Clinical Implications of Goblet Cells in
Dacryoadenosis and Normal Human Lacrimal
Glands
FREDERICK A. JAKOBIEC, RALPH C. EAGLE JR, MARTIN SELIG, LINA MA, AND CAROL SHIELDS
PURPOSE:
The purpose of this study was to investigate
an enlarged dacryoadenotic lacrimal gland and normal
lacrimal glands for the presence of goblet cells (mucocytes).
DESIGN: Retrospective clinicopathologic series.
METHODS: An enlarged lacrimal gland (dacryoadenosis) without obvious histopathologic alterations was
extensively evaluated histochemically, immunohistochemically, and ultrastructurally to detect the presence
of goblet cells and to compare the findings with those in
five normal lacrimal glands.
RESULTS: Granular, zymogen-rich pyramidal acinar
cells in normal glands predominated over a previously
not reported subpopulation of nongranular, palestaining cells in both dacryoadenotic and normal lacrimal
glands. These cells histochemically stained positively
with mucicarmine and Alcian blue. Immunohistochemical and electron microscopic evaluations established
that there was a displacement or replacement of cytoplasmic gross cystic disease fluid protein-15 and CK 7positive tonofilaments in the pale acinar cells by myriad
mucus granules. The goblet cells constituted approximately 2% of the normal acinar cells and 5% of dacryoadenotic acinar cells. A depletion of myoepithelial cells and
ectopic intra-acinar ductular cells were also observed in
dacryoadenosis.
CONCLUSION: Dacryoadenosis is caused by an increase
in the number of acini without individual acinar cell hyperplasia. A normal cytologic feature of the lacrimal gland
is the presence of acinar goblet cells that had been long
overlooked; they are increased in number in dacryoadenosis. Intra-acinar ductular cells and the scattered loss
of myoepithelial cells are other abnormalities in dacryoadenosis. The presence of lacrimal gland goblet cells may
Accepted for publication Jan 19, 2020.
From the David G. Cogan Laboratory of Ophthalmic Pathology and the
Department of Ophthalmology (F.A.J., L.M.), Massachusetts Eye and Ear
Infirmary and Harvard Medical School, Boston, Massachusetts, USA;
Department of Pathology (R.C.E.), Wills Eye Hospital, Sidney Kimmel
Medical College of Thomas Jefferson University, Philadelphia,
Pennsylvania, USA; Department of Pathology (M.S.), Massachusetts
General Hospital, Harvard Medical School, Boston, Massachusetts,
USA; and the Ocular Oncology Service (C.S.), Wills Eye Hospital,
Philadelphia, Pennsylvania, USA.
Inquiries to Frederick A. Jakobiec, David G. Cogan Laboratory of
Ophthalmic Pathology, Department of Ophthalmology, Massachusetts
Eye and Ear Infirmary, Suite 328, 243 Charles Street, Boston,
Massachusetts 02114, USA; e-mail: Fred_Jakobiec@meei.harvard.edu
0002-9394/$36.00
https://doi.org/10.1016/j.ajo.2020.01.029
©
2020
have physiologic implications for the precorneal tear
film and its derangements as well as for the histogenesis
of mucus-producing carcinomas. (Am J Ophthalmol
2020;213:267–282. Ó 2020 Elsevier Inc. All rights
reserved.)
S
IALADENOSIS IS AN UNUSUAL NON-NEOPLASTIC AND
non-inflammatory condition of the salivary glands.1
The term designates a diffuse enlargement without
any discernible microscopic abnormality of the involved
glandular parenchyma. The parotid is involved most often,
followed by the submandibular gland. Based on clinical information and behavior, this disorder is probably acquired
rather than congenital. Head and neck pathologists regard
the lacrimal gland as a minor salivary gland because of their
similar structures, which would imply that a condition like
sialadenosis may have an analog in the lacrimal gland.
Such a lacrimal gland lesion has not yet been described
in the medical literature, nor is it alluded to in the recently
published World Health Organization (WHO) Classification of Tumors of The Eye (2018).2 Moreover, the salivary
and lacrimal glands share many of the same neoplastic and
non-neoplastic lesions.1–3 The minor ophthalmic accessory
lacrimal glands of Wolfring (tarsi) Krause (fornices) and
Popoff (caruncle) may also be considered analogs of the
minor salivary glands of the labial, buccal, palatal, and
lingual tissues.4,5
This report describes the first corroborated diffuse,
strictly parenchymal enlargement of the lacrimal gland,
which probably is identical to sialadenosis of the major salivary glands.1 This structure was designated the dacryoadenosis. In the course of thorough histopathologic,
immunohistochemical, and electron microscopic investigations of this condition, a distinct population of mucusproducing, morphologically classic goblet cells (mucocytes) was found within many secretory acini. This led to
an assessment of the prevalence of such cells in five normal
lacrimal glands, in which smaller numbers of goblet cells
also were found.
During the previous 75 years, the presence of lacrimal
gland goblet cells in human tissue has been completely
overlooked in anatomic and pathologic studies.4–7 No
convincing histopathologic or illustrative evidence has
ever been adduced to confirm the existence in the human
lacrimal gland of morphologically acceptable goblet cells.
ELSEVIER INC. ALL
RIGHTS RESERVED.
267
The acinar cells, in addition to synthesizing zymogen
secretory granules, recently have been considered to be
the putative source of any mucosubstances that the
lacrimal gland produces.6,7 This paper provides, for the first
time, histochemical and ultrastructural proof that goblet
cells indisputably exist in the lacrimal gland.
uations in this study were interpreted in the context of
comparative data reported in relevant ophthalmic and general pathologic scientific publications.
RESULTS
SUBJECTS AND METHODS
THIS WORK IS A RETROSPECTIVE CLINICOPATHOLOGIC
study conducted under a Massachusetts Eye and Ear institutional review board-approved protocol (2019P000339) and
in compliance with Health Insurance Portability and
Accountability Act regulations and the tenets of the
Helsinki Declaration. The patients’ surgical consent form
allows publication of nonidentifiable clinical and medical
data and appropriately cropped clinical photographs. No
additional procedures or tests were performed in the patient
beyond the indicated clinical care and diagnostic and treatment regimens. After a review of clinical photographs,
medical-records and imaging studies, a case of an excised,
dramatically enlarged lacrimal gland with no apparent light
microscopic cytologic or inflammatory abnormalities was
documented with hematoxylin and eosin (H&E) staining.
Additionally, the specimen was intensively evaluated with
histochemical and immunohistochemical stains and transmission electron microscopy for the detection of any subtle
abnormalities. For electron microscopy, formalin-fixed tissue was deparaffinized and reprocessed with appropriate
glutaraldehyde fixation and osmium staining. The histochemical stains included periodic acid–Schiff (PAS),
Masson trichrome, Alcian blue, mucicarmine, phosphotungstic acid hematoxylin (PTAH), reticulin silver, and
Gomori methenamine silver (for mucus). Immunohistochemical staining included cytokeratins (CK) 7, 14, 19,
and 20, smooth muscle actin (SMA), gross cystic disease
fluid protein-15 (GCDFP-15), S-100, SOX 10, DOG-1,
chromogranin, synapsophysin, and CD 3, CD 20, CD 138,
immunoglobulin A (IgA) and IgG.
