Synchronous Pulmonary Adenofibroma and Solitary Fibrous Tumor: Case Report and Review of the Literature

Introduction

Pulmonary adenofibroma (PAF) is a rare benign lesion that is thought to be related to pulmonary hamartoma. ¹ It is usually found incidentally on chest imaging but can present with vague chest pain that may or may not be related to the lesion.^2,3 The average age of presentation is 57 years and occurs more commonly in males (4:1). ² Histologically, PAF is a fibroepithelial tumor consisting of irregular branching spaces lined by a single layer of columnar to cuboidal epithelial cells and surrounded by a sclerotic stroma with scattered spindle cells. ¹

Solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm of fibroblastic differentiation that can also occur in the lung and has a similar histological appearance to the stromal component of PAF. In some instances, SFT can entrap normal respiratory epithelium within the tumor, usually at the periphery, making the distinction between the two challenging.^1,4 The identification of the fusion between NAB2 and STAT6 on chromosome 12 has consistently been identified in SFTs, and it is considered to be a distinct molecular alteration. ⁵ While the histogenesis of PAF has been debated, recently the same NAB2-STAT6 fusion was found in many PAFs tested. ⁶ This has led to the speculation that PAF is perhaps a histological variant of SFT.

We report the first case of a single patient who synchronously developed a PAF and SFT in the same lung. The SFT demonstrated the typical NAB2-STAT6 fusion, while the PAF was negative. Immunohistochemistry (IHC) profiles and morphologies also differed slightly, in concordance with the current literature. Although it is possible that some PAFs harbor the identical fusion classically found in SFT, many do not.

Case Report

A 60-year-old male with a history of cigar smoking was incidentally found to have 2 pulmonary nodules on chest X-ray. Computed tomography showed 1 nodule to be located in the left lower lobe adjacent to the diaphragm and measured 2.5 cm (Figure 1A), while a smaller nodule in the lingula measured 0.9 cm (Figure 1B). The larger nodule grew to 5 cm over the next year. A fine needle aspiration was attempted but was nondiagnostic. As a result, the larger nodule was resected and grossly appeared tan, ovoid, and rubbery. Microscopically, the lesion was composed of bland spindle cells arranged in a patternless pattern in a collagenous stroma, with scattered “staghorn” blood vessels (Figure 2). At the time of resection, STAT6 immunostains were unavailable, but the spindle cells were positive for CD34 while they were negative for calretinin. The findings were consistent with a SFT, and the lingular nodule was followed clinically. Twelve years after the initial resection, the lingular nodule began to grow and its size increased to 1.7 cm. As a result, the patient elected to proceed with surgical resection for definitive diagnosis and underwent a successful and uneventful wedge resection.

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Figure 1.

(A) Axial computed tomography image showing a 2.5-cm noncalcified mass (arrow) in the left lower lobe. (B) A subsequent 0.9-cm nodule (arrow) was found in the left lingula.

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Figure 2.

(A, B) The larger nodule was resected and consisted of bland spindle cells in a patternless pattern with staghorn vessels scattered throughout (hematoxylin and eosin 40× and 200×, respectively). (C) The cells were diffuse and strongly positive for CD34 (200×). (D) Retrospectively, the cells were stained with STAT6, which confirmed the diagnosis of solitary fibrous tumor (SFT; 200×). (E) The SFT showed focal staining for ER (200×) and (F) PR (200×).

On gross examination, the nodule was 1.5 × 1.5 × 1.2 cm, well circumscribed, and consisted of coarse, tan, rubbery tissue (Figure 3). Histologically, the lesion had complex branching spaces lined by simple cuboidal/columnar epithelium (Figure 4). The stroma was sclerotic with benign-appearing spindle cells. There was no mitotic activity or necrosis present. The stroma was positive for CD34 and negative for CKAE 1/3, EMA, TTF-1, and STAT6. Conversely, the epithelial cells were positive for CKAE 1/3, TTF-1, and EMA, while they were negative for STAT6 and CD34. The nodule was felt to be most consistent with a PAF. Since this lesion was similar in appearance to SFT, his prior SFT specimen was reevaluated and the diagnosis was confirmed by exhibiting diffuse, strong, nuclear STAT6 positivity. In addition, based on the work by Fusco et al, ⁶ suggesting these could be the same entity, both lesions were stained with a battery of immunostains including TTF1, E-cadherin, ER, and PR (Table 1). The PAF showed positivity for E-cadherin within the epithelial layer, while only the stromal component showed strong positivity for ER and PR. The SFT was completely negative for TTF1 and E-cadherin but did show focal positivity for ER or PR. In the 2 years since the resection, the patient has had an uneventful recovery with no evidence of local recurrence or metastasis.

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Figure 3.

Gross image of the coarse and yellow lingular nodule resected 12 years following excision of the solitary fibrous tumor.

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Figure 4.

(A, B) Histologically, the smaller nodule was composed of a stromal component similar to the solitary fibrous tumor (SFT); however, it also had a prominent epithelial component consisting of columnar cells with a phyllodes-like growth pattern (hematoxylin and eosin 40× and 200×, respectively). (C) The stromal component was positive for CD34, while the epithelial component was negative (200×). (D) The tumor was completely negative for STAT6 (200×). (E) The stromal component showed strong reactivity to ER (200×) and (F) PR (200×).

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Table 1.

Morphological and Immunohistochemical Differences Between the 2 Tumors.

