A Reappraisal of Eyelid Eccrine and Apocrine Hidrocystomas: Microanatomic and Immunohistochemical Studies of 40 Lesions




Purpose


To establish reliable criteria for diagnosing eyelid eccrine and apocrine hidrocystomas.


Design


Retrospective clinicopathologic and immunohistochemical study.


Methods


Twenty-two specimens of normal portions of eyelids were evaluated to establish the distribution and microanatomy of eccrine and apocrine glands. Immunostaining for cytokeratin 7 (CK7), gross cystic disease fluid protein-15 (GCDFP-15), alpha-smooth muscle actin (α-SMA), epithelial membrane antigen (EMA), and carcinoembryonic antigen (CEA) was performed on these tissues and on 40 lesions in 33 patients diagnosed with eccrine or apocrine hidrocystomas by unaided light microscopy.


Results


Eccrine glands were not present in the eyelid margins, the lower half of the upper eyelid pretarsal skin, or the pretarsal lower eyelid skin. Apocrine glands were restricted to the eyelid margins and canthi where the cysts were located. GCDFP-15, CK7, and α-SMA immunoreacted with the eccrine secretory coils but not their ducts; apocrine gland secretory spirals also stained positively for these markers throughout their extended courses, but not their short terminal ducts. Positivity was found in 37 of 40 hidrocystomas for α-SMA and 19 for GCDFP-15; lesions tested for CK7 displayed positivity.


Conclusions


Alpha-SMA-, CK7-, and/or GCDFP-15-positive apocrine hidrocystomas were the only type discovered in this series and arose from glandular secretory spirals within the marginal, perimarginal, or canthal skin. Three lesions did not stain for α-SMA, initially suggesting an absent myoepithelium and therefore an eccrine ductal origin; they manifested CK7 positivity, however, another characteristic of the apocrine secretory spiral but not ducts. Our findings disprove the contention that eccrine predominate over apocrine hidrocystomas in the eyelids.


After chalazia, the most common benign lesions of the eyelids are papillomas, seborrheic keratoses, melanocytic nevi, and cysts, the last encompassing epidermoid, hybrid, and Meibomian keratinous cysts, as well as ectasias of the ducts of the eccrine and apocrine glands (hidrocystomas) and mildly proliferative ectasias of the follicular infundibulum (dilated pore of Winer). Histopathologically, hidrocystomas exhibiting a deeply eosinophilic cuboidal to columnar cellular lining with oval to round basal nuclei and apical cytoplasmic decapitations (shedding of adlumenal snouts, which are incorporated into the eosinophilic secretions along with specific granules) have conventionally been designated as apocrine. In contrast, cysts lined by a low cuboidal or flattened epithelium with paler cytoplasm, no snouts, and a watery secretion without cytoplasmic contributions have been classified as eccrine. All hidrocystomas are bereft of goblet cells, which separates them from conjunctival cysts. Eccrine hidrocystomas have long been regarded as retention cysts and believed to be more common in the eyelids than apocrine cysts. The latter, by contrast, are believed to be proliferative in nature, most conspicuously when papillary formations or a solid adenoma within a stalk are found projecting from the wall into the lumen in a subset of lesions (cystadenomas).


Some dermatopathologists have totally forsaken making distinctions between supposed eccrine and apocrine hidrocystomas, positing that secondary or degenerative changes within the cysts’ linings can efface any meaningful cytologic differences. The more neutral diagnostic term “ductal hidrocystoma” has instead been recommended. It has furthermore been suggested that most if not all such cysts are truly apocrine with variably induced secondary cytologic modifications. With regard to these issues, there is no comparative study of eccrine and apocrine hidrocystomas of the eyelids that has critically assessed the validity of the standard clinicopathologic criteria that are employed in their diagnosis. This lacuna, which the present study addresses, is more urgent in view of numerous contradictions regarding hidrocystomas contained in the ophthalmic literature.


It is remarkable that the fundamental anatomic-distributional differences between apocrine and eccrine glands in the eyelids are beclouded in the minds of many ophthalmologists. Unfamiliarity also persists regarding their microscopic differences and the sources of hidrocystomas (secretory vs ductular regions). Preoperative clinical diagnostic accuracy would be considerably enhanced (particularly with reference to early basal cell carcinoma and melanoma when the cyst is pigmented) if valid differences in the locations of putative eccrine and apocrine eyelid hidrocystomas and their differential growth characteristics were discovered. At the same time, their pathologic diagnosis would have a sounder foundation if consistent immunohistochemical differences were elucidated. The accurate diagnosis of multiple periocular hidrocystomas as an ophthalmic emblem of certain systemic metabolic and rare inherited cutaneous and musculoskeletal disorders would also be facilitated. Such developments could represent a major advance since the Dutch ophthalmologist Jacob Moll (1832–1914), over 100 years ago, first described the apocrine glands of the eyelids that are named after him. Our findings confirm the primacy of Moll glands rather than eccrine glands in generating most eyelid hidrocystomas in contravention of contemporary orthodoxy.


