Nasal Chondromesenchymal Hamartoma in Older Children and Adults: Series and Immunohistochemical Analysis

Nasal chondromesenchymal hamartoma (NCMH) is a benign mass lesion of the nasal cavity that usually presents in young infants and children. The characteristic morphology includes a proliferation of mesenchymal and chondroid or cartilaginous elements. Several different types of hamartomatous lesions can involve the nasal tract, including angiomatous, lipomatous, purely chondroid, and neurogenic hamartomas. The pathogenesis of hamartomas of the sinonasal tract is poorly understood.

Nasal chondromesenchymal hamartoma typically forms a mass lesion arising from the nasal septum or vestibule, although rare cases have been reported to involve the ethmoid and maxillary sinuses. Patients may present with nasal obstruction, epistaxis, or persistent rhinorrhea.1 In the literature, purely chondroid lesions have been referred to as nasal chondroid lesions, nasal hamartoma, and nasal cartilaginous tumors,2–9 whereas chondromesenchymal lesions have been referred to as chondroid hamartoma, nasal hamartoma, and mesenchymoma. To date, 15 cases with the diagnosis of nasal chondromesenchymal hamartoma have been reported in the English medical literature. All but 1 patient presented as neonates or young children.1,6,10–14 One case describes an NCMH lesion in a 16-year-old adolescent.15 

On pathologic examination, NCMH is typically firm and white, with some areas grossly resembling cartilage. Some may be soft, fleshy, and tan. Microscopically, the lesions have a variably cellular, fibroblastic-type stroma with admixed islands of benign cartilaginous tissue. Two studies have examined the immunohistochemical staining profile of a total of 8 cases to define cellular characteristics of the 2 morphologic elements, that is, the mesenchymal and cartilaginous components of NCMH.11,14 They found that all lesions were vimentin positive. S100 stained focally within spindle cell areas and in the mature cartilage. The spindle cell areas were variably positive for both smooth muscle and all muscle actin and CD68. Cytokeratins and epithelial membrane antigen are typically negative.11 

We describe a series of 4 cases of NCMH occurring in 1 older child, an adolescent girl, and 2 adults. We performed a panel of immunohistochemical analyses to further define the cell characteristics of the mesenchymal and stromal components.

This study was approved by our Research Review and Human Experimentation Committee as an exempt protocol (IRB 0310111). Nasal chondromesenchymal hamartomas with available slides and paraffin-embedded tissue samples were retrieved from the pathology archives at the University of Pittsburgh Medical Center. Detailed clinical data were available in 3 cases. The original hematoxylin-eosin–stained slides were reviewed to confirm the diagnosis and to collect histologic data.

Immunohistochemical analyses were performed on formalin-fixed, paraffin-embedded tissue sections. Antibodies were chosen based on the types of tissue seen on the hematoxylin-eosin sections and what has been studied in the literature. Primary antibodies were directed against the following antigens: cytokeratin AE1/3 (1:100), smooth muscle actin (1:50), S100 (1:300), CD68 (KP1) (1:2000), all muscle actin (clone HHF35), and epithelial membrane antigen (clone E29) (1:25) (DakoCytomation, Carpinteria, Calif). All immunostaining was performed according to standardized protocols in our developmental pathology laboratory. Standard avidin-biotin complex technique was used for detection. Staining intensity was graded as follows: 0 indicates negative; 1+, weak intensity; 2+, moderate intensity; and 3+, strong intensity.

An 11-year-old boy presented with a tumor of the left nasal cavity. The tumor was biopsied and after initial pathologic evaluation was sent to the University of Pittsburgh for consultation.

A 69-year-old woman presented with a mass within the right ethmoid sinus. Intraoperatively, a smooth purple mass was found medial to the right turbinate. The mass crossed the attachment of the middle turbinate and involved the right ethmoid air cells. The middle turbinate was transected and removed, and the superior portion of the tumor was removed from the skull base. There was no evidence of invasion of the orbit or skull base. The inferior half of the mass was transected and submitted to pathology.

A 17-year-old adolescent girl presented with a history of chronic nasal congestion and facial pain that was refractory to medical therapy. At the time of operation, the middle turbinate was thickened to approximately 6 times the normal diameter. This was reduced, and the mass was resected with sparing of the mucosa.

