about half of the hyperplastic glands were still visible on the 12. Vogel RA. Kirch D, Lefree M, et al. A new method of multiplanar emission tomography using a seven pinhole collimator and an Anger scintillation camera. J Nucí planar view 1 hr after tracer injection compared to more than Med 1978:19:648-654. 80% of adenomas. 13. Jarritt PH, Ell PJ, Myers MJ, et al. A new transverse section brain imager for single gamma emitters. J NucíMed 1979:20:319-328. 14. Jarritt PH, Ell PJ. A new emission tomographic body scanner. NucíMed Commun CONCLUSION 1980:1:94-101. SPECT increases the sensitivity and specificity of parathy 15. Budinger TF. Physical attributes of single-photon tomography. J NucíMed 1980:21: roid scintigraphy. It appears particularly useful for the location 579-592. 16. Cullum ID. Jarritt PH, Ell PH. Performance parameters, minimal detectable lesions and of mediastinal glands. Our method, which combines the advan partial volume effects for two emission tomographic body units. NucíMed Commun tages of 99mTc-MIBI, FADS and SPECT, allows increased 1980:1:153. 17. Jaszczak RJ. Chang LT. Murphy PH. SPECT using a multi-slice fan beam collimator. scintigraphic accuracy. IEEE Trans NucíSci 1979:26:610-618. 18. Ell PJ. Khan O. Emission computerized tomography: clinical applications. Semin Nucí Med 1981:11:50-60. REFERENCES 19. Billotey C, Aurengo A. Najean Y, et al. Identifying abnormal parathyroid glands in the 1. Potts JT. Ackerman IP. Barker CF. et al. Diagnosis and management of asymptomatic thyroid uptake area using Tc-99m-sestamibi and factor analysis of dynamic structures. primary hyperparathyroidism: consensus development conference statement. Ann J NucíMed 1994:35:1631-1636. Intern Med 1991;! 14:593-597. 20. Coakley AJ, Kettle AG, Wells CP. et al. Technetium-99m-sestamibi: a new agent for 2. Norton JA Controversies, advances in primary hyperparathyroidism. Ann Surg parathyroid imaging. NucíMed Commun 1989:10:791-794. 1992:215:297-299. 21. O'Deherty MJ, Kettle AG, Wells CP, et al. Parathyroid imaging with Tc-99m- 3. Beazley RM, Costa J, Ketcham AS. Reoperative parathyroid surgery. Am J Surg sestamibi: preoperative localization and tissue uptake studies. J NucíMed 1992:33: 1975:130:427-429. 313-318. 4. Brennan MF, Marx SJ, Doppman J, et al. Results of reoperation for persistent and 22. Geatti O. Shapiro B. Prolo G. et al. Location of parathyroid enlargement by recurrent hyperparathyroidism. Ann Surg 1981:194:671-676. Tc-99m-MIBI and 2U1T1scintigraphy, ultrasound and CT [Abstract]. J NucíMed 5. Granberg P-O. Johansson G, Lindval! N, et al. Reoperation for primary hyperparathy 1992:33:894. roidism. Am J Surg 1982:143:296-300. 23. Casara D, Rubello G, Saladini G, et al. Preoperative imaging of pathologic parathyroid 6. Wang CA Parathyroid re-exploration. A clinical and pathological study of 112 cases. glands (PG): comparison of Tc-99m-MIBI scintigraphy. Tl-201 scintigraphy. neck Ann Surg 1977;186,n°2:140-145. echography (NE), computed tomography (CT) and magnetic resonance (MR) [Ab 7. Prinz RA. Gamvros OI. Allison DJ. Flechter DR. Lynn AL. Reoperations for stract]. Eur J NucíMed 1992:19:684. hyperparathyroidism. Surg Gynecol Obslet 1981:152:760-764. 24. Sarfati E, De Ferron P, Gossot D, Assens P, Dubost C. Parathyroid adenoma: atypical 8. Katz AD. Hopp D Parathyroidectomy. Review of 338 consecutive cases for histology, sites ectopie or not? J Chir 1987;l:24-29. location and reoperation. Am J Surg 1982:144:411-415. 25. Miller DL, Doppman JL. Shawker, et al. Localization of parathyroid adenomas in 9. Palmer JA, Rosen IB. Reoperative surgery of hyperparathyroidism. Am J Surg patients who have undergone surgery. Radiolog)- 1987:162:133-137. 1982:144:406-410. 26. Brennan MF, Doppman JL, Kurdy AG, et al. Assessment of techniques for preoper 10. Anger HO. Tomography and other depth discrimination techniques. In: HiñeGJ, ative parathyroid gland localization in patients undergoing reoperation for hyperpara Sorenson JA, eds. Instrumentation in nuclear medicine, vol. 2. New York. NY: thyroidism. Surgen- 1982:91:6-11. Academic Press; 1974:61-100. 27. Aufferman W, Gooding GAW. Okerlund MD, et al. Diagnosis of recurent hyperpara 11. Mathieu L, Budinger TF. Pinhole digital tomography. In: Proceedings of the First thyroidism: comparison of MR imaging and other imaging techniques. Am J Roent- World Congress of Nuclear Medicine. Tokyo, Japan: 1974:1264-1266. genol 1988:150:1027-1033.

