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Nasal chondromesenchymal hamartoma in children with pleuropulmonary blastoma—A report from the International Pleuropulmonary Blastoma Registry registry
International Journal of Pediatric Otorhinolaryngology 74 (2010) 1240–1244
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Nasal chondromesenchymal hamartoma in children with pleuropulmonary blastoma—A report from the International Pleuropulmonary Blastoma Registry registry John R. Priest a,*, Gretchen M. Williams b, William A. Mize c, Louis P. Dehner d, Michael B. McDermott e a
International Pleuropulmonary Blastoma Registry, Children’s Hospitals and Clinics of Minnesota, 2525 Chicago Ave. S., MS 17-412, Minneapolis, MN 55404, USA Department of Pediatric Hematology/Oncology, Children’s Hospitals and Clinics of Minnesota, 2525 Chicago Ave. S., MS 17-412, Minneapolis, MN 55404, USA Department of Pediatric Radiology, Children’s Hospitals and Clinics of Minnesota, 2525 Chicago Ave. S., MS 32-1403, Minneapolis, MN 55404, USA d Lauren V. Ackerman Lab of Surgical Pathology, Barnes-Jewish & St. Louis Children’s Hosp, Washington University Medical Center, Division of Anatomic Pathology, 660 South Euclid Avenue, Box 8118, St. Louis, MO 63110, USA e Department of Pathology, Our Lady’s Hospital for Sick Children, Crumlin, Dublin 12, Ireland b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 18 May 2010 Received in revised form 26 July 2010 Accepted 28 July 2010 Available online 6 September 2010
Objectives: Nasal chondromesenchymal hamartoma (NCMH) is an uncommon chondro-stromal tumor of the nasal cavity and paranasal sinuses in infancy and childhood. Pleuropulmonary blastoma (PPB) is also a rare malignancy of lung and pleura in childhood and is the sentinel disease of an important familial tumor and dysplasia syndrome. This study identified NCMH in PPB patients. Methods: The International PPB Registry collects cases of PPB using central pathology review and evaluation of clinical records. The Registry also evaluates PPB literature. Examples of NCMH occurring with PPB were identified. Clinical records, digital radiography and pathologic specimens of PPBassociated NCMH cases were analyzed. Results: Among approximately 625 cases of PPB, four children developed NCMH. These cases are among 28 total reported NCMH cases. NCMH presented with sinonasal congestion and visible polypoid nasal masses and were diagnosed from ages 7 to 15 years, similar to older reported NCMH cases. NCMH involved the nasal cavity, paranasal sinuses and upper nasopharynx, was bilateral in three children and locally recurrent in one. In two children, NCMH had the characteristic pathologic spectrum of immature nodules of cartilage surrounded by spindle cell stroma, whereas the other two NCMH displayed mature chondroid nodules and a less varied fibrous stroma. NCMH was not identified in family members with PPB. Conclusions: NCMH developing in four children with PPB indicates that NCMH is part of the heredofamilial disease complex associated with PPB. Otorhinolaryngologists and pediatric oncologists should be aware that these two rare conditions occur together and that affected patients may have a familial predisposition to childhood malignant and dysplastic disease. ß 2010 Elsevier Ireland Ltd. All rights reserved.
Keywords: Nasal chondromesenchymal hamartoma Pleuropulmonary blastoma Cancer predisposition PPB NCMH DICER1
1. Introduction Nasal chondromesenchymal hamartoma (NCMH) is an uncommon chondro-stromal proliferation of the nasal and sinus cavities [1]. Twenty-six NCMH cases have previously been reported, predominantly in infants [1–16]. NCMH has a mixed morphologic composition of immature cartilage surrounded by spindle cell stroma with or without fibro-osseous and aneurysmal bone cystlike features [1]. NCMH may be expansile, locally destructive and extend into the intracranial space [1,3,4,6], leading to uncertainty about a hamartomatous versus neoplastic designation. * Corresponding author. Tel.: +1 612 813 7115; fax: +1 612 813 7108. E-mail address: [email protected] (J.R. Priest). 0165-5876/$ – see front matter ß 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijporl.2010.07.022
Pleuropulmonary blastoma (PPB) is a rare childhood dysembryonic sarcoma of lung and pleura [17,18]. It is the pulmonary analog of more common early childhood dysontogenetic tumors such as neuroblastoma, Wilms tumor, embryonal rhabdomyosarcoma [17]. A PPB patient with NCMH was included in the original description of NCMH [1], and a second PPB-associated NCMH has been reported [15]. PPB is the sentinel neoplasm of a distinctive heredofamilial tumor predisposition syndrome (OMIM #601200, Online Mendelian Inheritance in Man [19]). Heterozygous, germline, loss-of-function mutations in gene DICER1 are responsible for the PPB and the syndrome [20]. We describe four NCMH occurring in PPB patients and propose that NCMH belongs in the distinctive set of diseases associated with PPB.