Immunostains	PAF	SFT
H&E/epithelium	Fibroepithelial lesion with phyllodes-like pattern, lined by cuboidal epithelium throughout tumor	Spindle cell lesion with ± entrapped pulmonary epithelium, mainly at periphery of tumor
H&E/stroma	“Patternless pattern” of bland spindle cells	Spindle cells in a “patternless pattern” with staghorn-shaped blood vessels. May be bland or rarely show malignant features.
CD34	Positive in stroma	Positive
STAT6	Negative	Positive
E-cadherin	Positive in epithelium	Negative
TTF1	Positive in epithelium	Negative
ER	Positive in stroma	Focally positive
PR	Positive in stroma	Focally positive

Abbreviations: PAF, pulmonary adenofibroma; SFT, solitary fibrous tumor; H&E, hematoxylin and eosin.

Molecular analysis was assessed by next-generation sequencing using the Archer FusionPlex Sarcoma Panel (ArcherDx, Inc, Boulder, CO). RNA from both of the patient’s SFT and PAF samples were extracted, converted into cDNA, and library preparation was performed according to the manufacturer’s protocol. Archer Analysis platform was used for data analysis, and a gene fusion involving the breakpoint between exon 4 of the NAB2 gene and exon 2 of the STAT gene was detected in the SFT sample, which was confirmed by reverse transcription polymerase chain reaction. The PAF and negative control samples did not have any identifiable translocations.

Discussion

PAF is a rare and benign pulmonary tumor with less than 20 cases reported. Furthermore, owing in part to its rarity, it was not listed in the most recent edition of the WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. ⁷ The exact origin of PAFs has been controversial with some supporting a hamartomatous origin, while others have argued in favor of a neoplastic proliferation.^1,3,8 One of the main entities in the differential diagnosis of PAF is SFT. SFT can have a wide variety of morphologic patterns but is classically described as a well-circumscribed tumor consisting of bland spindle cells in a patternless pattern. ⁴ They often have linear “rope-like” collagen flanked by parallel rows of spindle cells. They are highly vascular lesions with small- to medium-sized, thin-walled blood vessels with a “staghorn” appearance scattered throughout. NAB2-STAT6 fusions appear to be a distinct molecular alteration in SFTs and are present in 90% to 100% of cases.^5,9,10 Additionally, the immunohistochemical stain for the fusion product, STAT6, has proven to be both sensitive and specific for SFT. ¹¹

Recently, Fusco et al ⁶ identified the NAB2ex4-STAT6ex2 fusion in 5 of 7 PAFs tested. This identical fusion was discovered to be one of the most common fusion variants within SFTs and typically displays the classic pleuropulmonary histology with a benign appearance and clinical course. ¹² In contrast, SFTs with NAB2ex6-STAT6ex16/17 tended to occur in deep-seated and cellular SFTs with increased mitotic activity and were prone to frequent recurrences. ¹² The 2 fusion-negative PAFs in the study by Fusco et al ⁶ had a more cellular stroma that strongly expressed ER and PR, identical to our PAF. We successfully identified the NAB2-STAT6 fusion in our patient’s SFT both by IHC and by molecular analysis. More specifically, the SFT was noted to harbor the aforementioned NAB2ex4-STAT6ex2 fusion. However, the PAF was negative for the fusion but did display strong positivity for ER and PR. ⁶

While there have been no reports of PAF metastasizing or behaving in a malignant fashion, some have theorized the possibility exists since adenofibromas of other locations have undergone malignant transformation. ² On the other hand, SFTs can behave in an unpredictable fashion. Demicco et al^13,14 have developed a 4-tier risk stratification model based on patient age, tumor size, mitotic figures, and tumor necrosis. Tumors greater than 10 cm had a poor prognosis, and tumors greater than 15 cm were the most predictive of metastases. The highest risk group included patients older than 55 years old, with tumors greater than 15 cm and mitoses over 4/10 high-power field. Tumor cellularity and pleomorphism had no prognostic significance. With regard to PAF, Fusco et al ⁶ hypothesized that the NAB2ex4-STAT6ex2 fusion, commonly seen in benign appearing/low-risk SFTs, contributes to their indolent behavior. ⁶

While it has become clear that PAF is a neoplastic entity, its relationship to SFT remains uncertain. A significant proportion of PAFs do not have an identifiable fusion involving STAT6, which is unlike SFT where 98% of cases are positive for STAT6 immnohistochemically. ¹² We identified the NAB2ex4-STAT6ex2 fusion in our patient’s SFT, which is frequently encountered in pleuropulmonary SFTs. However, our patient’s PAF was negative for STAT6 and did not have an identifiable translocation. This is the first report of both tumors arising in the same patient. Furthermore, it raises the possibility that PAFs with a NAB2-STAT6 translocation are truly SFTs, misclassified due to entrapped pulmonary epithelium. Entrapment of pulmonary epithelium has produced diagnostic pitfalls in other mesenchymal tumors of the lung. For example, it is well known that primary monophasic synovial sarcoma of the lung can entrap native epithelium and be misdiagnosed as a biphasic synovial sarcoma. ¹⁵ This issue can be readily resolved with TTF1 IHC, which will highlight the pulmonary epithelium. Further studies are needed to determine the relationship between SFT and PAF with a NAB2-STAT6 translocation. Nevertheless, there is a subset of PAFs that strongly express ER/PR, lack a NAB2-STAT6 translocation, and have an indolent clinical course.