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Review Articles

Mucous Gland Adenoma: The Spectrum of Growth Patterns and the Diagnostic Challenges

Zaleski, Michael P. DO; Kalhor, Neda MD; Moran, Cesar A. MD

Author Information
Advances In Anatomic Pathology: November 2020 - Volume 27 - Issue 6 - p 371-379
doi: 10.1097/PAP.0000000000000283
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The existence of a mucous gland adenomas of the lung has been known for some time. However, these tumors have also been described in other locations including the trachea.1,2 Most of what is known about bronchial mucous gland adenomas has been reported predominantly in single case reports or relatively small series of cases.3–25 However, in the past, similar tumors were included in reviews with other more common neoplasms, namely with other tumors that were considered to arise from bronchial glands, namely adenoid cystic carcinoma, mucoepidermoid carcinomas, and mixed tumors (pleomorphic adenoma).24 Interestingly, the term “adenoma” in the past was also used to designated tumors that now are considered neuroendocrine neoplasms (carcinoid—atypical carcinoid), which also creates a problem attempting to determine the exact occurrence of this type of mucous gland adenomas.

It was not until 1995,25 in a description of 10 cases that the authors were able to define the histopathologic criteria for diagnosis in these tumors. However, one important factor that is still to some extent “debatable” is the existence of these tumors in the periphery of the lung. It is well accepted that these tumors are predominantly central tumors; however, peripheral tumors with similar histology, although rare, have been reported in the literature. Furthermore, due to the unusual occurrence of these tumors, exact diagnostic imaging features and immunohistochemical properties are not available; thus, stressing the need for a careful histopathologic assessment with good radiologic correlations.

The current review will highlight the spectrum of histopathologic changes that can occur in mucous gland adenomas, whether in central or peripheral location as well as the importance of proper radiologic, immunohistochemical and if available molecular correlations.


Clinically, patients with mucous gland adenoma may be asymptomatic. On the other hand, the symptomatology present may be nonspecific as patients may present with dyspnea, chest pain, hemoptysis, and cough. Cases of massive hemoptysis, patients recovering from treated pneumonia, or patients simulating asthma, with atelectasis, or associated with cysts have been reported.11,12,15,16 However, there is not specific symptomatology that can be linked to mucous gland adenoma.


Because of the unusual nature of these tumors, the radiologic features of mucous gland adenomas have not been well characterized in the literature. In the 10 cases reported by England and Hochholzer,25 only 3 cases had radiographic imaging and the reports referred to the tumors as opaque or dense, discrete or infiltrating. Kwon et al22 reported 2 cases in which the authors stated that the presence of air-meniscus on computed tomography as a radiologic feature for these tumors. Cho et al23 reported an fluorodeoxyglucose-avid tumor.


Gross Features

In general, these tumors are small and rarely >3 cm in greatest diameter. These tumors are fairly well circumscribed, soft, tan in color and without areas of necrosis and/or hemorrhage.

Histologic Features

As it has been defined, when these tumors occur in central locations, they characteristically are between the overlying epithelium and the cartilaginous plate. Even though in some cases, it may appear that the tumor is encroaching around the cartilage, the vast majority of the tumor is confined above the cartilaginous plate. On the other hand, when these tumors occur in the periphery of the lung, they are commonly located adjacent to a small airway. However, contrary to the definition of the central tumors in which the tumor is not beyond the cartilaginous plate, when the tumor is in the periphery of the lung, the presence of a cartilaginous plate in the small airway is much more difficult to identify. Nevertheless, the histologic pattern should be similar to that described in central tumors. In addition, similarly to central tumors, peripheral tumors are also small and rarely >3 cm in greatest diameter.