This 25-year-old man had a history of multiple intracranial vascular aneurysms and a longstanding nasopharyngeal tumor. He had undergone clipping of the right internal carotid artery bifurcation and right ophthalmic artery aneurysm as well as a biopsy of the nasal tumor at age 13. The nasal tumor biopsy was interpreted then as consistent with a chronically inflamed nasal polyp. In 2000, he underwent an emergent tracheotomy with excision of a large obstructing oropharyngeal tumor and right nasal biopsy. The oropharyngeal tumor was diagnosed as an edematous polyp with mucous retention cysts and squamous metaplasia. The nasal biopsy showed papillary epithelial hyperplasia and squamous metaplasia with a background of chronic inflammation and fibrosis. A subsequent computed tomographic scan demonstrated a 4.5 × 5.5-cm ossified mass extending from the posterior aspect of the vomer, resulting in obstruction of the oropharynx and continuing from the posterior nasal septum inferiorly to the level of the hyoid. The radiologic differential diagnosis of this mass included osteochondroma, chondrosarcoma, and enchondroma. Cerebral angiogram demonstrated the large nasopharyngeal mass to be relatively avascular. Additionally, multiple other soft tissue lesions, possibly representing lipomatous lesions, were seen posterior to the right mandibular ramus. A large right nasal mass extending into the right maxillary sinus and a calcified or ossified mass was seen in the sella turcica. In September 2000, he was taken back to the operating room for removal of the right bulbar mass and nasal tumor. The nasal tumor again revealed nasal polyps with foci of sclerotic bone, mucous retention cysts, and acute and chronic inflammation. Six days later, he was taken back to the operating room and underwent a Le Fort I osteotomy for removal of the polypoid lesions and nasal tumor in a staged operation involving otolaryngology and maxillofacial surgery. At the time of surgery, a large mass was seen in the posterior pharynx displacing the uvula (Figure 1, A).

As an example, the gross appearance of the specimen from case 4 showed a firm, tan-yellow, 8 × 5 × 3.5-cm mass (Figure 1, B). The external surface was covered by a verrucoid mucosa, with numerous small, semitransparent polyps. Cut section revealed cancellous bone separated by bands of gray-tan fibrous tissue and focal nodules of blue-gray glistening tissue.

Microscopic examination in all cases demonstrated a variably cellular fibrous and spindle cell stroma with admixed areas showing predominantly nodular hyaline and fibrocartilage formation (Figure 2). Generally, the mesenchymal components in some cases displayed a lobular architecture, whereas in others a more fascicular pattern was noted. The stromal and cartilage elements were seen admixed with bone and sometimes surrounding bony islands. Most areas with cartilage differentiation showed a vague nodular configuration and occasionally appeared discretely nodular, although most nodules blended imperceptibly with the surrounding dense fibrous stroma. In case 1 (Figure 2, A and B), the cartilaginous nodules were mostly hypocellular compared to other cases with a more eosinophilic matrix. A spectrum of apparent cartilage differentiation was seen, with the more cellular mesenchymal areas blending with spindle cell areas showing a myxoid matrix and then blending into nodules of mature cartilage. The lesion in case 2 demonstrated numerous eosinophilic and myxoid nodules interspersed between bony trabeculae (Figure 2, C) composed of spindle cells amid a variably dense collagenous matrix (Figure 2, D). This case also demonstrated focal areas with round, clear spaces among the spindle cell stroma (Figure 2, E). Case 3 had very recognizable cartilaginous nodules at low power (Figure 2, F) composed of cellular cartilage with variably sized chondrocytes (Figure 2, G). Case 4 demonstrated distinctly cartilaginous nodules with overlying polypoid inflamed mucosa (Figure 2, H). The nodules have a fibrocartilaginous appearance (Figure 2, I). Cases 1 and 4 (Figure 2, A and H, respectively) demonstrated nearby edematous polypoid sinus tissue with a mild to moderate degree of chronic inflammation. Case 4 also demonstrated admixed adipose tissue in and around proliferative mesenchymal elements and cartilage formation (Figure 2, H). Case 4 had focally scattered glandular elements within the chondromesenchymal stroma. No cases showed atypia of the stromal or cartilaginous cells, and mitotic figures within the mesenchymal component were rare.