J.R. Priest et al. / International Journal of Pediatric Otorhinolaryngology 74 (2010) 1240–1244
2. Methods and materials The International PPB Registry is a collaboration of the Department of Pediatric Hematology and Oncology at Children’s Hospitals and Clinics of Minnesota (St. Paul, MN), the Department of Surgical Pathology at Children’s National Medical Center (Washington, DC) and the Department of Pathology and Immunology, Washington University Medical Center (St. Louis, MO). Registry activities are approved by the Institutional Review Boards at each of the cooperating institutions. PPB cases are identified from physician or family referral and from publications and are accessioned consecutively when Registry pathologists confirm the PPB diagnosis after reviewing original diagnostic materials. Unreviewed literature PPB cases are also tabulated when consistent with PPB (http://www.ppbregistry.org/sources/index.php). For enrolled cases, the Registry collects data on clinical presentation, surgery, pathology, family medical history, radiology, chemoradiotherapy, course, additional diagnoses and long-term follow-up. A search for NCMH diagnoses in Registry-enrolled and literature PPB cases form the basis for this report. We sent email and postal messages to 24 authors of 11 NCMH literature reports to determine whether their patients had unreported PPB or associated diseases; three responses provided unpublished information on five reported cases of NCMH. 3. Results Four children with PPB developed NCMH at ages 7, 10, 11, and 15 years. The clinical presentation, imaging features and surgical
1241
management are summarized in Table 1. Two cases have been previously reported [1,15]. The four NCMH cases are among 295 Registry PPB cases; we have patient and family details on 170 cases, patient details on 42, and no information other than pathology report and diagnosis confirmation on 83. NCMH has not been observed in relatives of PPB patients. The four PPB-associated NCMH presented with nasal congestion; parents observed tissue in the nasal cavity in two children. Computerized tomographic (CT) scans revealed sinonasal opacification in three cases; the expansile nature of NCMH causing distortion of boney structures is illustrated in Fig. 1. In one patient, CT was considered normal (reviewed by authors JRP and WAM as normal). Disease in four children involved the nasal cavity and, in one child, also the paranasal sinuses; three NCMH were bilateral. One NCMH patient required several resections over 3 years. All children survive both PPB and NCMH. Pathologic review was done on all cases (MMcD, LPD). Gross specimens involved resected polyps (Fig. 2) or multiple tissue fragments, some with glistening, firm features of cartilage. Two of the cases displayed the presence of large nodules of cellular cartilage with somewhat immature, but non-malignant features (Fig. 3). A hypercellular spindle cell stroma surrounded the nodules of cartilage. Rhabdomyoblastic elements were not identified. In the other two cases, the nodules of cartilage were smaller, less cellular and the stroma had a more fibrous appearance. Unpublished information on five NCMH from authors revealed no known PPB or lung cysts. Four patients had no other known conditions. One child had complex cervicocraniofacial anomalies, defined radiographically: probable lipomas, a boney retrophar-
Table 1 Clinical presentation, imaging features and surgical case management. Case Gender
NCMH symptoms
1 M
Nasal congestion; mother noted nasal mass
2 F
Chronic sinusitis, facial pain and nasal congestion
15
3 F
Nasal congestion
10
4 M
Age at NCMH diagnosis (years) 7
11 Nasal congestion
Radiologic findings on computed tomographic scans
Unilateral or bilateral NCMH
Extent of NCMH
Treatment for NCMH
Follow-up after NCMH diagnosis (months)
Age at PPB diagnosis (months)
PPB type
Other PPB FTDS findings in patienta,b
Tumor originating from the sphenoid sinus filling the nasal cavity, compressing middle turbinate laterally
Initially unilateral; bilateral at recurrence
Four resections over 37 months
157
33
II–III NOS
Lung cysts contralateral to PPBa
Extensive opacification of the paranasal sinuses except for the right sphenoid sinus; boney destruction; disease extending into the nasopharynx Severe, diffuse sinus opacification; right maxillary sinusitis; nasal polyp
Bilateral
Initially unilateral nasal cavity/ sphenoid sinus tumor; upon recurrence bilateral nasal masses with involvement of the ethmoid and sphenoid sinuses Extensive bilateral nasal polyps with boney erosion of the posterior septum; maxillary and sphenoid sinuses not involved
Resection
51
22
II
Sertoli-Leydig cell ovarian tumora congenital phthisis bulbib Stickler syndromeb
Resection
21
40
III
None
Nasal and sinus cavities within normal limits
Right
Bilateral intranasal polyps, each arising between the nasal septum and the middle turbinate Nasal cavity with attachment to inferior surface of anterior skull base
Resection
4
54
III
None
Bilateral
Abbreviations: PPB, pleuropulmonary blastoma; NCMH, nasal chondromesenchymal hamartoma; FTDS, family tumor and dysplasia Syndrome; m, male; f, female; NOS, not otherwise specified. a Part of PPB Family Tumor and Dysplasia Syndrome. b Uncertain status as part of the PPB Family Tumor and Dysplasia syndrome.