Five microscopically normal lacrimal glands that were
biopsied for suspected disease but with negative results
served as controls. The medical records of all the patients
in this study were carefully reviewed to establish the
absence of any diabetic, systemic, endocrine, metabolic,
auto-immune or viral diseases that might have had an
impact on the cytomorphology or inflammatory cell populations of the evaluated tissues. No evidence of these conditions was found in the patients’ records whose lacrimal
glands were selected for inclusion in this study. The
selected glands were studied with H&E, PAS, Alcian
blue, mucicarmine, Masson trichome, reticulin silver, and
Gomori methenamine silver stains. The immunohistochemical stains that were used were CK7, CK14,
GCDFP-15 and IgA. The findings from the performed eval268
CLINICAL HISTORY: A 45-year-old white female developed a painless swelling of her lateral left upper eyelid and
lateral canthal region that had first appeared 3 years earlier
and had slowly become more prominent (Figure 1, upper
left). Other symptoms included arthritis, dry eyes, and dry
mouth. She had undergone surgery for sinusitis 3 years previously and was receiving latanoprost eye drops for primary
open angle glaucoma, fluoxetine for depression, and desloratadine and mometasone for allergies and sinusitis. There was
no history or family history of neoplasia. Ocular examination
disclosed a prominent S-shaped configuration to her left upper eyelid without skin erythema. There was a firm subcutaneous lacrimal gland. The right gland also felt somewhat
enlarged. The palpebral lobe of the left lacrimal gland was
prominently visible when the eyelid was retracted and
partially everted (Figure 1, top right). Visual acuity, intraocular pressures, fundus examinations, ocular motility evaluation, and visual field results were within normal limits in
each eye. Palpation of the head and neck lymph nodes and
the parotid and submandibular regions was unremarkable.
Magnetic resonance imaging revealed bilateral lacrimal
gland enlargement, greater on the left. The glands appeared
to be well outlined (Figure 1, middle left and middle right,
bottom left and bottom right) with an exaggerated oblong
shape protruding beyond the orbital rim and lacking intralesional cysts that might be suggestive of dacryops
(Figures middle left and middle right). The entire left
lacrimal gland was excised in December of 2008 through
an incision in the upper eyelid crease with an extraperiosteal
approach. A distinctly enlarged, lobulated, soft, unencapsulated white-pink mass was encountered during surgery. Postoperatively, the patient healed well without ptosis or a
motility disturbance. Eleven years after surgery, there was
no evidence of a local recurrence nor of any further enlargement of the right lacrimal gland.
HISTOPATHOLOGIC FINDINGS IN THE DACRYOADENOTIC GLAND: The gross specimen that was received fresh
in the eye pathology laboratory was a single piece of pink
and white tissue measuring 26 3 18 3 6 mm. Under lowpower microscopy, lobules of lacrimal tissue displayed varying sizes (Figure 1, bottom left). The largest lobules
measured 8-10 mm in greatest diameter and were composed
of sheets of acini without any obvious internal septation or
a discernible ductular system (Figure 1, bottom right). Most
lobules were smaller, in the range of 2.0-2.5 mm in diameter, which may have reflected different levels of tissue
sectioning. At intermediate and higher power microscopy,
AMERICAN JOURNAL OF OPHTHALMOLOGY
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FIGURE 1. Clinicopathologic features of dacryoadenosis. (Top left) A 48-year-old woman developed a painless left upper eyelid and
lateral canthal swelling (crossed arrow). The right lacrimal gland was also mildly enlarged (arrow). (Top right) Retraction of the left
upper eyelid discloses an enlarged palpebral lobe (arrow) of the lacrimal gland. (Middle left) An axial computed tonogram reveals
oblong bilateral enlargements of the lacrimal glands (arrow), greater on the left (crossed arrow). The lesion is contoured to the adjacent bone and sclera. (Middle right) Coronal tomogram displays the larger left gland (crossed arrow) in comparison with the mildly
enlarged right gland (uncrossed arrow). (Bottom left) Varying sizes of the lobules of the excised right gland. (Bottom right) A
massively enlarged lobule dominates the field. Smaller glandular subunits are also seen (arrows), perhaps at different levels of the
enlarged lobules (bottom left and right, H&E stain, original magnification 34 and 312.5).
rare interlobular ducts were observed and were sometimes
enveloped by collagen (Figure 2, top left). Clusters of ductules with larger lumens occasionally were situated in close
proximity to the acinar units (Figure 2, top left, inset).
Small periductal lymphoid aggregates were occasionally
identified but were fewer in number than usual.
The acini were composed of cuboidal to columnar cells
that created small lumens and had nuclei positioned in
the mid-level of the cytoplasm. They were stuffed with
myriad eosinophilic and retractile (zymogen) granules
that extended from their apices to their bases (Figure 2,
top right). These granules were PAS-positive and diastase
resistant. Multiple clustered duct formations emerging
from the acini had larger lumens and agranular cytoplasm
(Figure 2, upper right). Close inspection of several microscopic fields revealed paler cells without granules
VOL. 213
(Figure 2, middle left) that sometimes manifested a delicate, reticulated cytoplasm. Their nuclei were displaced
to the basal region (Figure 2, middle right). The cells
with pale cytoplasm were accentuated with the Masson
trichrome (Figure 2, bottom left) and PTAH (Figure 2,
bottom right) stains, which revealed a blue-gray cytoplasmic hue. These stains also demonstrated the presence,
respectively, of myriad cytoplasmic red and blue granules
in some acinar cells, with absence of granular staining in
the pale acinar cells. The Alcian blue stain disclosed that
the pale cells were positive for mucus; these cells were
either singly dispersed in the acini (Figure 3, top left
and top right) or completely replaced them (Figure 3,
middle left). The mucicarmine stain also verified the presence of cytoplasmic mucus (Figure 3, middle right) in the
pale cells.
GOBLET CELLS IN LACRIMAL GLANDS
269
FIGURE 2. Histopathologic features of dacryoadenotic lesion. (Top left) An interlobular duct (D) is surrounded by fibrous tissue
with many nearby secretory acini. The inset depicts a cluster of nongranular ductules (D) on the right with granular secretory acini
on the left. (Top right) A nongranular trifurcating ductule (arrows) is present in the center of this field amid many granular secretory
acini. (Middle left) Pale acini (arrows) are dispersed among granular acini. (Middle right) Higher power photomicrograph of pale
staining nongranular acini (arrows). Some of the pale staining cells have a reticulated cytoplasmic appearance. (Bottom left) Masson
trichrome stain highlights the pale blue-gray cytoplasm (arrows) that lack red staining granules compared with the surrounding granular acinar cells. (D) Intralobular ductule. (Bottom right) The PTAH (PTAH) stain also demonstrates the absence of blue staining
granules in the pale-blue cytoplasm (arrows). (Hematoxylin and eosin stain; top left, original magnification 3200; top right, original
magnification 3400; middle left, original magnification 3200; middle right, original magnification 3600; bottom left, original magnification 3600; bottom right original magnification 3400).
IMMUNOHISTOCHEMICAL FINDINGS OF THE DACRYOADENOTIC GLAND: Immunostaining for CK7 revealed clus-
ters of clear cells in which the cytoplasmic tonofilaments
were dislocated peripherally beneath the cells’ limiting
membranes (Figure 3, bottom left). GCDFP-15 positivity
was strong in the granular acinar cells (Figure 3, bottom
right, left panel), negative in the ductules, and mostly
effaced in the pale acinar cells due to an absence of cytoplasmic zymogen granules (Figure 3, bottom right, right
panel). S-100, CK14, and SMA established a reduction
270
in myoepithelial cells which were only sporadically present
at the peripheries of the acini. CK14 but not SMA immunostained the basal cells of the ductules. CK19 was mildly
positive in the acini and strongly positive in the ducts. The
nuclear stain SOX10 and the luminal membrane stain
DOG-1 were both positive; chromogranin and synaptophysin were negative in all cells. CD3, CD20, CD138, and IgG
and IgA were detected throughout the stroma, with CD3þ
T-lymphocytes outnumbering CD20þ B lymphocytes.