The histopathologic features of mucous gland adenomas are varied. On the basis of review of the literature and in our own experience, we have observed 5 different growth patterns in these benign tumors:

  • Pure mucinous
    • Acinar: the tumor characteristically shows a tightly packed glandular proliferation in a back-to-back growth pattern. The glands are rather small and composed of mucin producing cells. The glandular proliferation lacks cellular atypia and mitotic activity (Figs. 1A, B). The tumor does not show hemorrhage or necrosis.
    • Acinar with basal cell hyperplasia: in this growth pattern, the tumor has essentially the same glandular proliferation as the acinar pattern. However, the tumor shows more cellularity due to the presence of basal cell hyperplasia that makes the tumor appear as a cellular neoplasm (Figs. 1C, D). Necrosis and/or hemorrhage are absent.
    • Microacinar: The tumor characteristically shows a proliferation of small tightly packed glandular proliferation, which imparts the tumor a more solid growth pattern. In focal areas, the tumor may show signet-ring cell-like areas, or adenomatoid-like pattern (Fig. 1E).
  • Pure cystic
    • These tumors are characterized by the presence of dilated glandular proliferation of different sizes and containing acellular mucoid material within their lumens. These cystic structures are lined by flattened epithelium, cuboidal epithelium, or attenuated squamous epithelium. The glands are distributed in a haphazard manner and do not show any cytologic atypia (Figs. 2A, B). Necrosis and mitotic activity are absent.
  • Combined cystic—microcystic—papillocystic
    • In this growth pattern, the tumor characteristically shows easily identifiable dilated glandular structures with varying amounts of mucoid material in their lumens. In addition, the tumor shows a subtle microcystic proliferation composed of small glands that can be lined by cuboidal, mucinous, or attenuated squamous epithelium (Figs. 3A, B). Areas of hemorrhage and necrosis are absent.
    • Papillocystic or associated with a squamous papilloma: In some cases, it is possible to observe the presence of focal squamous papillary areas, which we consider should not be interpreted as either papillomas or papillocystic pattern. In some tumors this squamous papillary proliferations are in the surface of the tumor and not within the cystic glandular structures of the tumor (Fig. 3C). In one of the cases depicted by England and Hochholzer,25 judging by the illustration provided, it appears that the 2 components are more closely related. Also, important to mention is that similar structures were also observed by Spencer.24
  • Combined cystic and acinar
    • The tumor shows the features of cystically dilated structures lined by flattened epithelium (Figs. 4A, B) combined with a glandular component characterized by small glands with mucinous epithelium and containing acellular mucoid material in their lumens and without displaying cellular atypia or mitotic activity. Areas of calcification are often identified in these cases (Fig. 4C).
  • Mucoepidermoid-like
    • This histologic pattern mimics low grade mucoepidermoid carcinoma in terms of a cystic proliferation composed of glands lined by mucoid cells and squamous epithelium separated by thin fibroconnective tissue (Figs. 5A, B). In some areas, the tumor appears to show a syringomatous-like pattern, which imparts the tumor a salivary gland-like appearance.

Low power view of mucous gland adenoma composed exclusively of mucous producing glands (A). Higher magnification showing mucin producing glands without atypia or mitotic activity (B). Cellular mucous gland adenoma with basal cell hyperplasia (C). Basal cell hyperplasia in a mucous gland adenoma giving the appearance of a cellular neoplasm (D). Mucous gland adenoma with microacinar growth pattern (E).
Low power view of a pure cystic mucous gland adenoma (A). Note the tumor is above the cartilaginous plate, cystically dilated glands lined by flattened epithelium without atypia (B).
Mucous gland adenoma showing combined features of cystic and microscystic growth patterns (A). Closer view of the combined cystic structures and small mucinous glands (B). Mucous gland adenoma with a focal area in the surface showing squamous papillary proliferation (C).
Low power view of a combined cystic and acinar mucous gland adenoma (A). Note the tumor is above the cartilaginous plate; closer view showing the 2 components of cysts and acinar glandular proliferation (B). Calcification may be present in some tumors in the acinar component (C).
Mucous gland adenoma with mucoepidermoid carcinoma-like features (A). Note the presence of small cystic structures separated by fibrocollageous stroma; admixture of mucin producing glands and cystic structures (B).

Peripheral Mucous Gland Adenoma

  • Essentially, tumors in the periphery of the lung show similar histologic features as those centrally located. One important problem that we have recognized is the identification of bronchial cartilage in small airways. Therefore, one may be limited to the morphology of the tumor rather than applying the strict criteria of “above the cartilaginous plate.” In addition, in some cases, identification of the small airways may be difficult and possibly the reason why some cases are coded under “intraparenchymal” tumors (Figs. 6A, B).

