Original Investigation
Potential Correlation Between Menopausal Status and the Clinical Course of Orbital Cavernous Hemangiomas Anupam Jayaram, M.D.*, Gary S. Lissner, M.D.*, Liza M. Cohen, B.A.*, and Achilles G. Karagianis, D.O.† *Department of Ophthalmology and †Department of Radiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, U.S.A.
avernous hemangiomas are the most common benign lesion of the orbit in adults and are often found incidentally on imaging and often present asymptomatically.1–3 They most commonly affect middle-aged women, typically presenting around the age of 40.3 Their clinical course can range from remaining stable upon long-term follow up to enlarging and causing progressive optic nerve compression and thus visual field
defects.1,3,4 A study by Orcutt et al.4 followed 11 asymptomatic patients with intraconal orbital cavernous hemangiomas with both CT and MRI. All cavernous hemangiomas in their study were found incidentally, and none of the lesions enlarged during a follow up of 8 months to 10 years. By contrast, Harris and Jakobiec2 presented 66 cases of orbital cavernous hemangiomas that were surgically removed, of which almost all patients had presenting symptoms. Thus, overall, the behavior of this tumor can exhibit great variability and warrants further examination. It is well described in the literature that cavernous hemangiomas of the liver, uterus, and breast may increase in size and cause pain during pregnancy or with hormone replacement therapy/oral contraceptive use.5–9 Furthermore, immunohistochemical analyses have shown that estrogen receptors are present within the endothelial cells of cavernous hemangiomas of the uterus.10 It can therefore be hypothesized that levels of estrogen and progesterone may promote the growth of these lesions in the orbit and that postmenopausally, when these hormone levels are decreasing, the lesions may cease growing or possibly even regress in volume. This theory has been investigated on a histochemical level. Di Tommaso et al.11 evaluated 12 orbital cavernous hemangioma specimens and found that all lesions stained positive immunohistochemically for progesterone receptor antibody in smooth muscle and endothelial cells. Eight of these lesions had intense and diffuse positivity, while 4 displayed focal positivity. Also of note, none of the 12 specimens stained positive for estrogen receptor antibody, although this study noted that the estrogen staining may have had inadequate sensitivity. Similarly, in a study by Gupta et al.,12 3 of 11 orbital cavernous hemangiomas studied showed positivity for progesterone receptors localized around endothelium. These data suggest that orbital cavernous hemangiomas may have the potential to grow in response to the presence of progesterone or estrogen. The purpose of this study was to investigate the likelihood of stabilization or regression of orbital cavernous hemangiomas in postmenopausal women. This will allow clinicians to more appropriately counsel this patient population on the natural history of this lesion and lend support for observation over surgical resection in the asymptomatic postmenopausal patient.
Accepted for publication May 18, 2014. Presented, in part, at the Association for Research in Vision and Ophthalmology Annual Meeting, May 2013, Seattle, WA. Supported, in part, by an unrestricted educational grant from Research to Prevent Blindness Inc., New York, NY. The authors have no conflicts of interest to disclose. Address correspondence and reprint requests to Anupam Jayaram, M.D., Department of Ophthalmology, Northwestern University Feinberg School of Medicine, 645 N. Michigan Ave., Suite 440, Chicago, IL 60611. E-mail: [email protected] DOI: 10.1097/IOP.0000000000000240
The study was approved by the Northwestern University Institutional Review Board as a retrospective chart review. Clinical data were collected from Northwestern Medical Faculty Foundation outpatient ophthalmology charts that contained the diagnosis of orbital cavernous hemangioma and from the Northwestern Memorial Hospital radiologic database that contained reports deemed “consistent with cavernous hemangioma of the orbit” between January 1, 1983, and January 1, 2013. Through this search, a total of 57 cases were identified, and of
Purpose: To evaluate the clinical course of radiologically diagnosed orbital cavernous hemangiomas in the setting of presumed changes in estrogen/progesterone levels. Methods: An institutional review board–approved retrospective cohort chart review of patients from January 1, 1983, to January 1, 2013, was undertaken searching both outpatient ophthalmology diagnoses and radiologic diagnoses, identifying 32 orbital cavernous hemangiomas, which were subsequently divided into group 1, presumed to have stable levels of estrogen/progesterone, and group 2, presumed to have decreasing levels of estrogen/progesterone. Patients were then categorized as having short-term, mid-range, or long-term follow up. Serial imaging studies were evaluated and graded as having increased, decreased, or remained stable in size. Results: In group 1, no lesions decreased in size, 69% remained stable, and 31% increased in size. In group 2, no lesions increased in size, 45% remained stable, and 55% decreased in size. When evaluating only those patients with long-term follow up, many masses in group 1 increased in size, while the majority in group 2 decreased in size. Conclusions: In this study evaluating orbital cavernous hemangiomas over a span of 30 years, the authors found that in postmenopausal women with assumed decreasing levels of circulating estrogen/progesterone, the vast majority of lesions either remained stable or decreased in size, suggesting the effect of hormone levels on such vascular lesions and supporting the role for observation in asymptomatic individuals in this patient population. (Ophthal Plast Reconstr Surg 2015;31:187–190)