[(Fig._1)TD$IG]
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Fig. 1. (A) Coronal CT image at the level of the anterior aspect of the nasal cavity, displayed with soft tissue windows. An ovoid soft tissue mass representing NCMH occupies the left nasal cavity (Case 3). (B) Axial CT image at the level of the maxillary sinuses, displayed with bone windows. There is asymmetric expansion of the nasal cavity by NCMH polyp formation. Expansion of the posterior portion of the left nasal cavity produces outward remodeling of the medial wall of the left maxillary sinus. Expansion of the anterior aspect of the right nasal cavity results in leftward distortion of the anterior aspect of the nasal septum. There is also extensive opacification of the maxillary sinuses (Case 2). (C) Axial CT image at the level of the globes, displayed with bone windows. There is expansion of the anterior aspect of the left nasal cavity by NCMH polyp formation. There is also extensive opacification of the ethmoid sinuses bilaterally and the left sphenoid sinus. A small right globe with a calcified lens is consistent with patient’s history of congenital phthisis bulbi (Case 2).
yngeal mass, carotid and ophthalmic artery aneurysms (which were clipped), and extensive partially calcified vascular malformations causing defects in soft tissue, mandible and cranial bone. 4. Discussion Four NCMH were identified among 295 Registry and 300–325 non-Registry literature PPB cases. The NCMH were diagnosed at ages 7–15 years, from 4 to 12 years after the child’s PPB diagnosis. In 24 NCMH not associated with PPB, ages at diagnosis were birth
[(Fig._2)TD$IG]
Fig. 2. Gross specimen of polypoid nasal chondromesenchymal hamartoma (Case 3).
to 69 years, median 8 months, with seven cases between ages 11 and 25 years [1–14,16,21]. The anatomic extent of PPB-associated NCMH (Fig. 1) was similar to reported cases, except that none entered intracranial spaces. Histopathologic features of reported NCMH reveal complex mixed solid and cystic masses characterized by a prominent myxoid, spindle cell stroma, hemorrhagic cysts and immature nodules of cartilage [1]. In two PPB-associated NCMH, the features were typical (Fig. 3). In two others, the findings did not demonstrate the full range of immature mesenchymal tissue patterns: cartilaginous components were more mature and surrounding fibrous stroma less cellular than described in reported NCMH of all ages. The restricted pattern in these two patients may be explained by older diagnosis age of PPB-associated NCMH or may be a feature of NCMH in the PPB setting. With 28 reported NCMH, more remains to be learned about the histologic spectrum of NCMH. Maturation is recognized in other hamartomas such as mesenchymal hamartoma of the liver. Could NCMH in a PPB patient result from prior antineoplastic therapy? For PPB, each child received standard sarcoma chemotherapy regimens. Case 1 also received chest radiation, and Cases 3 and 4 received radiation to frontal cranial vault for cerebral PPB metastases. All therapies preceded NCMH. NCMH is not reported as a second tumor in childhood cancer patients [22], nor has any reported NCMH patient had prior radiotherapy. Hamartomas occur in other familial cancer predisposition syndromes such as Cowden’s and Peutz-Jegher’s syndromes [23,24]. We believe NCMH in a PPB patient is an expression of a genetic predisposition, although we recognize that cytotoxic therapy could present a unique challenge to genetically predisposed individuals. Highly varied dysplastic and neoplastic conditions occur in PPB patients and their young relatives, including various childhood sarcomas, cystic nephroma, Wilms tumor, ovarian tumors,
[(Fig._3)TD$IG]
J.R. Priest et al. / International Journal of Pediatric Otorhinolaryngology 74 (2010) 1240–1244
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Conflict of interest statement John R. Priest is named in a patent registration involving genetic sequencing methodology of DICER1 gene. Acknowledgements The authors thank physicians and data managers who supply information, and thank the many families who allow their children to be studied by the International PPB Registry. Appreciation also goes to Kris Doyle and Nancy Battaglia for background data supporting the manuscript. The Pine Tree Apple Tennis Classic and the Theodora H. Lang Charitable Trust support the International PPB Registry and its staff. References
Fig. 3. Nasal chondromesenchymal hamartoma presented as a polypoid mass in this 11-year-old boy (Case 4). (A) The low magnification shows the presence of a nodule of cartilage surrounded by a uniform spindle cell stroma. (B) The spindle cell stroma blends into the nodule of cartilage. These spindle cells have somewhat immature features, but no evidence of rhabdomyoblastic differentiation (HSE, 10, 60).
