab has recently been shown to shorten progression free survival with some adverse effects and is no longer recommended (24).

Vascular endothelial growth factor (VEGF). Angiogenesis, the formation of new blood vessels, is a fundamental process for the development of solid tumors and the growth of secondary metastatic lesions. Vascular endothelial growth factor (VEGF) acts to promote normal and tumor angiogenesis. Bevacizumab, a recombinant, humanized, monoclonal antibody against VEGF, was previously recommended as first-line therapy in stage IV NSCLC patients without a contraindication. However, the most recent ASCO guidelines finds insufficient evidence to recommend bevacizumab in combination with chemotherapy as first-line treatment (24).

Other Kinase Inhibitors. Receptor tyrosine kinase 1 (ROS1) and the structurally similar anaplastic lymphoma kinase (ALK) are enzymes that are critical regulators of normal cellular activity. In NSCLC rearrangements of these genes can cause them to act as oncogenes, or genes that transform normal cells into cancer cells. Rearrangements in the ROS1 or ALK genes are found in a small percentage of patients with NSCLC. Crizotinib is a molecule that blocks both the ROS1 and ALK proteins. Crizotinib reduced tumor size in ALK+ or ROS1+ positive patients although the most recent ASCO guidelines consider the evidence only moderate with ALK+ and weak with ROS1+ patients (24,36-8).

Checkpoint Inhibitors. An important part of the immune system is its ability to tell the difference between normal cells and those that are “foreign”. To do this, it uses “checkpoints”, molecules on certain immune cells that need to be activated (or inactivated) to start an immune response (39). NSCLC can use these checkpoints to avoid being attacked by the immune system. Programmed cell death protein 1 (PD-1) is a checkpoint protein on T cells. It normally acts as an “off switch” when it attaches to programmed death-ligand 1 (PD-L1), a protein on some normal (and cancer) cells. Some NSCLCs have large amounts of PD-L1, which helps them evade immune attack. Monoclonal antibodies that target either PD-1 or PD-L1 can block this binding and boost the immune response against NSCLC cells. In patients with NSCLC with >50% of their tumor cells PD-1+ (tumor proportion score >50%), pembrolizumab, a monoclonal antibody against PD-1, significantly prolonged progression-free and overall survival compared to platinum-based chemotherapy (40). Based on this trial, pembrolizumab is now recommended by ASCO for patients with a tumor proportion score >50% for PD-1 (23). A number of other PD-1 (e.g., nibolumab) and PD-L1 inhibitors (e.g., atezolizumab, avelumab, durvalumab) exist but ASCO recommends only pembrolizumab at this time (39,40). As more of these checkpoint inhibitors are developed and tested this will likely change.

Second and Third-Line NSCLC Therapy

Second and third-line therapy for NSCLC is beyond the scope of this brief review. It is a rapidly evolving field which should include close collaboration between the pulmonologist, oncologist and other members of the patient’s NSCLC treatment team.

After an initial response, lung cancers can become resistant to therapy. One example mentioned above is the development of the T790M mutation in EGFR+ NSCLC.  In selected instances rebiopsy of the primary tumor or metastases can direct a new, effective therapy. Obviously, it is not possible to rebiopsy every NSCLC patient after failure of the initial therapy. However, other techniques are being investigated. One is liquid biopsy where blood is drawn and subjected to molecular techniques to determine a possible cause for tumor resistance.  Multiple liquid biopsy molecular methods are presently being examined to determine their efficacy as surrogates to the tumor tissue biopsy (41).

Future Directions

The combination of a variety of existing therapies for NSCLC is being evaluated. These will likely yield revised recommendations for therapy. In addition, a variety of therapies, both existing for other cancers, or newer therapies in development are being tested.  These include both monoclonal antibodies and biologic inhibitors (Table 3).

Table 3. Potential new targeted therapies for NSCLC (42,43).

The numbers of pathways and drugs being tested is very impressive and the clinical responses can be dramatic in some patients. One might be tempted to conclude that these therapies might result in a “cure” for NSCLC. However, most of these mutations occur in a small minority of NSCLCs. Furthermore, even if initially successful, resistance to targeted therapies may quickly develop limiting their clinical usefulness in NSCLC.