Bone Scans in Neurofibromatosis: Neurofibroma, Plexiform Neuroma and Neurofibrosarcoma

Richard T. Kloos, Vittoria Rufini, Milton D. Gross and Brahm Shapiro Division of Nuclear Medicine, Department of Internal Medicine, University of Michigan, and Department of Veterans Affairs Medical Centers, Ann Arbor, Michigan

Key Words: bone diseases; neurofibroma; neurofibrosarcoma; Neurofibromatosis type 1 or von Recklinghausen's disease is one of peripheral nerve neoplasms the most common autosomal dominant genetic disorders. Between J NucíMed 1996; 37:1778-1783 29% and 77% of patients may suffer from a wide range of skeletal abnormalities and, thus, patients with neurofibromatosis frequently undergo skeletal scintigraphy, at which time the common peripheral IN eurofibromatosis type 1 or von Recklinghausen's disease nerve soft-tissue tumors that occur in this syndrome (neurofibro- (1-4) is one of the most common autosomal dominant disor mas, plexiform neuromas and neurofibrosarcomas) may be demon strated. Methods: Single or multiphase 99nTc methylenediphos- ders with a frequency rate of 1 in 3000 live births, an estimated prevalence of 30 patients per 200,000 population. This disease phonate (MDP) bone scans were performed in five patients with affects about 100,000 people in the United States with about neurofibromatosis as part of their clinical evaluation. Results: We 50% of cases representing new mutations (5-8). The gene imaged neurofibrosarcomas in three patients, cutaneous neurofi- bromas in one patient and a plexiform neuroma in one patient. responsible for its genesis has recently been mapped and cloned Conclusion: Single- or multiphasic bone scans may localize com (9,10). Affected tissues include those of neuro-ectodermal, mon soft-tissue tumors in neurofibromatosis. mesenchymal and endoderma! origins. The phenotypic mani festations are protean and may vary from no more than six cafe-au-lait spots 15 mm in diameter (5 mm in prepubescent Received Aug. 21, 1995; revision accepted Dec. 13, 1995. patients) to amongst the most grotesque deforming lesions For correspondence or reprints contact: B. Shapiro, MB, ChB, PhD, University of encountered in clinical medicine (5-7). The diagnostic criteria Michigan Medical Center, Division of Nuclear Medicine, Box 0028, 1500 E. Medical Center Drive, Ann Arbor, Ml 48109-0028. are listed in Table 1. The syndrome of bilateral acoustic

1778 THE JOURNALOFNUCLEARMEDICINE•Vol. 37 •No. 11 •November 1996 TABLE 1 Diagnostic Criteria for von Recklinghausen's Disease (Neurofibromatosis Type 1)*

Type 1 Genetic: (a) Identification of the presence of the gene. (b) One or more first degree relatives meeting the clinical criteria for diagnosis of neurofibromatosis 1. Cutaneous: (a) Café-au-laitmacules, 6 or more with greatest diameter over 15 mm (5 mm in prepubescent children). (b) Two or more neuroflbromas of any type. (c) One or more plexiform neuromas. (d) Axillary or inguinal freckling. Ocular: (a) Optic glioma. (b) Two or more hamartomas of the iris (Lisch nodules). Skeletal: (a) Distinctive sphenoid dysplasia. (b) Cortical thinning of long bones (with or without pseudarthrosis).