IgGþ plasma cells (CD138þ) predominated over IgA-
AMERICAN JOURNAL OF OPHTHALMOLOGY
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FIGURE 3. Histochemical and immunohistochemical findings in dacryoadenotic lesion. (Top left) The Alcian blue stain shows mucous globules in several acinar cells. (Top right) More diffuse distribution of Alcian blue-positive mucus in the acinar cells. (Middle
left) Several adjacent acini are completely replaced by blue staining goblet cells. (Middle right) The mucicarmine test for mucin is
magenta-positive but stains the mucus less vividly than the Alcian blue stain. (Bottom left) Cytokeratin 7 immunostaining reveals
clearing of the cytoplasm of the acinar cells (arrows) caused by peripheral margination of the cytoplasmic tonofilaments due to the
presence of abundant intracellular mucus inclusions in the goblet cells. (Bottom right, left panel) Intense positive cytoplasmic immunoreactivity for GCDFP-15 (GCFGP-15) reflects staining of the acinar cytoplasmic zymogen granules. (Bottom right, right panel)
Clearing of the acinar cell cytoplasm (arrows) because of GCFGP-15 negativity due to replacement zymogen granules by goblet cell
mucous inclusions. The faint central luminal positivity represents the secretions of zymogenic cells elsewhere in the acinus. (Top left
and top right, original magnification 3600; middle left and middle right, original magnification 3600; bottom left and bottom right,
original magnification 3400).
positive plasma cells. Small scattered periductular lymphocytic aggregates were mostly composed of B-lymphocytes.
ULTRASTRUCTURAL FINDINGS OF THE DACRYOADENOTIC GLAND: The acini possessed small central lumens
created by surrounding pyramidal cells replete with bounteous electron–dense and electron-lucent cytoplasmic
zymogenic granules (Figure 4, top left) that had a mean
diameter of 1.3 mm. The electron-dense granules were
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overall more numerous than the electron-lucent granules,
which had a mean diameter of 1 mm (Figure 4, top right).
Outside of the pyramidal cells, along their basal borders,
there was an interrupted and incomplete layer of flattened
contractile myoepithelial cells (Figure 4, middle left), a
finding consistent with the immunohistochemical studies
(Figure 4, middle right inset). Many myoepithelial cells
had degenerated and disappeared leaving the acinar pyramidal cells resting directly on a basement membrane that
GOBLET CELLS IN LACRIMAL GLANDS
271
FIGURE 4. Ultrastructural features of dacryoadenotic lesion. (Top left) Acinar secretory pyramidal cells delimit a small central
lumen (L) and contain bounteous electron-dense zymogen granules. (Top right) Some of the secretory zymogen granules are comparatively electron-lucent and are admixed with the dark granules. (Middle left) Contractile myoepithelial cell (MYE) possesses cytoplasmic actin filament (F). This cell is applied to the base of a pyramidal acinar cell. (Middle right) A degenerated myoepithelial
cell (MED) has left behind remnants of its actin myofilaments, A pyramidal cell endowed with dark zymogen granules is separated
from the stroma only by its basement membrane (white arrows). The acinar cell possesses prominent rough endoplasmic reticulum.
The inset discloses the discontinuities in the myoepithelial layer with SMA immunostaining. (Bottom left) A light cell with a subplasmalemmal aggregate of small granules (open white arrows) that represents a heterotopic intracinar terminal ductular cell. Mitochondria (M) and lysosomal type granules (G) are present in the perinuclear cytoplasm. Note the large zymogen-rich adjacent acinar cells.
Crossed arrow [ nucleolus; L [ acinar lumen; N [ nucleus. (Bottom right) Electron micrograph of an intracinar goblet cell replete
with flocculo-granular mucus inclusions (MG and insert) with the exclusion of the zymogen granules. A few scattered dark granules
are either lysosomes or phagocytized melanin granule released from adjacent acinar cells. (Top left, original magnification 32,200;
top right, original magnification 32,000; middle left, original magnification 35,600; middle right, original magnification 35,600;
bottom left, original magnification 33,400; bottom right, original magnification 32,800; bottom right inset, original
magnification 31,800).
abutted the stroma. Myofilamentous remnants were sometimes the only trace of the once intact myoepithelial cells
(Figure 4, middle right). Sparsely distributed within the
acini were scattered heterotopic ductular cells with cyto272
plasmic apical granules that were much smaller (mean
diameter of 0.4 mm) than the acinar zymogen granules
(Figure 4, bottom left). The mucus-rich goblet acinar cells
were swollen with mucous granules that evinced an
AMERICAN JOURNAL OF OPHTHALMOLOGY
MAY 2020
FIGURE 5. Microscopic and histochemical features of normal lacrimal glands. (Top left) Multiple lacrimal parenchymal lobules are
generally smaller than those in the dacryoadenotic lesion. The inset demonstrates the dense granularity of the acinar cells. (Top right)
Many of the acinar cells display hypogranularity (arrows) due to discharge of most of their cytoplasmic zymogen granules into the
tears. Such relatively clear cells differ from the complete agranularity of the intra-acinar pale staining goblet cells. (Middle left)
Pale eosinophilic acinar cells lack zymogen granules intimating the presence of cytoplasmic mucous inclusions. (Middle right) Masson
trichrome stain discloses light blue cytoplasm of pale cells (arrows) that lack red staining zymogen granules, which are observed in the
adjacent serous acinar cells. (Bottom left) The arrows indicate the presence of Alcian blue-positive mucus material occupying the
entire cytoplasm of scattered intra-acinar cells. (Bottom right) Alcian blue positive material sub-totally occupies the supranuclear
cytoplasm. (Top left, H&E stain, original magnification 312.5; inset, original magnification 3400; top right and middle left,
H&E stain, original magnification 3600; middle right, original magnification 3600; bottom left, original magnification 3600; bottom right, original magnification 3600).
amorphous or flocculent, relatively electron-lucent content (Figure 4, bottom right and inset). There were
extremely rare zymogen granules in some of the mucusproducing cells.