Results of the immunohistochemical staining are shown in the Table. One case (case 2, Figure 3, A) showed focal, weak staining of scattered cells with the macrophage marker KP1 (CD68) within the mesenchymal stromal areas. Two cases (cases 3 and 4) had moderate- to strong-intensity staining within the stromal component for all muscle actin (HHF35) (Figure 3, B). All cases demonstrated moderate- to strong-intensity staining of the stromal component for smooth muscle actin (Figure 3, C). S100 was positive in all cases, showing strong-intensity staining of the cytoplasm and nuclei of the cartilaginous component (Figure 3, D and E, respectively). The cells in loose areas with microcystic spaces (case 2) stained with S100 (Figure 3, F). All 4 cases demonstrated focal and weak staining of both stromal and cartilaginous components with epithelial membrane antigen (case 2, Figure 3, G). Cytokeratin was negative in all cases.

The classification of mesenchymal hamartomatous lesions of the nasal cavity is somewhat confusing because of the nomenclature and our incomplete understanding of their pathogenesis. Nasal chondromesenchymal hamartoma has been described as chondroid hamartoma, mesenchymoma, nasal hamartoma, and possibly as other stromal lesions in the nasal cavity of neonates.1,6,12,14 McDermott et al11 coined the preferred diagnostic term nasal chondromesenchymal hamartoma in 1998 to reflect a consistent mass lesion consisting of intimately associated chondroid and mesenchymal elements occurring in the nasal cavities of young children. This lesion was similar morphologically to the chest wall lesion seen in neonates designated as chest wall mesenchymal hamartoma. In the original series of NCMH by McDermott et al,11 all but 1 of the patients were 3 months old or younger at the time of presentation. To our knowledge, this is only the second report of NCMH in a child or adult older than 7 years.

Previous series of NCMH have described a male predominance (10 male and 4 female patients). In our 4 cases, lesions occurred in 2 female and 2 male patients. The patients in our series presented with a nasal mass, similar to those reported previously. Recurrence is not a feature of NCMH, and likewise, to our knowledge none of the lesions in our current series has shown recurrence.

The pathologic findings in our cases are commensurate with those in previous case reports and series. A variably cellular fibrous mesenchymal component was interspersed with nodules of mature cartilage. Interestingly, 1 of our cases (case 4) displayed epithelial and possibly adipose components embedded within the mesenchymal tissue, directly adjacent to cartilaginous areas. Previous reports have introduced the concept that NCMH may be along a spectrum of lesions encompassing both mesenchymal and epithelial-mesenchymal sinonasal hamartomatous lesions.11 Included in the differential diagnosis in mixed lesions, such as case 4, is respiratory epithelial adenomatoid hamartoma. However, the epithelial component resembled seromucinous glands, not the characteristic glands with thickened and hyalinized basement membrane or its chondro-osseous variant, chondro-osseous respiratory epithelial adenomatoid hamartoma.

Unlike some of the cases described in the series of McDermott et al11 and case reports of Shet et al,10 we did not appreciate an aneurysmal bone cystlike component in any of the lesions, nor were giant cells apparent. One case (case 2) had a distinctive “microcystic” area with small cysts containing somewhat vacuolated and myxoid material variably lined by flattened nuclei resembling the surrounding, more cellular mesenchymal component. Many of the cells in this area also stained with antibody to S100 protein, possibly indicating a form of cartilaginous differentiation. These cells displayed deeply eosinophilic cytoplasm and had processes extending from the cell body. Many of these cells were also binucleated, possibly indicating a transition from a fibroblastic cell to a cell with chondrocyte terminal differentiation.