neuroblastoma and intra-ocular medullo-epithelioma [20,25–27]. We believe that NCMH is also a manifestation of this familial predisposition because it is highly unlikely that coincidence would explain NCMH and PPB in the same individual. The extensive cervicocranial anomalies in one reported NCMH patient have not been observed in PPB patients or kindreds. DICER1 mutations are found in 50–70% of PPB patients [20,28]. Three PPB/NCMH patients included here participated in the exploratory genetic research which revealed DICER1 mutations. Unfortunately, we cannot disclose results because the exploratory study was approved under ethical guidelines preventing release of results to families. Disclosing results here would violate the guidelines. As open DICER1 sequencing becomes widely available, DICER1 mutation in the entire range of PPB-associated diseases will be elucidated. In summary, NCMH appears to be biologically associated with PPB. Pediatric oncologists and otorhinolaryngologists should be aware of this possibility. Persistent nasal congestion or ‘‘sinusitis’’ or presence of a nasal mass in a PPB patient should raise suspicion, and careful radiographic diagnosis may reveal unexpectedly extensive sinonasal involvement. Other familial disease may be present in these patients or kindreds.
[1] M.B. McDermott, T.B. Ponder, L.P. Dehner, Nasal chondromesenchymal hamartoma: an upper respiratory tract analogue of the chest wall mesenchymal hamartoma, Am. J. Surg. Pathol. 22 (4) (1998) 425–433. [2] C. Hsueh, S. Hsueh, F. Gonzalez-Crussi, T. Lee, J. Su, Nasal chondromesenchymal hamartoma in children: report of 2 cases with review of the literature, Arch. Pathol. Lab. Med. 125 (March (3)) (2001) 400–403. [3] B. Kim, S.H. Park, H.S. Min, J.S. Rhee, K.C. Wang, Nasal chondromesenchymal hamartoma of infancy clinically mimicking meningoencephalocele, Pediatr. Neurosurg. 40 (May–June (3)) (2004) 136–140. [4] D.W. Kim, W. Low, G. Billman, J. Wickersham, D. Kearns, Chondroid hamartoma presenting as a neonatal nasal mass, Int. J. Pediatr. Otorhinolaryngol. 47 (March (3)) (1999) 253–259. [5] J.E. Kim, H.J. Kim, J.H. Kim, Y.H. Ko, S.K. Chung, Nasal chondromesenchymal hamartoma: CT and MR imaging findings, Korean J. Radiol. 10 (July–August (4)) (2009) 416–419. [6] K. Kato, R. Ijiri, Y. Tanaka, M. Hara, K. Sekido, Nasal chondromesenchymal hamartoma of infancy: the first Japanese case report, Pathol. Int. 49 (8) (1999) 731–736. [7] H.J. Chae, J.H. Suk, S.K. Lee, Nasal chondromesenchymal hamartoma, Korean J. Pathol. 33 (3) (1999) 225–227. [8] R.Z. Silkiss, S.S. Mudvari, D. Shetlar, Ophthalmologic presentation of nasal chondromesenchymal hamartoma in an infant, Ophthal. Plast. Reconstr. Surg. 23 (May–June (3)) (2007) 243–244. [9] T. Shet, A. Borges, C. Nair, S. Desai, R. Mistry, Two unusual lesions in the nasal cavity of infants—a nasal chondromesenchymal hamartoma and an aneurysmal bone cyst like lesion. More closely related than we think? Int. J. Pediatr. Otorhinolaryngol. 68 (March (3)) (2004) 359–364. [10] S. Finitsis, C. Giavroglou, S. Potsi, I. Constantinidis, A. Mpaltatzidis, D. Rachovitsas, et al., Nasal chondromesenchymal hamartoma in a child, Cardiovasc. Intervent. Radiol. 32 (May (3)) (2009) 593–597. [11] E.S. Norman, S. Bergman, J.K. Trupiano, Nasal chondromesenchymal hamartoma: report of a case and review of the literature, Pediatr. Dev. Pathol. 