Radiotherapy for the treatment of thyroid eye disease-a prospective comparison: Is orbital radiotherapy a suitable alternative to steroids?

BACKGROUND AND AIMS: To evaluate the efficacy of orbital radiotherapy (OR) for the treatment of thyroid eye disease (TED). METHODS: Thirty-five consecutive patients with active TED with contraindications to steroid therapy received a course of OR. Bilateral retrobulbar irradiation was performed with a total dose of 20 Gy. 7-points clinical activity score (7-CAS), ocular motility, visual acuity (VA), exophthalmos and eyelid retraction were prospectively evaluated at 3, 6 and 12 months and compared with baseline data. RESULTS: There was a statistically significant improvement in 7-CAS at 3, 6 and 12 months post-treatment (p < 0.05). Ocular motility disturbances improved at 6 and 12 months (p < 0.05). Visual acuity remained stable; there was no significant change in exophthalmos (mean 24 mm, SD 3 mm) or eyelid retraction (marginal reflex distance mean 6 mm, SD 1.5 mm) during the follow-up period. No side effects were registered. CONCLUSIONS: This study suggests that OR might be effective in reducing 7-CAS and ocular motility disturbances. No significant improvement in proptosis or eyelid retraction should be expected from this treatment. OR might be considered a suitable alternative treatment in TED for patients who cannot tolerate steroids.

Spheno-orbital meningiomas: surgical approaches and outcome according to the intraorbital tumor extent.

OBJECT: This study proposes a topographical classification of spheno-orbital meningiomas. Its aim was to define whether the different intraorbital localizations require different surgical approaches and have different recurrence rates and outcomes. MATERIAL AND METHODS: Sixty patients with spheno-orbital meningiomas operated upon between 1983 and 2003 were reviewed. Four types were identified according to the extent of intraorbital tumor invasion: I: lateral or superolateral (15 cases); II: medial and inferomedial (8 cases); III: orbital apex (25 cases); IV: diffuse (12 cases). Three surgical approaches were used: lateral orbitotomy (15 cases with lateral or superolateral tumors), supraorbital-pterional approach (42 cases, including all 8 inferomedial cases, all 25 orbital apex cases, and 9 of 12 diffuse tumors), and a fronto-temporal-orbitozygomatic approach (only 3 cases with diffuse meningiomas and large-scale tumor invasion in the infratemporal fossa and cavernous sinus). RESULTS: Tumor removal was complete (Simpson grades I and II) in 40 cases, and incomplete in 20 (33.3%). There were two postoperative deaths (3.3%). A sufficient clinical follow-up was obtained in 52 cases. The clinical outcome was excellent in 26 patients (50%), good in 16 (30.8%), moderate in 6 (11.5%), and poor in 4 (7.7%). Twenty-two of 52 patients (42.3%) had tumor recurrence; however, 44 (84.6%) achieved tumor control after surgery alone through two or more operations. The recurrence rate was correlated with the Simpson grade of resection and the intraorbital tumor location. Significantly higher rates of recurrence were recorded for the orbital apex type (50%) and diffuse forms (60%), than for the inferomedial (28.5%) and superolateral forms (23%). CONCLUSIONS: Spheno-orbital meningiomas may be classified according to the location and extent of the intraorbital tumor invasion. The different localizations may require different surgical approaches, with different chances of complete removal. The location and extent of the intraorbital tumor results in different recurrence rates, lower for superolateral and inferomedial forms than for orbital apex and diffuse forms.

Tumor infiltrating lymphocytes in uveal melanoma: a link with clinical behavior?

