The clinicopathological challenges of symptomatic and incidental pulmonary hamartomas diagnosis

Abstract

Pulmonary hamartomas (PHs) are the most common benign lung tumors. Usually, they are asymptomatic and incidentally discovered during assessment for other diseases or during the autopsy exam. In this context, we have performed a retrospective analysis of surgical resections in a 5-year series of patients diagnosed with PHs in the Clinic of Pulmonary Diseases, Iaşi, Romania, aiming to evaluate their clinicopathological features. A total of 27 patients with PH (40.74% males and 59.26% females) were evaluated. 33.33% of patients were asymptomatic, while the others exhibited variable symptoms, such as chronic cough, dyspnea, chest pain or weight loss. In most cases, PHs presented as solitary nodules, predominantly disposed in the right upper lobe (40.74% of cases), followed by the right lower lobe (33.34%), and left lower lobe (18.51%). The microscopic examination revealed a mixture of mature mesenchymal tissue, such as hyaline cartilage, adipose tissue, fibromyxoid tissue, and smooth muscle bundles, in variable proportions, associated with clefts of entrapped benign epithelium. A dominant adipose tissue component was observed in one case. PH was associated with a history of extrapulmonary cancer diagnosis, in one patient. Although considered benign lung tumors, PHs diagnosis and therapy may be challenging. Having in mind the possibility of recurrence or their occurrence as a part of specific syndromes, PHs should be thoroughly investigated for an appropriate patients’ management. Their complex significance and the correlation with other types of lesions, including malignancies, may be further studied, by more extensive studies of surgical and necroptic cases.

Introduction

Pulmonary hamartomas (PHs), also known as chondroid hamartomas, are the most common benign lung tumors, with an incidence range between 0.025% and 0.032%, in adult population [1], representing 8% of solitary lung lesions and 77% of benign lung nodules [2, 3]. Usually incidentally discovered in the fifth and sixth decades of life, with a male predominance (M/F ratio: 4/1), these tumors are rarely diagnosed in children [4,5]. Most hamartomas occur in the peripheral lung parenchyma, while 10% of lesions are endobronchial [5]. Commonly, they present as solitary nodules, measuring less than 4 cm in diameter, in thorax computed tomography (CT) images [4]. Additionally, a radiological pattern of “popcorn” or “comma-shaped” calcification, observed in 10–15% of cases, is highly suggestive of PH diagnosis [6, 7]. According to PH location and size, patients can develop chronic cough, dyspnea, hemoptysis, chest pain, and obstructive pneumonia [1, 4]. The surgical removal of the lesion is the primary treatment option in PHs, especially in symptomatic cases. From a morphological point of view, PHs are benign tumors composed of variable amounts of at least two mature mesenchymal tissues (cartilage, smooth muscle tissue, adipose tissue, bone or fibromyxoid tissue), combined with entrapped benign epithelium [8]. Although they display a non-infiltrative and slow-growing feature, patients with PHs have a 6.3 times greater risk for lung cancer development compared to the general population [9]. Considering these features, it is important to be alerted by a rapid enlargement or by the presence of malignant imaging features in PHs cases.

Aim

In this context, our study was focused on the identification of clinicopathological features and possible pathological associations of PHs, in a retrospective series of cases.