7 (September– October (5)) (2004) 517–520. [12] J.A. Ozolek, R. Carrau, E.L. Barnes, J.L. Hunt, Nasal chondromesenchymal hamartoma in older children and adults: series and immunohistochemical analysis, Arch. Pathol. Lab. Med. 129 (November (11)) (2005) 1444–1450. [13] I. Ganske, W. Faquin, M. Cunningham, Pathology quiz case 2. Nasal chondromesenchymal hamartoma (NCMH), Arch. Otolaryngol. Head Neck Surg. 135 (September (9)) (2009), 945, 947–948. [14] S.E. Low, R.K. Sethi, E. Davies, J.S. Stafford, Nasal chondromesenchymal hamartoma in an adolescent, Histopathology 49 (September (3)) (2006) 321–323. [15] C. Johnson, U. Nagaraj, J. Esguerra, D. Wasdahl, D. Wurzbach, Nasal chondromesenchymal hamartoma: radiographic and histopathologic analysis of a rare pediatric tumor, Pediatr. Radiol. 37 (January (1)) (2007) 101–104. [16] M. Alrawi, M. McDermott, D. Orr, J. Russell, Nasal chondromesynchymal hamartoma presenting in an adolescent, Int. J. Pediatr. Otorhinolaryngol. 67 (June (6)) (2003) 669–672. [17] L.P. Dehner, Pleuropulmonary blastoma is THE pulmonary blastoma of childhood, Semin. Diagn. Pathol. 11 (May (2)) (1994) 144–151. [18] J.C. Manivel, J.R. Priest, J. Watterson, M. Steiner, W.G. Woods, M.R. Wick, et al., Pleuropulmonary blastoma. The so-called pulmonary blastoma of childhood, Cancer 62 (October (8)) (1988) 1516–1526. [19] OMIM, Online Mendelian Inheritance in Man OTJHU, Baltimore, MD, MIM Number: {601200}: {10/21/2009}, World Wide Web URL: http://ncbi.nlm.nih.gov/ omim/. [20] D.A. Hill, J. Ivanovich, J.R. Priest, C.A. Gurnett, L.P. Dehner, D. Desruisseau, et al., DICER1 mutations in familial pleuropulmonary blastoma, Science 325 (August (5943)) (2009) 965. [21] R.G. Wang, S.C. Jiang, R. Gu, The cartilaginous nasal capsule and embryonic development of human paranasal sinuses, J. Otolaryngol. 23 (August (4)) (1994) 239–243. [22] J.P. Neglia, D.L. Friedman, Y. Yasui, A.C. Mertens, S. Hammond, M. Stovall, et al., Second malignant neoplasms in five-year survivors of childhood cancer: childhood cancer survivor study, J. Natl. Cancer Inst. 93 (April (8)) (2001) 618–629.
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[23] V.P. Krymskaya, E.A. Goncharova, PI3K/mTORC1 activation in hamartoma syndromes: therapeutic prospects, Cell Cycle 8 (February (3)) (2009) 403–413. [24] J.A. Hobert, C. Eng, PTEN hamartoma tumor syndrome: an overview, Genet. Med. 11 (October (10)) (2009) 687–694. [25] J.R. Priest, G.M. Williams, D.A. Hill, L.P. Dehner, A. Jaffe, Pulmonary cysts in early childhood and the risk of malignancy, Pediatr. Pulmonol. 44 (January (1)) (2009) 14–30. [26] F. Boman, D.A. Hill, G.M. Williams, A. Chauvenet, J.C. Fournet, D. BouronDalSoglio, et al., Familial association of pleuropulmonary blastoma with cystic nephroma
and other renal tumors: a report from the International Pleuropulmonary Blastoma Registry, J. Pediatr. 149 (December (6)) (2006) 850–854. [27] J. Priest, J. Watterson, L. Dehner, S. Friend, J. McIntyre, L. Strong, et al., Pleuropulmonary blastoma: a marker for familial disease, J. Pediatr. 128 (February (2)) (1996) 220–224. [28] D.A. Hill, J.D. Wang, P. Schoettler, L. Dehner, J. Ivanovich, D. Bracamontes, et al., Germline DICER1 mutations are common in both hereditary and presumed sporadic pleuropulmonary blastoma [Abstract], Lab. Invest. 90 (2010) 311.