Methods


To evaluate the distribution and normal microscopic features of eccrine and apocrine glands of the eyelid skin, hematoxylin-eosin–stained paraffin-embedded perpendicular sections of normal skin at the borders of lesions in 7 full-thickness eyelid excisions; longitudinal sections of 8 preseptal blepharoplasty skin specimens excised parallel to the eyelid margins during cosmetic surgery; and 6 exenteration specimens that included the eyelids were selected from the files of the David G. Cogan Laboratory of Ophthalmic Pathology at the Massachusetts Eye and Ear Infirmary. The eyelid resections had been performed mostly for basal cell carcinomas and occasional chalazia with undisturbed anatomic features at their medial and lateral surgical margins, and the exenterations had been undertaken for malignancies that had involved the orbital contents but had left the eyelid architecture intact. In addition, 17 vertical (sagittal) step-sections stained with Masson’s trichrome of 1 example of normal exenterated orbital contents with preserved eyelids (specimen obtained postmortem) were retrieved from the Malcolm Carpenter Teaching File Collection bequeathed to the Infirmary. All specimens were thoroughly examined with respect to any notable distributional differences of the apocrine and eccrine glands in the upper and lower eyelids.


Forty pathologic specimens obtained from 33 patients were culled from the slide files that had been diagnosed microscopically as eccrine hidrocystoma, apocrine hidrocystoma, sudoriferous cyst, ductal cyst, or adnexal cyst of the eyelids or medial and lateral canthi. The slides of the lesions were critically reviewed and rediagnosed in hematoxylin-eosin–stained sections. Cases were included in the study if 50% or more of the cystic epithelial lining could be identified, and if sufficient tissue remained in the paraffin blocks to permit deeper sections for additional immunohistochemical staining. All tissue preparations were performed in the laboratories of the Pathology Department at the Massachusetts General Hospital, Boston, Massachusetts. Well-standardized special staining included periodic acid–Schiff (PAS) with and without diastase, Perl’s reaction for cytoplasmic iron, and Masson’s trichrome. A panel of immunohistochemical probes ( Table 1 ) was employed according to methods described elsewhere: cytokeratin 7 (CK7), epithelial membrane antigen (EMA), carcinoembryonic antigen (CEA), gross cystic disease fluid protein-15 (GCDFP-15), and alpha-smooth muscle actin (α-SMA). Sections of both the normal eyelid tissues and the cysts’ epithelial linings were stained with the same probes and the immunohistochemical results were compared.



TABLE 1

Immunohistochemical Probes and Their Antigenic and Cellular Targets














































Probe Antigen Cell Specificities Staining Pattern Source a Dilution
Gross cystic disease fluid protein-15 (GCDFP-15) 15 kDa glycoprotein from breast cystic fluid Breast tissue and tumors with apocrine features; apocrine, ceruminous, Montgomery and Moll glands; secretory zones of cutaneous eccrine and apocrine glands; serous cells of acini of lacrimal, submandibular, sublingual, and minor salivary glands; serous cells of nasal and bronchial glands; apocrine tumors and cysts; Paget’s disease, prostate Ca; absent in ducts Cytoplasmic (Golgi zone) and membranous (lumenal cuticles) Mouse monoclonal IgG2α 1:10
Alpha-smooth muscle actin (α-SMA) 42–45 kDa monomer polymerizes to form cytoskeletal protein subserving motility Smooth muscle cells, myoepithelial cells, myofibroblasts, leiomyoma, leiomyosarcoma Cytoplasmic Mouse monoclonal IgG/κ Prediluted
Cytokeratin 7 (CK7) 54 kDa intermediate cytoskeletal protein filament subserving cellular stabilization and conformation Epithelia of large number of simple glands; lung and breast tissue; complex and transitional (urothelial) epithelia; mesothelia; diseased but not normal corneal endothelium; secretory portions of apocrine and eccrine glands but not ducts Cytoplasmic Mouse monoclonal IgG1/κ Prediluted
Epithelial membrane antigen (EMA) 75 kDa transmembrane glycoprotein related to breast mucin Glandular epithelial and mesothelial cells (epithelial differentiation supplemented by cytokeratins); breast and thyroid papillary carcinomas; cuticles of apocrine and eccrine secretory coils and ducts; plasma cells, perineural fibroblasts, notochord, chordoma, meningioma, epithelial mesothelioma; not present in hepatocellular carcinoma Membranous Mouse monoclonal IgG2α/κ Prediluted
Carcinoembryonic antigen (CEA) 180 kDa glycoprotein of glycocalyx Epithelial cells of endodermal derivation or differentiation (lung, stomach, pancreas, biliary system and liver, colon); cuticles of apocrine and eccrine gland ducts; breast carcinoma Membranous Mouse monoclonal IgG1 Prediluted

kDa = kilodalton.

a All monoclonals supplied by Ventana Medical Systems, Oro Valley, Arizona, USA.