Experimental and clinical evidence indicate that immunological mechanisms might be important in the clinical course of uveal malignant melanoma (UMM). We analyzed the amount and phenotype of tumor infiltrating lymphocytes (TIL) and the expression of the apoptosis-inducing molecule Fas and its ligand, FasL, on tumor cells and TIL in a selected series of UMM with the aim to establish if a correlation between their expression and the clinical behavior of UMM exists. TIL phenotype and Fas/FasL expression were evaluated by immunohistochemistry in 61 cases of formalin-fixed, paraffin-embedded UMM. Results were compared with the follow-up data of patients. Most of the UMM showed a prevalence of CD8+ CD3+ T lymphocytes, or CD4+ and CD8+ cells in equal amounts. UMM showed a variable expression of FasL, ranging from 0 to > 40% of neoplastic cells. Fas was always expressed in TIL, although with a variable extent. A subgroup of UMM showed in TIL a strongly reduced or even absent expression of TCR zeta-chain, involved in activation of T-lymphocytes. This subgroup was characterized by a worse outcome. We hypothesized that an impaired cytotoxic immune response due to the loss of the zeta-chain expression plays a primary role in the biological course of UMM. Our results indicate that the overcoming of the impairment of TCR function may represent a prerequisite for the development of new therapeutic strategies for managing UMM, suggesting that elimination of tumor cells may be possible by activation of cytotoxic cells present within ocular melanomas.

Unilateral exophthalmos associated with ipsilateral mucosal turbinate hypertrophy: benign exophthalmos syndrome (BES). A description of a new clinical condition.

PURPOSE: To report the clinical and radiologic characteristics of a group of patients who experienced unilateral exophthalmos associated with ipsilateral mucosal turbinate hypertrophy. The clinical features of these patients are presented and a hypothesis proposed to explain this condition for which the authors introduce the term benign exophthalmos syndrome (BES). METHODS: Retrospective, noncomparative case series. PARTICIPANTS: Four patients experienced slow progressive unilateral exophthalmos associated with ipsilateral mucosal turbinate hypertrophy, with no evidence of orbital mass or extraocular muscles involvement. INTERVENTION: Main Outcome Measures. Symptomatic outcome and measurement of the degree of relative exophthalmos. RESULTS: The onset of exophthalmos was associated with clinical and radiologic features that resemble BES. In all patients, radiologic examination demonstrated an ipsilateral mucosal turbinate hypertrophy and not the presence of orbital disease or expanding lesions of paranasal sinus. After daily intranasal spray of steroid, in three of the four cases the globe returned to within 1 mm of exophthalmometry of the contralateral eye. CONCLUSIONS: The relationship between the feature of paranasal sinus disease and the development of ipsilateral exophthalmos has been described in the literature. The four cases described herein appear peculiar for the slow progressive onset of the exophthalmos, without inflammatory and mass effect signs. This condition associated in all cases with ipsilateral hypertrophy of the nasal mucosa provides a guide to a hypothetical mechanism for BES. According to these hypothesis, the therapy should be devoted to the nasal disease more than the orbital.

[Somatostatin receptor genes expression and effects of octreotide on orbital fibroblasts from Graves' ophthalmopathy]. / I recettori della somatostatina ed effetto in vitro dell'octreotide nei fibroblasti retro-orbitari di pazienti con oftalmopatia di Graves'.

BACKGROUND: Recent data demonstrated that somatostatin (SRIH) analogues octreotide is effective in Graves' ophthalmopathy (GO), but their mechanism of action in GO is still unclear. In this study we investigated the expression of SRIH receptor (sst1-5) genes and the effect of octreotide treatment on primary cultures of fibroblasts established from retroorbital tissue of GO patients and of control subjects. METHODS: Retro-orbital connective tissue was obtained from 10 patients with GO and from 6 control subjects undergoing eye surgery. Fibroblasts were established in MEM with 5-10% FCS. The expression of sst1-5 genes was studied by RT-PCR using specific primers and GAPDH as internal control. Cells were treated with octreotide (10-8M, 10-9M) for 48-72-96 h to evaluate cell growth by MTT, cAMP accumulation by RIA and apoptosis by TUNEL techniques. RESULTS: All primary cultures expressed one or more ssts genes that have a high affinity for the two analogues (class 1 sst). The sst2 transcript was found in 9, sst3 in 5 and sst5 in 8 out of 10 GO cell cultures. sst2 was detected in all 6, and sst3 in 4 of the 6 control cell cultures. Octreotide (10-6 and 10-7M) significantly inhibited cell growth (p<0,01-0,05), significantly decreased forskolin-induced-cAMP accumulation, and determined apoptosis (10-18%). CONCLUSIONS: Our study demonstrated that sst transcripts are expressed and functional in cultured retroorbital fibroblasts. The presence of class 1 sst in GO tissue and the inhibition exerted by octreotide on retroorbital cell growth and activity in vitro may account for the effects of SRIH analogue administration in vivo in GO.