Targeted therapies may also have potential as adjuvant therapies. In support of this concept, a recent phase 3 study compared durvalumab as consolidation therapy with placebo in patients with stage III NSCLC who did not have disease progression after two or more cycles of platinum-based chemoradiotherapy (44). The progression-free survival was 16.8 months with durvalumab versus 5.6 months with placebo (p<0.001). It seems likely that more trials using targeted therapy earlier in cancer therapy will be done.

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Cite as: Robbins RA, Kummet TD. First-line therapy for non-small cell lung cancer including targeted therapy: A brief review. Southwest J Pulm Crit Care. 2018;16(3):157-67. doi: https://doi.org/10.13175/swjpcc038-18 PDF 

March 2018 Pulmonary Case of the Month

Thomas D. Kummet, MD

Sequim, WA USA

Pulmonary Case of the Month CME Information

Completion of an evaluation form is required to receive credit and a link is provided on the last panel of the activity. 

0.25 AMA PRA Category 1 Credit(s)™

Estimated time to complete this activity: 0.25 hours

Lead Author(s): Thomas D. Kummet, MD.  All Faculty, CME Planning Committee Members, and the CME Office Reviewers have disclosed that they do not have any relevant financial relationships with commercial interests that would constitute a conflict of interest concerning this CME activity.

Learning Objectives: As a result of completing this activity, participants will be better able to:

1. Interpret and identify clinical practices supported by the highest quality available evidence.
2. Establish the optimal evaluation leading to a correct diagnosis for patients with pulmonary, critical care and sleep disorders.
3. Translate the most current clinical information into the delivery of high quality care for patients.
4. Integrate new treatment options for patients with pulmonary, critical care and sleep related disorders.

Learning Format: Case-based, interactive online course, including mandatory assessment questions (number of questions varies by case). Please also read the Technical Requirements.

CME Sponsor: University of Arizona College of Medicine at Banner University Medical Center Tucson

Current Approval Period: January 1, 2017-December 31, 2018

Financial Support Received: None

History of Present Illness

The patient was a 62-year-old woman who complained of a sudden severe increase in a three-month history of mild left upper extremity pain. 

PMH, SH and FH

The patient had no significant past medical history. She is a non-smoker. Family history is non-contributory.

Physical Examination

• Vital Signs: Pulse 102 beats/min, blood pressure 140/84 mm Hg, respirations 16 breaths/min, Temperature 37.4º C, SpO2 94% on room air.
• Lungs: Clear.
• Heart: Regular rhythm.
• Abdomen: without organomegaly, masses or tendernesses.
• Extremities: Both upper extremities were unremarkable. The left shoulder had a full range of motion. Pulses were intact bilaterally and equal.
• Neurologic: Upper extremity strength was good and equal. Light touch and pin prick were intact. Deep tendon reflexes were well preserved.

Which of the following are indicated in management at this time? (Click on the correct answer to proceed to the second of seven pages)

1. Reassurance that the pain will improve
2. Shoulder x-ray
3. Treatment with oxycodone
4. 1 and 3
5. All of the above

Cite as: Kummet TD. March 2018 pulmonary case of the month. Southwest J Pulm Crit Care. 2018;16(3):110-6. doi: https://doi.org/10.13175/swjpcc033-18 PDF

February 2018 Pulmonary Case of the Month

Lewis J. Wesselius, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ USA

History of Present Illness

A 75-year-old woman was diagnosed with a thymic carcinoid tumor in April, 2015 (Figure 1).

Figure 1. Representative image from the preoperative CT scan performed in April 2015 showing an anterior mediastinal mass (arrow).

This was treated with surgical resection followed by radiation therapy.

She began having cough and dyspnea 1 to 2 months later and in August, 2015 had a thoracic CT scan of her chest (Figure 2).

Figure 2. Representative image in lung windows from the second thoracic CT scan performed in August 2015.

Which of the following are true? (Click on the correct answer to proceed to the second of six pages)

1. Bronchoscopy should be performed
2. She should be given an empiric course of antibiotics
3. The most like diagnosis is radiation pneumonitis
4. 1 and 3
5. All of the above

Cite as: Wesselius LJ. February 2018 pulmonary case of the month. Southwest J Pulm Crit Care. 2018;16(2):55-61. doi: https://doi.org/10.13175/swjpcc020-18 PDF 

January 2018 Pulmonary Case of the Month

Lewis J. Wesselius, MD

 Departments of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ USA

History of Present Illness

A 67-year-old man from Idaho was seen in November 2017 for a second opinion. He has a history of slowly progressive dyspnea on exertion for 7 to 8 years. He has a significant smoking history of 50 pack-years, but is still smoking “a few cigarettes”.