"Clinical diagnosis is made if a patient has positive proof of carrying the FIGURE 1. Plexiform neuroma radiographie features (Patient 1). Note the gene or manifests two or more of the clinical criteria [based on reference extensive lobulated soft tissue masses, abnormal atrophie metacarpals and phalanges affecting the 3rd, 4th and 5th rays of the right hand. (11)]- sparse (27-29) and the phenomenon is listed are "rare" in a neuromas (neurofibromatosis type 2) should not be confused standard compendium of scintigraphic findings (30). with von Recklinghausen's disease, as they are genetically distinct (5-7). There are rare cases of neurofibromatosis which METHODS share characteristics of both syndromes. Patients Von Recklinghausen's disease is relatively common and Patient 1. A 34-yr-old man with neurofibromatosis, previous 29%-77% of cases are associated with various with skeletal cosmetic facial surgery for disfiguring neurofibromas, right abnormalities (5,6,12-14) (Table 2). Consequently, patients hand plexiform neuroma (Fig. 1) and thoracic kyphosis, devel with this disorder commonly are referred to nuclear medicine oped an enlarging, painful, left forearm mass (17 cm). Fine specialists for skeletal scintigraphy. In addition to the expected depiction of skeletal abnormalities (26), 99mTc methylene- needle aspiration (FNA) demonstrated neurofibrosarcoma. CT revealed significant soft tissue and bone destruction by the diphosphonate is taken up on three phase and delayed bone forearm mass. A 99mTc-MDPbone scan (Figs. 2, 3) excluded scintigraphy by a variety of soft-tissue lesions in von Reckling distant osseous metastatic disease in anticipation of an above- hausen's disease, including neurofibromas, plexiform neuromas elbow amputation. Pre-operative MR1 demonstrated a 6 cm and neurofibrosarcomas. Prior reports of such uptake have been paraspinal (C2-C5) mass confirmed by FNA to represent neurofibrosarcoma. Despite five cycles of palliative chemother TABLE 2 apy with adriamycin, ifosfamide, mesna and external beam Typical Skeletal Lesions of von Recklinghausen's radiation therapy to the paraspinal mass, the disease progressed. Neurofibromatosis Taxol therapy was initiated and fever, chills and night sweats with progressive forearm mass ulcérationwere accompanied by Hypoplasia of the walls of the orbit (11,13) a foul smelling discharge. Those symptoms were present at the Calvarial defects: especially involving the parietal bones and left lambdoid suture (75-77) scheduled admission for the second cycle of therapy. The patient refused an above the elbow amputation. A follow-up CT Kyphoscoliosis (both idiopathic type and a short, sharp angulating type involving 4-6 vertebral segments with associated vertebral and rib demonstrated paraspinal mass enlargement and spinal canal abnormalities) (11,13,14,16,18) Vertebral body erosion or scalloping (11,14,16,18) Spinal and cranial nerve foramina erosion or enlargement (11,16,18) Hypoplastic vertebral pedicles (79) Thoracic and lumbar meningocele (11,15,16) Hip and pelvic deformities (11,12,20) Costal scalloping, rib notching, and ribbon-like ribs (11,16,18,19) Greater and lesser sphenoid wing abnormalities (11,15,16) Macrocranium (Õ7,27 ) • Zygomatic dysplasia (77) Mandibular and maxillary deformity (11,13,15,22) Long bone cortical dysplasia (78,27 ), metaphysial and diaphysial sclerosis (14), intramedullary linear sclerosis (23), subperiosteal hematoma (11,14,18), bowing (13,14,16,24), subperiosteal or cortical cystic lesions (11,13,14,21,24,25), pathological fracture (24), and pseudarthrosis FIGURE 2. Technetium-99m-MDP three-phase bone scan (Patient 1). (A) (77,73,74,76,78) Selected frames from the nuclear angiogram shows increased blood flow to Localized or hemi-hypotrophy (77,73,14 ) plexiform neuroma of right hand and neurofibrosarcoma of left forearm (which has hyperemic rim and "cold" center) (arrows). (B) Marked increase in Localized or hemi-hypertrophy (14,16,25) blood pool affecting the same regions.

BONESCANSINNEUROFIBROMATOSIS•Kloos et al. 1779 B B l V

FIGURE 3. Technetium-99m-MDP bone scan delayed images (Patient 1). FIGURE 5. Technetium-99m-MDP bone scan after 3-hr delay (Patient 3). (A) (A)Abnormal bone uptake in the 3rd, 4th and 5th metacarpals and extensive Anterior and (B) posterior thigh views. Note the large area of irregular soft soft-tissue uptake in the plexiform neuroma of the hand. (B) Abnormal soft- tissue tracer uptake involving the left thigh (arrow heads); there is no tissue uptake in the soft-tissue neurofibrosarcoma of the forearm. Increased abnormality of the underlying bone. bone uptake in the proximal radius is due to direct tumor invasion. reflexic. The patient likewise had bilaterally impaired vocal invasion. Palliative measures were requested. Death soon there cord function and was experiencing shortness of breath. after was believed to result from diaphragmatic paralysis. The patient underwent debulking of the cervical schwannoma Patient 2. A 45-yr-old female was diagnosed with Charcot- with C1-C2 laminectomy and elective tracheostomy. Future Marie Tooth disease as a child and suffered progressive surgical considerations include interventions aimed at the vocal bilateral equinovarus deformity. This was treated with bilateral cord dysfunction, the right trigeminal neuroma filling the ear triple arthrodesis with a transfer of the anterior tibial tendons to and temporal bone, both acoustic neuromas and auditory brain the cuboid bones. She also had lifelong hand and lower stem implantation. The patient's form of neurofibromatosis extremity weakness, including bilateral foot drop, muscle atro currently been considered a variant of type 2. No family phy and recurrent left patella dislocation. The female developed members have neurofibromatosis the patient does not have multiple neurofibromas at 16 yr of age and was diagnosed with cafe-au-lait spots or Lisch nodules. The bilateral acoustic neurofibromatosis at age 18 yr. She underwent multiple surgical neuromas and extensive meningiomas are consistent with neu resections of painful or disabling neurofibromas, including rofibromatosis type 2. Such patients may develop peripheral those from the ulnar nerves bilaterally, both hands, the right neurofibromas in the cervical region which are frequently large. perilumbar area and the right forearm. There was long standing Neurofibromas of the hands are also commonly observed. No proptosis and exophthalmos. Right facial and trigeminal nerve definitive genetic studies are available regarding this patient. neuromas caused right sided facial paralysis which led to Patient 3. A 29-yr-old man with a family history of neuro multiple subsequent cosmetic and partial function restoring fibromatosis, cafe-au-lait spots, status postresection of a medial facial surgical procedures. Removal of a 7 cm by 10 cm right left thigh plexiform neurofibroma 14 yr prior to evaluation and neck vagus nerve neurolemoma was complicated by right vocal one other neurofibroma above the left eye was studied. Follow cord paralysis. A three-phase 99mTc-MDP bone scan was ing resection, the residual lesion slowly increased in size until obtained to rule out a left ankle stress fracture (Fig. 4). rapid growth associated with an increasingly hard and irregular Subsequent serial head and neck CT examinations demon consistency, increased lesion pigmentation and mild pain with strated the progressive appearance of a mass involving the right activity began 10 mo prior to evaluation. CT demonstrated the petrous bone, bilateral acoustic neuromas, multiple expanding mass to be centered medially in the soft tissues and inseparable intracranial meningiomas, a high cervical mass within the from the adjacent adductors with overall dimensions of 20 X cervical canal with spinal cord compression at Cl and C2, left 18X15 cm. Suspicion of right symphysis/inferior pubic ramus orbital schwannomas and trachéalcompression. The patient osseous metastatic disease prompted Tc-MDP bone scintig- was rendered deaf, dysarthric, visually impaired and hyper- raphy (Fig. 5). Chest radiograph and CT demonstrated innu-