Patients, Materials and Methods

The study group comprised patients diagnosed with PHs who underwent radical lesion resection in the Pneumology Clinical Hospital, Iaşi, Romania, between 2017 and 2022. For each patient, the clinicopathological and radiological data were collected by medical files review. Hematoxylin–Eosin (HE)-stained slides of the surgical pathology specimens were reviewed by two independent pathologists. The criteria for PHs diagnosis included: (i) presence of at least two mesenchymal mature tissues (hyaline cartilage, fat tissue, bone, and/or fibromyxoid tissue) and (ii) invaginated or entrapped bronchial respiratory epithelium. The study protocol had obtained the approval of the Research Ethics Committee of the Pneumology Clinical Hospital, Iaşi (No. 91/27.06.2022), consistent with the Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects. The immunohistochemical (IHC) exam was performed in selective cases to certify the diagnosis and for the exclusion of possible differentials, such as lipoma, chondroma, fibroma, and malignancies. The sections were deparaffinized in xylene and then gradually hydrated in ethanol to distilled water. The slides were pretreated with Epitope Retrieval Solution (pH 6, 96ºC, 20 minutes) and incubated overnight with the primary antibodies. Then, the slides were cooled at room temperature, followed by washing of the sections with distilled water, and the endogenous peroxidases were inhibited with hydrogen peroxide (H2O2) for 10 minutes. Primary antibodies specific for Ki-67 (monoclonal antibody, mouse, clone MM1, 1:200 dilution, Novocastra, UK), S100 (polyclonal antibody, rabbit, clone 4C4.9, 1:300 dilution, Novocastra, UK), SMA (smooth muscle actin, monoclonal antibody, mouse, clone ASM-1, 1:100 dilution, Novocastra, UK), and ER (estrogen receptor, monoclonal antibody, mouse, clone 6F11, 1:80 dilution, Novocastra, UK) were used. 3,3’-Diaminobenzidine (DAB)–H2O2 was used as a chromogen, and the sections were counterstained with diluted Hematoxylin. The positive external controls were used, and the primary antibody was omitted and replaced with normal serum at equivalent concentration, for negative controls. The statistical analysis was performed using Excel files and the results were expressed as means ± standard deviation (SD), or median (range) for continuous variables.

Results

The study group included 27 patients diagnosed with PHs, 40.74% (n=11) men and 59.26% (n=16) women, 51.85% (n=14) patients being from urban area. The patients’ ages were ranged between 32 and 78 years old, with a median age of 60 years (62 years for men and 59.5 years for women) and a mean of 58.51±10.67 years. 33.33% (n=9) of patients from the study group were asymptomatic, being incidentally diagnosed during a routine thoracic radiography, while 66.67% (n=18) of them displayed variable symptoms that included, in a decreased order of frequency: chronic cough (22.22%; n=6), dyspnea (18.51%; n=5), chest pain (11.11%; n=3), and weight loss (7.4%; n=2). Variable comorbidities were registered in most cases, such as hypertension ± chronic ischemic heart disease (40.74%; n=11), chronic obstructive pulmonary disease (COPD) (14.81%; n=4), diabetes mellitus (11.11%; n=3), and obesity (7.4%; n=2). Additionally, a history of mammary carcinoma without evidences of recurrence was registered in one patient. All PHs presented as solitary nodules, exhibiting a “popcorn” calcification pattern in four (14.81%) patients, in thorax chest radiography (chest X-ray) (Figures 1 and 2). Most lesions were located in the right upper lobe (40.74% of cases), followed by right lower lobe, and left lower lobe location (Table 1). The tumors were mostly identified in the peripheral region of the lung parenchyma, while they were detected in subpleural areas, in 11.11% (n=3) of cases, and the nodular lesion was located in the central region of the lung, in perihilar area, in only one case (3.7%). PHs were removed by thoracotomy, without any postoperative complications registered in early follow-up.

Figure 1.

Well-defined micronodule, containing a focal area of increased density (“popcorn feature”), located in the right lower pulmonary lobe (chest X-ray).

Figure 2.

A solitary well-delimitated, homogeneous radiodense nodule, located in the right upper pulmonary lobe (chest X-ray).

Table 1.

The pathological features of patients diagnosed with PH, in the study group

	Lesion size [mm]	Lesion location	n (%)
Median	20	Right upper lobe	11 (40.74%)
Mean ± SD	23.51±17.59	Right middle lobe	–
Range, minimum–maximum	8–95	Right lower lobe	9 (33.34%)
	Left upper lobe	2 (7.4%)
Left lower lobe	5 (18.51%)

n: No. of cases; PH: Pulmonary hamartoma; SD: Standard deviation.