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these, 32 patients met the data criteria for being included in this study— specifically those having at least 2 CT or MRI scans performed at least 2 months apart. The other 25 patients, who either had only one radiologic study or who went on to have surgery with a pathologic diagnosis of something other than cavernous hemangioma, were eliminated from this study. Of the 32 cases that satisfied the eligibility requirements set forth, 31 were then divided into 3 groups. The first group (group 1) was composed of those with presumed stable levels of estrogen and progesterone—namely men of all ages and women who presented and were followed prior to the age of 51. The second group (group 2) was composed of women initially presenting at or after the age of 51, and these women were presumed to have decreasing levels of estrogen/progesterone. The age of 51 was chosen because this age has been cited as the worldwide average age of menopausal onset in large-scale epidemiologic studies.13 A third group (group 3) was composed of women presenting after age 51 but who were on hormone replacement therapy at the time of presentation, making their exact hormonal status ambiguous. One of the 32 cases was a woman who presented at age 45 and was followed until age 56; she was excluded from analysis as she crossed the parameters of both group 1 and group 2. Of note, no women in this study had hormone-altering conditions such as hormone-secreting tumors or paraneoplastic syndromes, became pregnant while being followed, or underwent oophorectomy or any type of hormone-altering surgery during the period of time being followed. No women took oral contraceptive pills or chemotherapeutic medications during the evaluation period. The 3 groups were then further categorized based on duration of follow up in the following groups: short-term follow up with serial imaging over a period of less than 1 year, moderate follow up with serial imaging over a period of between 1 and 2 years, and long-term follow up with serial imaging over a period of 2 years or greater. MRI and CT examinations of the brain/orbits of these patients were re-analyzed for this study under the guidance of a single neuroradiologist, who was blinded to the grouping. First, the lesions were confirmed on imaging to be consistent with orbital cavernous
hemangiomas. Then, measurements were obtained in 3 dimensions, 1 anterior-posterior, 1 transverse, and 1 cephalad to caudad, and the dimensions were multiplied to obtain the cubic volume of the lesion. The lesions were then categorized as having enlarged, regressed, or remained stable over short-term, mid-range, or long-term follow up. Dimensional variations in volume equal to or exceeding 500 cubic mm qualified as a change in size, as determined by the distribution of sizes in the sample.
RESULTS Of the 31 radiologically identified cavernous hemangiomas that fell into 1 of the 3 described groups (Table 1), 12 of them (38%) presented with symptoms while 20 of them (62%) were asymptomatic. Five of those 12 (42%) that were symptomatic at presentation ultimately required surgery, and surgical pathology was consistent with cavernous hemangioma. The remainder were managed with observation and underwent subsequent scans that continued to be consistent with cavernous hemangioma. In group 1, consisting of all men and those women who presented under the age of 51, there were a total of 16 cases, and notably none of these lesions decreased in size on follow up (Table 2). In total, 5 (31%) of these lesions increased in size, as exemplified by one subject’s CT examinations (Fig. 1), while 11 (69%) remained stable; however, this factor was strongly dependent on length of follow up. Of the 6 cases that had only short-term follow up defined as less than 1 year, 1 lesion (17%) increased in size and 5 (83%) remained stable. Of the 4 cases that had mid-range follow up defined as between 1 and 2 years, all 4 (100%) remained stable. Of the 6 cases that had long-term follow up defined as greater than 2 years, 4 (67%) increased in size while 2 (33%) remained stable. In group 2, consisting of women who initially presented over the age of 51, there were a total of 11 cases, none of which increased in size (Table 2). Six (55%) of these lesions regressed, as exemplified by one subject’s MRI examinations (Fig. 2), and 5 (45%) remained stable, although this was also dependent on length of follow up. Two cases had
TABLE 1. Demographic data table depicting age distribution for all subjects in study Number of subjects
Average age
Standard deviation
Median age
Mode
Range
13 3 11 4 31
52.2 39.3 62.6 59 55.6
16.3 7.4 7.9 9.3 13.8
50 42 63 59 59.5
67 — 63 — 67
30–91 41–47 52–78 51–68 30–91
Men Women 51 years old Women on HRT Total HRT, hormone replacement therapy.
