Post-Irradiation Leiomyosarcoma of the Maxilla: Report of a Case In a Patient With Prior Radiation Treatment for Retinoblastoma

Post-Irradiation Leiomyosarcoma of the Maxilla: Report of a Case In a Patient With Prior Radiation Treatment for Retinoblastoma
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  See discussions, stats, and author profiles for this publication at: Post-irradiation leiomyosarcoma of themaxilla: Report of a case in a patient with priorradiation treatment for...  Article   in  Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology · July 2004 DOI: 10.1016/S1079210403007285 · Source: PubMed CITATIONS 18 READS 97 6 authors , including: Some of the authors of this publication are also working on these related projects: Novel bisphosphonate-antibiotic bioconjugates for targeted treatment of infectious bone diseaseView projectParish P SedghizadehUniversity of Southern California 94   PUBLICATIONS   1,477   CITATIONS   SEE PROFILE Francesca AngieroUniversità degli Studi di Genova 80   PUBLICATIONS   720   CITATIONS   SEE PROFILE Carl M AllenThe Ohio State University 45   PUBLICATIONS   1,184   CITATIONS   SEE PROFILE John KalmarThe Ohio State University 65   PUBLICATIONS   2,393   CITATIONS   SEE PROFILE All content following this page was uploaded by Parish P Sedghizadeh on 18 January 2017. The user has requested enhancement of the downloaded file. All in-text references underlined in blue are added to the srcinal documentand are linked to publications on ResearchGate, letting you access and read them immediately.  ORAL AND MAXILLOFACIAL PATHOLOGY   Editor: Alan R. Gould  Post-irradiation leiomyosarcoma of the maxilla: Report of a casein a patient with prior radiation treatment for retinoblastoma Parish P. Sedghizadeh, DDS, a  Francesca Angiero, MD, b Carl M. Allen, DDS, MSD, a  John R. Kalmar, DMD, PhD, a  Yeshwant Rawal, BDS, MDS, a  and Eric A. Albright, MD, c Columbus, Ohio, and Milan, Italy THE OHIO STATE UNIVERSITY COLLEGE OF DENTISTRY AND UNIVERSITA` DI MILANO Post-irradiation sarcoma is a well-defined complication of radiation therapy, yet few reports document suchlesions in the head and neck. A 30-year-old man presented for evaluation of an expansile lesion of the left posteriormaxilla. His medical history was significant for a childhood ocular malignancy - unilateral retinoblastoma - which wastreated with a combination of surgical enucleation of the eye and external beam radiation therapy. Biopsy of hismaxillary lesion revealed a spindle cell malignancy that was morphologically and immunohistochemically consistentwith a diagnosis of leiomyosarcoma. Further investigation into the case revealed that the patient had three children,every one of whom developed unilateral retinoblastoma in infancy. Compared to the more frequent presentation of bilateral tumors in hereditary cases of retinoblastoma, such cases of heritable unilateral retinoblastoma are exceptional.Importantly, heritable forms of retinoblastoma confer a significant risk for development of second primary cancers,necessitating long-term clinical follow-up in these patients.  (Oral Surg Oral Med Oral Pathol Oral Radiol Endod2004;97:726-31) INTRODUCTION Post-irradiation sarcoma is a well-documented,though r elat ively uncommon, complication of radiationtherapy. 1,2,3 These tumors typically develop more than10-15 years after radiation therapy for the primarymalignancy. 4 While many types of malignancy havebeenreportedinthissetting,osteosarcoma,fibrosarcoma and malignant fibrous hist iocytoma generally predomi-nate in most series. 5,6,7,8,9 Less commonly, subsequent development  of leiomyosarcoma has been re-ported. 10,11,12 Leiomyosarcomas are malignant mesenchymalneoplasms of smooth muscle differentiation that account for 5-10% of all soft tissue sarcomas. These tumors areoften divided into three anatomic groups: soft tissue,cutaneous, and vascular. 3 The most common sites wherethey develop are the gastrointestinal tract, the urinarytract and the female genital tract. Primary int raosseousleiomyosarcoma has also been documented. 