Ophthalmic complications after surgery for nasal and sinus polyposis.

PURPOSE: To describe ophthalmic complications after nasal and sinus surgery. METHODS: Four cases with orbital complications were retrospectively selected from among more than 2000 cases of orbital pathologies. RESULTS: Motility disturbances due to extraocular muscle injury occurred in two patients after intranasal ethmoidectomy and in one patient after a Caldwell-Luc procedure. In the fourth case an orbital apex syndrome was noted after intranasal ethmoidectomies. CONCLUSIONS: Ophthalmic complications may occur after nasal and sinus surgery, even using an endoscopic procedure. Successful handling of these complications could be reached by on their early recognition and treatment.

Orbital venous-lymphatic malformations (lymphangiomas) mimicking cavernous hemangiomas.

PURPOSE: To illustrate that orbital venous-lymphatic malformations (lymphangiomas) may rarely simulate cavernous hemangiomas. METHODS: Retrospective case review. RESULTS: Five patients were identified from a series of 85 patients with venous-lymphatic malformations. The age range was 21 to 69 years, and all cases presented with a history of slowly progressive or long-standing proptosis. Computerized tomography revealed relatively homogeneous intraconal masses that were well defined anteriorly. Two of the cases had expansion of the orbit, and one had focal calcification. The three who had magnetic resonance imaging showed heterogeneous contrast enhancement. The preoperative diagnosis in every case was cavernous hemangioma, and intraoperatively the lesions resembled cavernous hemangiomas. However, posterior dissection was difficult in all patients because of dense adhesions and, in one case, led to a central retinal artery occlusion. The histology was characteristic of orbital venous-lymphatic malformations in all five cases. CONCLUSIONS: Deep orbital venous-lymphatic malformations presenting in adulthood may be rarely confused with cavernous hemangiomas. In doubtful cases, significant intralesional heterogeneity, best seen on magnetic resonance imaging, and focal calcification may help distinguish the two entities. This differentiation is important, because dissection of venous-lymphatic malformations is fraught with more complications than surgical excision of a cavernous hemangioma.

Traumatic displacement of the globe into the ethmoid sinus.

PURPOSE: To describe displacement of the globe into the ethmoid sinus after an orbital trauma. METHOD: Case report. A 58-year-old man sustained trauma of the left eye and orbit, which resulted in displacement of the globe into the ethmoid sinus. One day after injury, surgery was performed to restore the intact globe into position within the orbit. RESULTS: After operation, the globe held in its anatomical site, and 10 months after surgery the visual acuity was 20/100, slight pallor of the optic disk was present, and there was no limitation of the horizontal and vertical ductions. CONCLUSIONS: To our knowledge, this is the first case of traumatic displacement of the globe into the ethmoid sinus with satisfactory restoration of normal globe position and preservation of vision.

Somatostatin receptor gene expression and inhibitory effects of octreotide on primary cultures of orbital fibroblasts from Graves' ophthalmopathy.

To explore the mechanism underlying the effects of the somatostatin (SST) analogue octreotide in Graves' ophthalmopathy (GO), we investigated the expression of SST and of SST receptor (sst(1-5)) genes in primary cultures of fibroblasts established from retroorbital tissue of GO patients and of control subjects. We determined also SST specific binding sites by competitive binding of [(125)ITyr(11)]SST-14 and the effect of octreotide on cell growth, cAMP accumulation, Bcl-2 intracellular levels and apoptosis in GO fibroblast primary cultures. All primary cultures expressed the SST gene transcript and one or more ssts that have a high affinity for the two analogues (class 1 sst. The sst(2) transcript was found in nine, sst(3) in five and sst(5) in eight out of ten GO cell cultures. Sst(2) was detected in all six, and sst(3) in four out of the six control cell cultures. Sst(4) was absent from all samples, and sst(1) was found only in six out of the ten GO samples. SST-14 and octreotide inhibited the binding of [(125)I-Tyr(11)]SST-14 with a half-maximal inhibition of binding (IC(50)) of 0.80+/-0.37 and 33. 7+/- 33.1 nmol/l respectively in GO cell cultures, and with an IC(50) of 0.9 and 1.5 nmol/l in control cultures. Octreotide (10(-6) and 10(-7) M) significantly decreased (P<0.001) forskolin-induced but not basal cAMP accumulation; at both doses for 72 h it inhibited cell growth (20 and 55% respectively), and induced apoptosis (20 and 40%), and abolished Bcl-2 protein in cell lysates. In conclusion, SST and sst transcripts are expressed and functional in cultured retroorbital fibroblasts. The presence of class 1 sst in GO tissue and the inhibition exerted by octreotide on retroorbital cell growth and activity in vitro may account for the effects of SST analogue administration in vivo in GO.