FIGURE 6. Posterior chest, abdo men and pelvic 99mTc-MDP bone FIGURE 4. Technetium-99m-MDP bone scan (Patient 2). Anterior blood scan in a 35-mo-old child with neu flow (A), pool image (B) and 3-hr delayed image (C). Note the intense patchy rofibromatosis and severe kypho- blood flow and focal blood-pool uptake in multiple cutaneous neurofibromas scoliosis (Patient 4). There is no over the legs and ankles only some of which are visualized on the delayed tracer uptake in soft tissue neurofi image. bromas.

1780 THEJOURNALOFNUCLEARMEDICINE•Vol. 37 •No. 11 •November 1996 of the thoracic mass revealed many plexiform extensions which could not be excised. The sympathetic chain was invaded by tumor and soft-tissue infiltrations. Tissue pathol ogy diagnosed ganglioneuroma and ganglioneuroblastoma, and Shimada classification, including: stroma rich, nodular and intermediate differentiation (unfavorable histology). Surgery was complicated by left Horner's syndrome. Fol

FIGURE 7. Anterior pelvic "Tc- low-up neck, chest, abdominal and pelvic CT demonstrated a MDP bone scan showing subtle soft low attenuation mass which encased the celiac axis, superior tissue uptake overlying the region of mesenteric artery and splayed the pancreas and splenic vein. the left sacroiliac joint (arrow heads) Bone marrow aspirate and biopsy, 24 hr catecholamines, at the site of a retroperitoneal neuro- ferritin, and 13II- and [123I]MIBG scintigraphy studies fibrosarcoma (Patient 5). There is no showed no abnormalities. A 99mTc-MDP bone scan showed uptake by benign neurofibromas in the field of view. no osseous metastatic disease. Biopsy of the celiac mass demonstrated ganglioneuroma. Serial follow-up bone scans merable widespread, and diffuse pulmonary nodules varying in (Fig. 6), MIBG studies and CT scans have not shown size from several millimeters up to 5 cm. A core needle biopsy evidence of local progression or metastatic disease. Ortho of the thigh mass demonstrated a malignant peripheral nerve pedic consultation documented rigid kyphoscoliosis and sheath tumor (spindle cell) in association with neurofibroma spinal bracing was instituted which she tolerated subopti- consistent with a neurofibrosarcoma. mally. Despite careful follow-up, her curvatures progressed Patient 4. A female infant was diagnosed with pulmonary to 95°levoconvex thoracic kyphoscoliosis and 100°dextro- valve stenosis at age 2 mo, > 20 cafe-au-lait spots noted at age 3 mo, axillary and inguinal freckling, neurofibromas and convex thoracolumbar scoliosis by 45 mo of age. progressive kyphoscoliosis also beginning at age 3 mo. A Patient 5. A 23-yr-old woman was diagnosed at age three thoracic, abdominal and pelvic CT scan at age 10 mo demon with a presumptively new mutation causing neurofibromatosis strated a left paraspinal thoracic mass at the point of levosco- based on > 6 cafe-au-lait spots and Lisch nodules, with the liosis with a density of 34 Hounsfield units. A cervical, thoracic subsequent development of multiple neurofibromas by age 16 and lumbosacral MRI study demonstrated the mass to be 6 X (which increased in number during two subsequent pregnancies 3 X 2 cm in diameter with heterogeneous enhancement and and oral contraceptive use), and a neurofibromatosis affected penetration of at least one neural foramina. Operative resection child with unaffected parents. During a prenatal visit, a left