TABLE 2. Data table depicting duration of follow up and number of subjects in each group whose lesion decreased in size, remained stable, or increased in size over the course of follow up Number of subjects (%) Duration of follow up Group 1 2 years Group 2 2 years Group 3 2 years
188
Sample size
Decreased
Stable
Increased
16 (52) 6 (38) 4 (25) 6 (38) 11 (35) 2 (18) 3 (27) 6 (55) 4 (13) 1 (25) 0 3 (75)
0 0 0 0 6 (55) 0 1 (33) 5 (83) 3 (75) 0 0 3 (100)
11 (69) 5 (83) 4 (100) 2 (33) 5 (45) 2 (100) 2 (67) 1 (17) 1 (25) 1 (100) 0 0
5 (31) 1 (17) 0 4 (67) 0 0 0 0 0 0 0 0
© 2015 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.
Copyright © 2014 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc. Unauthorized reproduction of this article is prohibited.
Ophthal Plast Reconstr Surg, Vol. 31, No. 3, 2015
Menopausal Status on Course of Orbital Cavernous Hemangiomas
FIG. 1. Contrast-enhanced axial CT image through the orbits performed in (A) December 2003 demonstrates a large right retrobulbar mass that partially enhances and results in right globe proptosis. The CT imaging characteristics are most compatible with an orbital cavernous hemangioma. A follow-up contrast-enhanced axial CT image through the orbits performed in (B) October 2006 demonstrates a significant increase in size of the previously present orbital cavernous hemangioma. There is also a greater amount of right globe proptosis on (B).
FIG. 2. A, Contrast-enhanced axial T1 with fat suppression MR image through the orbits performed in May 2001 demonstrates a homogeneously enhancing left retrobulbar mass. The MR findings are most consistent with an orbital cavernous hemangioma. B, Contrast-enhanced axial T1 with fat suppression MR image through the orbits performed in August 2008 demonstrates a significant reduction in size of the previously present left orbital cavernous hemangioma. short-term follow up of less than 1 year, and both of them (100%) remained stable. Three cases had mid-range follow up of between 1 and 2 years, and one of these (33%) decreased in size while 2 (67%) remained stable. Six cases had long-term follow up of greater than 2 years, and 5 (83%) of these decreased in size while 1 (17%) remained stable. Group 3, a subset of 4 women initially presenting over the age of 51, was followed while on hormone replacement therapy (Table 2). The most common hormone replacement agent used in this group was Premarin (Pfizer, Inc, New York, NY, U.S.A.) a conjugated estrogen compound. These women were analyzed separately, as it was unclear whether they truly exhibited declining circulating levels of estrogen and progesterone. Of these 4 women, 1 had short-term follow up and exhibited a stable sized lesion. Three had long-term follow up and, despite hormone replacement therapy, had lesions that decreased in size.
DISCUSSION In this study, a clear pattern was noted in group 1 (men and presumed premenopausal women), in that none of these lesions decreased in size (Table 2). The women in this group ranged from 41 to 47 years of age, and it must be noted as a limitation of the study that there was no way to unequivocally determine the menopausal status of each patient, as we did not
measure sequential hormone levels. However, it has been shown that 51 is the average age of menopause onset13; therefore, using this age cutoff is a reasonable method to differentiate pre- and postmenopausal women. Overall, the trend demonstrated that while the majority (69%) of the lesions in this group remained stable, the majority (67%) of those followed in the long-term actually showed an overall increase in size. Interestingly, when the men were analyzed separately, all but one remained stable, further suggesting that a lack of hormonal fluctuations may result in lesion stability. Of those in group 2 (presumed postmenopausal women), none of the tumors increased in size (Table 2). The majority of these lesions, 55% overall and 83% of those followed over the long-term, actually decreased in size. This suggests that decreasing hormone levels may result in a decrease in cavernous hemangioma tumor volume. When evaluating the subjects in group 3 (postmenopausal women on hormone replacement therapy), 3 of 4 of these women had lesions that decreased in size despite the therapy, and the one lesion that remained stable was only observed over the short-term and could have potentially decreased in volume if followed for a longer period. These data imply that hormone replacement therapy may not influence the size or behavior of orbital cavernous
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hemangiomas in postmenopausal women. It should also be noted that 2 of these women were on Premarin, which may support the hypothesis that progesterone is the primary promoter of growth in orbital cavernous hemangiomas, and supplemental estrogen does not play a role. Attempting to make retrospective correlations between the variables of menopausal status and cavernous hemangioma size is difficult, and the most obvious concern is the uncertainty of actual estrogen and progesterone levels. However, it should be noted that even a prospective study with direct questioning of menopause status would leave some ambiguity, as the time frame in question is a window rather than an exact date. Thus, short of a prospective study in which hormone levels are actually drawn, inferring menopausal status based on an established published age is likely the best indicator of such information. Of note, no standard deviation of age was cited in the study determining the mean age of menopausal