13 Leiomyo-sarcomas occurring in the head and neck region, includ-ing the oral cavity, are uncommon. 14 In this report, wedescribe the development of leiomyosarcoma of themaxilla that was identified 28 years after the patient was treated with radiation therapy for unilateralretinoblastoma. Finally, we review the role of theretinoblastoma gene (RB1) in the pathogenesis of retinoblastoma, and discuss current concepts regardingpost-irradiation sarcoma and second primary cancers infamilial retinoblastoma. CASE REPORT A 30-year-old Amish man presented with the chief complaint of pain and expansion of his left upper jaw. Thepatient stated that a dental extraction had been performed threemonths earlier in an attempt to relieve the pain, but this had noimpact on his symptoms. His medical history was significant  a  Department of Oral and Maxillofacial Pathology, College of Dentistry, The Ohio State University, Columbus, Ohio. b Istituto di Anatomia Patologica, Universita` di Milano, Italy. c Children’s Hospital, Anatomic Pathology and College of Medicineand Public Health, The Ohio State University.Received for publication Feb 24, 2003; returned for revision Apr 17,2003; accepted for publication Nov 26, 2003.1079-2104/$ - see front matter    2004 Elsevier Inc. All rights reserved.doi:10.1016/j.tripleo.2003.11.017 726  Vol. 97 No. 6 June 2004  for unilateral retinoblastoma, diagnosed at two years of age,and treated with exenteration of his left eye in addition toexternal beam radiation therapy. The patient did not know if there was any family history of this condition. Clinicalexamination revealed absence of the left eye and markedatrophyoftheorbitalandsuperiormaxillaryregionsbilaterally.Intraorally, a diffuse unilateral enlargement involving the left posterior maxilla was noted (Fig 1). The area was firm onpalpation and showed no evidence of ulceration or color change. A periapical radiograph showed a homogenous loss of trabecular architecture in the form of ill-defined radiolucent change in the left posterior maxilla. Existing maxillary teeth inthe area showed aberrant or abbreviated root development andloss of lamina dura (Fig 2).Computerized tomography scans of the area, with andwithout contrast enhancement, confirmed the prior exentera-tion of the left eye in addition to demonstrating the maxillarytumor. Coronal, axial and sagittal sections revealed a maxillarytumorwithitsepicenterintheregionoftheleftmaxillarysinus.The tumor destroyed the lateral wall of the maxillary sinus andextended to the ipsilateral infratemporal fossa. It could not be determined unequivocally whether the epicenter wasintraosseous or extraosseous. The lesion measured approxi-mately 4.6 cm antero-posteriorly, 3.2 cm in its widest lateraldimension, and protruded posteriorly 2.5 cm into the left infratemporal fossa. The inferior portion of the mass involvedthe left maxillary alveolar ridge, while the superior portion of the lesion extended into the inferior orbital fissure, producingdeformation of the fat planes.An incisional biopsy of the intraoral mass was performedunder local anesthesia. Histopathologic examination of hema-toxylinandeosin-stainedsectionsofthebiopsysampleshowedan infiltrating cellular neoplasm composed of relativelyuniform interlacing fascicles of spindle-shaped lesional cells(Fig 3). Lesional cells exhibited eosinophilic condensation of the cytoplasm, intranuclear and perinuclear vesiculation, andrare abnormal mitotic figures with no evidence of necrosis (Fig4). The preliminary diagnosis of a spindle cell malignancy wasmade, and a panel of antibodies was applied to additionalsections of the tissue using routine immunohistochemicaltechniques with high temperature antigen retrieval. Antibodiesdirected against cytokeratins (Novocastra, clone AE1/3),  a -smooth muscle actin (Novocastra, clone asm-1), musclespecific actin (Novocastra, clone HHF35), vimentin(Novocastra, clone V9) and S-100 protein (Novocastra, cloneS1/61/69) were used. These immunohistochemical studiesindicated that the tumor cells were strongly reactive withantibodies directed against   a -smooth muscle actin (Fig 5) and vimentin, modestly positive