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Primary ductal adenocarcinoma of the lacrimal gland: A review and report of five cases
Journal Pre-proof Primary ductal adenocarcinoma of the lacrimal gland: A review and report of five cases Thonnie Rose O. See, Gustav Stålhammar, Tina Tang, Joshua S. Manusow, David R. Jordan, Jeffrey A. Nerad, Robert C. Kersten, Marc Yonkers, Nasreen A. Syed, Seymour Brownstein, Hans E. Grossniklaus PII:
S0039-6257(19)30289-9
DOI:
https://doi.org/10.1016/j.survophthal.2019.11.002
Reference:
SOP 6912
To appear in:
Survey of Ophthalmology
Received Date: 1 August 2019 Revised Date:
11 November 2019
Accepted Date: 18 November 2019
Please cite this article as: See TRO, Stålhammar G, Tang T, Manusow JS, Jordan DR, Nerad JA, Kersten RC, Yonkers M, Syed NA, Brownstein S, Grossniklaus HE, Primary ductal adenocarcinoma of the lacrimal gland: A review and report of five cases, Survey of Ophthalmology (2020), doi: https:// doi.org/10.1016/j.survophthal.2019.11.002. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.
1
Primary ductal adenocarcinoma of the lacrimal gland: A review and report of five
2
cases.
3
Thonnie Rose O. See1, Gustav Stålhammar2, Tina Tang3, Joshua S. Manusow3, David
4
R. Jordan3, Jeffrey A. Nerad , Robert C. Kersten6, Marc Yonkers7, Nasreen A. Syed4,
5
Seymour Brownstein3, Hans E. Grossniklaus1
5
6 7
1
8
Atlanta, Georgia, USA.
9
2
Departments of Ophthalmology and Pathology, Emory University School of Medicine,
Oncology and Pathology Service, St. Erik Eye Hospital and Department of Clinical
10
Neuroscience, Karolinska Institutet, Stockholm, Sweden.
11
3
12
Ottawa, Ottawa, Ontario, Canada.
13
4
14
5
15
6
16
California, U.S.A.
17
7
Departments of Ophthalmology and Pathology, The Ottawa Hospital, University of
F.C. Blodi Eye Pathology Laboratory, University of Iowa, Iowa City, IA, USA. Cincinnati Eye Institute, Cincinnati, Ohio, USA.
Department of Ophthalmology, University of California San Francisco, San Francisco,
Kaiser Permanente, South San Francisco, California, U.S.A
18 19
Corresponding author
20
Hans E. Grossniklaus MD
21
BT 428 Emory Eye Center, 1365 Clifton Rd, Atlanta, GA 30322
22
Email: [email protected]
23
ABSTRACT
24
Primary ductal adenocarcinoma (PDA) is a rare epithelial tumor of the lacrimal gland.
25
Herein we report 5 cases and reviewed 29 published cases of PDA of the lacrimal
26
gland. Among these 5 cases, the most common clinical presentation was painless
27
swelling and/or proptosis of their eye. The size of the lesions ranged from 1.6 to 2.5 cm.
28
Histopathologic examination revealed proliferations of ductal or gland-like cells with
29
vesiculated pleomorphic nuclei and prominent nucleoli. Tumor cells stained positive for
30
epithelial and apocrine differentiation markers. Immunohistochemistry for human
31
epidermal growth factor 2 (HER- 2/neu) were positive in 2 of the 4 cases. Four of the
32
five patients were alive at last follow-up. One died with bone metastases, which were
33
diagnosed 25 months post exenteration, and then survived an additional 51 months. On
34
reviewing of twenty-nine previously published cases of PDA, the mean age of diagnosis
35
was 58 years, with a male predominance (75%). Fifteen patients (54%) had distant
36
metastases, 1 (4%) had local recurrence, and 10 (37%) suffered from a PDA-related
37
death. PDA is a high-grade aggressive epithelial tumor of the lacrimal gland. Though
38
rare, awareness and recognition of this malignancy is important in order to help
39
determine prognosis and treatment options.
40 41
Keywords: primary ductal adenocarcinoma, lacrimal gland, immunohistochemistry,
42
metastases.