He saw an outside pulmonologist in September 2017 and was noted to have abnormal pulmonary function testing with the primary abnormality being a low DLco. A thoracic CT Scan was reported to be abnormal with evidence of interstitial lung disease. He underwent video-assisted thorascopic surgery and the biopsies were reported to show usual interstitial pneumonitis (UIP). His pulmonologist questioned whether this was interstitial pulmonary fibrosis or UIP associated with rheumatoid arthritis.

PMH, SH and FH

He has a history of rheumatoid arthritis and had been treated with methotrexate for approximately 8 years. His methotrexate had been discontinued in September with no change in symptoms. FH is noncontributory.

Medications

Prednisone 5 mg/daily and tiotropium (these also did not change his dyspnea).

Physical Examination

• Chest:  bibasilar crackles.
• Cardiovascular:  regular rhythm without murmur.
• Ext:  no clubbing, no edema, no joint deformity noted

Which of the following are indicated at this time? (Click on the correct answer to proceed to the second of five pages)

1. Obtain a complete blood count and rheumatoid factor
2. Begin pirfenidone or nintedanib
3. Review his pulmonary function testing and radiographic studies
4. 1 and 3
5. All of the above

Cite as: Wesselius LJ. January 2018 pulmonary case of the month. Southwest J Pulm Crit Care. 2018;16(1):8-13. doi: https://doi.org/10.13175/swjpcc157-17 PDF

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia in a Patient with Multiple Pulmonary Nodules: Case Report and Literature Review

Hasan S. Yamin, MD¹

Feras Hawarri, MD¹

Mutaz Labib, MD¹

Ehab Massad, MD²

Hussam Haddad, MD³

Departments of ¹Internal Medicine Pulmonary & Critical Care Division, ²Thoracic Surgery and ³Pathology

King Hussein Cancer Center

Amman, Jordan

Abstract

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare pulmonary disease, where carcinoid tumorlets invade the pulmonary parenchyma and bronchioles. These nests of cells release a variety of mediators including bombesin and gastrin releasing peptide that cause heterogeneous bronchoconstriction, creating a mosaic appearance on chest imaging studies, especially on expiratory scans. Clinically patients usually have long standing symptoms of shortness of breath (SOB) and cough that are difficult to distinguish from asthma. In this article we describe a case of DIPNECH in a patient with several years’ history of SOB and cough, and review 179 cases of DIPNECH reported in the literature since 1992.

Case Presentation

A 72-year-old, non-smoking lady was admitted to the hospital in preparation for bilateral mastectomy. She recently received a diagnosis of bilateral breast invasive ductal carcinoma grade 2, estrogen receptor/progesterone receptor/human epidermal growth factor receptor 2 (HER-2) positive in the left tumor but negative in the right tumor.

Her past medical history was significant for hypertension, long standing cough and dyspnea on exertion labeled as asthma poorly responsive to nebulizers. Socially, she was a house wife with no history of occupational exposure.

The patient was found to be tachypneic (respiratory rate 22 breaths/minute) and hypoxemic (oxygen saturation 86% on room air). Heart rate and blood pressure were within normal limits. She had bilateral decreased breath sounds and diffuse expiratory wheezes.

Chest CT scan revealed diffuse mosaic pattern and multiple pulmonary nodules in both lungs suggestive of metastases (Figure 1).

Figure 1. Representative images form chest CT scan showing a diffuse mosaic pattern and multiple pulmonary nodules in both lung fields suggestive of metastases.

These lesions did not take up fludeoxyglucose (FDG) on positron emission tomography (PET) scan. Her pulmonary function tests (PFT) were unremarkable except for reduction in expiratory reserve volume (ERV) at 22%, and increased residual volume to total lung capacity ratio (RV/TLC) at 136% probably related to air trapping. Diffusion lung capacity was within normal limits.

Video assisted thoracoscopic biopsy of one of the nodules in left lower lobe was done. Pathology showed both a carcinoid tumor and tumorlets invading lung bronchioles (Figure 2A & B) and these tumorlets were positive for chromogranin (Figure 2C & D) and pancytokeratin (Figure 2 E & F).