The patients’ clinical records, including line diagrams and any clinical photographs of the lesions, were closely scrutinized to assemble the following data: age and sex; duration of any symptoms created by the lesions; unilaterality, bilaterality, and multiplicity; size, color, and any other distinguishing features; upper or lower (or both) eyelid distribution; and specific topographic location in the eyelids. Regarding the last feature, the following designations for the topography of the eyelid skin were adopted: marginal if the lesion’s epicenter involved the region of the mucocutaneous junction and gray line; perimarginal or pericilial if the lesion involved the skin adjacent to the margin, including where the cilia emerged and slightly beyond; pretarsal for the skin in front of the tarsus commencing unambiguously above (in the upper eyelid) or below (in the lower eyelid) the lashes; preseptal (supratarsal or infratarsal depending on upper or lower eyelid) or preorbital for the skin extending from the poles of the superior or inferior tarsi to the brow or inferior orbital rim, respectively; and canthal for the roughly oval portion of skin overlying the medial and lateral canthal tendons beyond the lateral and medial commissures up to the orbital rim laterally and the base of the nasal pyramid medially. The pretarsal and preseptal regions of the lower eyelid skin were less clearly separable from each other clinically than in the upper eyelid because of the smaller size of the inferior tarsus, but microscopically the distinction could be readily made.




Results


Normal Eyelid Eccrine and Apocrine Glands


Histopathologic findings


Eccrine glands were not present at the eyelid margin or in the perimarginal eyelid skin near the cilia ( Figure 1 , Top left and right); they first appeared in the pretarsal skin in small numbers at or above the midpoint of the tarsus of the upper eyelid and at the inferior pole or below the lower eyelid tarsus. Eccrine glands were much more profuse in the preseptal (preorbital) skin ( Figure 1 , Middle left). Conversely, apocrine glands of Moll were discovered only at the eyelid margin in association with the strong cilial hairs (eyelashes) of the upper and lower eyelids ( Figure 1 , Middle right) and nowhere else in the eyelid skin. No normal canthal tissues were found for inclusion in this study; uninvolved skin surrounding excised canthal cysts, however, sometimes displayed an adjacent apocrine gland, but no eccrine glands were seen. In terms of their microanatomy, eccrine and apocrine glands were strikingly different. Eccrine glands were located in the mid portion of the thin reticular dermis of the eyelid skin. (Elsewhere in the integument, they are located at the interface between the lowest portion of the reticular dermis and the subcutaneous fat or hypodermis, which is nonexistent or exiguous in the pretarsal eyelid skin.) The deepest portion of the eccrine gland, referred to as the secretory coil (a convoluted tube), appeared as a loosely organized lobular structure (smaller than elsewhere in the skin); it was invested with its own delicate fibrous adventitia containing vessels and nerves ( Figure 1 , Bottom left).




FIGURE 1


Normal anatomy of the sweat glands of the eyelids. (Top left) A full-thickness microscopic section of the upper eyelid reveals the epidermis (crossed arrow) and conjunctival epithelium (C), which merge on the right at the mucocutaneous junction of the eyelid margin (EM). The orbicularis muscle (O) is situated between the dermis of the skin and the tarsus (T). The arrows indicate dilated apocrine glands at the eyelid margin adjacent to 2 hairs (H) (cilia); note the absence of eccrine glands in the dermis of the skin above and at the eyelid margin. Near the eyelid margin Meibomian gland (MG) alveoli are present within the tarsus (T), which for the most part is scarred and devoid of these structures. (Top right) A full-thickness somewhat oblique microscopic section of the lower eyelid discloses patulous lumens of an apocrine gland (arrows) in close association with marginal hairs (H) (cilium). Meibomian gland alveoli (MG) are present in the tarsus (T), which is smaller in the lower eyelid than in the upper. No sweat glands are present within the dermis of the lower eyelid skin. The orbicularis muscle (O), as in the upper eyelid, is interposed between the dermis of the skin and the tarsus (T). (Middle left) Preseptal portion of the eyelid skin obtained from a blepharoplasty contains many lobules of sweat glands (arrows) in the dermis. The inset depicts the loosely aggregated secretory acinar units with an intrinsic interstitium and early ductal components of the glandular secretory coil and their small lumens. (Middle right) The ascending secretory spiral of an apocrine gland (AG) of Moll is located to the right of a hair (H) (cilium). The lumens of apocrine glands contrast in being much wider than those of eccrine glands. Note that the cytoplasm of the columnar cells is deeply eosinophilic with basal nuclei and focal adlumenal surface irregularities, indicative of decapitation secretion. (Bottom left) The cytoplasm of the cells constituting the acini of the eccrine secretory coil is lightly eosinophilic and delineates small lumens. A segment of a vertically oriented duct (D) is composed of smaller cells. The inset depicts a cluster of coiled ducts composed of smaller cells that lie adjacent to the secretory lobule. (Bottom right) The terminal duct (D) of an apocrine gland inserts into the wall of a hair follicle that is sectioned obliquely. The inset portrays the uppermost portion of the apocrine secretory spiral (arrow) with its intensely eosinophilic cytoplasm. As it moves upwards it undergoes ductalization (D), with the lining cells becoming low cuboidal. (Hematoxylin-eosin, top left, ×10; top right, ×10; middle left, ×25, inset ×100; middle right, ×200; bottom left, ×200, inset ×200; bottom right, ×100, inset, ×100.)