The gross findings of surgical specimens showed firm, round to multilobulated, well-circumscribed nodules, with a white-bluish color, in most cases. The tumors size has ranged from 8 mm to 95 mm (Table 1). A tumor mass larger than 40 mm was detected in three (11.11%) cases and a tumor ≤10 mm was surgically removed in four (14.81%) cases. No cystic changes were identified. As a particular characteristic, a tumor mass of 25 mm, with decreased consistency and yellowish color was detected in one case. The microscopic examination revealed a nodular hyaline cartilage proliferation, with epithelial invaginations, associated with myxoid change intermingled with variable amounts of adipose cells and fibrous tissue (Figures 3, 4, 5, 6). A predominant fibromyxoid stroma, admixed with focal lobular masses of hyaline cartilage, and few adipocytes were observed in three cases (Figure 7). Variable areas of calcified cartilage were registered in 18.51% (n=5) cases (Figure 8), while the presence of smooth muscle cells was noted in 11.11% (n=3) cases. No cellular atypia was detected. A prominent adipose tissue proliferation associated with inconspicuous benign epithelial inclusions, few smooth muscle bundles, and reduced hyaline cartilage areas were noticed in a case (Figures 9 and 10).

Figure 3.

Overall image of a PH specimen (HE staining). HE: Hematoxylin–Eosin; PH: Pulmonary hamartoma.

Figure 4.

Detail of the previous figure showing invaginated benign respiratory epithelium and typical hyaline cartilage areas, in a PH (HE staining).

Figure 5.

Hyaline cartilage associated with epithelial invaginations, along with fibromyxoid tissue, in a PH (HE staining).

Figure 6.

Hyaline cartilage proliferation associated with fibromyxoid tissue, white adipose cells, and entrapped benign epithelium, in a PH (HE staining).

Figure 7.

Fibromyxoid tissue and white adipose cells, in a PH (HE staining).

Figure 8.

Hyaline cartilage proliferation with areas of calcification and white adipose cells, in a PH; a peripheral bronchus exhibits a moderate inflammatory cell infiltration (HE staining).

Figure 9.

Prominent adipose tissue proliferation associated with smooth muscle cells, and benign epithelial inclusions, in a PH (HE staining).

Figure 10.

Extensive areas of adipose tissue associated with an area of hyaline cartilage, in a PH (HE staining).

The IHC exam revealed S100 positivity of chondrocytes and adipocytes, with cytoplasmic and nuclear expression (Figures 11–13). ER-positive expression, mainly in the entrapped benign epithelium, along with an intensely positive SMA immunostaining of smooth muscle component was observed (Figures 14 and 15). Additionally, a weak positive Ki-67 expression was noticed in all PH cases (Figure 16).

Figure 14.

ER intensely positive expression predominantly in the entrapped benign epithelium, along with moderately positive expression in the fibromyxoid area, in PH (Anti-ER antibody immunomarking). ER: Estrogen receptor.

Figure 15.

SMA smooth muscle cells positive expression, in PH (Anti-SMA antibody immunomarking). SMA: Smooth muscle action.

Figure 16.

Focal Ki-67 positive expression in the entrapped epithelium, in BALT, and in chronic bronchial inflammatory infiltrate, in PH (Anti-Ki-67 antibody immunomarking). BALT: Bronchus-associated lymphatic tissue.

Figure 11.

S100 chondrocytes positive expression, in PH (Anti-S100 antibody immunomarking).

Figure 12.

S100 adipocytes and chondrocytes positive expression, in PH (Anti-S100 antibody immunomarking).

Figure 13.

S100 adipocytes positive expression, in PH (Anti-S100 antibody immunomarking).

