Journal of Neuro-Ophthalmology, June 2000, Volume 20, Issue 2

Neuro-Ophthalmologic Manifestations of Neuroendocrine Carcinoma

The neuro-ophthalmologic findings of parasellar neuroendocrine carcinoma are reported. Two patients with parasellar neuroendocrine carcinoma had headache, ptosis, and ophthalmoplegia. In both patients, neuroimaging revealed a parasellar mass with extension into the cavernous sinus. The tumors initially were believed to be pituitary adenomas, but histopathology confirmed neuroendocrine carcinoma. Clinicians should be aware of neuroendocrine carcinoma in the differential diagnosis of sellar/parasellar lesions causing ophthalmoplegia.

Journal of Neuro- Ophthalmology 20( 2): 106- 110, 2000. © 2000 Lippincott Williams & Wilkins, Inc., Philadelphia Neuro- ophthalmologic Manifestations of Neuroendocrine Carcinoma Andrew G. Lee, MD, Amit Chokshi, MD, and J. Clay Goodman, MD « i- : " • • • ? • * - • • • % *£.*{ " ^ The neuro- ophthalmologic findings of parasellar neuroendo­crine carcinoma are reported. Two patients with parasellar neu­roendocrine carcinoma had headache, ptosis, and ophthal­moplegia. In both patients, neuroimaging revealed a parasellar mass with extension into the cavernous sinus. The tumors ini­tially were believed to be pituitary adenomas, but histopathol-ogy confirmed neuroendocrine carcinoma. Clinicians should be aware of neuroendocrine carcinoma in the differential diagno­sis of sellar/ parasellar lesions causing ophthalmoplegia. Paranasal sinus neuroendocrine carcinoma ( NEC) is a rare tumor ( 1- 10). We report two patients with cavern­ous sinus involvement from a paranasal NEC and review the English- language literature on paranasal NEC ( 1- 10). Although proptosis is a relatively common present­ing sign, diplopia and visual loss with NEC have infre­quently been reported. CASE REPORTS Casel A 70- year- old man experienced headache, ptosis, and progressive ophthalmoplegia. His medical history was significant for noninsulin dependent diabetes mellitus for 10 years, hypertension for 20 years, peptic ulcer disease, hypothyroidism, degenerative arthritis, cholelithiasis, and a 1992 cerebrovascular accident with residual mild right hemiparesis. Surgical history was significant for benign testicular tumor resection in 1982 and cataract Manuscript received December 28, 1998; accepted February 8, 2000. From the Departments of Ophthalmology, Neurology, and Neuro­surgery ( AGL), Baylor College of Medicine, Houston, Texas; the De­partment of Neurosurgery, the M. D. Anderson Cancer Center, Univer­sity of Texas, Houston, and the Department of Pathology, Baylor Col­lege of Medicine, Houston, Texas ( JCG); and the University of Miami School of Medicine ( AC), Miami, Florida. Dr. Lee is currently Associate Professor of Ophthalmology, Neurol­ogy, and Neurosurgery at the University of Iowa Hospitals and Clinics, Iowa City, Iowa. This work was supported in part by an unrestricted grant from Re­search to Prevent Blindness, Inc., New York, New York. Address correspondence to Andrew G. Lee, MD, Department of Ophthalmology, the University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242. extraction without intraocular lens placement OS in 1971. He developed new- onset moderate headaches in June 1998. A magnetic resonance ( MR) scan of the head on June 16, 1998 revealed an intrasellar mass with mini­mal suprasellar extension and displacement of the infun-dibulum to the right. This was believed to represent a pituitary adenoma. Endocrinologic evaluation revealed only mild hypothyroidism. A second MR scan of the sella on June 23, 1998 revealed a homogenous intrasellar mass with effacement of the left cavernous sinus ( Figs. IA and B). On June 27, 1998, the patient had increased severity of headache, numbness on the left side of his face, and new- onset binocular horizontal diplopia. He developed progressive ophthalmoplegia, a new left- sided ptosis, and increasing headache. A neuro- ophthalmologic ex­amination on August 16, 1998 revealed a visual acuity of 20/ 30 OD and 20/ 50 with aphakic correction OS. The pupils measured 5 mm OU, but they reacted poorly to light and near testing. There was no afferent pupillary defect. There was a mild ptosis of the eyelid OD and an almost- complete ptosis of the eyelid OS. Slit- lamp biomicroscopy revealed a mild nuclear cataract OD con­sistent with 20/ 30 visual acuity and aphakia OS. A mo­tility examination revealed a marked limitation of upgaze and downgaze, and there was essentially no horizontal movement in either eye ( Fig. 2). Doll's head maneuver could not overcome the bilateral ophthalmoplegia. Re­sults of intraocular pressure measurement and an oph­thalmoscopic