for muscle specific actin, and non-reactive for antibodies directed against cytokeratins and S-100protein.Based on immunohistochemical and histopathologicfindings, a diagnosis of leiomyosarcoma was rendered.Subsequent imaging studies of the lungs and brain showedno evidence of metastatic disease. Surgical treatment consistedof a hemi-maxillectomy procedure that was performed under general anesthesia. A denture was fabricated to obturate thesurgical defect, and the patient exhibited adequate speech andswallowing functions with the prosthesis in place. Thehistopathologic findings in the resected specimen were verysimilar to the srcinal incisional biopsy specimen, with noevidence of necrosis, the rare presence of mitotic figures ( \ 1figure/10 high power field [HPF]; 0.174 mm 2  /HPF), andarelativelywell-differentiatedspindlecellmalignancythatwasmorphologically and immunohistochemically consistent withthe previous diagnosis of leiomyosarcoma. The tumor wasclassified as Grade I using the FNCLCC (Fe´de´ration Nationaledes Centres de Lutte Contre le Cancer ) or the NCI (NationalCancerInstitute)gradingsystem. 15,16,17 BymeansoftheAJCC(American Joint Committee on Cancer) soft tissue sarcoma staging system, the tumor was assigned as T1 (tumor size \ 5cm), N0 (no nodal involvement), and M0 (nometastasis), classifying it as a Stage I grouping. 18 During a follow-up appointment three years after treat-ment there was no indication of tumor recurrence. Further questioningrevealed thatsince thepatient waslast seen,he andhis wife had three children - twins and one other child. It wasalso discovered that all three children developed unilateral eyetumors that were treated surgically at the neighboringChildren’s Hospital. Each of these tumors proved to beretinoblastoma. Microscopic review of the histologic sectionsof each child’s resected eye revealed a round blue cell tumor that completely filled the corpus vitreous of the involved eye(Fig 6). Flexner-Wintersteiner rosettes, a characteristic histo-logicfeatureinsomecasesofretinoblastoma,wereidentifiedintwo of the tumors (Fig 7). DISCUSSION Post-irradiation sarcoma represents an uncommoncomplication of radiation therapy, and a relatively smallproportion of tumors arising in this setting can actuallybe designated as leiomyosarcoma. There are severalcriteria for the diagnosis of post-irradiation sarcoma:a previous history of radiotherapy to the area where thesarcoma arose; a long period of latency between Fig 1. Clinical photograph showing a firm and non-ulceratedenlargement of the left posterior maxilla. ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY Volume 97, Number 6 Sedghizadeh et al   727   radiation and the appearance of the tumor; and thehistopathologic diagnosis of sarcoma. 3 The latencyperiod between radiotherapy and the diagnosis of leiomyosarcoma ha s varied between 12-50 years inreported cases. 19-23 For cases described prior to 1980(before the widespread use of immunohistochemistry),the diagnosis was based mainly on histopathologic, or less commonly, ultrastructural features. More recently,immunohistochemicaltechniqueshaveallowedformoreaccurate characterization of this sarcoma, althoughlimitations exist. In our case, for example, immunore-activity for smooth muscle actin does not permit anunequivocal diagnosisofasmoothmuscletumorsuchasleiomyosarcoma. Most actin antibodies commerciallyavailable are pan-actin moieties that cluster around 45kd, so they are not muscle epitope-specific enough todemonstrate‘‘pure’’myogenousdifferentiation. 24 There-fore, these antibodies can react with many other celltypes beside muscle, as seen by actin positivity in re-active lesions and in non-smooth muscle tumors such assynovial sarcoma, malignant fibr ous histiocytoma,fibromatosis and nodular fasciitis. 