Uncommon Tumors of the Lung: Recently Described and Rediscovered Tumors

This benign tumor was originally described under the term ciliated muconodular papillary tumor, and the credit for such description is given to Ishikawa.¹  Over the years, several descriptions have been presented in the literature as either a single case report or a small series of cases; some of these reports have included molecular findings for these tumors.^2–6  In those descriptions, the morphologic features described appear to be rather consistent regarding the ciliated type of epithelium and the presence of mucinous cells, as in the original description. However, Chang et al,⁷  in a study of 25 cases, expanded the histopathologic features and immunohistochemical characteristics of these tumors and divided them into 2 more specific types, proximal and distal bronchiole, and introduced the term bronchiolar adenoma. Following such designation, numerous other cases have been reported, not only with expansion of the histologic/immunohistochemical features but also with additional molecular findings.^8–13 

Although most cases of bronchiolar adenoma have been reported in adult individuals, the tumor appears to have a more ubiquitous distribution, as it has been described in younger individuals. Initially, most cases reported were in the Asian population; however, it is very possible that the tumor is underreported in Western populations. The tumors may appear in any portion of the lung parenchyma. In general, these tumors are rather small and rarely are larger than 3 cm in greatest diameter; on average, these tumors are likely to be smaller than 2 cm. Symptoms are rarely produced by the intrapulmonary mass or nodule, and the tumor is often encountered during chest imaging for unrelated reasons. Diagnostic imaging may show ground-glass opacities, which may also be seen in other tumoral and nontumoral conditions.^14–17 

The histopathologic features of bronchiolar adenoma are summarized in the Table. The main characteristics of the tumor are those of a nonencapsulated tumor replacing normal lung parenchyma. The tumor nodules appear to be well demarcated and with the characteristic glandular pattern arranged in a papillary growth pattern, with ciliated epithelium and mucinous cells. This type of histopathology was the original description of this tumor, and it is what now is considered bronchiolar adenoma of proximal type (Figure 1, A through D). However, even though the distal type of this tumor may show some of these features, the tumor is more characterized by the presence of cuboidal cells with or without the presence of papillary pattern, ciliated cells, or mucinous cells (Figure 2, A through E). One important element that is present in both tumors is the presence of a continuous basal layer. Even though some of these features may not be difficult to identify on permanent sections, the diagnosis of these tumors on frozen section may pose significant problems, as in some cases in which the histology is not the typical and conventional, the interpretation in a frozen section may be that of adenocarcinoma.^18,19  Also important to highlight is that the association of bronchiolar adenoma and lepidic adenocarcinoma has been reported in the same tumor.²⁰ 

By immunohistochemistry, there are some differences that may aid in the distinction of distal from proximal type. It has been reported that tumors of the distal type are more likely to be TTF-1 positive, and napsin A may also show positive staining. To the contrary, tumors of the proximal type may or may not show positive staining for TTF-1. Both variants of the tumor would show p40 and keratin 5/6 positivity in the basal layer.

Regarding molecular analysis of these tumors, several reports of small series of cases have been presented in the literature. Higashiyama et al²¹  evaluated by molecular means genetic profiles of lung cancer coexisting with bronchiolar adenoma and identified no shared mutations. However, the authors acknowledged that the most frequent mutation identified in bronchiolar adenoma was BRAF mutation (V600E) in approximately 60% of the cases evaluated. Also, Takeda-Miyata et al¹²  evaluated 5 bronchiolar adenomas and identified in 2 of 3 cases of proximal type EML4 exon 20–ALK exon 20 fusion and NRAS codon 12/13 mutation. On the other hand, Yang et al⁸  reported a single case of bronchiolar adenoma, distal type, in which they identified the presence of epidermal growth factor receptor (EGFR) exon 21 p.l858R missense mutation. More recently, Zheng et al²²  compared the histologic, immunohistochemical, and genetic features of 10 peripheral squamous cell neoplasms of uncertain malignant potential and 6 cases of bronchiolar adenoma. EGFR exon 20 insertions were identified in the squamous cell neoplasms, which in the context of a bland squamous proliferation with entrapped pneumocytes raises the possibility of a variant of bronchiolar adenoma that may represent a potential pitfall in diagnosis.

Complete surgical resection appears to be the treatment of choice for these patients, and it appears to be curative. However, in cases in which the patients may not be good candidates for surgery, the possibility of stereotactic body radiation therapy has been suggested.²³ 

Adenofibromas in the lung have been recognized for the last 30 years; however, it is very likely that these benign tumors are coded under different names, which makes a true incidence difficult to estimate. The original description of these tumors dates back to 1993 with a description of 2 cases.²⁴  Since that description, most of the cases in the literature have been essentially described through case reports.^25–29  On the other hand, some authors have described what in their opinion represents pulmonary hamartoma with adenofibromatoid features.³⁰  More recently, Lindholm et al,³¹  in a report of 13 cases of pulmonary adenofibroma, further defined the entity and clarified previous reports on the subject.

The tumor has been essentially reported in adult individuals without any specific gender predilection. In the report of 13 cases by Lindholm et al,³¹  the average age at diagnosis was 57 years. The patients present with varying nonspecific symptomatology, and in some cases the tumor is discovered during routine diagnostic imaging. In general, the intrapulmonary tumors are rarely larger than 2.5 cm in greatest diameter and can be as small as 1 cm.