HISTOLOGICAL AND IMMUNOHISTOCHEMICAL STUDIES
OF NORMAL LACRIMAL GLANDS COMPARED WITH THE
DACRYOADENOTIC LACRIMAL GLAND: Five samples of
normal lacrimal glands obtained from biopsies negative for
suspected disease were evaluated microscopically for the
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detection of goblet cells (mucocytes). The patients in this
group were 3 men and 2 women ranging in age from 17 to
62 years old and an average age of 48 years old. The only
clinical correlations that were discovered were a mild increase in intralobular fibrosis and an increase in adipocytes
in the septa. The individual lobules were generally smaller
than those in the dacryoadenosis case, although there
were also occasional larger ones (Figure 5, top left). Acinar
cells with pale cytoplasm devoid of zymogen granules were
dispersed among cells with the usual endowment of granules
GOBLET CELLS IN LACRIMAL GLANDS
273
FIGURE 6. Additional histochemical and immunohistochemical features of normal lacrimal glands contrasted with the dacryoadenotic gland. (Top left) Mucicarmine stain reveals the magenta staining of mucus in the acinar goblet cells (arrows). This stain is less
effective in disclosing the presence of cytoplasmic mucus in comparison with Alcian blue staining. (Top right) Several adjacent acini
are completely composed of mucicarminophilic cells. (Middle left, left panel) The reticulin stain of a normal gland demonstrates a feltwork of inter-acinar stromal fibers separating the lacrimal acini. (Middle left, right panel) There is scant stroma separating the acinar
units in the dacryoadenotic lesion. Note that the width of the acini in the normal and abnormal glands is approximately the same,
suggesting the absence of individual cellular hypertrophy or hyperplasia. (Middle right, left panel) Positive immunoglobulin A
(IgA) immunostaining of normal numbers of inter-acinar stromal plasma cells that are often found in clusters. (Middle right, right
panel) In the dacryoadenotic lesion, the population of IgA-positive plasma cells is reduced and widely dispersed. (Bottom left) In
both the normal and the dacryoadenotic glands, cytokeratin 7 stains all of the acini and an elongated ductule (arrows). No goblet cells
are present in this field. (Bottom right) Main panel on right. In contrast with the dacryoadenotic gland, in the normal lacrimal gland
the acini have a continuous outer investment of the secretory pyramidal cells by a layer of flattened myoepithelial cells, disclosed in
this panel with cytokeratin 14. Elongated and small panels on the left. In the normal and dacryoadenotic glands the intralobular, interlobular and excretory ducts (D) (shown at low power on top and high power below) manifest cytokeratin 14-positive basal cells. These
cells are probably reserve stem cells. They are not myoepithelial cells because they were SMA-negative. (Top left, original magnification 3400; top right, original magnification 3600; middle left, Immunoperoxidase stain, both panels, original magnification 3200
Immunoperoxidase stain; bottom left, original magnification 3400; bottom right panel original magnification 3400; elongated and
small bottom panels, original magnification 3200 and 3600, respectively).
(Figure 5, top right). Another cell type to be distinguished
from the typical acinar cells had a reduction of identifiable
granules due to their discharge during the cells’ metabolic
274
cycle; they sometimes had a vaguely reticulated cytoplasm
(Figure 5, middle left). The PAS stain highlighted a full
complement of zymogen granules in the acinar cells, fewer
AMERICAN JOURNAL OF OPHTHALMOLOGY
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in the hypogranular acinar cells, and none in the ductular
and pale acinar cells. The Masson trichrome stain
(Figure 5, middle right) disclosed a similar blue-gray cytoplasmic appearance of the pale cells. Also demonstrated
was the absence of red zymogen granules in the ducts and
pale cells, which contrasted with the Masson-positive bright
eosinophilic-red granules in the normal pyramidal granular
cells (Figure 5, middle right). Likewise, the PTAH stain
failed to uncover any blue-staining granules. The Alcian
blue stain demonstrated a blue mucus content in individual
agranular pale cells (Figure 5, bottom left) or in clusters of
these cells (Figure 5, bottom right). The mucicarmine and
Gomori methenamine silver stains also corroborated the
presence of mucus is the pale staining cells (Figure 6, top
left and top right).
The reticulin stain highlighted a larger number of delicate
stromal fibers in the normal glands (Figure 6, middle left, left
panel) than in the dacryoadenotic gland (Figure 6, middle
left, right panel). Immunostaining for IgA plasma cell was
substantially reduced in the inter-acinar stroma of the
dacryoadenotic lesion (Figure 6, middle right, left panel)
in comparison with their comparative abundance in the
normal glands (Figure 6, middle right, right panel).
GCDFP-15 was seen in the acinar cells but was absent in
the ductules and the pale mucus-positive acinar cells. CK7
was diffusely positive in the granular acinar pyramidal cells
and in the intra- and extralobular ductules in both the
normal and the dacryoadenotic tissue (Figure 6, bottom
left) but undetectable in the pale cells (Figure 3, bottom
left). CK14 (Figure 6, bottom right, main panel) and
SMA each stained an intact, continuous outer myoepithelial layer around the normal acinar cells but showed discontinuities in the dacryoadenotic lesion. CK14 staining
demonstrated positivity in the basal cells of the intralobular
and extralobular ductules in normal and lesional ducts
(Figure 6, bottom right, elongated and small panels).
SMA, however, was negative within the basal cells in
both the normal and the dacryoadenotic glands but strongly
positive in the intact myoepithelial layer of the normal
glands along with CK14 (Figure 6, bottom right, main panel
on right). This finding contrasted with the discontinuities in
the myoepithelial layers in the dacryoadenotic gland.
DISCUSSION
THE NEW LACRIMAL GLAND LESION DESCRIBED IN THIS
report is unlike any other epithelial disorders of this structure that has been previously reported.2 It is therefore
essential to provide some background information and an
overall review of lacrimal gland structure and functioning
to grasp its distinctive and exceptional nature.
MICROANATOMY AND BASIC PHYSIOLOGY OF THE
LACRIMAL GLAND: To understand the fundamental path-
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ologic alterations of the lacrimal and salivary glands in
dacryoadenosis and sialadenosis, one must be familiar
with the obvious and subtle normal features of these analogous but not totally identical structures.4,5,8,9 The main
lacrimal gland and the accessory lacrimal glands, like the
parotid gland and other salivary glands, have a tubaloracemose (alternatively called tubuloacinar) architecture.
Grossly, the lacrimal gland is an almond-shaped and unencapsulated structure directly abutting the orbital fat and
located in the anterolateral superior orbit. The lateral
horn of the levator aponeurosis divides the gland into a
larger posterior orbital lobe (two-thirds of the total size)
and a smaller superficial anterior palpebral lobe (onethird). The lobules in the palpebral lobe are smaller than
those in the orbital lobe. Ten to fifteen excretory ducts,
many originating in the deep orbital lobe, pass through
the palpebral lobe to deliver tears to the superolateral
conjunctival sac. Hence, total excision of the palpebral
lobe results in ablation of tear flow from a major gland;
however, the accessory glands of Krause (conjunctival
fornix), Wolfring (tarsus), and Popoff (caruncle) continue
to secrete a baseline level of tears.
Microscopically, the lacrimal gland is constituted by lobules that are separated from each other by fibrous septa that
sometimes contain adipocytes. The lacrimal lobules
comprise of collections of acini with small lumens generally
believed to contain only serous granular cells,4,5 whereas
the parotid gland is composed of seromucinous acini
containing an admixture of goblet cells.9 The serous cells
produce zymogen granules. Throughout this discussion
the terms serous, granular, and zymogen-producing have
been used interchangeably. There are intralobular and
interlobular collecting ducts without zymogen granules
that converge to create the terminal excretory ducts that
contain scattered goblet cells.4,6,10,11 In addition to the serous cells of the parotid and lacrimal glands, zymogen granules are also found in the chief cells of the gastric mucosa,
the Paneth cells of the small intestine, and the acinar cells
of the exocrine pancreas.9 It has been a matter of dogma
that the lacrimal acini lack a separate population of
mucus-producing goblet cells (mucocytes), despite the
gland’s known ability to synthesize mucosubstances.6,7,11,12
The latter have been regarded as another secondary product of the acinar cells that primarily synthesize zymogen
granules. Like the parotid gland, the accessory salivary
glands (labial and buccal) are also composed of seromucinous cells. The glands in the lingual circumvallate papillae,
however, are completely serous; on the other hand, the
palatal glands are entirely mucinous.9 The accessory
lacrimal glands are currently regarded as entirely serous,
like the major lacrimal glands.