onset, but an age range of onset is delineated as 35 to 59.13 Finally, it is also reasonable to infer from published evidence-based data that levels of estrogen and progesterone in males do not significantly fluctuate over time.14,15 Thus, the groups were divided based on stability of hormone levels over time rather than similarity of hormone levels. Another limitation of this study is the limit of volumetric analysis on lesions that are not perfectly spherical or cuboidal. While it may be true that the actual volume of the lesion for a given scan may not be exactly accurate, the purpose of multiplying 3 standard dimensions was to track the trend of the size of the lesion rather than obtaining an exact volume. In trending lesions in this manner, as long as the 3 dimensions of measurement remain standard across scans as verified by a neuroradiologist, an accurate assessment of trend can be obtained. This study assumes that hormone levels correlate with age, which could possibly introduce the theory that lesion growth is actually inversely proportional to age and not hormonal status. To address this issue, we examined the male patients in this study, ranging in age from 30 to 91, who were assumed to have stable levels of estrogen and progesterone. It was found that over time, 11 of 13 males had lesions that remained stable, and 2 of 13 had lesions that increased in size. This clarifies that aging alone is not correlated with reduction in size of orbital cavernous hemangiomas. While the exact mechanism by which these lesions enlarge is unclear, it has been postulated that enlargement may be secondary to local hemodynamic shifts2; however, the role that hormonal levels may have on such hemodynamics or on endothelial behavior within these masses has not been fully elucidated. It has also recently been argued that on immunohistochemical investigations, these lesions are closer to venous malformations than benign neoplasms, and the term “encapsulated cavernous venous lesion” has been proposed.16 This study suggests that the presence of hormones may play a role in the growth orbital cavernous hemangiomas, while decreasing hormone levels may result in a decrease in tumor volume, which is in accordance with their tendency to possess progesterone receptors.11,12
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This study provides evidence-based data that allow for a more meaningful prognostic discussion with the pre- and postmenopausal patient regarding the natural history of their orbital cavernous hemangioma. Of course, there is still a strong need for close follow up in these patients and periodic imaging will likely be necessary; however, observation over surgical management in the patient without clear symptoms of vision changes, proptosis, field defects, diplopia, or pain may be more appealing given the data put forth by this study. In addition, it can offer some reassurance to the postmenopausal patient with anxiety regarding growth of this entity.
REFERENCES 1. Garrity JA, Henderson JW, Cameron JD. Henderson’s Orbital Tumors. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2007:192. 2. Harris GJ, Jakobiec FA. Cavernous hemangioma of the orbit: a clinicopathologic analysis of sixty-six cases. In: Jakobiec FA, ed. Ocular and Adnexal Tumors. Birmingham, AL: Aesculapius, 1978:741–81. 3. Harris GJ, Jakobiec FA. Cavernous hemangioma of the orbit. J Neurosurg 1979;51:219–28. 4. Orcutt JC, Wulc AE, Mills RP, et al. Asymptomatic orbital cavernous hemangiomas. Ophthalmology 1991;98:1257–60. 5. Saegusa T, Ito K, Oba N, et al. Enlargement of multiple cavernous hemangioma of the liver in association with pregnancy. Intern Med 1995;34:207–11. 6. Glinkova V, Shevah O, Boaz M, et al. Hepatic haemangiomas: possible association with female sex hormones. Gut 2004;53:1352–5. 7. Conter RL, Longmire WP Jr. Recurrent hepatic hemangiomas. Possible association with estrogen therapy. Ann Surg 1988;207:115–9. 8. Mesurolle B, Wexler M, Halwani F, et al. Cavernous hemangioma of the breast: mammographic and sonographic findings and followup in a patient receiving hormone-replacement therapy. J Clin Ultrasound 2003;31:430–6. 9. Chatzoulis G, Kaltsas A, Daliakopoulos S, et al. Co-existence of a giant splenic hemangioma and multiple hepatic hemangiomas and the potential association with the use of oral contraceptives: a case report. J Med Case Rep 2008;2:147. 10. Reggiani Bonetti L, Boselli F, Lupi M, et al. Expression of estrogen receptor in hemangioma of the uterine cervix: reports of three cases and review of the literature. Arch Gynecol Obstet 2009;280:469–72. 11. Di Tommaso L, Scarpellini F, Salvi F, et al. Progesterone receptor expression in orbital cavernous hemangiomas. Virchows Arch 2000;436:284–8. 12. Gupta A, Prabhakaran VC, Dodd T, et al. Orbital cavernous haemangiomas: immunohistochemical study of proliferative capacity, vascular differentiation and hormonal receptor status. Orbit 2012;31:386–9. 13. Kato I, Toniolo P, Akhmedkhanov A, et al. Prospective study of factors influencing the onset of natural menopause. J Clin Epidemiol 1998;51:1271–6. 14. Maggio M, Lauretani F, Ceda GP, et al. Estradiol and metabolic syndrome in older Italian men: the InCHIANTI study. J Androl 2010;31:155–62. 15. Oettel M, Mukhopadhyay AK. Progesterone: the forgotten hormone in men? Aging Male 2004;7:236–57. 16. Osaki TH, Jakobiec FA, Mendoza PR, et al. Immunohistochemical investigations of orbital infantile hemangiomas and adult encapsulated cavernous venous lesions (malformation versus hemangioma). Ophthal Plast Reconstr Surg 2013;29:183–95.