Emerging from the secretory coil after originating abruptly within its lobule, the duct (or syrinx) formed a convoluted cluster immediately next to the secretory coil ( Figure 1 , Bottom left, inset), then straightened out to vertically traverse the dermis, emptying onto the epidermis via a modified terminal intraepidermal spiral segment with a surface pore referred to as the acrosyringium. The secretory cells of the coil displayed a moderately eosinophilic cytoplasm; the constituent acini had small lumens delimited by an inner cuboidal layer and an outer, more flattened layer. Pale cells (glycogen-rich) and dark cells (endowed with scattered secretory granules that are discharged via merocrine secretion) were less readily distinguishable in the eyelids than elsewhere in the skin. Some of the inner cells had a faintly fibrillated cytoplasm attributable to overlapping lateral cell membranes that formed complicated imbrications, creating intercellular canaliculi. The ducts appeared darker because their cells had less cytoplasm. The inner adlumenal ductal cells were surrounded by an outer layer; a somewhat refractile cuticle was detectable around the lumen (attributable to microvilli and an electron microscopically demonstrable subplasmalemmal condensation of tonofilaments).


In contrast, the apocrine glands of Moll commenced deep at the eyelid margin at the level of the germinative bulbs of the cilia and near the anterior face of the tarsus. Rather than assuming a tightly coiled arrangement with a relatively long and straight duct, the secretory components appeared more like an open vertical spiral with patulous lumens that evinced variegated secretory features throughout their upward trajectory to the surface ( Figure 1 , Middle right). The adlumenal secretory cells frequently sported an apical snout of decapitation (apocrine secretion). Segments of the secretory coil were also composed of low cuboidal cells, probably indicative of a different state of metabolic and secretory activity. A distinctly separate ductal differentiation ( Figure 1 , Bottom right) was discerned only in a very short, modified segment of the most terminal region near the surface (a shorter segment than encountered in apocrine glands located elsewhere in the integument). The secretions emptied into the follicles of the cilia at approximately a right angle immediately below the level of the infundibulum through a straight apocrine acrosyringium. The secretory cells of the uppermost secretory spiral gradually converted to low cuboidal ductal cells with less eosinophilic cytoplasm; an outer layer was inconspicuous in the terminal duct and acrosyringium.


Immunohistochemical findings


The salient normal glandular reaction patterns and, in comparison, the hidrocystomas contained in this series are summarized in Table 2 . The eccrine secretory coils or lobules immunostained positively for CK7 and GCDFP-15 ( Figure 2 , Top left and inset) in the cytoplasm of the acinar cells; a thin cuticle on the apical pole or lumenal cell membrane was also observed. EMA and CEA both immunostained the cell membranes participating in the intercellular canaliculi as well as an apical adlumenal cuticle of the ducts ( Figure 2 , Top right, upper right inset); the intensities of the EMA and CEA reactions were variable from specimen to specimen. Alpha-SMA immunoreacted with the outer myoepithelial cells of the acinar secretory units ( Figure 2 , Top right, main panel and inset upper left) but not with the outer cells of the intralobular or ascending extralobular ducts ( Figure 2 , Top right, inset upper left and middle left). The eccrine ducts beginning in the secretory coils failed to express CK7, GCDFP-15, and especially α-SMA cytoplasmic reactivity; these negative staining results persisted throughout the ducts’ upward ascent in the dermis ( Figure 2 , Middle right). The negative α-SMA staining denoted the absence of a myoepithelial outer layer. EMA, CEA, and CK7 delineated a thin or faint lumenal ductal cuticle ( Figure 2 , Upper right, inset bottom right), which in the upper reaches of the ducts’ projection toward the acrosyringium became erratic, fainter, and frequently totally disappeared. No intercellular canaliculi were detected between the duct cells.



