Conjunctival Myxoma A Synopsis of a Rare Ocular Tumor Meng-Jun Xiong, MD; Daniel C. Dim, MD
Conjunctival myxoma is an exceptionally rare, slowgrowing, benign neoplasm of primitive mesenchyme origin. Forty-one cases of conjunctival myxoma from a literature review, including the authors’ case, are listed. The usual clinical history is a painless mass appearing during months to years. Grossly, the tumor is a wellcircumscribed, cystlike, gelatinous, yellow-to-pink, translucent-to-solid mass. Microscopically, the hypocellular tumor contains stellate- and spindle-shaped cells in a mucoid stroma with abundant hyaluronic acid mucopolysaccharides. Vimentin and a-smooth muscle actin highlight the spindle and stellate cells. S100 protein and desmin are negative for the tumor cells. Treatment is complete surgical excision, with no recurrence reported in the follow-up period. Notably, conjunctival myxoma may be associated with Carney complex, an autosomal-dominant disorder associated with skin pigmentation, endocrine abnormalities, and myxoma of the heart and eye. Physicians should appreciate this unique ocular tumor because of its potential association with Carney complex. (Arch Pathol Lab Med. 2015;139:693–697; doi: 10.5858/ arpa.2013-0532-RS)
C
onjunctival myxoma is a rare, benign tumor of mesenchymal origin. In 1913, Magalif1–3 presented the first case at the St Petersburg Ophthalmological Society, but it was uncertain whether her case was a pure or a mixed conjunctival myxoma tumor. The following year, Maucione4 described a conjunctival myxoma occurring in a 59-year-old man who had a 6-year history of painless growth located in the medial canthus of the eye near the limbus.1,2 Since 1913, there have been approximately 40 case reports of conjunctival myxoma described in the literature and PubMed (US National Library of Medicine, Bethesda, Maryland).1,2 Fortyone cases of conjunctival myxoma from the literature and the authors’ case are presented in the Table. The reported incidence of this tumor was estimated at 0.002% from a review of 2455 patients with conjunctival lesions by Accepted for publication April 22, 2014. Department of Pathology, University of Missouri, Kansas City, School of Medicine, Kansas City. The authors have no relevant financial interest in the products or companies described in this article. Reprints: Daniel C. Dim, MD, Department of Pathology, University of Missouri, Kansas City, School of Medicine, 2411 Holmes St, Kansas City, MO 64108 (e-mail: [email protected]). Arch Pathol Lab Med—Vol 139, May 2015
Grossniklaus et al5 and at less than 0.001% from a review of 1643 cases by Shields et al.6 Conjunctival myxoma can be appreciated as a distinct tumor entity, classically, with a paucicellular composition of spindle and stellate cells embedded in a fine reticular network, with a myxoid stroma and few vascular structures, few mast cells, and sparse lymphocytes or other inflammatory cells. These tumors often present as slow, painless growths and are diagnosed clinically as a ‘‘cyst.’’ However, the tumor presents a potentially challenging diagnosis for pathologists because of its rarity and its resemblance to other soft tissue tumors of the eye, such as spindle cell lipoma. Therefore, the authors hope to enlighten readers about some of the unique characteristics and distinguishing features of the conjunctival myxoma. HISTOGENESIS As a class, myxomas are derived from primitive mesenchyme and are said to resemble the umbilical cord core ‘‘Wharton jelly.’’7 Myxomas can occur as a primary tumor in a variety of tissues. They most commonly involve the atrial endocardium and jaw bones but can also arise in fascia, subcutaneous tissue, neurovascular sheaths, muscle, and the genitourinary tract. Myxomas of the upper respiratory tract, such as the nasal sinuses and pharynx, breast, and eyes (orbital, corneal, palpebral, or conjunctiva), are particularly rare.8,9 Conjunctival myxoma, specifically, develops in the substantia propria, and the tumors are covered by conjunctival epithelium.7,10 The tumor can occur as an isolated process, exhibiting local involvement without metastasis. However, conjunctival myxoma may be a presenting component of the Carney complex, an autosomal-dominant disease process characterized by myxomas, spotty skin pigmentation, and endocrine overactivity. Carney complex belongs to a spectrum of disease processes that includes McCuneAlbright syndrome, Mazabraud syndrome, and multiple endocrine neoplasias. The diagnosis of Carney complex requires 2 manifestations of the following: typical mucocutaneous pigmentation, cardiac myxoma, breast myxomatosis or adenoma, endocrine overactivity, testicular tumors, schwannoma, and pituitary adenoma. The diagnosis can also be established if patients demonstrate a single manifestation and has a ‘‘first hit’’ through either an affected first-degree relative or an inactivating PRKAR1A gene mutation.11 PRKAR1A is the regulatory subunit 1A of protein kinase A on 17q22–24.11,12 A Synopsis of a Rare Ocular Tumor—Xiong & Dim 693
Reported Cases of Conjunctival Myxoma Source, y
Age, y/Sex
Eye
Maucione,4 1914 Ffooks,2 1962
56/M 72/M
OD OD
Doughman and Wenk,24 1970 Stafford,1 1971 ´ Majewska-Cembrzynska and Majewski,27 1973 El-Rifai and Ghaly,25 1975 Strempel and von Domarus,22 1979 Patrinely and Green,9 1983
49/F
OD
54/F 76/F
OD OD
14/M
Mottow-Lippa et al,8 1983 Pe’er et al,10 1984 Pe’er and Hidayat,20 1986
Konari et al,13 1993 Horie et al,7 1995 Ramaesh et al,15 2001b Demirci et al,16 2006 Arya et al,17 2008 Kili¸c et al,18 2008 Chen et al,21 2008 Herwig et al,19 2010 Al-Ghadeer et al,23 2012 Herwig et al,14 2012
Chen et al,12 2012 Kini Rao and Nayal,26 2012 Current case
Location
Size, mm
Duration, mo
Recurrence (follow-up, mo)
Nasal limbus Superior limbus, near corneoscleral trephine site Temporal bulbar
83631 83434
72 6
None (?) ?
