Pulmonary mucinous cystadenocarcinoma: an unusual presentation and literature review

Abstract

Cystic lung disease is a group of heterogeneous pulmonary diseases resulting from hereditary/congenital disorders, systemic disorders and infectious causes among others. Pulmonary mucinous cystic neoplasia is a spectrum of neoplastic cystic diseases with abundant mucin, of which pulmonary mucinous cystadenocarcinoma (PMC) is a rare malignant subtype. We present a case of a 66-year-old man who presented with dyspnoea, cough, fatigue and weight loss. Imaging of his chest showed numerous cavitary lesions, and the diagnosis of PMC was made based on lung biopsy. He received palliative chemotherapy and died 1 year later. We present a literature review of PMC based on 26 reported cases, including our own.

Background

Pulmonary mucinous cystadenocarcinoma (PMC) is an extremely rare lung tumour, which was first described by Devaney et al in 1989.^{1 2} It is considered a part of the spectrum of pulmonary mucinous cystic neoplasia (PMCN) with cystic neoplasms that produce extracellular mucin secretion.³ We present a unique case of PMC with extensive diffuse and bilateral involvement of the lungs, and add to the documentation of this rare disease, of which we found only 25 other reports in our review of literature.

Case presentation

The patient was a 66-year-old male ex-smoker with a history of chronic obstructive pulmonary disease who presented with progressive cough. The cough was productive of mucoid whitish, non-bloody sputum and had associated symptoms of shortness of breath, fatigue, anorexia, generalised weakness and unintentional weight loss of 30 pounds for 3 months. On examination, the patient was noted to have rhonchi bilaterally, with the remainder of the examination being normal.

Investigations

Chest radiograph (CXR) revealed bilateral diffuse patchy alveolar infiltrates (figure 1). CT of the thorax revealed bilateral alveolar consolidations and numerous cavitary lesions with mediastinal and right hilar lymphadenopathy (figure 2). Bronchoscopy with bronchoalveolar lavage and transbronchial biopsy was performed. Histopathological analysis and cytology were negative for malignancy but yielded the growth of Streptococcus pneumoniae and yeast. Quantiferon-TB gold, acid fast stain, ß-D Glucan assay and serological testing for histoplasma, blastomyces as well as aspergillus serology were negative. He was treated with antibiotics and discharged. At follow-up, the patient reported no improvement in symptoms. Collagen vascular serology testing, including antinuclear antibody and antineutrophil cytoplasmic antibody, was negative.

Figure 1.

CXR demonstrating bilateral diffuse patchy alveolar infiltrate in the lungs. CXR, chest radiograph.

Figure 2.

CT scan demonstrating bilateral alveolar consolidation and cavitary lesions.

A repeat bronchoscopy with endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) of the paratracheal lymph nodes and parenchyma was non-diagnostic. Robotic-assisted thoracic surgery (RATS) with biopsies of the right upper lobe and right lower lobe was subsequently performed; histopathology revealed well-differentiated mucinous cystadenocarcinoma with rare non-caseating granulomas (figures 3 and 4). Further analysis with immunohistochemical testing and fluorescence in situ hybridisation analysis was negative for mutations in the endothelial growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) gene, with a PD-L1 expression less than 1%. Positron emission tomography-computed tomography (PET-CT) showed multiple bilateral cavitary pulmonary lesions with no hypermetabolic activity. Repeat RATS with wedge resection of the left upper and lower lobes and subsequent histopathology revealed well-differentiated metastatic mucinous cystadenocarcinoma in the left lower lobe.

Figure 3.

Histopathology with well-differentiated mucinous adenocarcinoma and cyst development.

Figure 4.

Single layered, tall columnar, mucin producing neoplastic epithelium growing in tufts and lepidic pattern.

Treatment

The patient was staged at pT4NxcM1a (Stage IV) given the metastasis to the contralateral lung, although it was unclear which side had been the site of the primary lesion. He was started on palliative chemotherapy with a combination of carboplatin, pemetrexed and pembrolizumab, of which he received four cycles over 3 months.

Outcome and follow-up

Throughout this time period, the patient’s respiratory status declined, and he developed chronic hypoxic respiratory failure, becoming oxygen dependent. A follow-up CXR (figure 5) and chest CT (figure 6) after initial treatment revealed progressive bilateral cavitary lesions with worsening ground glass opacities, prompting the initiation of docetaxel as a second-line treatment option. He was hospitalised 2 months later with acute and progressive hypoxic respiratory failure. A discussion regarding his dismal prognosis and goals of care ensued, resulting in the initiation of comfort-oriented conservative treatment, with the subsequent peaceful demise of the patient.

Figure 5.

Postchemotherapy CXR demonstrating progressive airspace opacities. CXR, chest radiograph.

Figure 6.

Postchemotherapy CT demonstrating worsening cavitary lesions.