TABLE 2

Forty Eyelid Hidrocystomas Diagnosed Microscopically in Hematoxylin-Eosin–Stained Sections




























Initial Pathologic Diagnoses Diagnoses After Critical Review
Eccrine hidrocystoma 6 13
Apocrine hidrocystoma 21 27
Ductal cyst 5 0
Hidrocystoma 1 0
Sudoriferous cyst 7 0



FIGURE 2


Immunohistochemistry of normal eyelid sweat glands. (Top left) Cytokeratin 7 (CK7) immunostains a secretory coil (lobule) of a sweat gland. The inset demonstrates gross cystic disease fluid protein-15 (GCDFP-15) positivity in the cytoplasm of the eccrine acinar cells, while there is no staining in the early emerging intralobular ducts (arrows). (Top right) Alpha-smooth muscle actin (SMA) is identified in the outer myoepithelial cells of the acinar units of the eccrine secretory lobule in the center of the field. The adjacent structures toward the bottom left are positively staining vessels with smooth muscle cells in their walls. The upper left inset contrasts the positively staining myoepithelium of the acini with its absence from the beginning ducts (arrows). The inset on the upper right reveals positive epithelial membrane antigen (EMA) staining of the acinar cell lumenal membranes and the intercellular canaliculi. The bottom right inset highlights a lumenal cuticle within the ducts stained for EMA. A similar pattern was observed with CEA staining. (Middle left) An eccrine duct (D) ascends through the dermis toward the epidermis, where it transforms into the intraepidermal portion, referred to as the acrosyringium (arrow). There are no SMA-positive cells in the wall of the duct, whereas they can be seen in the smooth muscle of the microvasculature of the dermis. The inset contains a cluster of ducts in the lower dermis, which are also negative for SMA but are intimately surrounded by positively staining vessels. (Middle right) The secretory spiral of an apocrine gland exhibits uniform and intense cytoplasmic staining for GCDFP-15. The inset discloses an adlumenal cuticle of GCDFP-15 positivity of the terminal duct as it empties into the wall of a hair follicle (arrows). Nonspecific staining is also displayed by an associated sebaceous gland (S). (Bottom left) As the secretory spiral of an apocrine gland rises toward the surface it loses its GCDFP-15-positive cytoplasmic staining at the point where it begins to undergo incomplete transformation into the terminal duct (arrow). The inset reveals CK7 cytoplasmic positivity of the uppermost region of the apocrine secretory spiral in the main panel, as well as of the unit (arrow) that was negative in the main panel for GCDFP-15, confirming only partial duct transformation at this level. (Bottom right) An apocrine gland spiral stretching upwards with wide lumens uniformly possesses an outer SMA-positive myoepithelial layer (arrows). The surrounding vessels are also SMA positive. The inset portrays the outer myoepithelial layer to better advantage. (Immunoperoxidase reaction, diaminobenzidine chromogen. Top left, ×100, inset, ×100; top right, ×100, upper left inset, ×100, upper right inset, ×100, bottom right inset, ×100; middle left, ×25, inset ×100; middle right, ×100, inset ×100; bottom left, ×100, inset, ×100; bottom right, ×100, inset, ×100).


In the apocrine secretory spirals, CK7 and GCDFP-15 ( Figure 2 , Middle right, and Bottom left) diffusely stained the cytoplasm, the lumenal cuticle, and any lumenal secretory material. GCDFP-15 cytoplasmic positivity disappeared and only an episodic lumenal cuticle persisted as the uppermost spiral underwent a transition into the short terminal duct ( Figure 2 , Middle right, inset). CK7 immunostaining remained when GCFDP-15 positivity had disappeared during ductalization ( Figure 2 , Bottom left and inset). Anti-α-SMA antibodies demonstrated an outer, positively staining myoepithelial layer along the full length of the secretory spiral ( Figure 2 , Bottom right and inset); it also began to disappear just before the short terminal duct disgorged the secretions into the follicle ( Figure 3 , Top left and right). EMA lightly stained the cytoplasm of the cells of the secretory spiral and highlighted a dense lumenal cuticle, which became fainter in the upper reaches of the spiral. CEA staining was observed only as a thin lumenal cuticle in the secretory spiral and paralleled the staining distributions of EMA; it also positively stained any intralumenal secretory material. Neither EMA nor CEA revealed the presence of intercellular canaliculi in the secretory spiral. CK7 immunoreacted with the cells’ cytoplasm throughout the full stretch of the secretory spiral ( Figure 2 , Bottom left), but became fainter and eventually disappeared, transforming into a cuticle in the uppermost region of the terminal duct.