The tumors appear to be well circumscribed but not encapsulated, replacing normal lung parenchyma. At low-power view, the tumors may show a distinct leaflike/phyllodes-like appearance with extensive areas of collagenization and invaginations of low cuboidal-type epithelium (Figure 3, A through C). At higher magnification, the tumor shows dense collagenization with minimal cellular component. Focal myxoid areas, inflammatory reaction, or calcifications may also be seen. However, in general the tumor does not show cartilage, adipose tissue, cellular atypia, necrosis, or hemorrhage (see Table).

By immunohistochemistry, the tumor shows strong positive reaction with vimentin but is negative for STAT6, CD-34, Bcl-2, muscle, and neural markers. Keratin shows positive staining in the epithelium that may be present. Currently, there is no molecular signature that has been defined for pulmonary adenofibroma.

The 2 most important differential diagnoses for pulmonary adenofibroma include pulmonary hamartoma and intrapulmonary solitary fibrous tumor. For the former, the absence of adipose tissue and cartilage would argue against this possibility. In addition, the growth pattern of adenofibroma appears to be unusual for pulmonary hamartoma. For the latter, the presence of extensive areas of collagenization would suggest solitary fibrous tumor. However, in this setting the use of immunohistochemical markers such as CD-34 and STAT6 would be of aid in properly excluding this possibility.

Because of the size of these tumors and often the equivocal interpretation that may be provided with small biopsies, the treatment of choice for these patients includes wedge resection. Once a resection has taken place, the complete histologic analysis of the entire lesion is of utmost importance. If the final diagnosis of pulmonary adenofibroma is established, the surgical resection of the tumor is the only method of treatment.

The existence of this tumor as a primary lung neoplasm has been recognized only for the last few years.^32,33  It is important to note that hemangioblastomas have also been recognized in other anatomic structures, including retroperitoneum, soft tissue, adrenal, and kidney, among others,^34–37  in patients without von Hippel–Lindau syndrome. In some cases, the occurrence of a pulmonary mass with features of hemangioblastoma possibly represents metastasis from prior hemangioblastomas in other anatomic locations.^32,38  However, credit may be given to Falconieri et al,³⁹  who described 2 patients with lung tumors that on histology the authors considered to represent tumors reminiscent of peripheral hemangioblastomas. By immunohistochemistry, the tumors were negative for numerous antibodies and showed only positive staining for vimentin. In one case, the tumor also showed focal staining for CD-34. Based on the available information, the authors coined the term hemangioblastoma-like clear cell stromal tumor of the lung. Further to this report, Lindholm and Moran³³  described the first series of cases using the previous name and establishing the condition as a primary lung neoplasm with the corresponding histologic and immunohistochemical features.

In the few reports of this entity in the lung, the patients have been adult individuals ranging in age from 39 to 68 years. In the cases described by Lindholm and Moran,³³  the patients presented with nonspecific symptoms including cough, chest pain, and dyspnea. Diagnostic imaging showed the presence of an intrapulmonary tumor. None of the patients described had any prior history of hemangioblastoma in other locations, and the tumors have been described as a single intrapulmonary mass. In addition, no history of von Hippel–Lindau disease has been associated with these tumors in the lung.

Grossly, the tumors vary from 2 to 6 cm in greatest diameter^33,39  and are centrally or peripherally located. The tumors are well circumscribed, with focal areas of hemorrhage but without necrosis.

Microscopically, the tumors are characterized by a rather homogenous cellular proliferation that can be arranged in a subtle nested pattern and with prominent dilated vascular structures. At higher magnification, the tumor shows medium-sized cells with ovoid to plump nuclei, clear cytoplasm, and inconspicuous nucleoli (Figure 4, A through C). The tumors generally show discrete areas of hyalinization. Mitotic activity and necrosis are generally not present in these tumors.

By immunohistochemistry, the tumors are generally negative for epithelial, muscle, neuroendocrine, neuroectodermal, and vascular markers. The only immunostain that has been consistently positive is vimentin; however, TFE3 immunohistochemical stain may also show positive staining in these tumors, but a series of these tumors using this stain is not available. In addition, TFE3 may also show positive staining in renal cell carcinoma and alveolar soft part sarcoma. Agaimy et al⁴⁰  evaluated 4 cases of this tumor and identified that 3 of the 4 cases harbored a YAP₁-TFE3 fusion. The evaluation of pulmonary hemangioblastoma-like clear stromal tumor of the lung by means of molecular analysis may represent another aid in the final interpretation of these unusual tumors (see Table).

Complete surgical resection appears to be the treatment of choice for these tumors. So far, no recurrence or metastatic disease has been reported in patients with those tumors of lung origin. Therefore, it appears that surgical resection may be curative in these patients.

Three different entities have been highlighted in this writing. The entities among themselves have no relationship. The only common denominator for these entities is the great challenge for final interpretation in cases in which there is limited tissue such as a small biopsy. It is likely that in such cases, an unequivocal interpretation is not possible, therefore leaving the final interpretation after complete surgical resection. However, in the surgical resection, it is also very possible that a wider immunohistochemistry panel may be used to exclude other tumoral conditions that may be more common. The most important aspect in dealing with the tumoral conditions herein presented is to be aware of their existence and to properly evaluate them from the morphologic aspect and supported by immunohistochemistry or molecular analysis in those cases in which such studies may be of help. Even though the 3 entities herein described represent benign or low-grade types of tumor, the separation from other more aggressive tumors is highly important.