43333
12
None (9)
93635 12
108 12
None (64) None (24)
OD
Temporal limbus Nasal limbus, near previous cataract wound Temporal limbus
93432
48
None (12)
53/M 73/M 50/F 53/F 18/F 42/M 54/M
OS OS OD OS OS OD OS
Superior limbus Nasal bulbar Nasal bulbar Temporal bulbar Superotemporal limbus Temporal limbus Temporal limbus
43332 ? 93832 63535 83433 93434 16 3 11 3 10
48 6 24 12 15 36 288
None (9) ? None (84) None (48) None (6) None (6) ?
18/F 48/M 61/M 34/M 64/M 33/F 20/M 50/M 50/F 76/M 65/F 54/F 80/F 36/M 31/M
OD ? ? ? ? ? ? ? ? ? ? ? OS OD OS
Nasal bulbar Inferior fornix ? Temporal bulbar Temporal bulbar Bulbar Temporal limbus Nasal bulbar Intrapalpebral fissure Superior limbus Temporal bulbar Superior bulbar Nasal bulbar Nasal bulbar Nasal bulbar
4 ? ? 36 ? 8 6 24 12 ? ? 1 wk 60 ? 24
None (8) None (10) ? ? ? ? ? None (24) ? ? None (5) None (48) None (21) ? None (132)
64/F 45/F 11/M 54/M 36/F 45/F 41/M 47/M 53/M 45/F 47/F 33/M
OD OS OS OD OS OS OD OS OS ? OS OS
Superonasal bulbar Temporal limbus Temporal bulbar Temporal bulbar Temporal bulbar Temporal bulbar Temporal bulbar Superior limbus Temporal bulbar ? Temporal bulbar Nasal bulbar
10 3 4 3 4 10 7 3 5 3 4.5 11 3 7 ? 5 5 5 53433 ? 10 16 3 12 3 8 12 3 10 131 12 3 11 3 6, 5 3 5 3 2a 15 3 7 53434 937 83532 63632 20 3 1.8 43534 33131 33331 ? 93634 8.5 3 8.5
24 ? 12 24 48 36 48 ? 1 wk ? 36 12
? None (8) None (12) None (10) None (10) None (12) None (180) None (84)c None (60) ? None (1) ?
46/F
OD
Temporal
43333
8
None (?)d
Abbreviations: ?, unknown; OD, right eye; OS, left eye. a Basal part measured 12 3 11 3 6 mm, and apical part measured 5 3 5 3 2 mm. b Patient had abnormal thickening of the interatrial septum and a history of Zollinger-Ellison syndrome, so it is unclear whether this was an isolated case of conjunctival myxoma or associated with an underlying syndrome. c Patient had amniotic membrane graft reconstruction surgery 5 years after excision of conjunctival myxoma. d Number of months of follow-up not specified because the authors are still monitoring the case.