FIGURE 3


Immunohistochemistry of apocrine terminal ducts and clinical appearances of hidrocystomas. (Top left) A short terminal apocrine duct (D) attaches to the upper follicular wall of a hair (H) (cilium). It is SMA negative, while the vessels of the surrounding dermis are positive. The inset reveals a profile of an incipient terminal duct, which retains an interrupted and attenuated outer myoepithelial layer (arrows). This region stained CK7 positive, whereas the terminal duct inserting into the hair follicle wall in the main panel did not. (Top right) There is an abrupt disappearance of the outer myoepithelial SMA-positive layer of the secretory coil (arrows) where the upper portion forms an early terminal duct (D), which empties into the follicle of the hair (H) (cilium). The epidermis (E) is present on the upper left. (Middle left) An 85-year-old woman had a 4.5 × 3.5-mm clear cystic lesion that transilluminated and had increased in size over 6 months. Its location at the medial eyelid margin of the left lower eyelid (arrow) near the punctum put it in close proximity to the canaliculus. The placement of an intracanalicular stint is desirable during excision of such lesions. (Courtesy of Dr Manoj Thakker.) (Middle right) A 60-year-old man had a skin-colored, smooth-surfaced cyst that enlarged over several months in the perimarginal/pericilial eyelid skin (arrow). (Courtesy of Dr Arthur Grove.) (Bottom left) Over 2 years a 63-year-old woman developed a faintly bluish, multilocular cyst located in the outermost portion of the right upper eyelid. (Courtesy of Dr Mark Hatton.) (Bottom right) The top panel shows a smooth-surfaced cyst in the medial canthus of a 64-year-old man next to the commissure of the eyelids. The bottom panel displays a smooth left lateral canthal cyst in a 53-year-old woman; a similar lesion was also present in the right lateral canthus. (Top, courtesy of Dr Arthur Grove; bottom, courtesy of Dr Peter A.D. Rubin.) (Immunoperoxidase reaction, diaminobenzidine chromogen. Top left, ×25, inset ×200; top right, ×25.)


Hidrocystomas


Clinical findings


Thirty-three patients had 40 cysts. There were 17 men and 16 women with ages at presentation ranging from 42 to 90 years (mean of 64 years). Patients had been aware of their lesions usually for several months and always for less than a year. The lesions in this series involved the eyelid margins ( Figure 3 , Middle left), perimarginal and pericilial skin ( Figure 3 , Middle right, and Bottom left), or canthal regions ( Figure 3 , Bottom right panels). No lesions were discovered in the pretarsal or preseptal eyelid skin. Very lateral or medial lesions of the eyelids were distinguished from those of the canthus if they impinged on the eyelid margin. Three patients had bilateral lesions. The largest number of lesions in a single patient was 4, which occurred bilaterally in 3 eyelids. Ten of 40 lesions involved the upper eyelids and 18 the lower; 3 were located near the inferior canaliculus and required a stent to be placed during excision. When clearly mentioned among the perimarginal lesions, 9 occurred in the medial third of the lid, 5 in the lateral third, and 2 were paracentral (in the middle third). Two medial and 5 lateral lesions were situated in the canthal regions as determined after careful verification of clinical diagrams or photographs. Five other lesions were initially designated as medial (3) or lateral (2) canthal without convincing documentation as to whether they were actually situated in the outer or inner extremities of the eyelids. Our considered opinion is that they probably occurred in the innermost or outermost boundaries of the eyelids, but we have treated them as being of indeterminate location. No significant differences in the patients’ ages, sex, or symptoms were observed in the group of canthal lesions. The cysts had a smooth surface with sharp, nonelevated, and regular margins and evinced a clear or skin-colored appearance in most instances; they were uniloculated or multiloculated, and 4 were either milky (2) or bluish (2) ( Figure 3 , Bottom left). Judging from the uneven quality and thoroughness of the preoperative clinical notes, we believe a fuller description would have resulted in a greater number of discolored cysts. Sizes ranged from 1 to 5 mm in diameter, with most in the 1- to 3-mm range. No patient complained of a foreign body sensation or ocular hyperemia. The lesions were all surgically excised, often incompletely, and no recurrences were reported in the patients’ records on follow-up.