TABLE 3 Radiopharmaceutical Uptake by Soft-Tissue Lesions in von Recklinghausen's Disease

Radiopharmaceutical Findings Significance References

""Tc-diphosphonates Uptake in neurofibromas, plexiform Soft-tissue uptake noted in all types of lesions, Current report (28 ) and neuromas and neurofibrosarcomas. perhaps more often in malignant tumors. (27) are the same Does not necessarily mean bone case, (29,30) involvement. Photon deficient subperiosteal hemorrhage (34) with uptake in elevated periosteum. Uptake in neurofibromas and Tracer uptake occurs in both benign and (35,36) neurofibrosarcomas. malignant lesions. [""Tcjpertechnetate Uptake in neurofibroma and plexiform Avoid confusion with parotid gland tumors. (37-39) neurofibroma. "Tc-DTPA Uptake in neurofibromas, malignant Scintigraphic uptake of "Tc-DTPA is (32,33,40-43) schwannomas and plexiform neuromas. analogous to Gd-DTPA used in nuclear magnetic resonance imaging. Uptake occurs in other soft-tissue pathologies and may reflect overall active fibroblast uptake. ""Tc-sulfur colloid Dilated lymphatics and enlarged lymph Abnormal lymphatic drainage depicted. (44) nodes in elephantiasis neuromatosa. 67Ga-citrate Uptake in neurofibrosarcoma. Gallium uptake may distinguish malignant from (26,45) benign lesions. 131|* Uptake in abdominal neurolemoma. Avoid false-positive diagnosis of functioning (46) thyroid cancer metastasis. 123lor[131l]MIBGt Uptake in pheochromocytomas but not in MIBG uptake helps to distinguish Current report, (47,48) ordinary neurofibromas. pheochromocytoma from most neurofibromas. MIBG uptake has been reported in atypical schwannoma. [18F]FDG Uptake greatest in malignant lesions. Generally [18F]FDG uptake is greatest in (49) malignant lesions. 197Hg-chlormerodrin Uptake in plexiform neurofibroma. Normal uptake occurs in the nasopharynx, (39) superior saggital sinus and parotid glands.

The same would probably be true of 123I. same would probably be true of 18Fand radiobromine-labeled analogs.