Peripheral mucous gland adenoma (A). Note the presence of adjacent lung parenchyma in the dilated small airway; closer view shows a small airway lacking bronchial cartilage (B).

Stromal Component

Even though the histologic features of mucous gland adenoma lie more specifically in the glandular proliferation. It is important to highlight, that these tumors may also display glandular proliferation embedded in different types of stroma. Essentially, the tumor may show 3 different types of stromal reaction:

  • Hyalinized: In this stromal reaction, the cystically dilated glands are embedded in a dense hyalinized acelluar material (Fig. 7A). This stromal reaction is rarely extensive.
  • Inflammatory: In some cases, the stromal reaction is that if fibroconnective tissue with marked inflammatory reaction containing lymphocytes and plasma cells predominantly (Fig. 7B).
  • Xanthomatous changes with cholesterol cleft granulomas: In some tumor, the inflammatory reaction is based on collections of xanthoma cells adjacent to cholesterol cleft granulomas (Fig. 7C).
  • Cellular: In some unusual cases, the stroma in which the glandular component is embedded becomes cellular. The cellular component is predominantly spindle fibroblastic or myofibroblastic (Fig. 7D). However, no cellular atypia or mitotic activity is generally observed in such stroma.

Hyalinized stromal reaction (A). Marked inflammatory stromal reaction (B). Presence of xanthomatous reaction with cholesterol cleft granuloma (C). Cellular spindle cell stroma (D).

Immunohistochemical Features

The immuohistochemical properties of mucous gland adenomas are basically limited due to the unusual nature of this tumor. There are only a few reports in which this information has been reported, which essentially have consisted of individual cases. In the series of 10 cases reported by England and Hochholzer,25 even though the authors performed a panel of immunohistochemical studies, their analysis may be regarded as incomplete in today’s current developments in immunohistochemistry. The issue is that in 1995, some of the current markers such as thryoid transcription factor (TTF)-1, p40, and others were not available at that time, in which case, the experience provided by the authors is limited. However, the authors reported positive staining for epithelial membrane antigen, keratin, carcinoembryonic antigen, s-100 protein, and actin, while neuroendocrine and muscle markers were negative. Important to highlight is that s-100 protein and actin were positive in the stroma and not in the glandular structures. In more recent cases, TTF-1 and napsin have been reported as negative while the conventional epithelial markers, keratin and keratin-7, have been described as positive.18,21

We have been able to performed molecular analysis for mastermind like transcriptional coactivator (MAML) in some cases of mucous gland adenomas (unpublished data), which have shown negative results.

Treatment and Prognosis

The treatment of choice for these tumors is complete surgical resection. However, for those tumors in central locations, the tumor may be resected via bronchoplastic procedure26 or via sleeve resection. For tumors that are in the periphery of the lung, wedge resection may be the best approach. Up to now, there are no reports of recurrences or metastatic disease. Also, there are no documented cases of malignant transformation in these tumors.


Historical Perspective

True mucous gland adenomas are rare benign tumors in the lung. It is possible that in the past literature, these tumors may have been grouped with other tumors that were also classified as “adenomas,” mainly what is known now as carcinoid tumors, adenoid cystic carcinomas, and mucoepidermoid carcinomas. The history of the term “adenoma” of the lung has essentially encompassed numerous entities that now are regarded as specific tumors for the vast majority of cases. Nevertheless, even in older literature, description of cases that were labeled as “mucous gland adenomas,” had been presented. Although in general terms, these tumors are considered to be central tumors, descriptions of peripheral tumors have been presented in the literature.3–26 One additional factor in the conundrum of these tumors is that in some publications, different names have been used for the same tumor. Names that in the past have been associated with “mucous gland adenomas” include: cystadenomas, adenomatous polyp, and adenomatous bronchial tumors.11–13,24 One argument for why these tumors are not common in the periphery of the lung is because of the absence of abundant mucous glands in the peripheral airway. However, in 1953 Ramsey and Reimann,5 reported an illustrative case under the designation of bronchial adenoma, mucous gland type. The tumor was a 1.3 cm centrally located in a 54-year-old patient. Two years after the description by Ramsey and Reimann.5 Weinberger et al4 reported a similar case in a 66-year-old patient with the difference that the 2.0 cm tumor was located in the periphery of the lung. However, the authors concluded that the tumor most likely arose from the bronchial mucous glands of a small airway. Interestingly, in the histologic description, the authors state that one third of the tumor was endobronchial while two thirds of the tumor were intramural and extra-bronchial. Histologically, based on the illustrations provided, both tumors appear to share similar histologic features, referred by the authors as “adult mucous glands.” Essentially, the descriptions of these 2 cases have set in motion the idea that mucous gland adenomas may not necessarily be tumors of central location. Also in 1955, Gilman et al3 reported another case of this type of tumor in a 28-year-old female. The interesting aspect of this case is the histopathologic features of the tumor, which based on the illustrations provided show a more acinar growth pattern. Since those earlier descriptions, numerous other single case reports have been presented in the literature, emphasizing different aspects of clinical, radiologic, or histopathologic features of this tumor.