Histopathologic findings


Table 3 summarizes the initial and revised pathologic diagnoses made from hematoxylin-eosin–stained sections alone of the 40 cysts included in this study. All lesions failed to display goblet cells. Thirteen lesions were ultimately diagnosed by us as eccrine hidrocystomas because of a unicameral architecture and because their linings were composed of a nonkeratinizing, low cuboidal epithelium with a comparatively pale-staining eosinophilic cytoplasm lacking apical snouts ( Figure 4 , Top left and right); an inconspicuous flattened outer layer enveloped the adlumenal cells. In many specimens, focal or spotty snouts of the inner cells had been previously overlooked ( Figure 4 , Top left, bottom right inset). Most of the lesions appeared collapsed and thrown into folds because of release of the cysts’ fluid contents during surgical removal. No traces of an eosinophilic secretory material were discovered in the lumens of these cysts. Sometimes the inner cells were also highly compressed, presumably from intracystic pressure. A thin compact circumferential fibrous wall was distinguishable from the surrounding dermis; the latter was looser and more haphazard in the arrangement of its collagen fibers.




FIGURE 4


Histopathologic and immunohistochemical features of eyelid hidrocystomas. (Top left) A collapsed cyst with a thin fibrous outer wall is lined by an inconspicuous flattened double-layered epithelium, shown in the inset on the bottom left. It was initially diagnosed as an eccrine hidrocystoma. On critical reevaluation, a small focus of the lining was discovered with more ample eosinophilic cytoplasm and a suggestion of apocrine decapitation snouts (inset, bottom right). (Top right) A full-thickness portion of the upper eyelid harbors a cyst (C) that displaces both the perimarginal skin and orbicularis muscle fibers. Because of its relatively deep location, it had a bluish color, which led to clinical suspicion of a melanocytic lesion and a wide excision. This lesion was initially diagnosed as an eccrine hidrocystoma with a flattened epithelium, but it displays an amorphous secretion, which is atypical for an eccrine lesion. Normal dilated apocrine glands (arrow) are present at the eyelid margin. In the wall of the cyst there are a few surviving apocrine glands (crossed arrow), also shown in the inset to have secretions. (Middle left) A multiloculated cyst (arrows) is present in the dermis of the perimarginal eyelid skin. Note the presence of amorphous eosinophilic secretory material in the cystic lumens. The bottom left inset shows the peculiar organization of some of the secretory material into spherical globules with a linear substructure referred to as Liesegang rings, known to occur in apocrine cysts. The cystic fibrous wall (W) is prominent. The inset on the bottom right reveals amorphous material in a lateral canthal cyst (C), a thick fibrous wall (W), and an adjacent apocrine gland (A). (Middle right) Columnar cells with intensely eosinophilic cytoplasm and prominent apical snouts (arrows) are present in the lining of this eyelid cyst with a prominent fibrous wall (W). The crossed arrow indicates a region of artifactual sloughing of the inner cells from the underlying myoepithelial cells. (Bottom left) Alpha-smooth muscle actin (α-SMA) staining demonstrates a continuous outer myoepithelial layer of ovoid to round cells in a hidrocystoma with a nonstaining inner layer; there are no observable apical snouts in this field. (Bottom right) Portions of the cyst’s lining lack an α-SMA-staining myoepithelial layer (crossed arrows); these alternate with regions harboring a positively staining flattened myoepithelium (arrows). (Hematoxylin-eosin. Top left, ×25, bottom left inset, ×200, bottom right inset, ×200; top right, ×10, inset, ×100; middle left, ×10, bottom left inset, ×100, bottom right inset, ×100; middle right, × 200; bottom left and bottom right immunoperoxidase reaction, diaminobenzidine chromogen, ×25.)


Twenty-five lesions were rediagnosed as apocrine cysts ( Figure 4 , Middle left) because they were multilocular (10 lesions) or exhibited a diffuse or focal lining composed of an inner layer of high cuboidal to columnar cells with glassy, opaque, or deeply eosinophilic cytoplasm manifesting at least spotty apical decapitation snouts ( Figure 4 , Middle right); there was a variably distinct outer layer composed of more flattened cells. An artifact encountered focally in 19 lesions was sloughing of the inner cells into the cysts’ lumen while the basilar cells remained attached to the fibrous capsule ( Figure 4 , Middle right). Other features favoring an apocrine diagnosis were an eosinophilic lumenal content occasionally organized into globoid bodies ( Figure 4 , Middle left, bottom left inset) (22 lesions); the discovery of adjacent, preexistent apocrine glandular epithelial units ( Figure 4 , Middle left, bottom right inset) in intimate relationship to some region of the cyst (22 lesions); or a comparatively thick, circumferentially oriented, intrinsic fibrous wall that was highlighted by Masson’s trichrome stain, which distinguished it from the surrounding looser reticular dermis (7 lesions). Papillations or focal cribriform cellular pileups or increscences of the epithelial lining were not observed in any of the lesions. Staining for cytoplasmic iron was negative in 5 tested lesions (Perl’s method); PAS staining erratically revealed small positive, diastase-resistant cytoplasmic granules in the cytoplasm of 8 tested lesions.