Discussions

PHs are benign tumors composed of an abnormal admixture of mature mesenchymal tissue, such as cartilage, smooth muscle, fat tissue, bone or fibromyxoid tissue, with entrapped benign epithelium [8]. The “hamartoma” term derives from “hamartia”, which means “erroneous” or “faulty”, in Greek [8]. From a historical perspective, Eugen Albrecht used, for the first time in 1904, the term “hamartoma”, to characterize a local cellular and tissular proliferation, typically found in the organ of origin [10]. Three decades later, Goldsworthy has defined PH as a local benign proliferation of hyaline cartilage and bone [10]. Usually, PHs are identified in middle and older age groups, with a men predominance [5, 11]. We found a median age of 60 years and a slightly women predominance, the differences in distribution among genders compared to literature data being probably related to the limited number of cases available for the study. Although a rare finding, PHs are the most common benign pulmonary tumors, representing about 8% of lung solitary nodules [2, 3]. PHs arise from the primitive mesenchymal tissue of the bronchial wall that can differentiate into variable mature mesenchymal tissues [12]. Cytogenetic analyses have revealed genetic aberrations of high mobility proteins, in chromosomal bands 6p21 or 12q14-15, or rarely in both bands, in PH patients [4, 13]. In this regard, a specific translocation, t(6;14)(p21;q24), was detected in most PHs, leading to a partial fusion between the high mobility group AT-hook 1 (HMGA1) gene and RecA-like protein L (RAD51L), a gene encoding a protein kinase with a relevant role in the repair process. Additionally, the rearrangement of 12q14-q15, involving the high mobility group AT-hook 2 (HMGA2) gene, can be detected in approximately 80% of patients [13, 14]. Recent data are suggesting that there is an association between PHs and lung or other extrapulmonary neoplasms [12, 15]. In this regard, 29.3% rate of malignancies (most frequently lung cancer) were detected in a series of 215 patients with PHs [16]. These data are supported by the results of a recent study, which demonstrated PHs and lung cancer association in 10.5% of cases [11]. Similar results were registered by another research team which revealed that 26% of patients had associated cancer, 12% of them being diagnosed with extrapulmonary malignancies (breast, gastric, and colon carcinoma) [10]. In our study group, a history of breast cancer was registered in one case, but the possibility of a secondary cancer was excluded. Analogous observations are available in the literature, Neacşu et al. presented an interesting case of PH associated with chronic eosinophilic pneumonia, in a patient with a history of gastric carcinoma [17]. In addition, PHs associated with concurrent gastrointestinal stromal tumor (GIST) and extra-adrenal paraganglioma were diagnosed especially in young women with Carney’s triad [13]. Moreover, patients with Cowden syndrome display multiple hamartomas in different body regions, being predominantly located in skin and internal organs, with an increased risk for their malignant progression due to germline mutations of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor gene [18, 19]. PHs are frequently identified in chest X-ray as lobulated, well-delimited, peripheral, solitary nodules. Although PHs have less than 4 cm in diameter when diagnosed, large PHs were also registered. Most of them were reported in adult patients, sometimes PHs measuring more than 26 cm in diameter [4, 20]. Currently, it is considered that PHs can double their diameter over time, having a growth rate of 3.2±2.6 mm/year [4]. The “popcorn” or “comma-shaped” calcification or the presence of fat tissue are also typical for PHs on posteroanterior chest radiography/CT [7, 11]. However, these features are absent in 30% of PHs cases [7]. In our study group, the largest PH size was 95 mm, while calcification was registered in only 14.81% of cases, probably due to the small size of the lesions. In this regard, the nodules mean size was 23.51 mm (range 8–95 mm), while the tumor size was larger than 40 mm in diameter in only in 11.11% of cases. Comparable results were reported by another research team, which registered PHs nodules of 13 mm diameter or less in their study [13]. However, large PHs are also described in literature, e.g., a PH of 28×18×17 cm and 2.1 kg weight, diagnosed in a 39-year-old man [21]. Although, PHs can develop in any lung lobe, they are more frequently observed in the right lower lobe [15]. In our study, in agreement with literature data, 40.74% of nodular lesions were located in the right upper lobe and only 7.4% of them in the left upper lobe. Additionally, the tumors were located in the lung parenchyma in all cases, without any endobronchial lesion registered. Similar results were also reported by another research team, which showed that PHs were predominantly diagnosed in the right upper lobe (31% of cases) [13]. In these cases, the distinction between PHs and lung tuberculosis or malignancy, in asymptomatic patients, had been further investigated. Commonly, as mentioned, PHs develop in the lung parenchyma and they grow as endobronchial tumors in only 10% of cases [5, 22]. Because of their slow growth, PHs are generally asymptomatic, being incidentally detected in routine chest radiographs or during