The secretory units of the lacrimal gland are composed of
pyramidal cells that form an inconspicuous central lumen.
A monolayer of continuous flattened, contractile myoepithelial cells buttresses the outer aspect of the acini and facilitates expulsion of the tears.2,4,5 Of interest is the fact
GOBLET CELLS IN LACRIMAL GLANDS
275
that myoepithelial cells are also found in mammary, prostate, eccrine, and apocrine glands.9 Electron microscopy
discloses that the pyramidal cells possess abundant profiles
of rough surfaced endofilament reticulum that synthesize
large electron-dense and electron-lucent zymogen granules
measuring 0.5 to 1.4 mm in diameter and that are preferentially located in the apical region of the cells.4,5,8 Golgi
lamellae for product packaging are concentrated in the
mid-level and the basal cytoplasm. Zymogen granules are
compact collections of inactive pro-enzymes that require
hydrolysis by a cofactor to be activated. In this regard,
they differ from others secretory granules. Zymogen granules containing different pro-enzymes are also found in
the pancreas, gastric and intestinal mucosae, and parotid
gland. The light-to-dark ratio of lacrimal zymogen granules
is variable from cell to cell, and differences in their exact
contents await further elucidation. The intralobular ducts
can be distinguished from acinar cells by their larger lumens and the absence of cytoplasmic zymogen granules
which can be highlighted by the PAS stain. The ductular
cells exhibit smaller granules measuring around 0.4 mm
in diameter8; the large excretory ducts lack granules but
have scattered mucocytes.6,7,10 Stimulation of the mostly
aqueous lacrimal secretion is supplied by autonomic parasympathetic post-ganglionic nerve radicles, while the sympathetic terminal nerves influence tear production through
regulation of vascular flow mediated by myoid mural cell
contractions.13
A delicate interacinar collagenous interstitium contains
myriad plasma cells (estimated to be 3 million in each
gland)14 that contribute IgA to the tears. T cells and
IgG-positive plasma cells are also present in the stroma.
B lymphocytes are fewer in number and usually located
in the periductular regions in small primary follicles.15
The B-cell aggregates may represent a reserve population
for the recruitment of IgG and IgA interacinar plasma cells.
These indigenous lymphocytic cells of the gland often
mislead general pathologists unfamiliar with the gland’s
normal structure into the trap of diagnosing dacryoadenitis.
This diagnosis requires prominent lymphoid aggregates,
often with follicular organization; an increased presence
of interacinar mononuclear inflammatory cells; progressive
interacinar and periductal fibrosis; focal, segmental or
diffuse acinar destruction; and, finally, the preferential survival of the preacinar ductules. The normal lining epithelium of the intralobular and interlobular ducts does not
display goblet cells, which do appear in the more distal segments of the excretory ducts6,7 along with small pseudoapocrine apical snouts.10 The excretory ducts are formed by the
confluence of the interlobular ducts and empty into the
superolateral conjunctival fornix. The excretory ducts
may therefore be expected to retain some of the features
of the adult conjunctival epithelium.4 Ultrastructurally,
the cells lining the lacrimal ducts display collections of
small apical granules whose contents are presumably
different from those of the larger acinar zymogen granules.8
276
All of the intralobular and extralobular excretory ducts
manifest a basal epithelial layer that does not show evidence of myoepithelial differentiation and probably represents a germinal cell type.4,8 Germinal cells are not found
in the acini, which are composed of cells in a terminal differentiation state (post-mitotic) serous-granular pyramidal
cells and myoepithelial cells. The acini consequently
cannot be replaced if destroyed by inflammation.
Despite its structural simplicity and monotonous architecture, the lacrimal gland has been determined to synthesize and secrete a wide variety of biologically active
products. Some of these molecules may be constituents of
the acinar zymogen granules. Thirty years ago, the main
proteins identified in the tears were lactoferrin and lysozyme.12 One of the more interesting recent discoveries of
lacrimal protein synthesis has been the identification of
lacritin.16–25 This moiety of acinar cell secretions (which
is also found in breast tissue) appears to sustain baseline
tear production, maintains cellular homeostasis, promotes
corneal surface integration, reduces autophagy, and plays
a role in the corneal neuropathy of Sjogren’s syndrome,
in which its tear levels are reduced, thereby exacerbating
the disease. Over the years, a remarkable number of other
secreted molecules has been documented.12 Antibacterial
factors consist of phospholipase A2, lysozyme, peroxidase,
tear specific pre-albumin, and around a half-dozen different
mucins. Also contributed to the tears are retinol and
growth factors such as epidermal, fibroblastic, hepatocytic,
keratinocytic, and transforming growth factor beta. In human lacrimal glands, mucins are contributed by acinar and
excretory duct goblet cells, which incidentally make up all
of the cells of the rabbit duct system.11
ADENOSIS OF THE LACRIMAL AND SALIVARY GLANDS:
Sialadenosis and its close if not identical relative dacryoadenosis are constituted by increased numbers of cells and
acini that result in the glands’ overall enlargement.1 The
parotid gland condition, the most common site that is
affected, is typically bilateral but rarely may be unilateral.
The disease causes a decrease in the production of saliva
and a dry mouth ensues; it usually becomes clinically
apparent in the fifth and sixth decades with a slight female
predominance. A systemic disorder is associated with the
salivary gland enlargement in most cases, for example, diabetes mellitus, chronic alcoholism, anorexia nervosa and
bulimia, and malnutrition.1,26 Recently the ingestion of
certain drugs has been incriminated in a subset of cases,
such as valproic acid for epilepsy27 and catecholamine
(epinephrine) inhalants for bronchodilation.28 According
to current knowledge, a minority of cases are idiopathic,
lacking any known underlying disease.1 The reigning theory about the common causation of sialadenosis is that it
is due to a neuropathy of the parasympathetic arm of the
autonomic nervous system.29 The parasympathetic supply
to the lacrimal glands travels for a short distance within
the facial nerve and then branches off to join the Vidian
AMERICAN JOURNAL OF OPHTHALMOLOGY
MAY 2020
nerve, which synapses in the pterygopalatine ganglion.5
The post-ganglionic nerves then are grouped into the
lacrimal nerve that stimulates tear production.13 Any pathologic impingement or damage inflicted along this
extended neural route could lead to dysfunction or denervation of the parasympathetically generated signals to the
acini, causing failure to discharge their zymogen granules
which consequently accumulate and mechanically bloat
the individual acinar cells. The patient develops a dry
mouth and dry eye.
ANALYSIS OF THE CURRENT DACRYOADENOTIC
LESION: The present case of lacrimal gland enlargement
developed in a 45-year-old female who presented with
mild left superolateral eyelid and lateral canthal swelling
of approximately 3 years’ duration. She also complained
of dry eyes and a dry mouth and had previously undergone
surgery for sinusitis. The eye and oral dryness implied concurrent decreased tear and saliva secretion, respectively. It
should be pointed out that dacryoadenosis may be undetected because the lacrimal gland is rarely if ever palpated,
nor is the upper eyelid everted often enough to permit examination of the palpebral lobe beneath the conjunctiva.
Eversion of the current patient’s upper eyelid disclosed a
prominent palpebral lobe. This failure to evert the eyelid
is especially true for head and neck specialists but, unfortunately, is also too frequent a lapse on the part of many ophthalmologists. This neglect may therefore account for the
previous failure to recognize the possibility of concurrent
parotid-lacrimal or isolated lacrimal adenotic disease.