CLINICAL FEATURES Conjunctival myxoma is a very rare clinical entity. We identified 41 cases of conjunctival myxoma that appear to be pure cases without the syndrome association of Carney complex (see the Table). There is equal male to female distribution (M:F, 22:19), showing that the disease has no sex predilection. This neoplasm generally affects older adults and is very uncommon in younger populations. The mean age at presentation is 47.6 years, and the median age is 49 years, with an age range of 11 to 80 years. Conjunctival myxoma has no associated history of trauma or family 694 Arch Pathol Lab Med—Vol 139, May 2015
history. The ocular and physical examinations are generally unremarkable, except for minimal changes in ocular mobility and acuity. Patients gave very similar clinical histories, reporting a slow-growing, painless mass that had been present from 1 week in 2 exceptional cases13,14 to a range from 4 to 288 months. Conjunctival myxoma was located in the temporal region of the eye in 20 cases (49%) including the authors’ case, the nasal region in 11 cases (27%), and other locations (superior or unknown) in 10 cases (24%). In addition, 14 cases (34%) involved the right eye, 15 cases (37%) involved the left eye, and for 12 cases (29%) location was unknown.1,2,4,7–10,12–27 A Synopsis of a Rare Ocular Tumor—Xiong & Dim
GROSS PATHOLOGY The conjunctival myxoma tumors varied from 1 by 1 mm15 to the largest at 16 by 12 by 8 mm.13 During gross examination, the tumor is soft and smooth, semitranslucent to fully translucent, and white, pink, pale, or fleshy. Characteristically, it is a solid to cystlike, rubbery or gelatinous, semiencapsulated or unencapsulated mass. The myxomas have sharp, well-circumscribed borders (but were described as ‘‘diffuse’’ in 2 cases) and may be finely granular throughout the cut surface. Hemorrhage, calcification, and necrosis were typically absent.1,2,4,7–10,12–27 HISTOPATHOLOGY The tumor matrix is composed predominantly of hyaluronic acid with lesser amounts of chondroitin sulfates. The stroma can be described as a network of delicate reticulin fibers in a loose, wavy arrangement with few vascular structures or mature, dense collagen elements (Figure 1).7,9,16 Conjunctival myxomas are paucicellular tumors containing a few spindle and stellate cells (Figure 2) and rare macrophages, lymphocytes, or mast cells (Figure 3).16 Some cells are mildly pleomorphic, but mitoses are absent.7 The nuclear membrane is sometimes invaginated, so that it appears like intranuclear vacuoles. Nucleoli may be present at rates of 1 or 2 per nucleus.10,11 Ultrastructural examination reveals abundant, rough, endoplasmic reticulum and intracytoplasmic inclusions. The intracytoplasmic inclusions represent dilated cisternae of rough endoplasmic reticulum, which are theorized to have the secretory function of producing the mucoid stroma.9,10,17
Figure 1. Mucoid stroma with sparse capillaries, predominantly stellate, and spindle cells (hematoxylin-eosin, original magnification 3 100). Figure 2. Tumor showing stellate cells and spindle cells (hematoxylineosin, original magnification 3 400). Figure 3. Tumor showing mast cell (hematoxylin-eosin, original magnification 3 400).
Arch Pathol Lab Med—Vol 139, May 2015
HISTOCHEMICAL AND IMMUNOHISTOCHEMICAL STUDY The conjunctiva myxoma cells stain positive for Alcian blue (Figure 4) with dissolution of the color after treatment with hyaluronidase, revealing cells that contain abundant hyaluronic acid mucopolysaccharides.7,11,16 The cells also stain positively with mucicarmine and colloidal iron. Periodic acid–Schiff stain is negative, demonstrating an absence of significant carbohydrate components, such as glycogen, glycoproteins, or proteoglycans.2,7 Oil red O stain for lipocytes and Bodian stain for neural material are negative.10,11 Immunostaining of conjunctival myxoma cells show extensive reactivity with vimentin (Figure 5) and focal staining for a-smooth muscle actin.7,9,17 Several authors18,19 have presented a few cases that stained negative for smooth muscle actin. In 2012, Herwig et al14 described a variant of conjunctival myxoma that stained positive for CD34. S100 protein, desmin, myoglobin, lysozyme, a1-antitrypsin, a1antichymotrypsin, cytokeratin, epithelial membrane antigen, Ulex europaeus agglutinin 1, and factor VIII–related antigen are typically negative.7,9,10,13,15,20 Herwig et al19 found little proliferative activity because less than 5% of the tumor cells in their 2 conjunctiva myxoma cases stained positively with the nuclear anti-Ki67. DIFFERENTIAL DIAGNOSIS Conjunctival myxoma can resemble other mixed or pure myxoma tumors, such as amelanotic naevus, amelanotic melanoma, dermal nerve sheath myxoma, myxoid neurofibroma, lymphangioma, lymphoma, reactive lymphoid hyperplasia, dermoid, myxoid liposarcoma, spindle cell lipoma, A Synopsis of a Rare Ocular Tumor—Xiong & Dim 695
containing plasma cells, endothelial cells, and lymphoblast cells. Dermoids often contain additional tissue elements, such as sebaceous and sweat glands or hair. Liposarcomas and spindle cell lipomas contain vacuolated lipoblasts and lipocytes, respectively. They may have signet-ring cells, are positive for oil red O stain, and often appear more cellular and vascular.11 Rhabdomyosarcoma usually affects children and adolescents and the tumors contain characteristic, small, round cells with mitotic activity or have ‘‘strap’’ rhabdomyoblasts that stain positive for myosin.9,11 Myxoid malignant fibrous histiocytoma can stain positive for Alcian blue, like conjunctival myxomas, but it can be distinguished by its prominent vascular structures and abundant pleomorphic nuclei.16 Nodular fasciitis tumors grow quickly and contain numerous fibroblasts with active mitosis, cleftlike spaces, and histologically varied patterns.9 PROGNOSIS AND TREATMENT Conjunctival myxoma is removed by complete surgical excision. No tumor recurrence has been reported in patients during the follow-up periods, ranging from 5 to 180 months.1,2,4,7–10,12–27 However, given the significant morbidity and mortality of myxoma associated with Carney complex and other syndromes, the presence of conjunctival myxoma, particularly in a younger patient, should prompt a systematic evaluation. The most lethal component of the Carney complex is the development of heart myxoma and emboli from them.11 The use of echocardiography to rule out cardiac pathology has been suggested.19,23 If patients present with more concerning symptoms, such as mucocutaneous skin pigmentation and positive family history, additional tests in the diagnostic workup may include thyroid-stimulating hormone, adrenocorticotropic hormone, and growth hormone levels and, possibly, PRKAR1A gene analysis.16 Figure 4. The tumor hyaluronic acid mucopolysaccharides matrix stained blue (Alcian blue, original magnification 3 400). Figure 5. The stellate and spindle cells are strongly positive for vimentin (original magnification 3 400).