43
I. Introduction:
44
Primary tumors of the lacrimal gland are rare, with an estimated incidence of
45
1.3/1,000,000 per year. (24) Malignant tumors account for 25% of all lacrimal gland
46
neoplasms. (24) A previous study by Andreoli and coworkers reviewing all cases of
47
malignant orbital tumors between 1973 and 2009 from the Surveillance, Epidemiology,
48
and End Results (SEER) database, demonstrated that the most common malignant
49
tumor of the lacrimal gland was lymphoma (58, followed by adenoid cystic carcinoma
50
(13.4%), adenocarcinoma (3.8%), and mucoepidermoid carcinoma (3.6%). (2) Primary
51
ductal
adenocarcinoma
(PDA)
is
currently
classified
under
52
adenocarcinoma of the lacrimal gland in the recent World Health Organization
53
Classification of Tumors (3). It is described as a malignant epithelial tumor forming
54
ductal and/or glandular structures. PDA makes up only 2% of all epithelial lacrimal gland
55
tumors. (25) It is a high-grade aggressive malignancy that resembles salivary duct
56
carcinoma and Invasive breast cancer (no special type, formerly known as ductal
57
carcinoma). (3,13,17,24) Previously, 29 cases have been reported in the English
58
language literature. Herein, we describe five new cases, and review the clinical,
59
histological, and immunohistochemical (IHC) characteristics of the previously reported
60
cases.
61
II. Methods
62
We collected clinical and histopathologic information on 5 new cases of PDA of
63
the lacrimal gland from 4 centers in USA (Cincinnati Eye Institute, Emory Eye Center,
64
University of California San Francisco and Gavin Herbert Eye Institute) and 1 in Canada
65
(University of Ottawa Eye Institute). The first three cases had been presented in the
66
Verhoeff-Zimmerman Society Meetings in the years 2010 (Sarasota, Florida), 2012 (Big
67
Island, Hawaii), and 2018 (Durham, North Carolina). Case studies do not require
68
approval by the institutional review board (i.e. have IRB exempt status) according to
69
each institution’s respective university and hospital standards. No animals were used.
70
Formalin-fixed and paraffin-embedded biopsies and surgical specimens were collected
71
by the authors and stained for hematoxylin-eosin and IHC at each respective center.
72
Histopathological features and electron microscopy findings were evaluated by
73
pathologists and discussed during the above-mentioned meetings.
74
III. Results
75
A. Case 1
76
A 64-year-old man presented with 8-months of painless left globe prominence
77
and diplopia on left gaze. Two months post biopsy, the patient underwent left
78
orbital exenteration, followed by radiotherapy. Twenty-five months later he
79
developed extensive bone metastases. Chemotherapy (cisplatin and navelbine)
80
was initiated, after which he survived for an additional 51 months.
81
B. Case 2
82
A 62-year- old man was evaluated for 6-months of painless progressive swelling
83
of his left upper eyelid. (Figure 1.A) He reported numbness of the lateral third of
84
his brow for three weeks. There was 3 mm proptosis and restricted motility in all
85
directions of his left eye. A trans-lid crease biopsy (Figure 1.C) revealed primary
86
ductal adenocarcinoma of the lacrimal gland. (Figure 2.A) Tumor cells were
87
positive for HER-2/nei, and he was started on Trastuzumab, in addition to
88
carboplatin and taxol. Currently, he is on his 4th cycle and has not developed
89
metastases during the 3 months since diagnosis.
90
C. Case 3
91
A 53-year-old man presented with 4-months of right ptosis, a sensation of right
92
eyelid fullness and dry eye. He underwent a right orbital incisional biopsy with
93
the original pathological diagnosis of “a poorly differentiated adenocarcinoma”. A
94
right orbital exenteration was done with burring of the bone, neck dissection, and
95
free flap, followed by external beam radiation. He is alive and well with no
96
evidence of disease at 6 months of follow-up.
97
D. Case 4
98
A 61-year-old man presented with 1-month of redness, pain and discharge
99
of the left upper eyelid. He was initially managed as a case of dacryoadenitis and
100
was started on cefalexin and difluprednate eye drops with no improvement. He
101
underwent lacrimal gland excisional biopsy via left anterior orbitotomy with
102
intralesional
103
adenocarcinoma with perivascular and perineural invasion. Few days after
104
biopsy, he was noted to have a palpable cervical lymph node. He underwent left
105
lateral orbitotomy with en bloc removal and cervical node core biopsy that
106
revealed ductal adenocarcinoma. He was advised to have neck dissection ,but
107
declined and opted to transfer care.