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Nasal chondromesenchymal hamartoma in children with pleuropulmonary blastoma—A report from the International Pleuropulmonary Blastoma Registry registry John R. Priest a,*, Gretchen M. Williams b, William A. Mize c, Louis P. Dehner d, Michael B. McDermott e a
International Pleuropulmonary Blastoma Registry, Children’s Hospitals and Clinics of Minnesota, 2525 Chicago Ave. S., MS 17-412, Minneapolis, MN 55404, USA Department of Pediatric Hematology/Oncology, Children’s Hospitals and Clinics of Minnesota, 2525 Chicago Ave. S., MS 17-412, Minneapolis, MN 55404, USA Department of Pediatric Radiology, Children’s Hospitals and Clinics of Minnesota, 2525 Chicago Ave. S., MS 32-1403, Minneapolis, MN 55404, USA d Lauren V. Ackerman Lab of Surgical Pathology, Barnes-Jewish & St. Louis Children’s Hosp, Washington University Medical Center, Division of Anatomic Pathology, 660 South Euclid Avenue, Box 8118, St. Louis, MO 63110, USA e Department of Pathology, Our Lady’s Hospital for Sick Children, Crumlin, Dublin 12, Ireland b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 18 May 2010 Received in revised form 26 July 2010 Accepted 28 July 2010 Available online 6 September 2010
Objectives: Nasal chondromesenchymal hamartoma (NCMH) is an uncommon chondro-stromal tumor of the nasal cavity and paranasal sinuses in infancy and childhood. Pleuropulmonary blastoma (PPB) is also a rare malignancy of lung and pleura in childhood and is the sentinel disease of an important familial tumor and dysplasia syndrome. This study identified NCMH in PPB patients. Methods: The International PPB Registry collects cases of PPB using central pathology review and evaluation of clinical records. The Registry also evaluates PPB literature. Examples of NCMH occurring with PPB were identified. Clinical records, digital radiography and pathologic specimens of PPBassociated NCMH cases were analyzed. Results: Among approximately 625 cases of PPB, four children developed NCMH. These cases are among 28 total reported NCMH cases. NCMH presented with sinonasal congestion and visible polypoid nasal masses and were diagnosed from ages 7 to 15 years, similar to older reported NCMH cases. NCMH involved the nasal cavity, paranasal sinuses and upper nasopharynx, was bilateral in three children and locally recurrent in one. In two children, NCMH had the characteristic pathologic spectrum of immature nodules of cartilage surrounded by spindle cell stroma, whereas the other two NCMH displayed mature chondroid nodules and a less varied fibrous stroma. NCMH was not identified in family members with PPB. Conclusions: NCMH developing in four children with PPB indicates that NCMH is part of the heredofamilial disease complex associated with PPB. Otorhinolaryngologists and pediatric oncologists should be aware that these two rare conditions occur together and that affected patients may have a familial predisposition to childhood malignant and dysplastic disease. ß 2010 Elsevier Ireland Ltd. All rights reserved.
Keywords: Nasal chondromesenchymal hamartoma Pleuropulmonary blastoma Cancer predisposition PPB NCMH DICER1
1. Introduction Nasal chondromesenchymal hamartoma (NCMH) is an uncommon chondro-stromal proliferation of the nasal and sinus cavities [1]. Twenty-six NCMH cases have previously been reported, predominantly in infants [1–16]. NCMH has a mixed morphologic composition of immature cartilage surrounded by spindle cell stroma with or without fibro-osseous and aneurysmal bone cystlike features [1]. NCMH may be expansile, locally destructive and extend into the intracranial space [1,3,4,6], leading to uncertainty about a hamartomatous versus neoplastic designation. * Corresponding author. Tel.: +1 612 813 7115; fax: +1 612 813 7108. E-mail address: [email protected] (J.R. Priest). 0165-5876/$ – see front matter ß 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijporl.2010.07.022
Pleuropulmonary blastoma (PPB) is a rare childhood dysembryonic sarcoma of lung and pleura [17,18]. It is the pulmonary analog of more common early childhood dysontogenetic tumors such as neuroblastoma, Wilms tumor, embryonal rhabdomyosarcoma [17]. A PPB patient with NCMH was included in the original description of NCMH [1], and a second PPB-associated NCMH has been reported [15]. PPB is the sentinel neoplasm of a distinctive heredofamilial tumor predisposition syndrome (OMIM #601200, Online Mendelian Inheritance in Man [19]). Heterozygous, germline, loss-of-function mutations in gene DICER1 are responsible for the PPB and the syndrome [20]. We describe four NCMH occurring in PPB patients and propose that NCMH belongs in the distinctive set of diseases associated with PPB.