Immunohistochemical findings


All but 3 of the 40 cysts had an outer layer of cells that at least focally stained positively for α-SMA ( Table 2 ). The most dramatic pattern ( Figure 4 , Bottom left) was that of a virtually uninterrupted layer (13 lesions), but negative regions alternating with positive ones ( Figure 4 , Bottom right) was a more common pattern (19 lesions). The most characteristic morphology was a thin outer cellular layer displaying a straight line ( Figure 5 , Top left) or even thread-like positivity indicative of myoepithelial compression and probably some degree of accompanying atrophy ( Figure 5 , Top left, inset). In some instances only a few adlumenal cells were underlain by short linear stretches of positively immunoreacting cells (5 lesions) ( Figure 5 , Top right and bottom left inset); adjacent apocrine glandular units showed more evidence of basal cell α-SMA reactivity in 3 of these cases. Staining of occasional myofibroblasts in the fibrous wall beyond the epithelial lining had to be distinguished from the positive staining of the intrinsic myoepithelium ( Figure 5 , Top right, bottom right inset). The latter often extended small processes between the basal regions of adjacent adlumenal cells, whereas a thin mantle of collagen was interposed between the epithelium and the myofibroblasts.




FIGURE 5


Immunohistochemical features of hidrocystomas of the eyelid. (Top left) Alpha-smooth muscle actin (SMA) heavy positivity is present as an uninterrupted outer myoepithelial layer (arrow) in the lesion illustrated in Figure 4 , Middle right. Some of the inner cells have shed on the upper left, leaving behind an artifactitiously naked outer myoepithelial layer (crossed arrow). This sloughing artifact was frequently seen in clear-cut apocrine cysts diagnosed by unaided light microscopy. The inset discloses another positive SMA-staining pattern created by a continuous outer linear myoepithelium with a flattened inner nonstaining cellular lining. Without the assistance of immunohistochemistry the compressed lining of this lesion would most likely provoke the diagnosis of an eccrine hidrocystoma. (Top right) SMA staining (arrows) is minimal in this region of the cyst (C). An adjacent elongated narrow lumen above and toward the right displays a more conspicuous outer myoepithelial SMA-positive layer (crossed arrows). In other regions of the same cyst (inset, bottom left) a comparatively uninterrupted myoepithelial layer (arrow) is juxtaposed to another portion of the cyst’s lining lacking any identifiable SMA staining (crossed arrow). The inset on the bottom right highlights with arrows the presence of a discontinuous myofibroblastic layer in the surrounding fibrous capsule, which has a mantle of collagen separating it from the cyst’s epithelial lining. Care must be taken to distinguish between myofibroblasts and the more intimately applied myoepithelium intrinsic to the cyst’s lining. (Middle left) Gross cystic disease fluid protein-15 (GCDFP-15) stains a portion (arrow) of the cytoplasm of the epithelial lining of an apocrine hidrocystoma. A smaller lumen above displays only cuticular staining (crossed arrow) of the cell membranes facing the lumen. A tangentially sectioned portion of the epithelial lining, shown toward the upper left of the main panel, manifests diffusely staining cytoplasm. The inset on the upper left portrays combined cuticular and cytoplasmic staining, whereas the inner inset on the bottom right demonstrates a thin cuticular staining at higher magnification and the outer inset reveals spotty cytoplasmic positivity. (Middle right) Cytokeratin 7 (CK7) cytoplasmic positivity was displayed by all tested cysts in this series, as shown particularly clearly in this serpiginous lesion and in the inset. (Bottom left) GCDFP-15 fails to stain the epithelial lining of the cyst (C), also shown in Figure 4 , Top right. However, the nearby apocrine gland units (arrows) located adjacent to the cyst and a hair (H) (cilium) stain positively. Meibomian gland alveoli (MG) display some associated dilated ducts (crossed arrows) that do not stain. (Bottom right) CK7 cytoplasmic positivity is present in the lining of the cyst (C) (main panel and inset) as well as in the wide-lumened apocrine glands (arrows) associated with a hair (H) (cilium). (Immunoperoxidase reactions, diaminobenzidine chromogen, top left, ×100, inset, ×200; top right, ×200, bottom left inset, ×200, bottom right inset, ×200; middle left, ×100, inset upper left, ×200, bottom outer inset, ×200, bottom inner inset, ×200; middle right, ×25, inset, ×200; bottom left, ×25; bottom right, ×25, inset, ×100).

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Jan 16, 2017 | Posted by in OPHTHALMOLOGY | Comments Off on A Reappraisal of Eyelid Eccrine and Apocrine Hidrocystomas: Microanatomic and Immunohistochemical Studies of 40 Lesions
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