examination were normal OU. There was decreased cutaneous sensation to pinprick in the first division of the trigeminal nerve on the left. A repeated MR scan of the head on August 17, 1998 demonstrated an increase in the size of the lesion ( Fig. 3) and bilateral cavernous sinus involvement. Results of computed to­mography ( CT) scans of the chest, abdomen, and pelvis were normal. A transsphenoidal subtotal resection of the lesion was performed. Histopathology revealed sinus mucosa, clus­ters, and numerous nests of malignant cells with scant cytoplasm and nuclei of variable size. Results of a mucin stain were negative. Immunohistochemical stains re­vealed strong staining with neuron- specific enolase, syn-aptophysin, chromogranin, and S- 100 ( a marker for neu- 106 NEUR0- 0PHTHALM0L0G1C MANIFESTATIONS OF NEC 107 FIG. 1. A: Sagittal and ( B) coronal view postcontrast T1- weighted MR scan reveals a homogenous intrasellar mass with minimal extension into the suprasellar space ( June 1998). ral crest origin cells) consistent with neurosecretory granules and neuroendocrine differentiation. The patho­logic lesion was consistent with neuroendocrine carci­noma ( Figs. 4A- D). Postoperatively, the patient was treated with confor-mal three- dimensional external beam radiation therapy ( 4,500 centigray), and there was moderate improvement of his bilateral ophthalmoplegia at a 2- month follow- up \ FIG. 2. External and motility photographs demonstrate bilateral ptosis greater on the left than on the right. There is marked limitation of upgaze and downgaze and essentially no horizontal movements in either eye. Arrows indicate attempted gaze direction. J Neuro- Ophthalmol, Vol. 20, No. 2, 2000 70S A, G. LEEETAL. 5 '• J FIG. 3. Sagittal postcontrast T1 - weighted MR scan reveals en­largement of the mass with extension to the sphenoid sinus ( Au­gust 17, 1998). examination. The patient subsequently developed fever, loss of consciousness, pneumonia, and meningitis, and he died on November 11, 1998. A postmortem examina­tion revealed multiple metastatic nodules involving the liver and several peripancreatic lymph nodes. Microab­scesses containing multiple fungal hyphae and spores were noted in the lungs. The primary tumor was believed to be arising from the sphenoid sinus, with extension into the cavernous sinus bilaterally. Case 2 A 40- year- old woman experienced left retroorbital pain, ptosis, and transient binocular horizontal diplopia &?* m ' ^ p^ T'Jfc - • » - » *• . C • • * * ' ' in May 1999. Results of a CT scan of the head, a lumbar puncture, and a cerebral arteriogram were unremarkable. An MR scan of the head revealed a sellar/ parasellar mass with extension into the left cavernous sinus. Neuro-ophthalmologic examination revealed a visual acuity of 20/ 20 OU. There was a mild ptosis of 2 mm of the left upper eyelid. The pupils were equal and reactive to light bilat­erally, and there was no afferent pupillary defect. A mo­tility examination revealed full ductions and versions, and the patient was orthotropic at distance and in the diagnostic positions of gaze. Results of slit- lamp biomi­croscopy and ophthalmoscopy were normal. Visual field testing by automated ( Humphrey 24- 2) technique was normal OU. She underwent a left temporal craniotomy with subtotal excision of the tumor on June 15, 1999. Microscopic pathology revealed small cells with dark nuclei and scant cytoplasm infiltrating a loose connective tissue stroma. Results of special immunohistochemical stains for lymphoma, melanoma ( HMB- 45), sarcoma, and germ- cell origin tumors ( H- PLAP) were negative. Tests for carcinoembryonic antigen and S- 100 were negative. Keratin markers ( pankeratin, AE1/ AE3, and CAM 5.2) and chromogranin stains were positive, which is consistent with NEC. An extensive metastatic evalu­ation ( including CT scans of the chest and abdomen) did not disclose a primary carcinoma. Postoperatively, the patient developed a diplopia due to a partial left third nerve palsy. She was stable until June 29, 1999, when she developed acute loss of vision OS. Visual acuity was 20/ 20 OD, and there was no light perception OS. There was a left afferent pupillary defect and complete ophthalmoplegia OS. Results of trigeminal sensation and facial nerve testing were normal. A re­peated MR scan revealed a dramatic increase in the size of the suprasellar, intrasellar, and prepontine component of the tumor, with new extension along the tuberculum FIG. 4. A: Hematoxylin- and eosin- stained low- magnification image ( original magnifica­tion, x40) shows nests of tumor cells ( solid arrow) infiltrating the submucosal of the sphendoid sinus. The respiratory epithelium is intact on