108
steroid injection.
Pathologic
diagnosis
was
primary ductal
E. Case 5
109
A 74-year- old woman presented with a 4-months of left proptosis with
110
restricted motility on up gaze. She underwent lacrimal gland excision via lateral
111
orbitotomy. After tumor excision, she underwent fractionated radiation therapy
112
with a total of 5,400 centigray (cGy). She is alive and well with no evidence of
113
disease on imaging at 12 months of follow-up.
114
IV. Discussion:
115
What is now known about the pathology of the epithelial neoplasms of the
116
lacrimal gland is largely derived from data regarding salivary duct carcinoma and
117
invasive breast cancer (no special type, formerly known as ductal carcinoma),
118
owing to their histological resemblance. (6) PDA was first described by Katz and
119
coworkers in 1996. (8) To date, there are 29 cases reported in the English
120
language literature. These cases, including our 5 new cases, are summarized in
121
Table 1.
122
PDA of the lacrimal gland is an aggressive tumor, with a 5-year disease-
123
specific survival rate of 44% in previous reports. (3, 10, 14) Treatments include
124
complete excision, lymph node dissection, orbital bone resection and
125
radiotherapy. (3, 14)
126
A. Clinical Features
127
A total of 34 cases of PDA of the lacrimal gland, including the 5 new cases
128
presented above, were included in the study. The demographic and clinical
129
features of the cases are shown in Tables 1 and 2. PDA appears to occur more
130
commonly in men than women (3:1), with an average age at diagnosis of 58
131
years (SD 11). Interestingly, this male predominance was greater than that seen
132
in the salivary counterpart. It remains unclear as to whether this is a true trend, or
133
whether females are underrepresented due to misdiagnosis of these tumors as
134
metastatic ductal adenocarcinoma of the breast. The average size of the tumors
135
measured from 1.1 to 5 cm, with a mean diameter of 3 cm. The most common
136
presenting symptoms were painless proptosis in 10 (31%) cases and palpable
137
mass in 8 (25%) cases. Other symptoms included swelling in 7 (22%) cases,
138
diplopia in 5 (16%) cases, mechanical ptosis in 5 (15%) cases, reduction of
139
vision in 4 (12%) cases and pain in 4 (13%) cases. The average duration of
140
symptoms was 25 months. Left and right lacrimal glands were equally affected.
141
The average follow-up was 3 years (SD 3.5), with a range of 2 months to 17
142
years. No bilateral tumors have been reported. Among 33 cases with available
143
metastatic status, 16 (50%) had distant metastasis and 1 (3%) had local
144
recurrence. The lacrimal gland cases overall do not seem to be quite as
145
aggressive, with 11 (34%) patients having suffered a PDA-related death (Table
146
2), compared to those occurring in the salivary gland with a mortality rate of 60-
147
80% at 5 years. (6) Note that we find a slightly better disease-specific survival
148
than previous reports. (3, 10, 14) This behavior may somewhat be due to a
149
relative lack of a lymphatic supply in the orbit and the physical barrier that the
150
orbital bones may pose compared with the soft tissue surrounding salivary
151
glands.
152
Orbital imaging (CT, MRI) was available in 22 cases. Imaging features
153
revealed irregular shaped, heterogenous, enhancing mass in contrast T1 MRI
154
(Figure 1.B and D). Bony erosions were present in 9 (41%), muscle involvement
155
in 4 (18%), and calcification in 2 (9%) of cases.