© 2015 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.
Copyright © 2014 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc. Unauthorized reproduction of this article is prohibited.
Potential Correlation Between Menopausal Status and the Clinical Course of Orbital Cavernous Hemangiomas Anupam Jayaram, M.D.*, Gary S. Lissner, M.D.*, Liza M. Cohen, B.A.*, and Achilles G. Karagianis, D.O.† *Department of Ophthalmology and †Department of Radiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, U.S.A.
avernous hemangiomas are the most common benign lesion of the orbit in adults and are often found incidentally on imaging and often present asymptomatically.1–3 They most commonly affect middle-aged women, typically presenting around the age of 40.3 Their clinical course can range from remaining stable upon long-term follow up to enlarging and causing progressive optic nerve compression and thus visual field
defects.1,3,4 A study by Orcutt et al.4 followed 11 asymptomatic patients with intraconal orbital cavernous hemangiomas with both CT and MRI. All cavernous hemangiomas in their study were found incidentally, and none of the lesions enlarged during a follow up of 8 months to 10 years. By contrast, Harris and Jakobiec2 presented 66 cases of orbital cavernous hemangiomas that were surgically removed, of which almost all patients had presenting symptoms. Thus, overall, the behavior of this tumor can exhibit great variability and warrants further examination. It is well described in the literature that cavernous hemangiomas of the liver, uterus, and breast may increase in size and cause pain during pregnancy or with hormone replacement therapy/oral contraceptive use.5–9 Furthermore, immunohistochemical analyses have shown that estrogen receptors are present within the endothelial cells of cavernous hemangiomas of the uterus.10 It can therefore be hypothesized that levels of estrogen and progesterone may promote the growth of these lesions in the orbit and that postmenopausally, when these hormone levels are decreasing, the lesions may cease growing or possibly even regress in volume. This theory has been investigated on a histochemical level. Di Tommaso et al.11 evaluated 12 orbital cavernous hemangioma specimens and found that all lesions stained positive immunohistochemically for progesterone receptor antibody in smooth muscle and endothelial cells. Eight of these lesions had intense and diffuse positivity, while 4 displayed focal positivity. Also of note, none of the 12 specimens stained positive for estrogen receptor antibody, although this study noted that the estrogen staining may have had inadequate sensitivity. Similarly, in a study by Gupta et al.,12 3 of 11 orbital cavernous hemangiomas studied showed positivity for progesterone receptors localized around endothelium. These data suggest that orbital cavernous hemangiomas may have the potential to grow in response to the presence of progesterone or estrogen. The purpose of this study was to investigate the likelihood of stabilization or regression of orbital cavernous hemangiomas in postmenopausal women. This will allow clinicians to more appropriately counsel this patient population on the natural history of this lesion and lend support for observation over surgical resection in the asymptomatic postmenopausal patient.