25,26,27,28 This isa common problem in the immunohistochemical de-tection of heteropolymeric proteins like actin. Therefore,we acknowledge that immunoreactivity for actin in thiscase does not provide definitive evidence of smooth Fig 2. Periapical radiograph of the left posterior maxilla showing ill-defined radiolucent changes in the bone, widening of theperiodontal ligament and loss of lamina dura.Fig 3. Low-power photomicrograph of the biopsy specimenshowing a spindle cell neoplasm with an interlacing fascicular arrangement suggestive of leiomyosarcoma. (hematoxylin &eosin, srcinal magnification 3 200)Fig 4. High-power photomicrograph demonstrating malignant cells with eosinophilic cytoplasm, hyperchromatic nuclei, andintranuclear and perinuclear vacuoles. (hematoxylin & eosin,srcinal magnification 3 600) ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY  June 2004 728  Sedghizadeh et al  muscle differentiation, but combined with histopatho-logic features, leiomyosarcoma is arguably the most appropriate diagnosis.The fact that this patient and all three of his childrenwere affected with unilateral retinoblastoma, or a hered-itary form of retinoblastoma, is significant to this case.Retinoblastoma is a rare malignant tumor of the retinalanlage that typically affects infants. The conditioncan be inherited or it can be acquired sporadically.Retinoblastoma arises when mutations induce a loss of function affecting both alleles at the ret inoblastoma (RB1) gene locus on chromosome 13q. 29,30 Analysis of retinoblastoma tumorDNA indicates that the mutation isautosomal recessive and that tumors develop only whenthe function of both alleles is destroyed, illustratingKnudson’s two-hit hypothesis. The mutant RB1 trait shows high penetrance and variable expressivity. Most individuals with germline RB1 mutations developbilateral retinoblastomas because mutations arise inseveral retinal cells in both eyes. In some exceptionalfamilies, as in this case, unilateral retinoblastoma isprevalent and ha s been referred to as low-penetranceretinoblastoma. 31 The RB1 gene product (P110) is animportant tumor suppressor gene and cell cycle regula-tor. The protein is unphosphorylated in the G0 and G1phase of the cell cycle and phosphorylated during the Sand G2 phase. In its unphosphorylat ed st ate, the proteinfunctions as a cell cycle suppressor. 32,33 In its absence,the cell proceeds to the next division without regulation,acriticalstep in theprocessofneoplastic transformation.In retinoblastoma patients, the impact of radiationtherapy in inducing second primary tumors has becomemoreevidentoverthepastfewdecades. 34,35 Originally,it was thought ionizing radiation-induced RB1 mutationwas the sole cause of second primary tumors. However,studies suggest that ionizing radiation is not the cause of secondprimarycancers,butratherposesanincreasedriskfor site-specific (field of radiation) ca rcinogenesis in thisgenetically susceptible population. 36 A dose-dependent carcinogenic effect has been demonstrated for most radiation-induced sarcomas. 37 In our case, however,records of radiation treatment details such as size of fieldand dosing could not be obtained from 30 years ago, sothepossibilityexiststhatthesarcomainthiscasewasnot radiation-inducedandaroseoutsidethefieldofradiation,orwouldhaveeventuallyoccurredevenintheabsenceof radiation exposure. Retinoblastoma patients are consid-ered genetically susceptible for the development of second primary tumors because all of their somatic cells Fig 7. High-power photomicrograph of the tumor in figure 6showing Flexner-Wintersteiner rosettes, characterized bycircular clusters of cuboidal cells palisading around a centralclear lumen outlined by eosinophilic apical cell membranes.(hematoxylin and eosin, srcinal magnification 3 600)Fig 6. Low-power photomicrograph of the resected eye fromone of the children in this case. Note the round blue cell tumor (retinoblastoma) filling the corpus vitreous of the eye. Thearrow points to the iris of the eye for specimen orientation.(hematoxylin & eosin, srcinal magnification 3 100)Fig 5. Lesional cells show diffuse strong cytoplasmicimmunoreactivity for   a -smooth muscle actin. (Harris hema-toxylin, with immunohistochemical marker   a -smooth muscleactin, srcinal magnification 3 600) ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY Volume 97, Number 6 Sedghizadeh et al   729
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