156 157
were equally
B. Histologic Features
158
Tumor cells from the 34 cases are described as polygonal cells with granular
159
eosinophilic cytoplasm, pleomorphic and vesicular nuclei, with prominent nucleoli
160
and mitoses. (Figure 2.C) These cells are arranged in ductal structures of varying
161
patterns (glandular, cribriform and solid) with frequent central comedonecrosis
162
(Figure 2.B) resembling intraductal adenocarcinoma of the breast and salivary
163
gland. (6) Extracellular mucin may also be present, as seen in 5 cases. (16)
164
Among 30 cases with available histopathologic findings, there was neural
165
invasion in 8 (26%) vascular invasion in 7 (23%), lymphatic invasion in 7 (23%),
166
and bone invasion in 8 (26%) of cases. Ultrastructural examination of the tumor
167
disclosed anaplastic and neoplastic cells containing pleomorphic nuclei,
168
prominent intracytoplasmic lumina with apical microvilli, whorls of rough surface
169
endoplasmic reticulum, scattered desmosomes, bundles of filaments, and
170
numerous vesicles. (Figure 3). (17)
171
C. Immunohistochemistry
172
Tumor cells of our 5 cases stained positive for markers for epithelium (AE1/AE3
173
in cases 1 and 3, CK7 in cases 2, 4 and 5, EMA in cases 1, 2 and 3), apocrine
174
differentiation (AR in cases 1, 2, 4 and 5, GCDFP-15 in cases 2 and 3), cell
175
growth (HER-2/neu in cases 2 and 5, and Ki-67 in cases 1 and 2). These staining
176
characteristics coincide with the previous literature, where it has been shown that
177
PDA of the lacrimal gland usually stains positive for AR, CK 7, GCDFP-15 and
178
EMA. PR, ER and PSA are usually negative, and the Ki-67 proliferation index
179
may reach 60%. (1, 3, 10, 27) Myoepithelial markers including SMA, p63 and
180
calponin
were
negative
in
most
of
the
cases.
A
181
immunohistochemical staining reactions is shown in Table 3.
summary
of
the
182
Among 19 cases tested for HER-2/neu, 13 (68%) stained positive. Poor
183
prognosis has been associated with overexpression of ERBB2 (HER2) and p53.
184
(8) GCDFP-15, AR and EBBR2 (HER2) have been proposed as biomarkers for
185
treatment guidelines and prognosis. (27)
186
D. Differential Diagnosis
187
Histologic differential diagnosis of PDA of the lacrimal gland includes
188
carcinoma ex-pleomorphic adenoma (Ca ex-PA), mucoepidermoid carcinoma
189
(MEC) polymorphous low-grade adenocarcinoma (PLGA), and adenoid cystic
190
carcinoma (ACC).
191
PDA may arise from acinar and/or ductal cells de novo or in relation to a
192
pleomorphic adenoma. (3, 12) It is one of the rare lacrimal gland neoplasms that
193
is immunopositive for AR. PDAs are usually Immunonegative for p63, S-100 and
194
SMA. Ca ex-PA exhibits mixed features of an adenocarcinoma NOS or poorly
195
differentiated carcinoma. Like PDA, it is immunopositive for p53 howevever it is
196
also immunopositive for S-100, p63 and negative for AR. PDA can be
197
differentiated from MEC in that the latter contains 4 types of cells namely
198
mucous,
199
immunopositive for p63 and rarely with SMA and S-100. PLGAs, similar to PDA,
200
are formed by cuboidal or columnar cells arranged in tubular, ductal or cribriform
201
pattern with perineural invasion; however, unlike PDA, necrosis and mitotic
202
figures are not seen in PLGA and they are immunopositive for SMA, p63 and S-
squamous,
columnar
and
transitional
cells.
Also,
MEC
are
203
100. In ACC, tumor cells are composed of dual population of intercalated duct
204
cell and myoepithelial cells arranged most commonly in cribriform pattern. ACC
205
like PDA also has risk of perineural invasion and vascular extension. However,
206
unlike PDA, necrosis and mitosis are uncommon and ACC are immunopositive
207
for p63, S-100 and SMA.
208
summarized in Table 4.
209
E. Treatment
(3, 15, 17, 21, 25). These histologic features are
Currently there is still no guidelines for the treatment for this rare entity.
210 211
The most common treatment was exenteration with radiation therapy (ET +RT)
212
(n=10); 7 (70%) were still alive after treatment. Other treatments options includes:
213
total resection of the tumor with radiation therapy (TR+RT, n=8); total resection
214
only (TR); exenteration only (ET); total resection with chemotherapy (TR+CT)
215
and excenteration with chemotherapy and radiation therapy (ET+CT+RT).
216
Outcomes for each of the treatment modalities are summarized in Figure 5.
217
V. Conclusion:
218
PDA is a high-grade aggressive epithelial tumor of the lacrimal gland. Though rare,
219
there are an increasing numbers of reported cases. Awareness and recognition of
220
this malignancyis important in order to help determine prognosis and possible future
221
treatment options. Cumulative data are therefore necessary to better characterize
222
PDA of the lacrimal gland and develop evidence-based treatment strategies for our
223
patients.