botryoid-type rhabdomyosarcoma, myxoid fibrous histiocytoma, and nodular fasciitis.7 However, conjunctival myxomas can be distinguished from other soft tissue tumors by subtle clues, such as the absence of significant cellularity, mitotic figures, or pleomorphic nuclei and by additional clues, such as the absence of prominent vascular structures, pigmentation, or dense collagen fibers. Specific features of the tumor variants described below can help distinguish conjunctival myxoma from other similar ocular pathologies. Conjunctival myxoma differs from amelanotic nevus or melanoma by the absence of pigmentation or vascular structures and the absence of nests of cells characteristic of melanoma.16 Nerve sheath myxomas and myxoid neurofibroma contain dense, wavy collagen structures; prominent, spindly nuclei; and occasional lymphocytes. The tumors are Bodian-positive on staining and can be associated with systemic neurofibromatosis. Lymphangiomas typically occur in younger individuals and are vascular, boggy tumors with hemorrhagic and inflammatory components.7,11 Lymphomas and reactive lymphoid hyperplasia tumors contain significant lymphocyte populations. Lymphomas have a monocellular arrangement of lymphocytes. Reactive lymphoid hyperplasia are arranged in follicular aggregates 696 Arch Pathol Lab Med—Vol 139, May 2015
References 1. Stafford WR. Conjunctival myxoma. Arch Ophthalmol. 1971;85(4):443– 445. 2. Ffooks OO. Myxoma of the conjunctiva. Brit. J. Ophthalmol. 1962;46(6): 374–377. 3. Magalif NI. Klin Monbl Augenheilkd. 1913;51:844. 4. Maucione L. Rare subconjunctival epibulbar tumor (pure myxoma) [in German]. Arch Ottamol. 1914;21:300–306. 5. Grossniklaus HE, Green WR, Luckenbach M, Chan CC. Conjunctival lesions in adults: a clinical and histopathologic review. Cornea. 1987;6(2):78– 116. 6. Shields CL, Demirci H, Karatza EC, Shields JA. Clinical survey of 1643 melanocytic and nonmelanocytic conjunctival tumors. Ophthalmology. 2004; 111(9):1747–1754. 7. Horie Y, Ikawa S, Okamoto I, Nagata M, Tamai A. Myxoma of the conjunctiva: a case report and a review of the literature. Jpn J Ophthalmol. 1995; 39(1):77–82. 8. Mottow-Lippa L, Tso MO, Sugar J. Conjunctival myxoma: a clinicopathologic study. Ophthalmology. 1983;90(12);1452–1458. 9. Patrinely JR, Green WR. Conjunctival myxoma: a clinicopathologic study of four cases and a review of the literature. Arch Ophthalmol. 1983;101(9):1416– 1420. 10. Pe’er J, Ilsar M, Hidayat A. Conjunctival myxoma: a case report. Br J Ophthalmol. 1984;68(9):618–622. 11. Courcoutsakis NA, Tatsi C, Patronas NJ, Lee CCR, Prassopoulos PK, Stratakis CA. The complex of myxomas, spotty skin pigmentation and endocrine overactivity (Carney complex): imaging findings with clinical and pathological correlation. Insights Imaging. 2013;4(1):119–133. 12. Chen Y, Tsung SH, Yet-Min Lin T. A rare presentation of conjunctival myxoma with pain and redness: case report and literature review. Case Rep Ophthalmol. 2012;3(1):145–150. 13. Konari K, Suzuki J, Oyachi H, Ueno T, Nakagawa T. Ocular pain as the initial sign of conjunctival myxoma [in Japanese]. Rinsho Ganka (Jpn J Clin Ophthalmol). 1993;47:1361–1364. 14. Herwig MC, Wells JR, Grossniklaus HE. Conjunctival stromal tumor. Ophthalmology. 2012;119(4);682–687.