an autopsy exam [5, 23]. Larger PHs or endobronchial lesions lead to symptoms, such as chronic cough, dyspnea, fever, hemoptysis, or obstructive pneumonia [4, 8]. In our series, patients presented variable symptoms, such as chronic cough, dyspnea, chest pain, and weight loss. However, it is difficult to determine whether the symptoms were related to PHs, especially as 74.06% patients had different categories of comorbidities, like hypertension with/without chronic ischemic heart disease, COPD, or diabetes mellitus. The chest radiography/CT scan may orientate the diagnosis, which is certified by the histological examination of the resection specimens. According to the dominant morphological component, PHs can be further divided in chondromatous, lipomatous, adenoleiomyomatous, and fibrous hamartomas [12]. Most PHs are predominantly composed of hyaline cartilage, intermingled with a variable amount of other mesenchymal components and clefts of benign epithelial tissue [12, 19]. Similar findings were registered in our study group, with one exception, which displayed a dominant adipose tissue feature. The differential diagnoses in PHs include chondroma, lipoma, intrapulmonary solitary fibrous tumors (SFTs), leiomyoma, and well-differentiated chondrosarcoma [4, 24, 25]. In these situations, routine histopathological examination, associated with IHC exam, in selective cases, may certify the diagnosis. Histopathology reveals that chondromas are surrounded by a fibrous pseudocapsule, frequently show calcification, or bone metaplasia, and lack entrapped benign epithelium [25]. Lung lipomas are very rare benign tumors composed of mature adipose cells, underlying respiratory epithelium, which are rarely associated with osteocartilaginous metaplasia. No atypical adipocytes and no lipoblasts are registered in these cases, and the fat cells express S100, as a marker of mature adipocytes [24, 26]. SFTs occasionally display an adenofibromatous pattern because of the entrapment of pulmonary epithelium, and these should be differentiated from PHs. However, SFTs rarely arise in lung, being composed of collagen fibers and fibroblastic spindle cells, which express immunopositivity for B-cell lymphoma-2 (Bcl-2), cluster of differentiation (CD)34, and CD99 [25]. Although excessive smooth muscle cells are not a specific feature for PHs, they may be sampled in lung biopsy that includes only one mesenchymal component and their presence can be certified by smooth muscular markers. In these cases, the tumoral cells display SMA-positive expression and negative immunostaining for S100 and ER [25]. Considering the differentials with lung well-differentiated chondrosarcoma, this tumor shows a minimally increased cellularity, nodular growth, occasional binucleated cells, myxoid changes, and chondroid matrix necrosis, while tumor cells are negative for cytokeratins (CKs) and have a variable expression of S100 [26, 27]. The differential diagnosis of PHs also includes myxoid peripheral nerve sheath tumor and primary pulmonary myxoid sarcoma, in lung biopsy samples that include only the fibromyxoid component. In these cases, the lack of atypical feature and the low proliferative index certified by Ki-67 support the PH diagnosis [25, 28, 29]. The conventional PHs treatment is usually the surgical resection [15]. This method is especially recommended in symptomatic patients, in PHs lesions larger than 2.5 cm or when malignancy cannot be excluded [11, 15]. Enucleation of the nodules was the surgical choice in our cases, without any postoperative complications registered in early follow-up of the patients included in our study group. The main limitation of our study was the reduced number of cases available, considering the slow growth rate associated with frequent asymptomatic cases, but still comparable to other literature reports.

Conclusions

PHs are benign lung tumors that most commonly occur in middle age or elderly people, especially in men. PHs have a slow growth, most patients being incidentally diagnosed by a routine chest X-ray or during autopsy, exhibiting a common location in the right lower lobe parenchyma. Usually, PHs diagnosis is suspected by thorax imagistic findings, being certified by microscopic examination of the surgical resection specimen. PHs lesions contain an abnormal mixture of mesenchymal tissue components, such as hyaline cartilage, fat, fibromyxoid or smooth muscle, with entrapped benign epithelium. The differentials from other benign or malignant tumors may be challenging for young pathologists but IHC features may support the diagnosis. However, recent studies are suggesting that there is an association between PHs and lung cancer. Moreover, considering the possibility that PHs may be components of Carney’s triad or Cowden syndrome, these entities should be thoroughly investigated for an appropriate patient management. Additionally, in this context, PHs must be considered in the clinicopathological differential diagnosis of nodular pulmonary lesions, in selected cases. Our results support the characteristics and complex significance of PHs features and further research, by prospective collection of more surgical and necroptic cases, may add important information regarding the association with other lesions, including malignancies.

Conflict of interests

The authors declare that they have no conflict of interests.