BONESCANSINNEUROFIBROMATOSIS•Kloos et al. 1781 lower quadrant abdominal mass was detected and subsequently CONCLUSION characterized by CT and MRI as being 9 X 8 X 7 cm in size and Scintigraphic techniques have a significant role to play in the medial to the left iliac wing displacing the abdominal muscu investigation of skeletal abnormalities and soft-tissue tumors in lature. The mass was heterogeneous in density with central low von Recklinghausen's neurofibromatosis. All three of the com attenuation necrosis, irregularly contrast enhancing and without mon peripheral nerve soft-tissue tumors that occur in this associated satellite lesions or lymphadenopathy. In retrospect, a syndrome may show uptake of 99mTc-labeled bone-seeking prickling, burning, itching intermittent pain was experienced for radiopharmaceuticals on three-phase or delayed bone scintigra 2 yr above the left knee which radiated to the left groin. This phy. pain was relieved by left hip flexion and worsened by hip extension. Examination revealed weakness of the left leg with ACKNOWLEDGMENTS decreased left knee reflex and impaired sensation in the distri Supported in part by Cancer Research Training in Nuclear bution of the anterior femoral nerve. Needle aspiration cytology Medicine Grant NCI 2 T32 CA09015-19 and the Department of of the mass was nondiagnostic, while incisional wedge biopsy Veterans Affairs, Ann Arbor, MI. demonstrated a high grade neurofibrosarcoma arising within a benign neurofibroma. A 99mTc-MDP bone scan was obtain to REFERENCES 1. Tiresius TC. Pathological investigation of an unusual deformity of the skin. Leipzig: exclude osseous metastatic disease (Fig. 7). Chemotherapy and S.L. Crusius; 1793. external beam radiation therapy were performed, and after 2. von Recklinghausen FD. On the multiple fibromas of the skin and their relationship to partial tumor regression the patient underwent primary tumor multiple neuromas. In: Festschrift Fur Rudolf Virchon: Berlin: August Hirschwald; 1882. resection without recurrence through 3.5 yr of follow-up obser 3. Fulton JF. Robert W. Smith's description of generalized neurofibromatosis (1849). vation. N Engl J Med 1929;200:1315-1317. 4. Worster-Drought C. Carnegie Dickson WE. McMenemey WH. Multiple meningeal and perineural tumors with analogous changes in the glia and ependyma (neurofibro- DISCUSSION blastomatosis). Brain 1937:60:85-117. Many of the neurogenic rumors in von Recklinghausen's 5. Mulvihill JJ, Parry DM. Sherman JL, Pikus A, Kaiser-Kupfer MI, Eldridge R. NIH conference. Neurofibromatosis 1 (Recklinghausen disease) and neurofibromatosis 2 disease may show significant uptake of diphosphonate bone (bilateral acoustic neurofibromatosis). An update. Ann Intern Med 1990:113:39-52. tracers. The increased vascularity and capillary permeability of 6. Riccardi VM. Von Recklinghausen neurofibromatosis. N Engl J Med 1981:305:1617- the tumors in this study also resulted in some of the lesions 1627. 7. Anonymous. Neurofibromatosis. Conference statement. National Institutes of Health showing tracer uptake on all three phases of the bone scan. In Consensus Development Conference. Arch Neural 1988:45:575-578. this respect, these lesions join the ever-growing group of tumors 8. Rubenstein AE. Neurofibromatosis: 1977-1987 [Editorial]. Conn Med 1987;51:261. 9. Cawthon RM. Weiss R. Xu GF. et al. A major segment of the neurofibromatosis type that manifest this phenomenon (which may or may not be 1 gene: cDNA sequence, genomic structure and point mutations [published erratum associated with soft-tissue calcification either macroscopically appears in Cell 1990:10:62]. Cell 1990:62:193-201. or microscopically) (31 ). The sensitivity of scintigraphy with 10. Viskochil D. Buchberg AM, Xu G. et al. Deletions and a translocation interrupt a diphosphonate bone tracers to detect these soft-tissue tumors is cloned gene at the neurofibromatosis type 1 locus. Cell 1990:62:187-192. 11. Feldman F. Tuberous sclerosis, neurofibromatosis and fibrous dysplasia. In: Diagnosis not known (32,33). of bone and joint disorders. 3rd ed. Resnick D, ed. Philadelphia: W.B. Saunders A wide range of radiopharmaceuticals have been employed Õ995;4353-4395. 12. Joseph KN, Bowen JR. MacEwen GD. Unusual orthopedic manifestations of neuro for various purposes to study the soft tissues tumors of von fibromatosis. Clin Orthop 1992:278:17-28. Recklinghausen's neurofibromatosis (Table 3). In addition, the 13. Holt JF. Wright EM. The radiologie features of neurofibromatosis. Radiology 1948:51:647-664. literature is extensive on the use of radioisotope brain scanning 14. Cole WG, Myers NA. Neurofibromatosis in childhood. AustNZJSurg 1978:48:360- for acoustic neuromas which occur in neurofibromatosis type 2 365. and other central nervous system tumors which occur in both 15. Davidson KC. Cranial and intracranial lesions in neurofibromatosis. Am J Roentgenol Radium Ther NucíMed 1966:98:550-556. neurofibromatosis types 1 and 2 and which lie outside the scope 16. Baltzell JW. Davis DO, Condon VR. Unusual manifestations of neurofibromatosis. of this study (15,50). The bone scan may be useful in the Med Radiogr Photogr 1974:50:2-15. 17. Handa J. Koyama T. Shimizu Y. Yoneda S. Skull defect involving the lambdoid suture management of some of the skeletal abnormalities associated in neurofibromatosis. Surg Neurol 1975:3:119-121. with neurofibromatosis (Table 2). This is particularly true for 18. Klane EC. Franken EA. Smith JA. The radiographie spectrum in neurofibromatosis. follow-up after surgical intervention (e.g., after surgical correc Semin Roentgenol 1976:11:17-33. 19. Gross ML, Soberman N. Dorfman HD, Seitnon LP. Case report 556: multiple tion of scoliosis or in the evaluation of the healing of cortical nonossifying fibromas of long bones in a patient with neurofibromatosis. Skeletal defects following repair (perhaps including the placement for Radial 1989;18:389-391. 20. Haga N. Nakamura S. Taniguchi K. Iwaya T. Pathologic dislocation of the hip in von bone grafts). Recklinghausen's disease: a report of two cases. J Pediatr Orthop 1994:14:674-676. It has been reported that sarcomatous change in neurofibro- 21. Weichen KA, Dine MS. Benton C, Silverman FN. Macrocranium and neurofibroma mas occurs in 2%-16.5% of patients (11,16,51). In attempting tosis. Radiologi- 1973:107:163-166. to distinguish between benign neurofibroma or plexiform neu 22. Van Gemert RJ, Yamashita DDR, Goodsell JF. Multiple neurofibromatosis (von roma and neurofibrosarcoma, gallium or [I8F]FDG avidity Recklinghausen's disease) with concurrent micrognathia. Review of the literature and report of a case. Oral Surg Oral Med Oral Pathol 1977:43:165-173. suggests malignancy (45,49). 23. Sharif HS, Tucker AK. Rare skeletal manifestations in neurofibromatosis complicated Pheochromocytoma occurs in l%-4% of patients with with sarcoma. Br J Radial 1985:58:371-374. 24. Smith CJ, Hatch FE. Johnson JG, Kelly BJ. Renal artery dysplasia as a cause of neurofibromatosis type 1 (47). The distinction of pheochro- hypertension in neurofibromatosis. Arch Intern Med 1970:125:1022-1026. mocytomas (and closely related neuroendocrine tumors) 25. Sane S, Yunis E. Greer R. Subperiosteal or cortical cyst and intramedullary neurofi bromatosis— uncommon manifestations of neurofibromatosis. A case report. J Bone from neurofibromas has posed a major challenge for anatom ical imaging modalities. Iodine-131- or [123I]metaiodoben- Joint Surg ¡Am]1971:53:1194-1200. 26. Hardoff R, Gips S, Front A. Diffuse jaw uptake. An unusual finding in neurofibro zylguanidine (MIBG), however, has proven efficacious in this matosis. Clin NucíMed 1991:16:527-531. 27. Anonymous. Image interpretation session. Plexiform neurofibromatosis. Radiograph task as neurofibromas ordinary are not MIBG-avid. The same ies 1995:15:223-225. would probably be true for related radiopharmaceuticals (e.g., 28. Holbert BL, Lamki LM, Holbert JM. Uptake of bone scanning agent in neurofibro "C-hydroxyephedrine and radio-Br or F-labeled analogs of matosis. Clin NucíMed 1987:12:66-67. 29. Nolan NO. Intense uptake of "9"'Tc-diphosphonate by an extraosseous neurofibroma. MIBG). There are rare reports of MIBG uptake by atypical J NucíMed 1974:15:1207-1208. schwannomas (48). The role of radiolabeled somatostatin 30. Datz FL. Bone imaging: son tissue uptake in any organ system. In: Gay S, Cery L, eds. analogs (e.g., " ' In-octreoscan) in distinguishing pheochromo- Gamuts in nuclear medicine, 3rd ed. St. Louis: Mosby Yearbook. Inc.; 1995:137-147. 31. Pellegrini AE. Scatamogna PA. Malignant melanoma with osteoid formation. Am J cytomas from neurofibromas is similar to that of MIBG. Dermatopathol 1990; 12:607- 611.