Orbital dermis-fat graft using periumbilical tissue.

Dermis-fat grafts are currently used in orbital reconstruction in a variety of procedures. The most frequent harvesting site is the gluteal area. However, we encountered some patients with anophthalmic socket who wished to avoid a visible scar on the buttock. In this article, we describe the effort to offer the patient an alternative donor site. Of the last 36 patients with anophthalmic socket who needed a dermal fat implant, 11 wished to avoid a visible scar on the buttock. To satisfy their requests we have endeavored to harvest the dermis graft from the periumbilical area. The rate of absorption, the motility, and the satisfaction of the patients were used as outcome measures and were analyzed carefully. Of 11 patients, 4 were women and 7 were men. The ages of these patients ranged from 24 to 56. The maximum follow-up was 137 months and the minimum 22 months, with a mean follow-up of 79 months. Some degree of absorption of the graft developed in one patient who had a severe absorption and required further operation. Of 11 cases, there were 7 with excellent motility, 3 with good motility, and 1 not evaluated. The motility was measured with the final prosthesis. The results for all patients were satisfactory. The periumbilical area has sufficient concentration of subdermal fat, and it is a relatively hair-free region as the lateral quadrant of the buttock. This area is a suitable alternative donor site of dermal fat implant for anophthalmic socket, especially in young women.

Radiation late effects in children treated for orbital rhabdomyosarcoma.

BACKGROUND AND PURPOSE: The experience resulting from large cooperative studies shows that correct radiation therapy at doses adequate to the tumor bulk are crucial for local control of rhabdomyosarcoma. The aim of the present study was to document the correlation between modalities and doses of radiotherapy and radiation side effects. PATIENTS AND METHODS: Between 1980 and 1997, 19 patients affected by primary orbital rhabdomyosarcoma have been followed at the University Federico II of Naples. All but three patients, who received 45, 54 and 55 Gy respectively, have been treated by immediate radiation at the dose of 60 Gy, delivered in 2 Gy fractions, five times per week, by cobalt 60 megavoltage equipment. Combined chemotherapy using vincristine and vincristine plus dactinomycin on alternate weeks was also administered as part of induction therapy. RESULTS: An overall survival rate of 94.7% was registered. In our patients the majority of radiation late effects were paid by orbit and ocular adnexa. Side effects to lens and ocular structures were fewer and of low grade. CONCLUSIONS: Radiation therapy is still essential for local control of orbital rhabdomyosarcoma, however radiation side effects have to be carefully considered together with the therapeutic goal to be obtained.

Morphometric analysis of AgNORs in uveal malignant melanoma.