224
VI. Method of Literature search
225
The literature review was conducted in a comprehensive PubMed search without
226
date restrictions at the end of April 2019, for references in English related to the
227
following key word: “ductal adenocarcinoma” OR “ductal carcinoma” AND lacrimal
228
gland”. Of the 22 results (abstracts), we reviewed every available full-length article
229
for specific clinical, histological and immunohistochemical reports of PDA of the
230
lacrimal gland. After this review, 3 articles were excluded due to the following: 1.)
231
two articles were metastatic lacrimal gland tumors, 2.) Chinese literature. Thereby,
232
19 articles reporting 29 patients were included in this study.
233
Funding: This work was supported in part by the National Institutes of Health [grant
234
number P30EY06360].
235
Conflict of interest: The authors declare no conflicts of interest to disclose.
236
Disclosures
237
The authors do not report any proprietary or commercial interest in the subject matter of
238
this article.
239
240
Abbreviations:
241
(α-SMA) alpha-smooth muscle actin
242
(AE1/AE3) pan-cytokeratin
243
(AR) androgen receptor
244
(CD117/cKit) tyrosine-protein kinase Kit
245
(CDX2) caudal-related homeobox gene
246
(CEA) carcinoembryonic antigen
247
(CK) cytokeratin
248
(DOG1) discovered on gastrointestinal stromal tumor 1
249
(EGFR) epidermal growth factor receptor
250
(EMA) epithelial membrane antigen
251
(ER) estrogen receptor
252
(GCDFP-15/ BRST-2) gross cystic disease fluid protein 15
253
(HER-2Nu) human epidermal growth factor receptor 2
254
(HMB45) human melanoma black
255
(HMWK) high molecular weight keratin
256
(IHC) immunohistochemical
257
(Ki-67/ MIB-1) antigen Ki-67
258
(LMWK/cam 5.2) low molecular weight cytokeratin
259
(Melan A) melanocytic antigen
260
(MMP) metalloproteinase
261
(PDA) primary ductal adenocarcinoma
262
(PSA) prostate specific antigen
263
(S-100) 100% soluble in ammonium sulfate
264
(TTF-1) Thyroid transcription factor
Legends: Table 1. Clinical features and receptor status of 29 published cases of primary ductal adenocarcinoma of the lacrimal gland. Table 2. Summary of 34 cases of primary ductal adenocarcinoma of the lacrimal gland. * Denominator for computing for the percentages are based on the number of cases with available data. Table 3. Summary of Immunohistochemical studies of the 34 cases. Table 4. Summary of histopathologic and immunohistochemical features of the differential diagnoses. Figure 1. Clinical presentation and imaging findings of case 2. A-D. A: 62-year- old man with progressive swelling of his left upper eyelid (arrow). B: trans-lid crease incisional biopsy showing gross appearance of the mass (arrow). C: Coronal MRI with contrast showed a large enhancing mass with irregular border of the left lacrimal gland (arrow). D: Axial MRI with contrast showed a large enhancing mass (arrow) extending to the posterior orbit. Figure 2. Histopathologic sections of case 2. A: Tumour cells displayed glandular configurations (arrow). (H.E, hematoxylin and eosin staining, 10x) B: areas with comedonecrosis (asterix). (H.E, hematoxylin and eosin staining, 200x) C: Tumour cells showed pleomorphic, vesiculated nuclei (arrow head), prominent nuclei, abundant eosinophilic cytoplasm and scattered mitotic figures. F. Nuclear expression of androgen receptor. (immunohistochemical staining, 400x).
Figure 3. Electron microscopy of case 1. Ultrastructural examination of case 1 anaplastic
and
neoplastic
cells
containing
pleomorphic
nuclei,
prominent
intracytoplasmic lumina (L) and nucleoli (N) with apical microvilli (arrow heads) (4000x); whorls of rough surface endoplasmic reticulum (arrow) (17000x). Figure 4. Histopathologic differential diagnosis of primary ductal adenocarcinoma. Figure 5. Summary of treatment strategy and their outcome. Excenteration with radiation therapy (ET +RT); total resection of the tumor with radiation therapy (TR+RT) total resection only (TR); excenteration only (ET); total resection with chemotherapy (TR+CT) and excenteration with chemotherapy and radiation therapy (ET+CT+RT).