the outer surface of the mucosa ( hollow arrow). B: Hematoxylin- and eosin-stained high- magnification image ( original magnification, x400) shows nests of tumor cells with nuclei with prominent nucleoli, open chromatin, and scant cytoplasm. Mi­totic figures as well as individual cell death are present. C: Hematoxylin- and eosin-stained cytologic imprint ( original magnifica­tion, x200) shows the tumor cells occurring as cohesive clusters characteristic of carci­noma. The cells have hyperchromatic nuclei with scant cytoplasm. D: Immunohistochem­ical preparation ( original magnification, x200) shows strong cytoplasmic immunore-activity for chromogranin ( arrow) in the sub­mucosal tumor cells ( solid arrow). This im­munohistochemical study is specific for neu­rosecretory granules. Note the absence of staining of the respiratory epithelium ( hollow J Neuro- Opluhalmol, Vol. 20, No. 2, 2000 NEURO- OPHTHALMOLOGIC MANIFESTATIONS OF NEC 109 • f <> • ' • '• - sella and involvement of the left optic nerve in the optic canal and of the left sphenoid sinus. There was enhance­ment along the superior and inferomedial aspect of the left optic canal after the administration of gadolinium. She was treated with conformal three- dimensional radio­therapy ( 5,080 centigray) and intravenous methylpred-nisolone 1000 mg/ d, and there was improvement in vi­sion OS. An examination on August 12, 1999 revealed a visual acuity of 20/ 20 OD and 20/ 30 OS. There was a left afferent pupillary defect. Humphrey automated visual field testing ( 24- 2) revealed a temporal hemianopic vi­sual field defect ( mean deviation, - 11.67 decibels). A motility examination revealed a mild underaction of el­evation OS with a left hypotropia of 5 prism diopters in primary position. Ophthalmoscopy showed mild optic atrophy OS. Postoperative MR scans revealed a residual tumor involving the left cavernous sinus. The patient received systemic methotrexate and has remained clini­cally stable. DISCUSSION Neuroendocrine carcinoma most commonly involves the lungs. Extrapulmonary NEC is uncommon, however, and paranasal sinus involvement is rare ( 1- 10). The com­mon paranasal malignancies, in order of their frequency, are adenocarcinoma, lymphoma, plasma cell tumors, melanoma, and olfactory neuroblastoma ( 2,4). Tumors with neuroendocrine differentiation demonstrated by electron microscopy or immunohistochemistry are ex­tremely rare and have been referred to in the literature by various terms, including NEC ( 1,2,4- 6,9), oat- cell carci­noma ( 7), small- cell carcinoma ( 8,10), and sinonasal un­differentiated carcinoma of the paranasal sinuses ( 3). Un­fortunately, this has created a great deal of confusion in the literature regarding the terminology and classifica­tion of these tumors. Silva et al. ( 9), in the largest series to date, reviewed the M. D. Anderson Cancer Center ex­perience and proposed a classification scheme in 1982. These authors reviewed 29 nasal tumors previously di­agnosed as neuroblastoma, unclassified carcinoma, or unclassified malignant neoplasm. They divided the tu­mors into two groups: neuroblastoma ( e. g., classical neu­roblastoma and esthesioneuroblastoma) and NEC. These authors classified 20 tumors as NEC, based upon a char­acteristic light microscopic pattern and cytologic features of remarkably uniform well- demarcated groups of cells growing from benign glandular epithelium. Membrane-bound granules were seen with electron microscopy in the cytoplasm of ten of these cases ( 9). Kameya et al. ( 4) postulated that NEC might be related to neoplasms de­rived from amine precursor uptake and decarboxylation cell series. Milroy and Ferlito ( 6) used immunohisto-chemical markers in the diagnosis of NEC. They defined three broad groups of antibodies: 1. antibodies that differentiate between epithelial neo­plasms ( e. g., antibodies to cytokeratins, such as CAM 5.2, epithelial membrane antigen, and carcinoembry-onic antigen), soft tissue neoplasms ( e. g., vimentin for connective tissue neoplasms), and lymphoma ( e. g., leukocyte common antigen); 2. general neuroendocrine markers ( e. g., chromogranin, protein gene product 9.5, synaptophysin, Leu 7, and neuron specific enolase); 3. specific neuropeptides. Neuroendocrine carcinoma of the paranasal sinuses ex­press neuroendocrine markers, stain consistently for neu­ron specific enolase and synaptophysin, and often stain for chromogranin. Leu 7 and neurofilament proteins are occasionally seen, but epithelial membrane antigen and carcinoembryonic antigen are not present. The specimen in our first case demonstrated strong staining with neu­ron- specific enolase, synaptophysin, chromogranin, and S- 100 consistent with