OBJECTIVE: To define the value of silver-stained nucleolar organizer regions (AgNOR) in the evaluation of uveal malignant melanomas (MM). STUDY DESIGN: Morphometric analysis of AgNORs was performed on 30 uveal MM of spindle A, B, epithelioid and mixed cell types. Findings were compared with cytotype, largest tumor dimension (LTD) and clinical outcome. RESULTS: AgNOR mean perimeter (MP) was 3.76 microns (SD 1.21, range 1.79-8.51 microns) in A, 5.05 microns (SD 1.96, range 1.79-16.41 microns) in B and 6.15 microns (SD 3.86, range 1.79-33.80 microns) in epithelioid MM; mean area (MA) was 0.86 micron 2 (SD 0.60, range 0.20-2.78 microns 2) in A, 1.58 microns 2 (SD 1.11, range 0.20-9.63 microns 2) in B and 2.34 microns 2 (SD 2.10, range 0.20-15.27 microns 2) in epithelioid MM; the aspect ratio (AR) was 3.10 (SD 0.19, range 2.90-3.35) in A, 5.80 (SD 2.07, range 3.77-9.32) in B and 12.22 (SD 2.84, range 8.11-15.81) in epithelioid MM. From comparing MA and RA with follow-up, it seemed that MM with a good prognosis (spindle A and a subgroup of B tumors, B1) exhibited the lowest MA and AR values, while MM with poorer clinical behavior (epithelioid and a second subgroup of spindle B MM, B2) showed the highest. No correlation was found between AgNORs and LTD. CONCLUSION: AgNORs may contribute to the prognostic evaluation of uveal MM.

Orbital scintigraphy with [111In-diethylenetriamine pentaacetic acid-D-phe1]-octreotide predicts the clinical response to corticosteroid therapy in patients with Graves' ophthalmopathy.

Corticosteroid treatment is successfully used in Graves' ophthalmopathy, and its effect varies according to the phase of the disease. The infiltration of the orbit by activated lymphocytes may explain the effectiveness of corticosteroid therapy. Scintigraphy with [111In-DTPA-D-Phe1]-octreotide was recently used to reveal the presence of activated lymphocytes in foci of autoimmune diseases, because elevated amounts of somatostatin receptors are expressed in the surface of these cells. The aim of the current study was to evaluate whether the degree of orbital [111In-DTPA-D-Phe1]-octreotide uptake is able to predict the response to corticosteroid therapy in patients with Graves' ophthalmopathy. Ten patients with Graves' ophthalmopathy entered the study. In all patients scintigraphy was performed, and subsequently, corticosteroid therapy (methylprednisolone, 1 g i.v. for 2 consecutive days a week for 6 weeks) was given. Clinical activity of Graves' ophthalmopathy was evaluated before and after treatment by calculating the ophthalmopathy index (OI). Planar and single photon emission computed tomography (SPECT) images of the head were obtained 24 h after the i.v. injection of 120-190 MBq of [111In-DTPA-D-Phe1]-octreotide. Radioligand uptake within each orbit (O) and brain (B) was measured using the region of interests (ROI) method and the O-to-B ratio was determined. According to the O-to-B ratio, the images were classified using the following three points score: 0 = O-to-B ratio < or =1; 1 = O-to-B ratio between 1 and 2.5; 2 = O-to-B ratio > or =2.5. The value of OI, measured before and after corticosteroid treatment, was correlated to the scintigraphic score. A significant change of OI was observed between posttreatment and pretreatment evaluation both in orbits with score 2 (OI: 15.4 +/- 1.5 vs. 9.6 +/- 0.5, P < 0.005) and in those with score 1 or 0 (OI: 12.9 +/- 1.5 vs. 11.5 +/- 1.4, P < 0.05) at the scintigraphy. However, when the OI was calculated excluding the changes in the soft tissue, which generally occur in all patients independently from the phase of the disease, a significant change of OI was observed only in the orbits with score 2 (OI: 12.9 +/- 1.3 vs. 8.3 +/- 0.5, P < 0.01) but not in those with score 0 or 1 (OI: 11.2 +/- 1.3 vs. 10.4 +/- 1.3). In particular, 6 weeks after corticosteroid treatment, the patients with orbital score 2 at the scintigraphy had a significant improvement of soft tissue changes, proptosis, lagophthalmos, extraocular muscle movements impairment, and diplopia, whereas patients with score 0 or 1 had only a significant improvement of the soft tissue inflammation. In conclusion, the current preliminary data suggested that [111In-DTPA-D-Phe1]-octreotide scintigraphy is able to predict the clinical response to corticosteroid treatment in patients with Graves' ophthalmopathy, and may be considered an useful approach to select the patients for the proper treatment.

Warthin tumor of the lacrimal gland.