Contemporary Perspective

To provide a perspective on the unusual nature of this tumor, 2 different publications in a period of 16 years may provide us with some insights about this unusual tumor. In 1979, Spencer24 presented a review of 26 cases of what the author designated as “bronchial mucous gland tumors.” In this description, the authors divided these tumors into 5 different categories, being one of them being “cystadenomas,” which is what currently is coded as mucous gland adenoma. The 5 cases of “cystadenomas” were described in adult patients between the ages of 43 and 67 years, and all the tumors were located either in the main or lobar bronchi. Two cases were described as having a “papillomatous proliferation.” In 1995, England and Hochholzer25 presented a study of 10 cases of what the authors titled “truly benign bronchial adenoma (mucous gland adenoma) from the files of the Armed Forces Institute of Pathology. The tumors were reported in 6 women and 4 men between the ages of 25 and 67 years. It is important to highlight that in these 2 publications with a reasonable number of cases of this unusual tumor, all the tumors were centrally located. In addition, England and Hochholzer25 stated a histologic definition for these tumors, which is essentially of a tumor limited to the bronchial wall above the cartilaginous plate. It is of interest however, that the great majority of these tumors from the past and current literature are described as tumors rarely >3 cm in greatest diameter but yet, in the description of England and Hochholzer,25 the size of the tumors ranged from 0.8 to 6.8 cm in greatest diameter. One wonders how a 6.8 cm centrally located tumor can be limited to the bronchial wall above the cartilaginous plate. Unfortunately, the authors do not provide much detail regarding this particular occurrence. However, it is possible that a tumor that measures 6 cm in greatest diameter, likely does not represent a mucous gland adenoma. Important to highlight is the acknowledgment by England and Hochholzer25 that peripheral tumors may occur; however, those tumors should not be considered intraparenchymal but rather arising from bronchial glands of distal small airway. Regarding the issue of peripheral tumors, Karpathiou et al18 reported a case of a 1.4 cm tumor that the authors designated as “intraparenchymal” and judging by the illustrations provided, the tumor shows similar histopathologic features as those described in central location. However, one could argue that the case possibly originated from a small airway that was not either identified or properly sample. Also, Zhang et al21 reported a 59-year-patient with a 1.6 cm tumor that the authors designated as “intraprenchymal.” However, in this particular case, there are a few other histopathologic features that are unusual and include the presence of an inflammatory reaction, presence of lymphoid follicles, and fibromyxoid stroma. In both of these cases, the authors argue that the negative staining in the glandular proliferation for TTF-1 and napsin, are features more in keeping with mucous gland adenoma. In terms of the stroma present in cases of mucous gland adenoma, the presence of fibroconnective tissue separating the cystically dilated glands appear to be in some cases a common finding. Needless to say, the presence of fibromyxoid stroma has been reported in some cases. However, it is important to highlight that the case described by Lee et al19 in a 66-year-old patient, the tumor was a peripheral tumor, which in addition to what the authors described as myxoid stroma, the tumor also contained cartilage, and a glandular proliferation. It is well known that pulmonary hamartomas may show all the features reported in the case by Lee et al,19 which raises some doubts whether the designation of mucous gland adenoma is appropriate for that case. More recently, the presence of fibromyxoid changes have also been associated with another uncommon benign pulmonary tumor—pulmonary adenofibromas.27