A Synopsis of a Rare Ocular Tumor—Xiong & Dim
15. Ramaesh K, Wharton SB, Dhillon B. Conjunctival myxoma, ZollingerEllison syndrome and abnormal thickening of the inter-atrial septum: a case report and review of the literature. Eye (Lond). 2001;15(pt 3):309–312. 16. Demirci H, Shields CL, Eagle RC, Shields JA. Report of a conjunctival myxoma case and review of the literature. Arch Ophthalmol. 2006;124(5):735– 738. 17. Arya SK, Gupta H, Gupta S, Malik A, Samra SG, Sood S. Conjunctival myxoma in a 64-year-old patient. Jpn J Ophthalmol. 2008;52(4):339–341. 18. Kili¸c A, Kosem M, Demirok A, Cinal ¸ A, Yasar T. Conjunctival myxoma: a ¨ clinicopathologic report. Ophthalmic Surg Lasers Imaging. 2008;39(6):514–516. 19. Herwig MC, Fischer HP, Holz FG, Loeffler KU. Conjunctival myxoma: two cases—histopathological examination and clinical course [in German]. Ophthalmologe. 2010;107(9):843–847. 20. Pe’er J, Hidayat A. Myxomas of the conjunctiva. Am J Ophthalmol. 1986; 102(1):80–86.
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21. Chen CL, Tai MC, Chen JT, Chen CH, Jin JS, Lu DW. A rare case of conjunctival myxoma and a review of the literature. Ophthalmologica. 2008; 222(2):136–139. 22. Strempel I, von Domarus D. Conjunctival myxomas [in German]. Klin Monbl Augenheilkd. 1979;175(4):544–547. 23. Al-Ghadeer H, Al-Assiri A, Al-Odhaib S, Alkatan H. Successful removal of a conjunctival myxoma. Middle East Afr J Ophthalmol. 2012;19(3):352–353. 24. Doughman DJ, Wenk RE. Epibulbar myxoma. Am J Ophthalmol. 1970; 69(3):483–485. 25. El-Rifai M, Ghaly AF. Myxoma of the conjunctiva. Bull Ophthalmol Soc Egypt. 1975;68:31–33. 26. Kini Rao AC, Nayal B. Conjunctival myxoma—a case report. Malays J Med Sci. 2013;20(1):92–94. ´ 27. Majewska-Cembrynska A, Majewski H. Myxoma of the eyebulb [in Polish]. Klin Oczna. 1973;43(7):827–830.
A Synopsis of a Rare Ocular Tumor—Xiong & Dim 697
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Conjunctival myxoma is an exceptionally rare, slowgrowing, benign neoplasm of primitive mesenchyme origin. Forty-one cases of conjunctival myxoma from a literature review, including the authors’ case, are listed. The usual clinical history is a painless mass appearing during months to years. Grossly, the tumor is a wellcircumscribed, cystlike, gelatinous, yellow-to-pink, translucent-to-solid mass. Microscopically, the hypocellular tumor contains stellate- and spindle-shaped cells in a mucoid stroma with abundant hyaluronic acid mucopolysaccharides. Vimentin and a-smooth muscle actin highlight the spindle and stellate cells. S100 protein and desmin are negative for the tumor cells. Treatment is complete surgical excision, with no recurrence reported in the follow-up period. Notably, conjunctival myxoma may be associated with Carney complex, an autosomal-dominant disorder associated with skin pigmentation, endocrine abnormalities, and myxoma of the heart and eye. Physicians should appreciate this unique ocular tumor because of its potential association with Carney complex. (Arch Pathol Lab Med. 2015;139:693–697; doi: 10.5858/ arpa.2013-0532-RS)
C
onjunctival myxoma is a rare, benign tumor of mesenchymal origin. In 1913, Magalif1–3 presented the first case at the St Petersburg Ophthalmological Society, but it was uncertain whether her case was a pure or a mixed conjunctival myxoma tumor. The following year, Maucione4 described a conjunctival myxoma occurring in a 59-year-old man who had a 6-year history of painless growth located in the medial canthus of the eye near the limbus.1,2 Since 1913, there have been approximately 40 case reports of conjunctival myxoma described in the literature and PubMed (US National Library of Medicine, Bethesda, Maryland).1,2 Fortyone cases of conjunctival myxoma from the literature and the authors’ case are presented in the Table. The reported incidence of this tumor was estimated at 0.002% from a review of 2455 patients with conjunctival lesions by Accepted for publication April 22, 2014. Department of Pathology, University of Missouri, Kansas City, School of Medicine, Kansas City. The authors have no relevant financial interest in the products or companies described in this article. Reprints: Daniel C. Dim, MD, Department of Pathology, University of Missouri, Kansas City, School of Medicine, 2411 Holmes St, Kansas City, MO 64108 (e-mail: [email protected]). Arch Pathol Lab Med—Vol 139, May 2015