The overhang of the orbital boney rim may further
impede detection of moderate degrees of gland enlargement. There was no specific comment in the current
patient’s medical record regarding the state of her parotid
glands: however, palpation of the head and neck lymph
nodes was unrevealing, which presumably would have
included the parotid glands during the examination. Magnetic resonance imaging demonstrated bilateral, diffuse,
oblong lacrimal gland enlargements, greater on the left,
with smooth contours. The larger of the 2 glands measured
26 3 18 3 6 mm; magnetic resonance images of normal
glands have exhibited average measurements of 20 3
12 3 5 mm.30 The bilateral glands’ anteroposterior oblong
shape suggested involvement of both the palpebral and the
orbital lobes.31 There was an absence of bone changes,
including no sign of an accentuation of the normal lacrimal
osseous fossa. In contrast, epithelial tumors of the gland
create round or ovoid shapes that usually arise from the
deep and larger orbital lobe and overwhelmingly spare the
palpebral lobe. The deep orbital lobe tumors are frequently
associated with contiguous osseous alterations, either
accentuating the lacrimal fossa in benign tumors, or producing frank osseous destruction in malignant tumors.31
A complete excision of the left lacrimal gland through
the upper eyelid was performed for diagnostic and cosmetic
reasons. The right lacrimal gland enlargement was not bioVOL. 213
psied because it was felt to represent the same process as that
on the left and had caused only minor eyelid fullness and
disfigurement. Grossly, the totally excised lacrimal gland
was obviously enlarged. The greatest enlargement was in
the anteroposterior dimension due to a limitation of other
directional expansions imposed by the lateral boney orbital
wall and the firm unyielding sclera. Histopathologically,
the acini in the present case of dacryoadenosis, like those
in sialadenosis, were tightly arranged and composed of
highly eosinophilic cells owing to constipation with myriad
granules that were clearly visible in H&E and PAS stained
sections. Overall there appeared to be many more acini
than usual, thereby creating larger lobules.
The accumulation of zymogen granules suggested cell
hypertrophy or even hyperplasia, but these impressions
were actually illusory, caused by the secondary factor of
cytoplasmic engorgement with zymogen granules. The
granules were observed microscopically and ultrastructurally to be located both apically and basally in the pyramidal
acinar cells. As in sialadenosis1 the outer myoepithelial
cellular layer was focally attenuated, degenerated or totally
absent, features confirmed with SMA immunohistochemical staining and electron microscopic examination (additional ultrastructural and immunohistochemical results are
analyzed below). In the regions lacking myoepithelial cells,
basement membrane material adhered to the basal plasmalemmas of the pyramidal cells and insulated them from the
interstitial stroma. Sometimes there were only myofilamentous remnants of degenerated myoepithelial cells near the
base of the acinar cells. Another lacrimal gland disorder
that has been described in Goldenhar syndrome32 displays
a semi-selective loss of lacrimal acinar and myoepithelial
cells caused by an overgrowth and replacement of the acini
by preacinar, terminal periductular squamous (presumably
germinal) cells (CK5/6, CK14, and P63-positive but
SMA-negative). These squamoid germinal cells were
sometimes admixed with rare surviving myoepithelial and
pyramidal acinar cells. Many lobules of the involved gland,
however, were unpredictably spared.
In the current case of dacryoadenosis, the intralobular
ducts were sparse and difficult to find. Occasional backto-back clusters of ducts were identified or malformations
were observed such as ductular trifurcations. These irregular ductular features may partially explain the low level
of tear secretion along with any parasympathetic autonomic dysfunction29 and may explain why the acinar cells
were stuffed with nondischarged granules, in other words,
there was a blockage of the egress of the acinar granules
into the tears because of a reduction in the number of
accessible ducts. The scant interstitial stroma was
composed of wispy collagen fibers with a reduction of
mononuclear inflammatory cells. Juxtaposed fields stained
immunohistochemically for IgG-A prepared from the
dacryoadenosis lesion compared to normal glands showed
fewer such cells in dacryoadenosis. Small lymphoid aggregates without follicular organization were occasionally
GOBLET CELLS IN LACRIMAL GLANDS
277
present periductally or near blood vessels, but again they
were less conspicuous than in normal lacrimal glands.
Reticulin silver stain, which has an affinity for delicate
protocollagen stromal filaments and basement membranes,
was highly revealing and deserves particular attention. In
comparison with the dacryoadenosis tissue, the normal
lacrimal tissue had more interacinar reticulin fibers, that is,
the acini in dacryoadenosis were more closely packed in comparison with those in normal glands. More insightful, however, was the discovery that the width of the individual acinar
units revealed by their reticulin outlines in dacryoadenosis
was no larger than those of normal acini. This finding provides additional evidence in support of the absence of true
hyperplasia or even hypertrophy of the acinar cells in
dacryoadenosis. The overall glandular enlargement was
consequently created by an increased number of acini.
Thus, the cytoarchitectural basis for the dacryoadenosis is hyperplasia of the number of acini composed of normal-sized
cells, rather than an increased number of cells per acinus.
IDENTIFICATION OF GOBLET CELLS (MUCOCYTES) IN
THE DACRYOADENOTIC LACRIMAL GLAND: The most
startling feature in the current case of dacryoadenosis was
the discovery of goblet cells in scattered acini, either
partially or completely or subtotally replacing the serous/
zymogen cells. A review of standard textbooks and recently
published review articles on lacrimal gland structure and
function have failed to provide any conclusive proof establishing the presence of lacrimal gland mucocytes.4–8 In
H&E-stained
sections the
goblet
cells
were
noneosinophilic and displayed a faint blue-gray cytoplasmic hue devoid of any stainable zymogen granules.
The nuclei were displaced to a basal location by the cytoplasmic mucus. Both the Masson trichrome and PTAH
stains highlighted the pale cytoplasm of the mucusproducing cells and the absence of cytoplasmic zymogen
granules, contrasting with the vividly Masson trichromepositive red granules or the PTAH-positive blue granules
of the adjacent acinar serous/granular cells.