At this point, it is important to highlight that even though the reports by Spencer and England and Hochholzer25 described these tumors in adult patients, similar tumors have also been described in the pediatric population. Dickerstein et al11 described a 12-year-old boy with a 1.5 cm polypoid mass obstructing the middle lobe bronchus, which the authors designated as mucous gland adenoma. The authors reviewed the literature and identified 6 additional cases in children,7,12–14 which had been reported under different designations. Thus, highlighting the issue that these tumors have a more ubiquitous distribution.

Diagnostic Challenges and Possible Solutions

Because mucous gland adenomas either in the central or peripheral location do not have any specific radiologic features, the final diagnosis is on histopathologic grounds. However, the diagnosis of these tumors not only represents a challenge in resected specimens but it can be more challenging in biopsy specimens. The differential diagnosis of these tumors will depend on the histologic features present. Table 1 depicts some of the most common diagnostic challenges based on the morphologic aspects of the tumor. In cases in which the tumor has a prominent acinar pattern, the most important pitfall will be with a conventional adenocarcinoma. In that respect, even though, there is not extensive experience with the immunohistochemical profile of mucous gland adenomas, in the reported cases, it has been stated that mucous gland adenomas are negative for TTF-1 and napsin while positive for keratin, keratin-7, and epithelial membrane antigen. This immunohistochemical profile coupled with the radiologic information of a small bronchial tumor should raise the possibility of mucous gland adenoma. In cases in which the histology of the tumor is of cystically dilated glands with squamous component, the most important differential diagnosis is with low-grade mucoepidermoid carcinoma. In this setting, it has been argued that low-grade mucoepidermoid carcinomas may show the presence of intermediate cells, which are not part of the diagnostic features of mucous gland adenoma. Important to highlight in this context is that in a small biopsy, the presence of intermediate cells may not be so apparent. It is possible that in difficult cases, the use of molecular techniques and the identification of MAML fusions will aid in the diagnosis. In our experience (unpublished data) with cases of mucous gland adenomas in which we have performed MAML fusion analysis, the tumors have been negative. However, the percentage of cases of low-grade mucoepidermoid carcinomas of the lung positive for MAML alterations is uncertain.28

TABLE 1 - Morphologic Features of Mucous Gland Adenoma and Their Differential Diagnosis
Histologic Growth Pattern (MGA) Differential Diagnosis
Pure mucinous
 Acinar Mucinous adenocarcinoma
 Acinar with basal cell hyperplasia Mucinous adenocarcinoma
Acinar cell carcinoma
 Microacinar Signet ring cell adenocarcinoma
Pure cystic
Combined cystic-microcystic-papillocystic
Mucoepidermoid carcinoma
 Papillocystic or associated with papilloma
Squamous papilloma
Combined cystic and acinar
Mucoepidermoid carcinoma
Squamous cell carcinoma
Adenosquamous carcinoma
MGA indicates mucous gland adenoma.

Treatment and Follow-up

As one would expect, the treatment of choice for mucous gland adenoma is complete surgical resection, which can be accomplished via brochoplastic surgery or via a sleeve resection. In essence, a conservative surgical approach with complete surgical resection of the tumor is curative and up to now, no documented cases of metastatic disease or malignant transformation have been described.


Mucous gland adenomas are unusual tumors with varied histology. The great majority of these tumors occur in central locations with rare tumors in the periphery of the lung. For tumors that may occur in the periphery of the lung, it is essential to properly sample the tumor to properly determine its origin from bronchial glands of a small airway before rendering the tumor as of intraparenchymal origin. Because of the infrequent nature of these tumors, pathologists need to be aware of this tumor and pursue radiologic information and immunohistochemical stains in cases in which the histology is suspicious or suggestive of mucous gland adenoma. We consider that these tumors are rarely over 3 cm in greatest diameter and tumors over 3 cm should be carefully analyzed and sampled to properly designate them.


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lung; adenoma; bronchus; immunohistochemistry

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