Grossniklaus et al5 and at less than 0.001% from a review of 1643 cases by Shields et al.6 Conjunctival myxoma can be appreciated as a distinct tumor entity, classically, with a paucicellular composition of spindle and stellate cells embedded in a fine reticular network, with a myxoid stroma and few vascular structures, few mast cells, and sparse lymphocytes or other inflammatory cells. These tumors often present as slow, painless growths and are diagnosed clinically as a ‘‘cyst.’’ However, the tumor presents a potentially challenging diagnosis for pathologists because of its rarity and its resemblance to other soft tissue tumors of the eye, such as spindle cell lipoma. Therefore, the authors hope to enlighten readers about some of the unique characteristics and distinguishing features of the conjunctival myxoma. HISTOGENESIS As a class, myxomas are derived from primitive mesenchyme and are said to resemble the umbilical cord core ‘‘Wharton jelly.’’7 Myxomas can occur as a primary tumor in a variety of tissues. They most commonly involve the atrial endocardium and jaw bones but can also arise in fascia, subcutaneous tissue, neurovascular sheaths, muscle, and the genitourinary tract. Myxomas of the upper respiratory tract, such as the nasal sinuses and pharynx, breast, and eyes (orbital, corneal, palpebral, or conjunctiva), are particularly rare.8,9 Conjunctival myxoma, specifically, develops in the substantia propria, and the tumors are covered by conjunctival epithelium.7,10 The tumor can occur as an isolated process, exhibiting local involvement without metastasis. However, conjunctival myxoma may be a presenting component of the Carney complex, an autosomal-dominant disease process characterized by myxomas, spotty skin pigmentation, and endocrine overactivity. Carney complex belongs to a spectrum of disease processes that includes McCuneAlbright syndrome, Mazabraud syndrome, and multiple endocrine neoplasias. The diagnosis of Carney complex requires 2 manifestations of the following: typical mucocutaneous pigmentation, cardiac myxoma, breast myxomatosis or adenoma, endocrine overactivity, testicular tumors, schwannoma, and pituitary adenoma. The diagnosis can also be established if patients demonstrate a single manifestation and has a ‘‘first hit’’ through either an affected first-degree relative or an inactivating PRKAR1A gene mutation.11 PRKAR1A is the regulatory subunit 1A of protein kinase A on 17q22–24.11,12 A Synopsis of a Rare Ocular Tumor—Xiong & Dim 693
Reported Cases of Conjunctival Myxoma Source, y
Age, y/Sex
Eye
Maucione,4 1914 Ffooks,2 1962
56/M 72/M
OD OD
Doughman and Wenk,24 1970 Stafford,1 1971 ´ Majewska-Cembrzynska and Majewski,27 1973 El-Rifai and Ghaly,25 1975 Strempel and von Domarus,22 1979 Patrinely and Green,9 1983
49/F
OD
54/F 76/F
OD OD
14/M
Mottow-Lippa et al,8 1983 Pe’er et al,10 1984 Pe’er and Hidayat,20 1986
Konari et al,13 1993 Horie et al,7 1995 Ramaesh et al,15 2001b Demirci et al,16 2006 Arya et al,17 2008 Kili¸c et al,18 2008 Chen et al,21 2008 Herwig et al,19 2010 Al-Ghadeer et al,23 2012 Herwig et al,14 2012
Chen et al,12 2012 Kini Rao and Nayal,26 2012 Current case
Location
Size, mm
Duration, mo
Recurrence (follow-up, mo)
Nasal limbus Superior limbus, near corneoscleral trephine site Temporal bulbar
83631 83434
72 6
None (?) ?
43333
12
None (9)
93635 12
108 12
None (64) None (24)
OD
Temporal limbus Nasal limbus, near previous cataract wound Temporal limbus
93432
48
None (12)
53/M 73/M 50/F 53/F 18/F 42/M 54/M
OS OS OD OS OS OD OS
Superior limbus Nasal bulbar Nasal bulbar Temporal bulbar Superotemporal limbus Temporal limbus Temporal limbus
43332 ? 93832 63535 83433 93434 16 3 11 3 10
48 6 24 12 15 36 288
None (9) ? None (84) None (48) None (6) None (6) ?