The cartilaginous and mesenchymal stromal component in all cases stained consistently with S100, with stronger staining in the cartilaginous components. This finding is not particularly surprising, because staining for S100 protein has long been known to be expressed in chondrocytes and chondroid lesions.16–19 At least in the rat model of cartilage development in the nose, the number of chondrocytes expressing S100 protein detected by immunohistochemistry increases from birth to adult life.20 The strong, diffuse staining of all cells within the “mature”-appearing cartilage and the lesser staining in those cells within the mesenchymal component suggests a simulation of the fibroblastic component as part of the normal development of hyaline cartilage. Smooth muscle actin tended to highlight the stromal components, and 2 cases showed strong staining of the stroma with all muscle actin (HHF35). The consistent staining of the mesenchymal stromal element with smooth muscle actin and strong staining in half of the lesions with HHF35 reflects the tendency of the mesenchymal element to display a myofibroblastic phenotype characteristic of many fibrous and myofibroblastic lesions. Only 1 case showed weak focal staining with CD68 (KP1) within scattered cells in the stromal component. The staining patterns seen for smooth muscle actin, S100, pancytokeratin, and HHF35 are consistent with the previously published series performing immunohistochemistry in lesions arising in young children.11,13 

Epithelial membrane antigen staining is contrary to other published reports, wherein the few cases examined were negative. All cases in this series demonstrated focal weak staining in the mesenchymal and cartilaginous areas, albeit in a cytoplasmic pattern. The epithelial membrane antigen belongs to a group of highly glycosylated transmembrane proteins in the family of human milk fat globule membrane proteins.21 Although the antibody reacts predominantly with nonneoplastic epithelial tissues and some epithelial-derived neoplasms, it is also reactive with neoplasms derived from mesenchymal tissues, such as synovial sarcoma,22 solitary fibrous tumors,23 and chordomas with spindle cell components.24 Interestingly, chordomas with spindle cell components show diffuse immunoreactivity with vimentin and staining with epithelial membrane antigen, often in transition from mesenchymal to epithelial areas. We believe that the histologic features and immunohistochemical staining profiles in NCMH in adults and older children are similar to those reported in very young children. Although our immunohistochemical findings are indicative of a mesenchymal origin for NCMH, the pathogenesis of these lesions is unknown and may reflect a “transitioning” mesenchyme.

In previous series, NCMH was thought to be present at birth, indicating a developmental or congenital origin. It is also possible that the NCMHs in older children and adults in our series were also present from birth but remained asymptomatic until later in life. An alternative explanation would be that the NCMH in adults was the result of a chronic inflammatory process. Evidence of chronic sinusitis was noted in 3 of the 4 cases presented here. In case 4, in particular, the patient had a long history of chronic sinusitis documented by biopsy, and indeed this lesion may have been present since the age of 13, when he had a “nasal tumor.” The question then arises as to whether the sinusitis is a primary or secondary phenomenon after a mass lesion is present and causing obstructive symptoms. Mesenchymal fibroblast atypia can occur in chronic inflammation in the nasal cavity and also in fibrosed nasal polyps.25 However, very little is known about the short- and long-term mesenchymal response to prolonged low-grade inflammation. In 2 of the cases here, a prolonged history of chronic nasal congestion or nasal polyps was identified. Work exploring chondrogenic differentiation has shown that several growth factors (chemokines) are critical for cartilage differentiation from primitive mesenchyme. Platelet-derived growth factor A is known to induce chondrogenesis from limb bud mesenchyme in the chick, whereas its absence results in lack of cartilage.26 Also, human mesenchymal stem cells from the bone marrow can be induced to form cartilage when cultured in medium containing dexamethasone and transforming growth factor β (3).27,28 Whether these uncommon lesions are linked to a chronic inflammatory presence with stimulation by released cytokines and transformation of mesenchymal tissue to chondroid tissue is speculative. The fact that the vast majority of those with chronic sinusitis or nasal congestion do not develop chondromesenchymal mass lesions in the sinonasal tract is indirect proof that the pathogenesis is much more complicated and may involve an underlying genetic predisposition in combination with the proper stimulation. This may apply to any of the fibroinflammatory lesions seen elsewhere (inflammatory myofibroblastic tumors, sclerosing mediastinitis, retroperitoneal fibrosis, and others), where autoimmune mechanisms in conjunction with an inflammatory process or malignancy may constitute the triggering event for fibroblastic proliferation and differentiation.29 

In conclusion, we present 4 cases of nasal chondromesenchymal hamartoma in a previously undescribed age group: the older child, the teenager, and adults. A future study of the role of inflammation, cytokines, and growth factors associated with inflammation within the sinonasal tract in children and adults may lead us to a better understanding of the pathogenesis of NCMH.

We gratefully acknowledge Jacqueline K. Trupiano, MD, for providing tissue samples for case 1.