References: 1. Andreasen S, Grauslund M, Heegaard S. Lacrimal gland ductal carcinomas: Clinical, Morphological and Genetic characterization and implications for targeted treatment. Acta Ophthalmol. 2017;95(3):299-306. 2. Andreoli MT, Aakalu V, Setabutr P. Epidemiological trends in malignant lacrimal gland tumors. Otolaryngol Head Neck Surg. 2015;152(2):279-83. 3. Alkatan H, Roberts F, White VA. Adenocarcinoma of the lacrimal gland. In Grossniklaus HE, Eberhart CG, Kivelä TT. WHO Classification of Tumours of the Eye. WHO Press, Geneva, 2018. 4. Damasceno RW, Holbach LM. Primary ductal adenocarcinoma of the lacrimal gland: case report. Arq Bras Oftalmol. 2012;75(1):64-6. 5. Dennie T. Metastatic, her-2 amplified lacrimal gland carcinoma with response to lapatinib treatment. Case Rep Oncol Med. 2015;2015:262357. 6. Ellis GL, Auclair PL, American Registry of Pathology., Armed Forces Institute of Pathology (U.S.). Tumors of the salivary glands. Washington, DC: American Registry of Pathology in collaboration with the Armed Forces Institute of Pathology; 2008. 7. Ishida M, Iwai M, Yoshida K, et al. Primary ductal adenocarcinoma of the lacrimal sac: the first reported case. Int J Clin Exp Pathol. 2013;6(9):1929-34. 8. Katz SE, Rootman J, Dolman PJ, et al. Primary ductal adenocarcinoma of the lacrimal gland. Ophthalmology. 1996;103(1):157-62. 9. Kim MJ, Hanmantgad S, Holodny AI. Novel management and unique metastatic pattern of primary ductal adenocarcinoma of the lacrimal gland. Clin Exp Ophthalmol. 2008;36(2):194-6. 10. Kubota T, Moritani S, Ichihara S. Clinicopathologic and immunohistochemical features of primary ductal adenocarcinoma of lacrimal gland: five new cases and review of literature. Graefes Arch Clin Exp Ophthalmol. 2013;251(8):2071-6. 11. Krishnakumar S, Subramanian N, Mahesh L, et al. Primary ductal adenocarcinoma of the lacrimal gland in a patient with neurofibromatosis. Eye (Lond). 2003;17(7):843-5. 12. Kurisu Y, Shibayama Y, Tsuji M, et al. A case of primary ductal adenocarcinoma of the lacrimal gland: histopathological and immunohistochemical study. Pathol Res Pract. 2005;201(1):49-53. 13. Lakhani SR, Ellis IO, Schnitt SJ, et al. WHO Classification of Tumours of the Breast: Invasive carcinoma of no special type. WHO Press, Geneva, 2012. 14. Lau LL, Lung CK, Ahmad SS. A benign presentation of primary ductal adenocarcinoma of lacrimal gland: A rare malignancy. Indian J Ophthalmol. 2015;63(11):856-8. 15. Lee YJ, Oh YH. Primary ductal adenocarcinoma of the lacrimal gland. Jpn J Ophthalmol. 2009;53(3):268-70. 16. Milman T, Shields JA, Husson M, et al. Primary ductal adenocarcinoma of the lacrimal gland. Ophthalmology. 2005;112(11):2048-51. 17. Min KW, Park HK, Kim WY,et al. Primary ductal adenocarcinoma of the lacrimal gland, associated with abundant intracytoplasmic lumens containing some eosinophilic hyaline globules: cytological, histological and ultrastructural findings. Ultrastruct Pathol. 2014;38(5):363-6.