18/F 48/M 61/M 34/M 64/M 33/F 20/M 50/M 50/F 76/M 65/F 54/F 80/F 36/M 31/M
OD ? ? ? ? ? ? ? ? ? ? ? OS OD OS
Nasal bulbar Inferior fornix ? Temporal bulbar Temporal bulbar Bulbar Temporal limbus Nasal bulbar Intrapalpebral fissure Superior limbus Temporal bulbar Superior bulbar Nasal bulbar Nasal bulbar Nasal bulbar
4 ? ? 36 ? 8 6 24 12 ? ? 1 wk 60 ? 24
None (8) None (10) ? ? ? ? ? None (24) ? ? None (5) None (48) None (21) ? None (132)
64/F 45/F 11/M 54/M 36/F 45/F 41/M 47/M 53/M 45/F 47/F 33/M
OD OS OS OD OS OS OD OS OS ? OS OS
Superonasal bulbar Temporal limbus Temporal bulbar Temporal bulbar Temporal bulbar Temporal bulbar Temporal bulbar Superior limbus Temporal bulbar ? Temporal bulbar Nasal bulbar
10 3 4 3 4 10 7 3 5 3 4.5 11 3 7 ? 5 5 5 53433 ? 10 16 3 12 3 8 12 3 10 131 12 3 11 3 6, 5 3 5 3 2a 15 3 7 53434 937 83532 63632 20 3 1.8 43534 33131 33331 ? 93634 8.5 3 8.5
24 ? 12 24 48 36 48 ? 1 wk ? 36 12
? None (8) None (12) None (10) None (10) None (12) None (180) None (84)c None (60) ? None (1) ?
46/F
OD
Temporal
43333
8
None (?)d
Abbreviations: ?, unknown; OD, right eye; OS, left eye. a Basal part measured 12 3 11 3 6 mm, and apical part measured 5 3 5 3 2 mm. b Patient had abnormal thickening of the interatrial septum and a history of Zollinger-Ellison syndrome, so it is unclear whether this was an isolated case of conjunctival myxoma or associated with an underlying syndrome. c Patient had amniotic membrane graft reconstruction surgery 5 years after excision of conjunctival myxoma. d Number of months of follow-up not specified because the authors are still monitoring the case.
CLINICAL FEATURES Conjunctival myxoma is a very rare clinical entity. We identified 41 cases of conjunctival myxoma that appear to be pure cases without the syndrome association of Carney complex (see the Table). There is equal male to female distribution (M:F, 22:19), showing that the disease has no sex predilection. This neoplasm generally affects older adults and is very uncommon in younger populations. The mean age at presentation is 47.6 years, and the median age is 49 years, with an age range of 11 to 80 years. Conjunctival myxoma has no associated history of trauma or family 694 Arch Pathol Lab Med—Vol 139, May 2015
history. The ocular and physical examinations are generally unremarkable, except for minimal changes in ocular mobility and acuity. Patients gave very similar clinical histories, reporting a slow-growing, painless mass that had been present from 1 week in 2 exceptional cases13,14 to a range from 4 to 288 months. Conjunctival myxoma was located in the temporal region of the eye in 20 cases (49%) including the authors’ case, the nasal region in 11 cases (27%), and other locations (superior or unknown) in 10 cases (24%). In addition, 14 cases (34%) involved the right eye, 15 cases (37%) involved the left eye, and for 12 cases (29%) location was unknown.1,2,4,7–10,12–27 A Synopsis of a Rare Ocular Tumor—Xiong & Dim
GROSS PATHOLOGY The conjunctival myxoma tumors varied from 1 by 1 mm15 to the largest at 16 by 12 by 8 mm.13 During gross examination, the tumor is soft and smooth, semitranslucent to fully translucent, and white, pink, pale, or fleshy. Characteristically, it is a solid to cystlike, rubbery or gelatinous, semiencapsulated or unencapsulated mass. The myxomas have sharp, well-circumscribed borders (but were described as ‘‘diffuse’’ in 2 cases) and may be finely granular throughout the cut surface. Hemorrhage, calcification, and necrosis were typically absent.1,2,4,7–10,12–27 HISTOPATHOLOGY The tumor matrix is composed predominantly of hyaluronic acid with lesser amounts of chondroitin sulfates. The stroma can be described as a network of delicate reticulin fibers in a loose, wavy arrangement with few vascular structures or mature, dense collagen elements (Figure 1).7,9,16 Conjunctival myxomas are paucicellular tumors containing a few spindle and stellate cells (Figure 2) and rare macrophages, lymphocytes, or mast cells (Figure 3).16 Some cells are mildly pleomorphic, but mitoses are absent.7 The nuclear membrane is sometimes invaginated, so that it appears like intranuclear vacuoles. Nucleoli may be present at rates of 1 or 2 per nucleus.10,11 Ultrastructural examination reveals abundant, rough, endoplasmic reticulum and intracytoplasmic inclusions. The intracytoplasmic inclusions represent dilated cisternae of rough endoplasmic reticulum, which are theorized to have the secretory function of producing the mucoid stroma.9,10,17
Figure 1. Mucoid stroma with sparse capillaries, predominantly stellate, and spindle cells (hematoxylin-eosin, original magnification 3 100). Figure 2. Tumor showing stellate cells and spindle cells (hematoxylineosin, original magnification 3 400). Figure 3. Tumor showing mast cell (hematoxylin-eosin, original magnification 3 400).
