Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH) with liver metastases

Abstract

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH) is a rare pulmonary disorder characterised by classic radiological findings and symptoms of obstructive lung disease. DIPNECH is considered a precursor to carcinoid tumours in the lungs. In this case, we describe a patient with years of unexplained dry cough presenting with 2 weeks of progressive nausea and vomiting, and found to have massive hepatomegaly on examination. By CT-PE, she was diagnosed with DIPNECH, and abdominal MRI revealed metastatic carcinoid tumours. Despite its non-specific presentation, DIPNECH has characteristic radiological findings of mosaic attenuation with numerous pulmonary nodules. DIPNECH requires early identification and close surveillance to prevent progression to carcinoid tumours. Thus, it is critical for frontline providers to consider this diagnosis as part of their differential when other common causes of obstructive lung disease have been ruled out.

Background

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH) is a rare pulmonary disorder recognised histologically as a proliferation of scattered pulmonary neuroendocrine cells (PNECs), tumorlets, and/or linear proliferations of these cells confined to the bronchial and bronchiolar epithelium.¹ Although the WHO definition is primarily based on histology, the disorder has been historically clinically diagnosed based on a classic constellation of radiological findings and symptoms of obstructive lung disease.^{2 3} DIPNECH is considered a precursor to carcinoid tumours in the lungs, but generally the risk of progression to malignancy is low.¹ We present a case of a patient diagnosed with DIPNECH along with numerous metastatic carcinoid tumours after years of unexplained pulmonary symptoms.

Case presentation

A woman in her 60s and a non-smoker presented to the emergency department with 2 weeks of progressive nausea, vomiting and abdominal pain. She also complained of a chronic non-productive cough despite no smoking history and a 20 pounds weight loss over the previous month. Past medical history included previous tuberculosis treatment and a documented history of diffuse bilateral pulmonary nodules by CT chest.

Vital signs on admission revealed blood pressure 146/78, pulse 117, temperature 37.4°C, respiratory rate 20 and SpO₂96%. Physical examination revealed bibasilar crackles in her lungs and a distended abdomen with hepatomegaly.

Investigations

An abdominal MRI (figure 1) was obtained that showed innumerable masses in both hepatic lobes consistent with metastatic lung carcinoid deposits. Patient became increasingly tachycardic over the course of the hospitalisation. A CT-PE study (figure 2) was obtained and was diagnostic for DIPENCH with findings of severe diffuse mosaic attenuation with innumerable bilateral lung nodules. Most of the nodules were along the small bronchovascular bundles, and many measured greater than 5 mm, with the largest (16.3 mmx12.9 mm, see figure 1) possibly representing the merging of multiple carcinoid tumours in the right middle lobe.

Figure 1.

Chest CT demonstrated severe mosaic attenuation with innumerable pulmonary nodules throughout the bilateral lung fields, mainly along the bronchovascular bundles. The largest nodules are located in the right lower lung, measuring 1.6×1.3 cm.

Figure 2.

MRI of the abdomen with contrast revealed hepatomegaly with numerous masses from metastatic disease in both lobes almost replacing the left lobe. Index lesions were 5.4×4.3 cm (pictured), 3.3×4.2 cm (pictured), and 4.3×3.4 cm (not pictured in this image).

An ultrasound-guided liver biopsy was performed and demonstrated atypical carcinoid tumour (WHO grade 2), likely metastatic from her lungs. Pathology confirmed that the biopsy was chromogranin and synpatophysin positive, consistent with a neuroendocrine tumour. The pathology specimen was also composed of neoplastic cells that were monomorphic in appearance, salt and pepper chromatin with focal areas of necrosis and nine mitosis per ten high power fields (9/10).

Additionally, a nuclear medicine spect scan for tumour localisation was performed which revealed a focal area of uptake in the right lower lung. There was physiological uptake noted in the kidneys and in the spleen and diffuse uptake was noted in the liver. 24 hours delayed images demonstrated some heterogenous uptake in the liver. However, there was no specific increased tracer concentration seen in the large tumour noted in the left lobe of the liver. SPECT-CT images were not obtained due to patient’s discomfort during scan.

Pulmonology, endocrine and oncology were consulted regarding the utility of a lung biopsy in diagnosis and development of a treatment plan. Given the liver metastases and radiological findings that strongly suggested the lung as primary source, it was decided that the biopsy results would not change the treatment plan. Patient was diagnosed with diffuse idiopathic neuroendocrine cell hyperplasia, leading to metastatic carcinoid tumour formation.

Differential diagnosis

Obstructive lung disorders, metastatic disease from intestinal source.

Treatment

Observation and surveillance, somatostatin analogues, such as octreotide, steroids or bronchodilators.