PURPOSE: To describe a case of Warthin tumor involving the lacrimal gland. METHODS: Case report. The patient underwent a lateral orbitotomy to remove a nodular lesion involving the lacrimal gland. The specimen was submitted for histopathologic examination. RESULTS: The lesion was characterized by epithelial columnar cells arranged in solid nests or lining cystic spaces containing an exudative fluid and by pronounced lymphoid infiltrate with focal follicular formation. CONCLUSIONS: To our knowledge, this is the first case of Warthin tumor involving the lacrimal gland. Management requires complete excision of the lesion.

Fine needle aspiration (FNA) biopsy of orbital masses: a critical review of 51 cases.

FNA biopsy of 51 orbital masses is critically reviewed. Aspiration was performed with a 23 G needle inserted by an ophthalmologist; the smears were prepared by a cytologist. Forty-two cases (83%) were correctly diagnosed as benign or malignant either with (68%) or without (15%) correct specification of the histology. There were two false-negative and seven inadequate cases. Immunocytochemical stains were performed in five cases using the following antibodies: L26 (Pan B), UCHL1 (Pan T), kappa and lambda immunoglobulin light chains (three cases) in order to distinguish inflammatory pseudotumours from low-grade non-Hodgkin's lymphomas. In two cases we used CAM 5.2 (a monoclonal cytokeratin cocktail) and vimentin to ascertain the epithelial origin of two metastatic tumours. In five other cases cytospins were not adequately cellular for immunocytochemistry. Insufficient material and one false-negative sample were obtained from very fibrotic lesions or from posteriorly located lesions. The results are discussed and compared with other series reported in the literature. Orbital FNA biopsy may be considered a useful tool in the diagnostic approach to orbital masses in which the relatively high number of inadequate aspirations is offset by a low cost-benefit ratio.

Primary Ewing's sarcoma of the maxilla, a rare and curable localization: report of two new cases, successfully treated by radiotherapy and systemic chemotherapy.

Primary maxillary localization of Ewing's sarcoma is unusual. Involvement of facial bones is characterized by clinical and radiological features distinct from those commonly observed in other sites. Because of the above peculiarities a delay in diagnosis and thus in starting treatment is very probable in such cases. We report here two new cases of Ewing's sarcoma localized to facial bones, successfully treated by local high dosage radiotherapy and systemic chemotherapy. Our experience suggests that, especially for particular sites not suitable to radical surgery, radiation therapy can represent an effective tool to achieve local control of the tumor.

Granulocytic sarcoma in nonleukemic children: report of two new cases successfully treated by local radiation therapy and systemic chemotherapy.

Granulocytic sarcoma (GS) is a rare tumor composed of immature myeloid cells. Exceedingly rare in childhood, it has more commonly been described in association with acute myeloid leukemia. Occasional nonleukemic patients generally go on to develop overt leukemia in a mean period of 10.5 months from diagnosis of GS. We report here two new cases of GS diagnosed in nonleukemic children. They were successfully treated with local radiation therapy and conventional systemic chemotherapy. The need to suspect more often this all too frequently misdiagnosed disease is emphasized. The role of optimally delivered radiation therapy in achieving and maintaining local control of the tumor is discussed.

Dermoid cysts: 16-year survey.

A total of 145 patients with orbital dermoid cysts examined at the Orbital Clinic, Institute of Ophthalmology, School of Medicine, University of Naples "Federico II" over a period of 16 years were reviewed. The orbital cysts were classified as exophytic and endophytic, according to their site of attachment in relation to the orbital rims. This classification can explain the different natural history of these lesions. The exophytic cysts growing externally are discovered in childhood, whereas the endophytic ones are discovered later in life when they produce bone damage, with or without invasion of the adjacent structures.

[Outcome of drug-induced pregnancies]. / Esiti di gravidanze farmacologicamente indotte.

The authors analysed 153 pregnancies achieved after different drug treatment to induce ovulation. The outcome of single and multiple pregnancies, the fetal malformation and male/female ratio were considered. The results obtained show that induction of ovulation seem to raise the risk of miscarriage when compared with outcome of spontaneous pregnancies; the malformation risk is not considerable.