Figure 2. A & B: histology (H&E stain) showing carcinoid tumorlets invading lung bronchioles; C & D: positive staining for chromogranin; E &F: positive staining for pancytokeratin.

A diagnosis of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) was made, and the patient was treated with intravenous steroids and nebulizers. Her oxygen saturation improved to 94% on room air. She was later discharged on oral steroids. Her CT scan also showed no significant improvement in changes described above.

Review of the Literature

Methods

We searched PubMed for all cases of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia reported in the English literature since 1992 when the entity was first described. A total of 179 patients were identified in 55 articles, in the form of case reports and case series. In this article we contribute an additional patient (1-55).

Patient Characteristics

A total of 180 patients (including our patient) were identified. There were 161 females (89.5%) and only 19 males (10.5%). Mean age at diagnosis was 57.75 years (males tended to present at a younger age of 52 years, compared to 58.4 years in females). Most patients were never smokers 52.8%, smokers/exsmokers 27.2%, and in 20% smoking status was not mentioned.

The majority of patients presented with cough (91 patients, 50.5%), followed by exertional dyspnea (81 patients, 45%), and hemoptysis (6 patients, 3.3%). Incidental imaging findings led to diagnosis in 22 patients (12.2%). Mean duration of symptoms before diagnosis was 8.25 years (Table 1).

Table 1. Patients` characteristics and presenting symptoms.

Diagnosis, Therapy and Outcome

Most patients underwent imaging with chest CT scan, the most common findings were nodules in 148 patients (82.2%), ground glass opacities/mosaic pattern in 66 patients (36.6%), and bronchial wall thickening in 37 patients (20.5%). Most patients had an abnormal spirometry: obstructive pattern (48.9%), restrictive (5%), or mixed obstructive restrictive pattern (6.7%) (Table 2).

Table 2. Spirometry and imaging.

Because of their symptoms, and spirometry findings 45 patients (25%) were labeled with another disease including asthma in 29 patients (16.1%), COPD in 12 patients (6.6%) and bronchiolitis in 4 patients (2.2%).

The diagnosis was made using surgical lung biopsy in 148 patients (82.2%), bronchoscopic biopsy in 10 patients (8 transbronchial biopsy, 2 endobronchial biopsy) (5.6%), CT-guided biopsy in 7 patients (3.9%), postmortem diagnosis in 3 patients (1.7%), post lung transplantation in 2 patients (1.1%) and clinically in 2 patients (1.1%). The diagnostic method was not mentioned in 8 patients (4.4%).

Patients received a variety of therapies including inhaled bronchodilators, inhaled or systemic steroids, and somatostatin analogues among others. Response to treatment was mentioned for 89 patients, (59 patients reported that their symptoms remained stable, 11 patients improved with treatment, while 18 patients reported symptom progression and 2 patients died. (Table 3).

Table 3. List of DIPNECH articles ordered by publication year. This table shows number of patients in each article, diagnostic method, therapy given and outcome.

Of note, 15 out of 23 patients who received a somatostatin analogue reported stable, or improvement in their symptoms (65.2%), which did not necessarily translate into improvement in air flows on spirometry (27, 29, 46, 51).

Discussion

Pulmonary neuroendocrine cell hyperplasia was described early in the previous century (56), however the significance and role of the pathologic changes were not precisely determined. It was thought that they were secondary to other lung diseases such as interstitial lung disease, bronchiectasis, cystic fibrosis, smoking exposure, or in people who live at high altitude. In addition to the previously mentioned associations, hyperplasia of pulmonary neuroendocrine cells was also thought to be a pre-neoplastic process, since the lesions can potentially progress to carcinoid tumors even without causing symptoms or airflow limitation. In 2004 the changes were recognized by WHO as one end of the spectrum of pulmonary neuroendocrine tumors.

The relationship between carcinoid tumorlets and other pulmonary diseases and its role in precipitating respiratory symptoms remains puzzling. The term DIPNECH was coined in 1992 by Aguayo (1) who described a new entity where idiopathic hyperplasia or dysplasia of pulmonary neuroendocrine cells occurred in the absence of other lung disorders. The changes were associated with physiologic and radiologic airflow limitation similar to obliterative bronchiolitis. This was the first description of pulmonary neuroendocrine hyperplasia as a primary process.