Outcome and follow-up

The patient’s tumour burden excluded her from being a candidate for surgical debulking. She was treated with octreotide but continued to decline. She developed sepsis, and the patient was eventually transitioned to home hospice.

Discussion

DIPNECH is a rare syndrome with only around 100 cases reported in the literature predominantly in case reports and case series. Aguayo and colleagues were the first to identify DIPNECH in a case series of six patients experiencing cough, dyspnea and obstructive lung disease.² The patients had diffuse neuroendocrine cell hyperplasia in their airways as well as fibrosis, and three also had carcinoid tumour.² Since that first report, numerous case reports and case series have been published, creating a profile of the DIPNECH patient. The majority of patients diagnosed with DIPNECH are middle-aged women and non-smokers, who present with symptoms of cough and dyspnea and have radiographic studies showing pulmonary nodules, bronchiectasis or mosaic attenuation.^4–6 Because of its non-specific presentation, DIPNECH can be a mimicker of sarcoidosis or tuberculosis and is commonly misdiagnosed. This underlines the importance of histological confirmation of pulmonary lung nodules. Surgical lung biopsy is the preferred method of diagnosis.¹ A specimen must have five or more neuroendocrine cells alone or clustered in the basement membrane of the epithelium of at least three bronchioles, and three or more carcinoid tumorlets.¹ These cells typically stain positively for the neuroendocrine markers synaptophysin, chromogranin and CD56.⁷

Patients with DIPNECH also have classic findings on radiological imaging. Chest CT scans typically show mosaic attenuation and numerous pulmonary nodules that are round, well-defined and without calcification.^{1 6}

DIPNECH is considered a precursor lesion for carcinoid tumour but generally, the clinical course remains stable. However, progression of the disease to subsequent carcinoid tumours does occur and can even progress to respiratory failure. The frequency of progression to carcinoid tumours remains unknown and varies in the literature. In a cohort study of 30 patients with DIPNECH, Carr and colleagues identified five of 18 patients who had pathological slides with carcinoid tumours present.⁸ In a separate cohort study by Myint and colleagues, five of 13 patients with DIPNECH had carcinoids identified.⁹

Carcinoid metastases can develop from sources other than the lung. In an epidemiologic study of neuroendocrine tumours and their primary sources, Riihimäki and colleagues demonstrated that the most common primary source of neuroendocrine tumour metastases to the liver is the small intestine.¹⁰ In 1842 cases, 56% of liver metastases originated in the small intestine, whereas 8% originated in the lung.¹⁰ Therefore, in patients with DIPNECH and carcinoid tumours, work-up should include other tumour markers, such as CDX2 or cytokeratin 20 to rule out gastrointestinal origin, or TTF1 or cytokeratin 7 to prove a lung origin. In our patient’s case, due to specialist recommendations and the patient’s prognosis and goals of care, this additional testing was not performed.

Management of DIPNECH usually consists of observation. No clinical guidelines exist for the use of octreotide, steroids or bronchodilators though they have been used per case reports.^{1 11} Several case reports and cohort studies have examined the effects of somatostatin analogues, such as octreotide, in patients with DIPNECH. Findings suggest that treatment with somatostatin analogues may improve symptoms of cough but do not improve pulmonary function tests.^{8 9} We identified a single study that included patients with metastatic disease. In contrast to our patient’s response to octreotide, in a study of three patients with DIPNECH and metastatic disease, Gorshtein and colleagues found that somatostatin analogues improved symptom of cough and stabilised disease progression.¹² Thus, a high index of suspicion is needed on the part of the internists to consider this diagnosis as part of their differential for patients with symptoms of obstructive lung disease along with subsequent close monitoring and surveillance.

DIPNECH is a rare disorder and can easily be misdiagnosed by the frontline provider because of its non-specific clinical presentation. We present this case of a patient who presented with DIPNECH and metastatic carcinoid tumours after years of unexplained symptoms to raise the awareness of DIPNECH and its risk of progression. DIPNECH should be considered as part of the differential diagnosis for patients who present with cough, dyspnea and classic radiology findings of DIPNECH on imaging so that patients may receive the proper monitoring and surveillance.

Learning points.

• Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH) is a rare pulmonary disorder that typically presents with symptoms of obstructive lung disease in middle-aged women who do not smoke.

• DIPNECH has a classic presentation on radiology as mosaic attenuation and numerous pulmonary nodules that are round, well-defined and without calcification.

• DIPNECH has rare consequences if left untreated, including carcinoid tumours, metastatic disease and respiratory failure.

• Primary care providers and hospitalists should include DIPNECH on their differential when other common causes of obstructive lung disease have been ruled out.