neurosecretory granules and neu­roendocrine differentiation. The specimen in case two was positive for chromogranin. Chaudhry et al. ( 2) reported one case and reviewed an additional 15 cases of paranasal sinus NEC in the En­glish- language literature through 1994. Patient age ranged from 16 to 70 years. Of the 15 patients, the max­illary sinus alone was involved in six cases, the ethmoid sinus alone in four cases, the sphenoid sinus alone in one case, and multiple sinus were involved in four cases. The treatments were known for ten of these 15 patients and included surgery alone in one case, surgery and radiation therapy in five cases, and radiation and chemotherapy in four cases. At last follow- up, three patients were disease free, four patients died of disease, and four patients had tumor- related deaths. Unfortunately, no information on visual function is available in this paper ( 2). Paranasal sinus NEC is believed to be locally recurrent and destructive, but distant metastasis ( including of the brain and spinal cord) are considered rare. In our first patient, distant metastases were found in the liver and peri- pancreatic lymph nodes, but no lung tumor was identified. The primary tumor in our patient is believed to have arisen from the sphenoid sinus. This patient died after developing severe pneumonia. The second patient developed a rapidly progressive ophthalmoplegia and optic neuropathy that responded to radiotherapy. She re­mains alive 5 months after diagnosis. Treatment of NEC is aimed at local control, with a combination of radiation therapy, chemotherapy, and surgery. In the paranasal sinus area, the treatment strat­egy is aimed at local control, with a combination of surgery and radiation therapy. Chaudry et al. ( 2) recom­mend ablative surgery and combination chemotherapy with cyclophosphamide, vincristine, methotrexate, and etoposide for recurrences. Bhattacharyya et al. ( 1) re­ported five cases of esthesioneuroblastoma and four cases of NEC. Two patients ( 22%) had a gaze palsy, four patients ( 44%) had proptosis, and one patient ( 11%) had visual loss. The combined use of cisplatin and etoposide chemotherapy with proton radiation ( 68 Gray) demon­strated initial success in eight out of nine patients ( 89%), with a mean disease- free interval of 14 months. Kameya et al. ( 4) reported four cases of paranasal ( ethmoid, max- J Neuro- Ophthalmol, Vol. 20. No. 2, 2000 110 A. G. LEE ETAL. illary, and frontal) NEC, two of which ( 50%) presented with proptosis. Silva et al. ( 9) reported a survival rate for NEC of 100% at 5 years, 88% at 7 years, and 77% at 10 years; they believed that NEC had a higher rate of local recur­rence ( 54%) than neuroblastoma ( 25%) and that the first recurrence or metastasis usually occurred after the third year ( 70%). Our patient in case 1 was found during au­topsy to have metastatic disease. To our knowledge, our case 1 is the only incidence of paranasal NEC with bilateral ophthalmoplegia reported in the English- language ophthalmologic literature. Clini­cians should be aware of the neuro- ophthalmologic manifestations of NEC and consider NEC in the differ­ential diagnosis of a rapidly progressive sellar or para-sellar mass, REFERENCES 1. Bhattacharyya N, Thornton AF, Joseph MP. Successful treatment of esthesioneuroblastoma and neuroendocrine carcinoma with combined chemotherapy and proton radiation. Arch Otolaryngol Head Neck Surg 1997; 123: 34- 40. 2. Chaudhry MR, Akhtar S, Kim DS. Neuroendocrine carcinoma of the ethmoid sinus. Eur Arch Otorhinolaryngol 1994; 251: 461- 3. 3. Frierson HF, Mills SE, Fechner RE, et al. Sinonasal undifferenti­ated carcinoma. Am J Surg Pathol 1986; 10: 771- 9. 4. Kameya T, Shimosato Y, Adachi I, et al. Neuroendocrine carci­noma of the paranasal sinus. Cancer 1980; 45: J( 30- 9. 5. McCluggage WG, Napier SS, Primrose WJ, et al. Sinonasal neu­roendocrine carcinoma exhibiting amphicrine differentiation, His-topathology 1995; 27: 79- 82. 6. Milroy CM, Ferlito A. Immunohistochemical markers in the diag­nosis of neuroendocrine neoplasms of the head and neck. Ann Olol Rhinol Laryngol 1995; 104: 413- 8. 7. Raychowdhuri RN. Oat- cell carcinoma and paranasal sinuses. J Laryngol Otol 1965; 79: 253- 5. 8. Rejowski JE, Campanella RS, Block LJ. Small cell carcinoma of the nose and paranasal sinuses. Otolaryngol Head Neck Surg 1982: 90: 516- 7. 9. Silva EG, Butler JG, MacKay B, et al. Neuroblastomas and neu­roendocrine carcinomas of the nasal cavity. Cancer 1982; 50: 2388- 405. 10. Weiss MD, deFries HO, Taxy JB, et al. Primary small cell carci­noma of the paranasal sinuses. Arch Otolaryngol 1983; 109: 341- 3. IK*, I . , . , . I t J Neuro- Ophthalmol, Vol. 20, No. 2, 2000