J.R. Priest et al. / International Journal of Pediatric Otorhinolaryngology 74 (2010) 1240–1244
2. Methods and materials The International PPB Registry is a collaboration of the Department of Pediatric Hematology and Oncology at Children’s Hospitals and Clinics of Minnesota (St. Paul, MN), the Department of Surgical Pathology at Children’s National Medical Center (Washington, DC) and the Department of Pathology and Immunology, Washington University Medical Center (St. Louis, MO). Registry activities are approved by the Institutional Review Boards at each of the cooperating institutions. PPB cases are identified from physician or family referral and from publications and are accessioned consecutively when Registry pathologists confirm the PPB diagnosis after reviewing original diagnostic materials. Unreviewed literature PPB cases are also tabulated when consistent with PPB (http://www.ppbregistry.org/sources/index.php). For enrolled cases, the Registry collects data on clinical presentation, surgery, pathology, family medical history, radiology, chemoradiotherapy, course, additional diagnoses and long-term follow-up. A search for NCMH diagnoses in Registry-enrolled and literature PPB cases form the basis for this report. We sent email and postal messages to 24 authors of 11 NCMH literature reports to determine whether their patients had unreported PPB or associated diseases; three responses provided unpublished information on five reported cases of NCMH. 3. Results Four children with PPB developed NCMH at ages 7, 10, 11, and 15 years. The clinical presentation, imaging features and surgical
1241
management are summarized in Table 1. Two cases have been previously reported [1,15]. The four NCMH cases are among 295 Registry PPB cases; we have patient and family details on 170 cases, patient details on 42, and no information other than pathology report and diagnosis confirmation on 83. NCMH has not been observed in relatives of PPB patients. The four PPB-associated NCMH presented with nasal congestion; parents observed tissue in the nasal cavity in two children. Computerized tomographic (CT) scans revealed sinonasal opacification in three cases; the expansile nature of NCMH causing distortion of boney structures is illustrated in Fig. 1. In one patient, CT was considered normal (reviewed by authors JRP and WAM as normal). Disease in four children involved the nasal cavity and, in one child, also the paranasal sinuses; three NCMH were bilateral. One NCMH patient required several resections over 3 years. All children survive both PPB and NCMH. Pathologic review was done on all cases (MMcD, LPD). Gross specimens involved resected polyps (Fig. 2) or multiple tissue fragments, some with glistening, firm features of cartilage. Two of the cases displayed the presence of large nodules of cellular cartilage with somewhat immature, but non-malignant features (Fig. 3). A hypercellular spindle cell stroma surrounded the nodules of cartilage. Rhabdomyoblastic elements were not identified. In the other two cases, the nodules of cartilage were smaller, less cellular and the stroma had a more fibrous appearance. Unpublished information on five NCMH from authors revealed no known PPB or lung cysts. Four patients had no other known conditions. One child had complex cervicocraniofacial anomalies, defined radiographically: probable lipomas, a boney retrophar-
Table 1 Clinical presentation, imaging features and surgical case management. Case Gender
NCMH symptoms
1 M
Nasal congestion; mother noted nasal mass
2 F
Chronic sinusitis, facial pain and nasal congestion
15
3 F
Nasal congestion
10
4 M
Age at NCMH diagnosis (years) 7
11 Nasal congestion
Radiologic findings on computed tomographic scans
Unilateral or bilateral NCMH
Extent of NCMH
Treatment for NCMH
Follow-up after NCMH diagnosis (months)
Age at PPB diagnosis (months)
PPB type
Other PPB FTDS findings in patienta,b
Tumor originating from the sphenoid sinus filling the nasal cavity, compressing middle turbinate laterally
Initially unilateral; bilateral at recurrence
Four resections over 37 months
157
33
II–III NOS
Lung cysts contralateral to PPBa
Extensive opacification of the paranasal sinuses except for the right sphenoid sinus; boney destruction; disease extending into the nasopharynx Severe, diffuse sinus opacification; right maxillary sinusitis; nasal polyp
Bilateral
Initially unilateral nasal cavity/ sphenoid sinus tumor; upon recurrence bilateral nasal masses with involvement of the ethmoid and sphenoid sinuses Extensive bilateral nasal polyps with boney erosion of the posterior septum; maxillary and sphenoid sinuses not involved
Resection
51
22
II
Sertoli-Leydig cell ovarian tumora congenital phthisis bulbib Stickler syndromeb
Resection
21
40
III
None
Nasal and sinus cavities within normal limits
Right
Bilateral intranasal polyps, each arising between the nasal septum and the middle turbinate Nasal cavity with attachment to inferior surface of anterior skull base
Resection
4
54
III
None
Bilateral
Abbreviations: PPB, pleuropulmonary blastoma; NCMH, nasal chondromesenchymal hamartoma; FTDS, family tumor and dysplasia Syndrome; m, male; f, female; NOS, not otherwise specified. a Part of PPB Family Tumor and Dysplasia Syndrome. b Uncertain status as part of the PPB Family Tumor and Dysplasia syndrome.