Accepted for publication May 18, 2014. Presented, in part, at the Association for Research in Vision and Ophthalmology Annual Meeting, May 2013, Seattle, WA. Supported, in part, by an unrestricted educational grant from Research to Prevent Blindness Inc., New York, NY. The authors have no conflicts of interest to disclose. Address correspondence and reprint requests to Anupam Jayaram, M.D., Department of Ophthalmology, Northwestern University Feinberg School of Medicine, 645 N. Michigan Ave., Suite 440, Chicago, IL 60611. E-mail: [email protected] DOI: 10.1097/IOP.0000000000000240
The study was approved by the Northwestern University Institutional Review Board as a retrospective chart review. Clinical data were collected from Northwestern Medical Faculty Foundation outpatient ophthalmology charts that contained the diagnosis of orbital cavernous hemangioma and from the Northwestern Memorial Hospital radiologic database that contained reports deemed “consistent with cavernous hemangioma of the orbit” between January 1, 1983, and January 1, 2013. Through this search, a total of 57 cases were identified, and of
Purpose: To evaluate the clinical course of radiologically diagnosed orbital cavernous hemangiomas in the setting of presumed changes in estrogen/progesterone levels. Methods: An institutional review board–approved retrospective cohort chart review of patients from January 1, 1983, to January 1, 2013, was undertaken searching both outpatient ophthalmology diagnoses and radiologic diagnoses, identifying 32 orbital cavernous hemangiomas, which were subsequently divided into group 1, presumed to have stable levels of estrogen/progesterone, and group 2, presumed to have decreasing levels of estrogen/progesterone. Patients were then categorized as having short-term, mid-range, or long-term follow up. Serial imaging studies were evaluated and graded as having increased, decreased, or remained stable in size. Results: In group 1, no lesions decreased in size, 69% remained stable, and 31% increased in size. In group 2, no lesions increased in size, 45% remained stable, and 55% decreased in size. When evaluating only those patients with long-term follow up, many masses in group 1 increased in size, while the majority in group 2 decreased in size. Conclusions: In this study evaluating orbital cavernous hemangiomas over a span of 30 years, the authors found that in postmenopausal women with assumed decreasing levels of circulating estrogen/progesterone, the vast majority of lesions either remained stable or decreased in size, suggesting the effect of hormone levels on such vascular lesions and supporting the role for observation in asymptomatic individuals in this patient population. (Ophthal Plast Reconstr Surg 2015;31:187–190)
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Ophthal Plast Reconstr Surg, Vol. 31, No. 3, 2015
A. Jayaram et al.
these, 32 patients met the data criteria for being included in this study— specifically those having at least 2 CT or MRI scans performed at least 2 months apart. The other 25 patients, who either had only one radiologic study or who went on to have surgery with a pathologic diagnosis of something other than cavernous hemangioma, were eliminated from this study. Of the 32 cases that satisfied the eligibility requirements set forth, 31 were then divided into 3 groups. The first group (group 1) was composed of those with presumed stable levels of estrogen and progesterone—namely men of all ages and women who presented and were followed prior to the age of 51. The second group (group 2) was composed of women initially presenting at or after the age of 51, and these women were presumed to have decreasing levels of estrogen/progesterone. The age of 51 was chosen because this age has been cited as the worldwide average age of menopausal onset in large-scale epidemiologic studies.13 A third group (group 3) was composed of women presenting after age 51 but who were on hormone replacement therapy at the time of presentation, making their exact hormonal status ambiguous. One of the 32 cases was a woman who presented at age 45 and was followed until age 56; she was excluded from analysis as she crossed the parameters of both group 1 and group 2. Of note, no women in this study had hormone-altering conditions such as hormone-secreting tumors or paraneoplastic syndromes, became pregnant while being followed, or underwent oophorectomy or any type of hormone-altering surgery during the period of time being followed. No women took oral contraceptive pills or chemotherapeutic medications during the evaluation period. The 3 groups were then further categorized based on duration of follow up in the following groups: short-term follow up with serial imaging over a period of less than 1 year, moderate follow up with serial imaging over a period of between 1 and 2 years, and long-term follow up with serial imaging over a period of 2 years or greater. MRI and CT examinations of the brain/orbits of these patients were re-analyzed for this study under the guidance of a single neuroradiologist, who was blinded to the grouping. First, the lesions were confirmed on imaging to be consistent with orbital cavernous
hemangiomas. Then, measurements were obtained in 3 dimensions, 1 anterior-posterior, 1 transverse, and 1 cephalad to caudad, and the dimensions were multiplied to obtain the cubic volume of the lesion. The lesions were then categorized as having enlarged, regressed, or remained stable over short-term, mid-range, or long-term follow up. Dimensional variations in volume equal to or exceeding 500 cubic mm qualified as a change in size, as determined by the distribution of sizes in the sample.