1782 THE JOURNALOFNUCLEARMEDICINE•Vol. 37 •No. 11 •November 1996 32. Mandell GA, Harcke HT, Sharkey C, Brooks KM, MacEwen GD. SPECT imaging of 42. Goshen E, Meiler I, Lantsberg S, et al. Radionuclide imaging of soft tissue masses with para-axial neurofibromatosis with WnTc DTPA. J NucíMed 1987;28:1688-1694. 99mTc-DTPA. Clin NucíMed 1991;16:636-642. 33. Mandell GA, Herrick WC, Harcke HT, Sharkey C, Brooks KM, MacEwen GD. 43. Ida M, Mashima Y, Mori Y, Kawakami K, Kondoh H. Evaluation of "Tc-DTPA as Neurofibromas: location by scanning with 99mTc-DTPA. Work in progress. Radiology tumor seeking agents for neurofibromatosis. Kaku Igaku 1988:25:205-212. 1985;157:803-806. 44. Sty JR, Starshak RJ, Woods GA. Neurofibromatosis: lymphoscintigraphic observa 34. Abdel-Dayem HM. Papademetriou T. Subperiosteal hemorrhage in neurofibromatosis: tions. Clin NucíMed 1981:6:264-265. appearance in bone scintigraphy. Clin NucíMed 1981;6:272. 45. Hammond JA, Driedger AA. Detection of malignant change in neurofibromatosis (von 35. Ohta H, Endo K, Fujita T, et al. Imaging of soft tissue tumors with 99mTc(V) Recklinghausen's disease) by gallium-67 scanning. Can Med Assoc J 1978:119:352- dimercaptosuccinic acid. A new tumor-seeking agent. Clin NucíMed 1984:9:568-573. 353. 36. Kobayashi H, Kotoura Y, Sakahara H, et al. Schwannoma of the extremities: 46. Wang PW, Chen HY, Li CH, Chen WJ. Uptake of m I by an abdominal neurilemoma comparison of MRI and pentavalent technetium-99m-dimercaptosuccinic acid and mimicking metastatic thyroid carcinoma. Clin NucíMed 1993:18:964-966. gallium-67-citrate scintigraphy. J NucíMed 1994:35:1174-1178. 47. Kalff V, Shapiro B, Lloyd R, et al. The spectrum of pheochromocytoma in 37. Wilkinson RH Jr., Goodrich JK. A neurofibroma mimicking a parotid gland tumor hypertensive patients with neurofibromatosis. Arch Intern Med 1982:142:2092-2098. both clinically and by scanning. J NucíMed 1971:12:646-648. 48. Von Moll L, McEwan AJ, Shapiro B, et al. Iodine-131 MIBG scintigraphy of 38. Koch KJ, Siddiqui AR, Wellman HN, Campbell RL. Localization of technetium-99m pertechnetate in peripheral nerve tumors. J NucíMed 1986:27:1713-1716. neuroendocrine tumors other than pheochromocytoma and neuroblastoma. J NucíMed 1987:28:979-988. 39. Grove AS Jr., Kotner LM Jr. Orbital scanning with multiple radionuclides. Arch Ophlhatmol 1973:89:301-305. 49. Borbely K, Fulham MJ, Brooks RA. Di Chiro G. PET-fluorodeoxyglucose of cranial 40. Siddiqui AR. Localization of technetium-99m DTPA in neurofibroma [Letter]. J Nucí and spinal neuromas. J NucíMed 1992:33:1931-1934. Med 1986;27:143-144. 50. Young DF, Eldridge R, Gardner WJ. Bilateral acoustic neuroma in a large kindred. 41. Mandell GA, Scott CI Jr., Harcke HT, Sharkey C, Harris L. Scintigraphic differenti JAMA 1970:214:347-353. ation of congenital soft-tissue extremity enlargement with 99mTc-DTPA. Skeletal 51. Baker ND, Tchang FK, Greenspan A. Liposarcoma complicating neurofibromatosis. Radial 1989:18:33-41. Report of two cases. Bull Hasp Jt Dis Orthop Inst 1982:42:172-186.