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HISTOCHEMICAL AND IMMUNOHISTOCHEMICAL STUDY The conjunctiva myxoma cells stain positive for Alcian blue (Figure 4) with dissolution of the color after treatment with hyaluronidase, revealing cells that contain abundant hyaluronic acid mucopolysaccharides.7,11,16 The cells also stain positively with mucicarmine and colloidal iron. Periodic acid–Schiff stain is negative, demonstrating an absence of significant carbohydrate components, such as glycogen, glycoproteins, or proteoglycans.2,7 Oil red O stain for lipocytes and Bodian stain for neural material are negative.10,11 Immunostaining of conjunctival myxoma cells show extensive reactivity with vimentin (Figure 5) and focal staining for a-smooth muscle actin.7,9,17 Several authors18,19 have presented a few cases that stained negative for smooth muscle actin. In 2012, Herwig et al14 described a variant of conjunctival myxoma that stained positive for CD34. S100 protein, desmin, myoglobin, lysozyme, a1-antitrypsin, a1antichymotrypsin, cytokeratin, epithelial membrane antigen, Ulex europaeus agglutinin 1, and factor VIII–related antigen are typically negative.7,9,10,13,15,20 Herwig et al19 found little proliferative activity because less than 5% of the tumor cells in their 2 conjunctiva myxoma cases stained positively with the nuclear anti-Ki67. DIFFERENTIAL DIAGNOSIS Conjunctival myxoma can resemble other mixed or pure myxoma tumors, such as amelanotic naevus, amelanotic melanoma, dermal nerve sheath myxoma, myxoid neurofibroma, lymphangioma, lymphoma, reactive lymphoid hyperplasia, dermoid, myxoid liposarcoma, spindle cell lipoma, A Synopsis of a Rare Ocular Tumor—Xiong & Dim 695
containing plasma cells, endothelial cells, and lymphoblast cells. Dermoids often contain additional tissue elements, such as sebaceous and sweat glands or hair. Liposarcomas and spindle cell lipomas contain vacuolated lipoblasts and lipocytes, respectively. They may have signet-ring cells, are positive for oil red O stain, and often appear more cellular and vascular.11 Rhabdomyosarcoma usually affects children and adolescents and the tumors contain characteristic, small, round cells with mitotic activity or have ‘‘strap’’ rhabdomyoblasts that stain positive for myosin.9,11 Myxoid malignant fibrous histiocytoma can stain positive for Alcian blue, like conjunctival myxomas, but it can be distinguished by its prominent vascular structures and abundant pleomorphic nuclei.16 Nodular fasciitis tumors grow quickly and contain numerous fibroblasts with active mitosis, cleftlike spaces, and histologically varied patterns.9 PROGNOSIS AND TREATMENT Conjunctival myxoma is removed by complete surgical excision. No tumor recurrence has been reported in patients during the follow-up periods, ranging from 5 to 180 months.1,2,4,7–10,12–27 However, given the significant morbidity and mortality of myxoma associated with Carney complex and other syndromes, the presence of conjunctival myxoma, particularly in a younger patient, should prompt a systematic evaluation. The most lethal component of the Carney complex is the development of heart myxoma and emboli from them.11 The use of echocardiography to rule out cardiac pathology has been suggested.19,23 If patients present with more concerning symptoms, such as mucocutaneous skin pigmentation and positive family history, additional tests in the diagnostic workup may include thyroid-stimulating hormone, adrenocorticotropic hormone, and growth hormone levels and, possibly, PRKAR1A gene analysis.16 Figure 4. The tumor hyaluronic acid mucopolysaccharides matrix stained blue (Alcian blue, original magnification 3 400). Figure 5. The stellate and spindle cells are strongly positive for vimentin (original magnification 3 400).
botryoid-type rhabdomyosarcoma, myxoid fibrous histiocytoma, and nodular fasciitis.7 However, conjunctival myxomas can be distinguished from other soft tissue tumors by subtle clues, such as the absence of significant cellularity, mitotic figures, or pleomorphic nuclei and by additional clues, such as the absence of prominent vascular structures, pigmentation, or dense collagen fibers. Specific features of the tumor variants described below can help distinguish conjunctival myxoma from other similar ocular pathologies. Conjunctival myxoma differs from amelanotic nevus or melanoma by the absence of pigmentation or vascular structures and the absence of nests of cells characteristic of melanoma.16 Nerve sheath myxomas and myxoid neurofibroma contain dense, wavy collagen structures; prominent, spindly nuclei; and occasional lymphocytes. The tumors are Bodian-positive on staining and can be associated with systemic neurofibromatosis. Lymphangiomas typically occur in younger individuals and are vascular, boggy tumors with hemorrhagic and inflammatory components.7,11 Lymphomas and reactive lymphoid hyperplasia tumors contain significant lymphocyte populations. Lymphomas have a monocellular arrangement of lymphocytes. Reactive lymphoid hyperplasia are arranged in follicular aggregates 696 Arch Pathol Lab Med—Vol 139, May 2015
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