RESULTS Of the 31 radiologically identified cavernous hemangiomas that fell into 1 of the 3 described groups (Table 1), 12 of them (38%) presented with symptoms while 20 of them (62%) were asymptomatic. Five of those 12 (42%) that were symptomatic at presentation ultimately required surgery, and surgical pathology was consistent with cavernous hemangioma. The remainder were managed with observation and underwent subsequent scans that continued to be consistent with cavernous hemangioma. In group 1, consisting of all men and those women who presented under the age of 51, there were a total of 16 cases, and notably none of these lesions decreased in size on follow up (Table 2). In total, 5 (31%) of these lesions increased in size, as exemplified by one subject’s CT examinations (Fig. 1), while 11 (69%) remained stable; however, this factor was strongly dependent on length of follow up. Of the 6 cases that had only short-term follow up defined as less than 1 year, 1 lesion (17%) increased in size and 5 (83%) remained stable. Of the 4 cases that had mid-range follow up defined as between 1 and 2 years, all 4 (100%) remained stable. Of the 6 cases that had long-term follow up defined as greater than 2 years, 4 (67%) increased in size while 2 (33%) remained stable. In group 2, consisting of women who initially presented over the age of 51, there were a total of 11 cases, none of which increased in size (Table 2). Six (55%) of these lesions regressed, as exemplified by one subject’s MRI examinations (Fig. 2), and 5 (45%) remained stable, although this was also dependent on length of follow up. Two cases had
TABLE 1. Demographic data table depicting age distribution for all subjects in study Number of subjects
Average age
Standard deviation
Median age
Mode
Range
13 3 11 4 31
52.2 39.3 62.6 59 55.6
16.3 7.4 7.9 9.3 13.8
50 42 63 59 59.5
67 — 63 — 67
30–91 41–47 52–78 51–68 30–91
Men Women 51 years old Women on HRT Total HRT, hormone replacement therapy.
TABLE 2. Data table depicting duration of follow up and number of subjects in each group whose lesion decreased in size, remained stable, or increased in size over the course of follow up Number of subjects (%) Duration of follow up Group 1 2 years Group 2 2 years Group 3 2 years
188
Sample size
Decreased
Stable
Increased
16 (52) 6 (38) 4 (25) 6 (38) 11 (35) 2 (18) 3 (27) 6 (55) 4 (13) 1 (25) 0 3 (75)
0 0 0 0 6 (55) 0 1 (33) 5 (83) 3 (75) 0 0 3 (100)
11 (69) 5 (83) 4 (100) 2 (33) 5 (45) 2 (100) 2 (67) 1 (17) 1 (25) 1 (100) 0 0
5 (31) 1 (17) 0 4 (67) 0 0 0 0 0 0 0 0
© 2015 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.
Copyright © 2014 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc. Unauthorized reproduction of this article is prohibited.
Ophthal Plast Reconstr Surg, Vol. 31, No. 3, 2015
Menopausal Status on Course of Orbital Cavernous Hemangiomas
FIG. 1. Contrast-enhanced axial CT image through the orbits performed in (A) December 2003 demonstrates a large right retrobulbar mass that partially enhances and results in right globe proptosis. The CT imaging characteristics are most compatible with an orbital cavernous hemangioma. A follow-up contrast-enhanced axial CT image through the orbits performed in (B) October 2006 demonstrates a significant increase in size of the previously present orbital cavernous hemangioma. There is also a greater amount of right globe proptosis on (B).
FIG. 2. A, Contrast-enhanced axial T1 with fat suppression MR image through the orbits performed in May 2001 demonstrates a homogeneously enhancing left retrobulbar mass. The MR findings are most consistent with an orbital cavernous hemangioma. B, Contrast-enhanced axial T1 with fat suppression MR image through the orbits performed in August 2008 demonstrates a significant reduction in size of the previously present left orbital cavernous hemangioma. short-term follow up of less than 1 year, and both of them (100%) remained stable. Three cases had mid-range follow up of between 1 and 2 years, and one of these (33%) decreased in size while 2 (67%) remained stable. Six cases had long-term follow up of greater than 2 years, and 5 (83%) of these decreased in size while 1 (17%) remained stable. Group 3, a subset of 4 women initially presenting over the age of 51, was followed while on hormone replacement therapy (Table 2). The most common hormone replacement agent used in this group was Premarin (Pfizer, Inc, New York, NY, U.S.A.) a conjugated estrogen compound. These women were analyzed separately, as it was unclear whether they truly exhibited declining circulating levels of estrogen and progesterone. Of these 4 women, 1 had short-term follow up and exhibited a stable sized lesion. Three had long-term follow up and, despite hormone replacement therapy, had lesions that decreased in size.