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Fig. 1. (A) Coronal CT image at the level of the anterior aspect of the nasal cavity, displayed with soft tissue windows. An ovoid soft tissue mass representing NCMH occupies the left nasal cavity (Case 3). (B) Axial CT image at the level of the maxillary sinuses, displayed with bone windows. There is asymmetric expansion of the nasal cavity by NCMH polyp formation. Expansion of the posterior portion of the left nasal cavity produces outward remodeling of the medial wall of the left maxillary sinus. Expansion of the anterior aspect of the right nasal cavity results in leftward distortion of the anterior aspect of the nasal septum. There is also extensive opacification of the maxillary sinuses (Case 2). (C) Axial CT image at the level of the globes, displayed with bone windows. There is expansion of the anterior aspect of the left nasal cavity by NCMH polyp formation. There is also extensive opacification of the ethmoid sinuses bilaterally and the left sphenoid sinus. A small right globe with a calcified lens is consistent with patient’s history of congenital phthisis bulbi (Case 2).
yngeal mass, carotid and ophthalmic artery aneurysms (which were clipped), and extensive partially calcified vascular malformations causing defects in soft tissue, mandible and cranial bone. 4. Discussion Four NCMH were identified among 295 Registry and 300–325 non-Registry literature PPB cases. The NCMH were diagnosed at ages 7–15 years, from 4 to 12 years after the child’s PPB diagnosis. In 24 NCMH not associated with PPB, ages at diagnosis were birth
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Fig. 2. Gross specimen of polypoid nasal chondromesenchymal hamartoma (Case 3).
to 69 years, median 8 months, with seven cases between ages 11 and 25 years [1–14,16,21]. The anatomic extent of PPB-associated NCMH (Fig. 1) was similar to reported cases, except that none entered intracranial spaces. Histopathologic features of reported NCMH reveal complex mixed solid and cystic masses characterized by a prominent myxoid, spindle cell stroma, hemorrhagic cysts and immature nodules of cartilage [1]. In two PPB-associated NCMH, the features were typical (Fig. 3). In two others, the findings did not demonstrate the full range of immature mesenchymal tissue patterns: cartilaginous components were more mature and surrounding fibrous stroma less cellular than described in reported NCMH of all ages. The restricted pattern in these two patients may be explained by older diagnosis age of PPB-associated NCMH or may be a feature of NCMH in the PPB setting. With 28 reported NCMH, more remains to be learned about the histologic spectrum of NCMH. Maturation is recognized in other hamartomas such as mesenchymal hamartoma of the liver. Could NCMH in a PPB patient result from prior antineoplastic therapy? For PPB, each child received standard sarcoma chemotherapy regimens. Case 1 also received chest radiation, and Cases 3 and 4 received radiation to frontal cranial vault for cerebral PPB metastases. All therapies preceded NCMH. NCMH is not reported as a second tumor in childhood cancer patients [22], nor has any reported NCMH patient had prior radiotherapy. Hamartomas occur in other familial cancer predisposition syndromes such as Cowden’s and Peutz-Jegher’s syndromes [23,24]. We believe NCMH in a PPB patient is an expression of a genetic predisposition, although we recognize that cytotoxic therapy could present a unique challenge to genetically predisposed individuals. Highly varied dysplastic and neoplastic conditions occur in PPB patients and their young relatives, including various childhood sarcomas, cystic nephroma, Wilms tumor, ovarian tumors,
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Conflict of interest statement John R. Priest is named in a patent registration involving genetic sequencing methodology of DICER1 gene. Acknowledgements The authors thank physicians and data managers who supply information, and thank the many families who allow their children to be studied by the International PPB Registry. Appreciation also goes to Kris Doyle and Nancy Battaglia for background data supporting the manuscript. The Pine Tree Apple Tennis Classic and the Theodora H. Lang Charitable Trust support the International PPB Registry and its staff. References
Fig. 3. Nasal chondromesenchymal hamartoma presented as a polypoid mass in this 11-year-old boy (Case 4). (A) The low magnification shows the presence of a nodule of cartilage surrounded by a uniform spindle cell stroma. (B) The spindle cell stroma blends into the nodule of cartilage. These spindle cells have somewhat immature features, but no evidence of rhabdomyoblastic differentiation (HSE, 10, 60).
neuroblastoma and intra-ocular medullo-epithelioma [20,25–27]. We believe that NCMH is also a manifestation of this familial predisposition because it is highly unlikely that coincidence would explain NCMH and PPB in the same individual. The extensive cervicocranial anomalies in one reported NCMH patient have not been observed in PPB patients or kindreds. DICER1 mutations are found in 50–70% of PPB patients [20,28]. Three PPB/NCMH patients included here participated in the exploratory genetic research which revealed DICER1 mutations. Unfortunately, we cannot disclose results because the exploratory study was approved under ethical guidelines preventing release of results to families. Disclosing results here would violate the guidelines. As open DICER1 sequencing becomes widely available, DICER1 mutation in the entire range of PPB-associated diseases will be elucidated. In summary, NCMH appears to be biologically associated with PPB. Pediatric oncologists and otorhinolaryngologists should be aware of this possibility. Persistent nasal congestion or ‘‘sinusitis’’ or presence of a nasal mass in a PPB patient should raise suspicion, and careful radiographic diagnosis may reveal unexpectedly extensive sinonasal involvement. Other familial disease may be present in these patients or kindreds.
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