Because of similar symptoms, an obstructive pattern on pulmonary function tests, and chest imaging suggestive of air trapping, many patients receive a diagnosis of asthma for several years before the correct diagnosis is made. This similarity to other obstructive lung diseases can be explained by the pathologic changes of airway obstruction seen on biopsy. Pulmonary neuroendocrine cells, or Kulchitsky cells, are normally present in small numbers in airways, where they release a myriad of bioactive amines and peptides like serotonin, chromogranin A, gastrin-releasing peptide (GRP), and calcitonin.

Airway obstruction is believed to occur both due to physical obstruction of bronchioles by tumorlets and smooth muscle constriction caused by active mediators released. Bombesin and related peptides like gastrin releasing peptide, neuromedin B and neuromedin C are thought to cause bronchoconstriction indirectly through the release of several other bronchoconstrictors that act on smooth muscle cells (57). However, in vitro studies in guinea pig lungs suggest that bombesin may act directly by binding to specific receptors on smooth muscle cells (58).

Pulmonary neuroendocrine pathology occurs in a spectrum of three forms: hyperplasia, tumorlets and carcinoid tumors. DIPNECH is characterized by proliferation of neuroendocrine cells initially limited to the basement membrane of airways, when disease extends beyond the lumen of airway it is called carcinoid tumorlets. Tumorlets larger than 0.5 cm become carcinoid tumors and appear as nodules on chest CT scans. Diagnosis requires lung biopsy, with a surgical biopsy procedure more likely to provide diagnostic tissue than bronchoscopic transbronchial biopsies.

According to Aguayo`s definition of DIPNECH, patients have pulmonary symptoms with radiographic and physiologic abnormalities suggestive of obstructive lung disease, but in our review 12.2% of patients had no symptoms at all, and 15.5% had normal spirometry. We believe hyperplasia, tumorlets and carcinoid tumors represent different aspects of the same disease, the occurrence of symptoms, radiologic and physiologic airflow limitation depends on the time frame at which diagnosis was made, should those patients be followed up, they could develop symptoms and airflow limitation in the future. Thus, we propose to expand the definition to include patients with no symptoms or spirometry abnormalities. However, it remains uncertain whether asymptomatic patients who are diagnosed at an earlier stage need specific treatment or not.

It is also clinically difficult to establish a causal relationship, or determine the direction of the relationship between pulmonary neuroendocrine cell hyperplasia and other concomitant lung disorders, or harmful exposures (1,59, 60). In our review 27.2% of patients were active or previous smokers, only one patient lived at high altitude (more than 2000m) (14), 29 patients had a history of previous or current malignancy including 8 lung cancers (not shown in table), 13 patients had evidence of bronchiectasis, and one patient had honeycombing on imaging. These findings are similar to data obtained from individual case reports and series (2, 6, 14, 17, 19, 22, 29, 33, 37, 46, 47 and 53).

When the diagnosis is made, therapeutic options may include observation for mild symptoms, inhaled or systemic steroids, in addition to bronchodilators, especially if patients who show reversible airway obstruction on PFT. Other potential therapies are somatostatin analogues, however more studies are needed to determine their precise role. (27, 29, 43, 46)

Conclusion

DIPNECH is a rare clinical entity that requires a high clinical suspicion. Because of clinical, spirometry, and imaging similarity to other obstructive lung diseases, and the requirement for lung biopsy to make the diagnosis, DIPNECH is probably an under-diagnosed entity, with still limited treatment options. The diagnosis should probably be considered in any patient with difficult to treat obstructive lung disease, unexplained bronchiolitis, particularly if there are multiple small lung nodules present on chest CT scan. We propose to expand the definition of DIPNECH to include patients with even no symptoms or spirometric evidence of airflow limitation, as development of these abnormalities depends on the time frame at which diagnosis is made. It is also difficult to establish a causal relationship with other concomitant lung conditions, the presence of which should not rule out a diagnosis of DIPNECH.

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Cite as: Yamin HS, Hawarri F, Labib M, Massad E, Haddad H. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia in a patient with multiple pulmonary nodules: case report and literature review. Southwest J Pulm Crit Care. 2017;15(6):282-93. doi: https://doi.org/10.13175/swjcc139-17 PDF