Discussion

PMC is considered a part of the spectrum of PMCN, along with other disease entities including mucinous cystadenoma and mucinous cystic tumour of borderline malignancy.³ PMCN was initially described by Gower in 1978.⁴ Gao et al propose a set of diagnostic criteria to define PMCN, summarised as follows:

1. Cystic gross appearance with or without a fibrous wall.

2. Solitary well-circumscribed lesion in the lung parenchyma with no evidence of carcinoma in situ in the bronchial mucosa to suggest endobronchial origin of the tumour.

3. Greater than 90% of the tumour bulk consisting of mucin.

4. Neoplastic epithelial cells are mucin-producing cells that can be floating in the mucin or lining the fibrous wall.

5. No other primary mucinous malignant neoplasm after extensive clinical workup.³

PMC, the malignant subtype of PMCN, was first reported by Devaney et al in 1989.² It is considered to be the pulmonary counterpart to similar tumours in the ovaries, pancreas and breast.⁴ We use the designation ‘pulmonary mucinous cystadenocarcinoma’ for the purposes of this discussion and for our literature review, but it should be noted that the 2015 WHO Classification of lung tumours does away with the term ‘mucinous cystadenocarcinoma’ and includes these cases under the category of colloid carcinoma.⁵ PMC is an extremely rare entity; our literature review yielded 25 reported cases of PMC,^{3 6–24} which we have summarised along with our case here.

PMC is a rare, slow growing tumour with limited malignant potential. There appeared to be no gender predilection in our review of cases (table 1). The median age at presentation was 63.5 years, and PMC has been diagnosed in patients as young as 29 years old. The presence of abundant mucin with only scarce neoplastic cells makes preoperative diagnosis with cytology and biopsy challenging. PMC is usually asymptomatic and is often found as an incidental finding on imaging. In symptomatic patients, the most common findings are shortness of breath, recurrent postobstructive pneumonia, cough, chest pain and haemoptysis. PMC usually has a slow progression where the cystic lesion grows without compromising breathing and without metastasising outside the lung.³

Table 1.

Review of reported PMC cases

Author	Year	Age	Sex	Risk factor	Lobe	Dimensions	Treatment	Outcome
Butnor et al13	2001	75	M	Smoker	RUL	3×2.5×2.5 cm	Lobectomy	Well at 2.5 months
Chhieng14	2008	64	M	Smoker, asbestos exposure	RUL	7.5×10 cm	Lobectomy	Well at 12 months
Choi et al6	2013	54	F		RML	4.5×3.5×2.5 cm	Lobectomy	Well at 9 months
Efstathiou et al15	2011	56	M	Smoker	RLL	9.3×7.5 cm	Lobectomy	Well at 6 months
Gaeta et al7	1999	45	M		LLL	5 cm	Surgery	Well at 6 years
Gaeta et al7	1999	60	F		LUL	4 cm	Surgery	Well at 2 years
Gaeta et al7	1999	55	F		RLL		Surgery	Well at 18 months
Gao and Urbanski3	2005	50	F	Smoker	RML	4 cm	Lobectomy	Death at 3 years (metastasis)
Gao and Urbanski3	2005	73	M		RUL	2.8 cm	Lobectomy	Death at 1 year (metastasis)
Gao and Urbanski3	2005	71	M	Smoker	RUL	1.5 cm	Lobectomy	Death at 2 years (metastasis)
Gao and Urbanski3	2005	64	F		RUL	4 cm	Lobectomy	Well at 1 year
Higashiyama et al16	1992	75	M	Smoker		2.4×1.6 cm	Segmentectomy	Death at 10 months (MI)
Higashiyama et al16	1992	73	M	Smoker	LLL	3.2×2.7 cm	Lobectomy	Well at 4 months
Imad et al17	2005	64	F		RUL	8×8×6 cm	Lobectomy	Well at 6 months
Ishibashi et al18	2003	42	F	Non-smoker	LLL	5.3×4×3.8 cm	Lobectomy	Well at 2 years
Iwasaki et al12	2007	75	F	Non-smoker	RLL	4.8×3.8 cm	Lobectomy	Well at 14 months
Kalkanis et al19	2016	63	M		RUL	18 mm	Pemetrexed, cisplatin	Death at 10 months
Kassir et al8	2013	49	M	Former smoker, asbestos exposure	RLL	5×7 cm	Wedge resection	Well at 5 years
Moneke et al20	2018	58	F		LUL	12×7.5 cm	LUL resection	Well at 12 months
Moon et al9	2013	35	M	Smoker	R hemithorax	10×7×3 cm	Wedge resection	Well at 12 months
Raza et al11	2019	67	F	Smoker	RUL			No follow-up
Sánchez-Carpintero Abad et al21	2011	67	F	Smoker	RUL	3.6 cm	Thoracotomy, chemotherapy	Death at 6 months
Sezer et al22	2006	29	M		RLL	2.9×1.3 cm	Lobectomy	Well at 10 months
Shannon et al23	2017	56	F		Bilateral	Diffuse	Pemetrexed, cisplatin	Death at 2 months
Wynveen et al24	2008	75	F	Smoker	RUL, RLL	5.5 cm	Lobectomy, segmentectomy	Well at 2 years
Our case	2019	66	M	Smoker	Bilateral, multilobar		Palliative chemotherapy	Death at 1 year

LLL, Left lower lobe; LUL, Left upper lobe; PMC, pulmonary mucinous cystadenocarcinoma; RLL, Right lower lobe; RML, Right middle lobe; RUL, Right upper lobe.