Quantitative Comparison of Planar and SPECT Normal Data Files of Thallium-201, Technetium- 99m-Sestamibi, Technetium-99m-Tetrofosmin and Technetium-99m-Furifosmin

Hitoshi Naruse, Edouard Daher, Albert Sinusas, Diwakar Jain, Donna Natale, Jennifer Matterà , Robert Makuch and Frans J.Th. Wackers The Cardiovascular Nuclear Imaging Laboratory, Departments of Diagnostic Radiology, Medicine, Epidemiology and Public Health, Yale University School of Medicine, New Haven, Conneticut

analysis of SPECT images. In recent years, several of ""Tc-labeied myocardial perfusion imaging agents have been developed, such as 99mTc-sestamibi, Key Words: normaldata files;quantification;thallium-201; sestamibi; 99mTc-tetrofosmin and 99nTc-furifosmin. Although images obtained tetrofosmin; furifosmin. with these new tracers have a general similar appearance, there are J NucíMed 1996; 37:1783-1788 differences in the myocardial kinetics, body distribution, general quality of images and imaging protocols. The aim of this study was to quantitatively compare normal exercise planar and SPECT data Several new radiopharmaceuticals have been introduced in files obtained with 201TI and ""Tc-labeled agents. Methods: recent years for stress myocardial perfusion imaging. Because Lower-limit-of-normal curves were generated for each specific ra- of unfavorable characteristics of the conventional imaging diopharmaceutical from normal subjects with low (<3%) pretest agent, 201T1 (7), 99mTc-labeled agents with better imaging likelihood of coronary artery disease using circumferential count properties have been developed such as 99mTc-sestamibi (2), distribution profiles from planar and SPECT exercise images. Lower- 99mTc-tetrofosmin (3) and 99mTc-furifosmin (4). These new limit-of-normal curves were statistically compared using the nonpara- metric Kruskall-Wallis and Wilcoxon tests. Results: Planar and radiopharmaceuticals provide improved image quality, particu SPECT lower-limit-of-normal curves generated for each radiophar- larly when used for SPECT. Normal images with each of the maceutical showed general similarities. Statistically significant differ above imaging agents, using either planar or SPECT imaging, ences among the lower-limit-of-normal curves were found in the have visually a similar general appearance i.e., more or less planar left anterior oblique view and in the planar left lateral view homogeneous myocardial uptake. Nevertheless, there are (p < 0.05 for each). No statistically significant differences existed marked differences in myocardial kinetics, body distribution, between lower-limit-of-normal curves of various radiopharma- general quality of images and imaging protocols (2,3,5-7). ceuticals on the planar anterior view and on SPECT imaging Conclusion: Forquantitativeanalysisof planarimages,radiopharma- Quantification of planar and SPECT images enhances confi ceutical-specific normal data files are mandatory. Although SPECT dence and reproducibility of image interpretation (8-10). In normal data files of various radiopharmaceuticals are not statistically addition, quantitative measurement of myocardial perfusion different, they are not identical. It appears, nevertheless, prudent to abnormalities has shown to be of importance for prognostic risk use radiopharmaceutical-specific normal data files for quantitative stratification in individual patients (11-13). The most important components of image quantification are graphic or color-coded Received Dec. 5,1995; revision accepted Mar. 22, 1996. display of relative myocardial radiopharmaceutical distribution For correspondence or reprints contact: Frans J.Th. Wackers, MD, Cardiovascular Nuclear Imaging and Exercise Laboratories, Yale University School of Medicine, 333 and normal data files for comparison with patient image data Cedar St. fTE-2) P.O. Box 208042, New Haven, CT 06520-8042. (9,14).

QUANTITATIVECOMPARISONNORMALDATAFILES•Naruse et al. 1783