DISCUSSION In this study, a clear pattern was noted in group 1 (men and presumed premenopausal women), in that none of these lesions decreased in size (Table 2). The women in this group ranged from 41 to 47 years of age, and it must be noted as a limitation of the study that there was no way to unequivocally determine the menopausal status of each patient, as we did not
measure sequential hormone levels. However, it has been shown that 51 is the average age of menopause onset13; therefore, using this age cutoff is a reasonable method to differentiate pre- and postmenopausal women. Overall, the trend demonstrated that while the majority (69%) of the lesions in this group remained stable, the majority (67%) of those followed in the long-term actually showed an overall increase in size. Interestingly, when the men were analyzed separately, all but one remained stable, further suggesting that a lack of hormonal fluctuations may result in lesion stability. Of those in group 2 (presumed postmenopausal women), none of the tumors increased in size (Table 2). The majority of these lesions, 55% overall and 83% of those followed over the long-term, actually decreased in size. This suggests that decreasing hormone levels may result in a decrease in cavernous hemangioma tumor volume. When evaluating the subjects in group 3 (postmenopausal women on hormone replacement therapy), 3 of 4 of these women had lesions that decreased in size despite the therapy, and the one lesion that remained stable was only observed over the short-term and could have potentially decreased in volume if followed for a longer period. These data imply that hormone replacement therapy may not influence the size or behavior of orbital cavernous
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Ophthal Plast Reconstr Surg, Vol. 31, No. 3, 2015
A. Jayaram et al.
hemangiomas in postmenopausal women. It should also be noted that 2 of these women were on Premarin, which may support the hypothesis that progesterone is the primary promoter of growth in orbital cavernous hemangiomas, and supplemental estrogen does not play a role. Attempting to make retrospective correlations between the variables of menopausal status and cavernous hemangioma size is difficult, and the most obvious concern is the uncertainty of actual estrogen and progesterone levels. However, it should be noted that even a prospective study with direct questioning of menopause status would leave some ambiguity, as the time frame in question is a window rather than an exact date. Thus, short of a prospective study in which hormone levels are actually drawn, inferring menopausal status based on an established published age is likely the best indicator of such information. Of note, no standard deviation of age was cited in the study determining the mean age of menopausal onset, but an age range of onset is delineated as 35 to 59.13 Finally, it is also reasonable to infer from published evidence-based data that levels of estrogen and progesterone in males do not significantly fluctuate over time.14,15 Thus, the groups were divided based on stability of hormone levels over time rather than similarity of hormone levels. Another limitation of this study is the limit of volumetric analysis on lesions that are not perfectly spherical or cuboidal. While it may be true that the actual volume of the lesion for a given scan may not be exactly accurate, the purpose of multiplying 3 standard dimensions was to track the trend of the size of the lesion rather than obtaining an exact volume. In trending lesions in this manner, as long as the 3 dimensions of measurement remain standard across scans as verified by a neuroradiologist, an accurate assessment of trend can be obtained. This study assumes that hormone levels correlate with age, which could possibly introduce the theory that lesion growth is actually inversely proportional to age and not hormonal status. To address this issue, we examined the male patients in this study, ranging in age from 30 to 91, who were assumed to have stable levels of estrogen and progesterone. It was found that over time, 11 of 13 males had lesions that remained stable, and 2 of 13 had lesions that increased in size. This clarifies that aging alone is not correlated with reduction in size of orbital cavernous hemangiomas. While the exact mechanism by which these lesions enlarge is unclear, it has been postulated that enlargement may be secondary to local hemodynamic shifts2; however, the role that hormonal levels may have on such hemodynamics or on endothelial behavior within these masses has not been fully elucidated. It has also recently been argued that on immunohistochemical investigations, these lesions are closer to venous malformations than benign neoplasms, and the term “encapsulated cavernous venous lesion” has been proposed.16 This study suggests that the presence of hormones may play a role in the growth orbital cavernous hemangiomas, while decreasing hormone levels may result in a decrease in tumor volume, which is in accordance with their tendency to possess progesterone receptors.11,12
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This study provides evidence-based data that allow for a more meaningful prognostic discussion with the pre- and postmenopausal patient regarding the natural history of their orbital cavernous hemangioma. Of course, there is still a strong need for close follow up in these patients and periodic imaging will likely be necessary; however, observation over surgical management in the patient without clear symptoms of vision changes, proptosis, field defects, diplopia, or pain may be more appealing given the data put forth by this study. In addition, it can offer some reassurance to the postmenopausal patient with anxiety regarding growth of this entity.
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Copyright © 2014 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc. Unauthorized reproduction of this article is prohibited.