A paper published in 197233 reported the existence of
mucosubstance in some lacrimal gland cells (large type
A), but tissue culture results pointed to smaller serous cells
(referred to as type B) as the site for sialic acid mucosubstance localization. Several reviews imply or state that
the presence of goblet cells in the lacrimal gland has not
yet been convincingly confirmed.6,7,12,34,35 A study of rabbit lacrimal glands demonstrated acinar cells with combined mucinous and serous features.11 The magnification
of the published illustrations was too low to ascertain
whether any of the acinar cells staining positively with
Alcian blue and mucicarmine displayed the morphology
of true goblet cells. In one major study of the human
lacrimal system6 a handful of anchoring mucins (MUC1,
4, and 16) and secretory mucins (MUC5B and MUC7)
were detected and shown to be associated with the acinar
cells. MUC subtypes were not observed in the inter-and
278
intralobular ducts, but MUC 5AC was found in the goblet
cells of the large terminal excretory ducts.6,35 In 2 papers, it
was explicitly stated that the mucinous material is localized
to the acinar cells.34,35 According to the foregoing research
findings, the investigators proposed that the main mucinpositive cells are acinar pyramidal cells, presumably
possessing a dual capacity to synthesize mucin and zymogen
granules as well as the other proteins or glycoprotein products found in the zymogen granules and tears. These findings are in a sense analogous to the characteristics of the
conjunctival epithelium, in which the tonofilament–rich
keratinocytes also synthesize small packets or vesicles of
mucosubstance,36 whereas the conjunctival goblet cells
are responsible for most of the mucus production.37 A
recent investigation reinforces the parallelism between
lacrimal acinar cells and conjunctival squamous cells,
both of which evince non-goblet cell types that produce
similar mucins in tandem.37
In H&E-stained sections, the acinar cells in normal human lacrimal glands have been noted for some time to have
variable degrees of cytoplasmic granularity and intensities
of eosinophilia, which has been interpreted to represent
different levels of discharge of the zymogen granules at
different stages of their metabolic cycle. Such relatively
‘‘clear’’ or degranulated cells should not be confused with
the authentic pale goblet cells. Although the trichrome
and PTAH stains accentuated the clear or gray cytoplasm
of the goblet cells in dacryoadenosis, they also revealed a
miniscule dispersion of cytoplasmic granules, many of
which may be admixed mitochondria. Scant cytoplasmic
small granules accompanied by more numerous mitochondria were also detected in the goblet cells with transmission
electron microscopy. The scenario that most likely explains these mucocytic granules is that they represent those
discharged from adjacent bloated acinar cells into the
intercellular space, wherefrom they were taken up secondarily through phagocytosis by the goblet cells.
ULTRASTRUCTURAL FEATURES OF DACRYOADENOSIS:
The electron microscopic studies disclosed remarkably
well-preserved subcellular details of the deparaffinized tissue from the dacryoadenosis lesion, especially the full
extent of the serous acinar cells’ endowment with bounteous large electron-dense and electron-lucent secretory
granules; no macrogranules, however, were observed.
Goblet cells that were engorged with amorphous or flocculent cytoplasmic mucous inclusions resembling those in the
goblet cells of the conjunctiva4 were also sporadically seen
in some acini and occasionally formed clusters that
completely replaced the pyramidal cells. A curiosity seen
in the ultrastructural photomicrographs was the rare presence in some acini of scattered heterotopic ductular cells.
The latter contained the usual cytoplasmic organelles but
also possessed small apical, subplasmalemmal granules
distinctively found in normal adlumenal ductular cells,8
which contrast with the large zymogen granules of the
AMERICAN JOURNAL OF OPHTHALMOLOGY
MAY 2020
acinar cells. These duct-like intra-acinar cells may be interpreted as evidence of the multipotentiality of the acinar pyramidal cells for a double-differentiation or even for
metaplasia into duct cells. Alternatively, they may simply
represent a displacement of preacinar terminal ductular
cells (a transition zone) into an acinus. The adlumenal,
subplasmalemmal small, dense, core granules in the heterotopic cells could also be considered, based on morphologic
grounds, presumptive evidence of neurosecretory differentiation. Support for a neuroendocrine cellular lineage was
sought with immunohistochemical cytologic staining for
S-100, chromogranin, and synaptophysin, all of which
were negative. On the other hand, both SOX10 and
DOG-1 stains were positive, lending some superficial support for the fundamental functional integrity of the
dacryoadenotic acinar units.
GOBLET CELLS IN NORMAL LACRIMAL GLANDS:
The
discovery of acinar goblet cells in the current case of
dacryoadenosis prompted a search for these cells in a group
of 5 normal lacrimal glands. These control glands were obtained from 3 males and 2 females who ranged in age from
17-62 years old and had negative lacrimal gland biopsies to
rule out a suspected disease (eg, sarcoidosis or idiopathic
dacryoadenitis). The main findings associated with progressive aging noted in this group of glands were a mild to moderate increase in the amount of interacinar fibrotic stroma
and an increase in interlobular septal adipocytes, both with
advancing age. The population of stromal lymphocytes and
plasma cells was not increased with aging, nor was there
dilation of the ductular system, a feature that has been reported before in a larger series.38
The normal lacrimal gland tissues were stained with
H&E, PAS, Alcian blue, mucicarmine, reticulin, Masson
trichome, and PTAH and evaluated at 3 levels of
sectioning. A handful of immunohistochemical stains was
used, the same used to evaluate the dacryoadenosis lesion.
In all 5 specimens, with careful microscopic examination
informed by experience derived from the dacryoadenotic
lesion, clear, nongranular cells (PAS- and PTAHnegative) were found in H&E-stained sections. These cells
were highlighted with the Masson trichrome stain that
showed them to have gray-blue cytoplasm. They were
dispersed individually, focally and sparsely, or else in a
pattern that partially or totally replaced the serous cells
of an entire acinus. The Alcian blue and mucicarmine
stains unequivocally disclosed that these clear cells
harbored abundant mucus in the morphologic form of
goblet cells (mucocytes). The latter accounted for approximately two percent of the acinar cells. This control group
of lacrimal glands compellingly establishes that mucus cells
lurk within lacrimal acini on a normal anatomic basis but
require meticulous scrutiny and special stains for their
convincing detection. The authors seriously doubt that
these cells represent exhausted serous cells depleted of their
discharged zymogen granules during tear secretions; nor is
VOL. 213
it likely that one differentiated cell type (acinar serous
cell) would undergo metaplasia into another fully differentiated cell type (goblet cell). A relevant observation is that
highly differentiated cells like the ciliated columnar respiratory epithelium may undergo metaplasia into a simpler
squamous epithelium, whereas the reverse is virtually never
seen. In dacryoadenosis there is an exaggerated population
of an already established population of mucocytes, which
can account for up to 5 percent of the acinar cells.
SUPPLEMENTAL IMMUNOHISTOCHEMICAL FINDINGS:
Besides demonstrating a selective loss of myoepithelial cells
in dacryoadenosis mentioned above, immunohistochemistry contributed other valuable ancillary information.
The 2 most useful cytokeratins were CK7 and CK14. In
common with normal lacrimal glands, CK7 immunostaining of the dacryoadenosis lesion was positive in the lachrymal zymogenic acinar (pyramidal) cells and the
adlumenal cells of the ductular system, but not in the myoepithelial cells. CK7 further demonstrated the clear cytoplasm of the goblet cells in which the mucous inclusions
had crowded out the cytoplasmic CK7-positive tonofilaments so that they were displaced to the periphery adjacent
to the cell membrane. CK 14 stained the myoepithelial cells
and ductular basal cells. CK20 was totally negative in all the
parenchymal and ductular cells. The clear cell phenomenon also displayed weak GCDPF-15 immunostaining,
which highlighted residual granules in the lumen and cytoplasm of the acinar pyramidal cells but did not stain the
cytoplasmic mucous inclusions of the goblet cells. The
duct system was negative for this biomarker because duct
cells do not synthesize zymogen granules. CK14 staining
of the myoepithelial cells coexisted with SMA and S-100
positivity. SMA was negative in the basal ductular cells,
establishing that they were not myoepithelial but rather
germinal cells. It is intriguing that the ectodermally derived
myoepithelial cells of the acini co-express both SMA and
cytokeratin. Ultrastructural evaluation in the dacryoadenosis lesion failed to disclose a dual filamentary system. Cytokeratin filaments are wider than the actin myofilaments, so
that the latter may be obscured. However, actin can also be
present in a soluble form in the cytoplasm of the myoepithelial cell as in other cell types (eg, endothelial cells39). Alternative immunohistochemical stains that are helpful in
identifying myoepithelial cells are desmin, caldesmon,
p63, and glial fibrillary acidic protein. Vimentin can be
coexpressed with cytokeratin in neoplastic myoepithelial
cells; these cells are found in many salivary/lacrimal tumors,
such as pleomorphic adenomas and to a lesser extent in
adenoid cystic carcinomas. In fact, there are rare monophasic myoepithial benign and malignant tumors that have
been well characterized in the lacrimal glands.2
PUTATIVE ORIGIN OF LACRIMAL GOBLET CELLS:
As an
out-growth into the anterolateral orbit from the embryonic
forniceal conjunctival epithelium, the major lacrimal
GOBLET CELLS IN LACRIMAL GLANDS
279
anlage probably retains the capacity to initially differentiate, or less likely undergo metaplasia, into mucusproducing goblet cells. There is a report of a lobule of
lacrimal glandular tissue (a dacryoadenoma) originating
in the lower epibulbar conjunctival epithelium that was
either an acquired or a congenital lesion40 and was separate
from the glands of Krause. This lesion contained a generous
admixture of goblet cells. A metaplastic phenomenon in
the lacrimal tissue may be triggered by the systemic diseases
associated with sialadenosis,1 but the current patient was
not known to have suffered from any of these conditions.