PMC typically presents as a uniform low attenuation, cystic mass with a contrast-enhancing wall on CT imaging. According to Choi et al, multilocular cystic or multilobulated low attenuation lesions that may or may not present with septal or wall enhancement were noted in most cases of PMC.⁶ Gaeta et al noted that mixed mucinous cystadenocarcinoma-bronchoalveolar carcinoma may have a ground-glass attenuation along with a cystic mass.⁷ PMC may also present as pleural-based lesions, as reported by Kassir et al and Moon et al.^{8 9} PMC can be differentiated from mucinous adenocarcinoma on CT scan, since the latter is diffuse and often bilateral with the appearance of an ill-defined lobar consolidation. Our case was unique, considering the presence of bilateral diffuse cystic masses, a very rarely reported presentation.

Furthermore, 18-fluoro-2-deoxy-D-glucose (FDG) PET-CT scan activity varies, but tends to be low, probably due to low tumour cellularity burden floating in abundant mucin.¹⁰ Raza et al and Iwasaki et al report cases with intense FDG uptake,^{11 12} and Choi et al speculate that the variation in FDG uptake may be attributable to differences in wall thickness.⁶ In our case, bronchoalveolar lavage (BAL), transbronchial biopsy and EBUS-TBNA of the mediastinal lymph nodes were non-diagnostic, necessitating a RATS wedge biopsy which showed well differentiated metastatic mucinous adenocarcinoma. The lack of non-pulmonary lesions on PET-CT scan and supportive immunohistochemical stain findings lead to the inference that the malignancy was likely pulmonary in origin in our case.

On microscopy, PMC is characterised by a cystic mass of copious extracellular mucin lined by malignant columnar epithelium containing atypical cells with small nuclei and relatively inconspicuous nucleoli.¹³ As a consequence of a relatively small number of malignant cells floating in abundant mucin, histopathology of BAL or EBUS-TBNA samples are often inconclusive, making the preoperative diagnosis of PMC extremely challenging. There is a single case report where a preoperative diagnosis was made with FNA.¹³ According to Gao et al, the diagnosis of PMC can only be established in resected specimens after other types of primary and secondary tumours have been excluded.³ Biopsy/cytology preparations may be suggestive but not diagnostic.⁶ When pathological specimens are obtained, immunohistochemical staining should be performed to narrow down the differential diagnosis and help differentiate the origin of the tumours, given their histological similarity to similar tumours arising in other organs. Positive immunohistochemical staining for TTF-1 and cytokeratin 7 with negative staining for cytokeratin 20 support a pulmonary origin.¹⁴

Due to the extreme rarity of PMC, its biological behaviour is unknown. There are limited data on PMC expression of targetable immunological markers such as EGFR, ALK and programmed death-ligand 1 (PLD-1). It appears that PMC has a low malignant potential and does not generally metastasise outside of the lungs. Our literature review suggests that lobectomy has a favourable outcome, likely due to the slow growth of the tumour. The role of adjuvant chemotherapy or radiotherapy has not been established due to the low number of cases. Administration of carboplatin, pemetrexed, pembrolizumab and docetaxel did not appear to significantly slow disease progression in our patient. Of 26 reviewed cases, only four patients received chemotherapy and all four passed away at 2, 6, 10 and 12 months. One case patient had extensive disease with poor lung reserve but was lost to follow-up. The remaining 20 cases were treated with lobectomy, segmentectomy or wedge resection with only four patient deaths, one of which was due to myocardial infarction. The calculated case fatality rate was 30.76%. Unfortunately, our patient had diffuse involvement of bilateral lungs, which limited the role of a surgical approach and favoured palliative chemotherapy. Our patient died 12 months following initial presentation and 5 months following the initiation of chemotherapy.

Learning points.

• Pulmonary mucinous cystadenocarcinoma is a rare malignant colloid tumour that presents as a cystic lesion on chest imaging.

• Preoperative diagnosis with fine needle aspiration cytology (FNAC) or biopsy is challenging, given that the tumour consists of relatively few malignant cells floating in abundant mucin.

• They are generally slow growing tumours, with a favourable prognosis, given that surgery with lobectomy or wedge resection is usually curative.