A more straightforward and favorable proposition is that
lacrimal goblet cells are intrinsic to the gland’s makeup
and are normally present from birth onwards.
A recent intriguing and possibly relevant finding
concerning lacrimal mucus cells is represented by 5 cases
of a new and exceptional parotid neoplasm designated
mucoacinar carcinoma that combines features of a mucoepidermoid carcinoma with those of an acinic cell carcinoma.41 In this tumor granular cells were admixed with
mucus cells. This entity has implications for the potentiality of salivary and possibly lacrimal acinar parenchymal
cells for dual cellular phenotypes emerging during
neoplastic transformation. Alternatively there might be
an origin from multipotential terminal (preacinar) basal
ductular cells.42 The transitional zone where ductules
emerge from the acini probably harbors a population of
reserve stem cells that are in all likelihood metastable, plastic and mutable due to their intact mitotic capability.2,8,43
Such cells are cognate with those in the corneoscleral
limbal epithelium and at the interface between the endocervix/exocervix and esophageal/gastric mucosae.
These germinal cells are visibly proliferative in idiopathic dacryoadenitis at its scarifying end stage, at which
a plethora of ductules follow atrophy of the acini. Such
transition-zone stem cells may well account for several
lacrimal gland tumors including pleomorphic adenoma,
adenoid cystic carcinoma, and benign and malignant
myoepithelial tumors.2,8,42 It is within the realm of possibility that these stem cells possess the ability to produce
hybrid or dual cellular phenotypes–an example being the
acinar cells and their sibling goblet cells. SOX10 has
been documented to play a role in the differentiation of
stem cells (the basal ductular cells next to the acini) into
full-fledged acinar secretory cells.43 The presence of ductular cells in some dacryoadenotic acini lends credence to
this hypothesis, as well as the invasion of acini by preacinar
duct cells in the lacrimal gland in Goldenhar’s syndrome.32
Presently, validation of the metaplastic theory of the origin
of goblet cells within normal and abnormal lacrimal acini is
questionable. Furthermore, as mentioned above, metaplasia generally proceeds from more differentiated cells
into less differentiated ones, rather than from one differentiated phenotype to another differentiated phenotype. A
more supportable proposition based on the present group’s
findings is that the goblet cells in the lacrimal parenchyma
280
are an intrinsic anatomic endowment from birth. Further
pathologic and experimental investigations will be necessary for a definitive resolution of this matter.
DIFFERENTIAL DIAGNOSIS OF DACRYOADENOSIS:
The
differential diagnosis of dacryoadenosis includes conditions
that cause diffuse, oblong enlargements of the lacrimal
gland, which indicate involvement of both the palpebral
and the orbital lobes. These are composed mostly of inflammatory conditions that extend from idiopathic dacryoadenitis (a component of the spectrum of idiopathic orbital
inflammations, formerly called ‘‘pseudotumors’’), lymphoid
tumors, sarcoidosis, Sjogren’s syndrome, vasculitis, and
IgG-4-related disease.31 Ingestion of certain drugs can
result in a diffuse, noninflammatory expansion of the parotid gland1; they may eventually be found to be responsible for cryptic cases of dacryoadenosis. The latter,
however, may be difficult to appreciate due to the overhang
of the orbital bony rim and the all too infrequent palpation
of the lacrimal gland region or eversion of the upper eyelid.
To date, drugs responsible for sialadenosis have been antifertility agents, valproic acid for epilepsy,27 drugs for treating systemic hypertension, and lately, epinephrine used for
controlling asthma.1,27,28 Withdrawal of the drugs can
reverse the swelling of the parotid gland. Resolution, on
the other hand, does not happen when there is a successful
treatment of the systemic disease (eg, hypertension,
anorexia nervosa, bulimia, malnutrition, alcoholism, and
others) associated with sialadenosis.
A conceptually rather confusing differential diagnostic entity is adenomatoid hyperplasia.44–46 This benign and rare
disorder occurs preferentially in men 30-60 years old rather
than in women. Instead of a diffuse process involving the
entirety of the gland, adenomatoid hyperplasia represents a
focal nodular lesion constituted by normal, hyperplastic
parenchymal glandular tissue composed of acini and ducts.
The nodules are uninflamed and encircled by a fibrous
pseudocapsule. The nodules may be somewhat larger than
normal lobules. Most cases arise in the palate, where the
accessory salivary tissue is entirely mucinous, as are the
nodules. The parotid and submandibular glands are
characteristically spared. When the small accessory oral
glands (lingual, buccal, labial) are rarely involved, there can
be difficulty in appreciating the nodule due to the small size
of the pre-existent normal accessory gland in which the lesion
arises. The lacrimal gland has not yet been reported to generate
this kind of lesion, probably because it is predominantly a nonmucinous serous gland. No specific cause for this lesion has
been found, that is, none of the systemic diseases associated
with sialadenosis are detected. Simple excision is performed
without recurrence and the clinical course is uneventful.
TREATMENT OF SIALADENOSIS AND DACRYOADENOSIS: The most common surgical treatment for persistent
and refractory parotid sialadenosis is subtotal excision of
the swelling.1 Oral pilocarpine has allegedly induced some
AMERICAN JOURNAL OF OPHTHALMOLOGY
MAY 2020
reduction in the swelling in a few patients with bulimia. For
patients whose parotid and sublingual swellings are left alone
there is progressive involution of the excessive parenchymal
tissue. Despite this event, the glands remain enlarged
because of replacement by the adipose tissue that is in
amounts equal to the involuted glandular tissue. In the current dacryoadenosis case total excision of the larger gland
was curative. The contralateral lacrimal lesion that was
excised has not undergone further enlargement from the
clinical vantage point after eleven years of follow up.
CRediT AUTHORSHIP CONTRIBUTION
STATEMENT
FREDERICK A. JAKOBIEC: CONCEPTUALIZATION, METHOD-
ology, Writing - original draft, Writing - review & editing.
Ralph C. Eagle: Writing - original draft, Writing - review
& editing. Martin Selig: Methodology. Lina Ma: Writing original draft, Data curation. Carol Shields: Writing - review & editing.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
and none were reported.
Funding/Support: Supported by the Massachusetts Eye and Ear Department of Ophthalmology discretionary research fund.
Financial Disclosures: The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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