18. Nasu M, Haisa T, Kondo T, et al. Primary ductal adenocarcinoma of the lacrimal gland. Pathol Int. 1998;48(12):981-4. 19. Patel SR, Cohen P, Barmettler A. Primary ductal adenocarcinoma of the lacrimal gland with changing genetic analysis mutations. Orbit. 2018;37(6):463-7. 20. Paulino AF, Huvos AG. Epithelial tumors of the lacrimal glands: a clinicopathologic study. Ann Diagn Pathol. 1999;3(4):199-204. 21. Ricci M, Amadori E, Chiesa F, et al. Single bone metastasis from adenocarcinoma of the lacrimal gland: a case report. Future Oncol. 2014;10(10):1735-9. 22. Takahira M, Minato H, Takahashi M, et al. Cystic carcinoma ex pleomorphic adenoma of the lacrimal gland. Ophthalmic Plast Reconstr Surg. 2007;23(5):407-9. 23. Touil A, El Abbassi S, Echchikhi Y, et al. Adenocarcinoma of the lacrimal gland: a case report. J Med Case Rep. 2017;11(1):257. 24. Von Holstein SL, Therkildsen MH, Prause JU, et al. Lacrimal gland lesions in Denmark between 1974 and 2007. Acta Ophthalmol. 2013;91(4):349-54. 25. Weis E, Rootman J, Joly TJ, et al. Epithelial lacrimal gland tumors: pathologic classification and current understanding. Arch Ophthalmol. 2009;127(8):1016-28. 26. Yang HY, Wu CH, Tsai CC, et al. Primary ductal adenocarcinoma of lacrimal gland: Two case reports and review of the literature. Taiwan J Ophthalmol. 2018;8(1):42-8. 27. Zhu MM, Cui HG, Teng XD. GCDFP-15, AR, and Her-2 as biomarkers for primary ductal adenocarcinoma of the lacrimal gland: a Chinese case and literature review. Onco Targets Ther. 2015;8:1017-24.
Table 1. Clinical features and receptor status of 29 published cases and 5 new cases of primary ductal adenocarcinoma of the lacrimal gland. Case
First author, year
Age/Sex/ Laterality
Complaint Prominence and diplopia Swelling of upper eyelid
IHC
TNM
Size (cm)
Duration
Her 2
AR
ER
PR
T2N0M0
2.5
8 months
-
+
-
-
ET+RT
76
Bone metastasis
DWD
T2N0M0
3.8
6 months
+
+
N/A
N/A
TR + CT
3
none
AWD
T1N0M0
1.6
4 months
-
N/A
-
-
ET + neck dissection and free flap +RT
6
none
AOD
T1aN1M0
1.9
1 month
+
+
N/A
N/A
ET + LN biopsy
2
Neck LN
AWD
1
See, 2019*
64/M/L
2
See, 2019*
62/M/L
3
See, 2019*
53/M/R
4
See, 2019*
61/M/L
5
See, 2019*
74/F/L
Pain, redness of upper lid Proptosis
T2N0M0
2.3
4 months
+
+
N/A
N/A
6
Yang, 2018(26)
64/M/L
Proptosis
T4N0M0
3.9
3 months
N/A
+
N/A
N/A
7
Yang, 2018(26)
64/M/R
Proptosis and diplopia
T4N0M0
5.0
3 weeks
N/A
+
N/A
N/A
8
Patel, 2018(19)
54/M/R
T2N1M1
3.4
3 years
+
+
N/A
N/A
9
Andreasen, 2017(1)
77/M/L
T4bN0M0
3.2
2 weeks
+
+
-
-
10
11
Andreasen, (1) 2017
Andreasen, 2017(1)
Ptosis, fullness and dry eye
Decreasing vision and proptosis Xerophthalmi a, diplopia and blepharitis
Treatment
TR +RT ET +CT + RT ET + bone removal + RT + CT
Follow-up (months)
Metastasis
Status
12
none
AOD
27
none
AOD
21
Neck LN, bilateral upper lobes of the lung
AWD
TR + bone flap +CT
10
Ipsilateral parotid gland and liver
AWD
ET + RT
19
none
DOC
DWD
53/M/L
Lumbar pain, severe headache and proptosis
T1N0M1
2.0
5 years
+
+
-
-
None
60
Lungs liver, suprarenal glands, vertebral column, cerebellum, LN of the neck, thorax, abdomen and groin
73/M/R
Progressive inferonasal globe displacement and proptosis
T4bN0M0
3.0
5 years
+
-
-
-
TR+RT
17
none
DWD
13
none
DWD
48
Vertebrae and
DWD
12
Touil, 2017(23)
55/M/R
Lower lid lesion
13
Dennie,
53/F/R
Progressive
N/A
4.0
7 years
N/A
N/A
N/A
N/A
T4cN0M0
3.0
2.5 years
+***
N/A
-
-
ET + LN dissection + ipsilateral parotidect omy Subtotal
2015(5)
14
Lau, 2015(14)
34/F/R
15
Zhu, 2015
(27)
49/F/L
16
Ricci, 2014(21)
71/M/R
17
**Min, 2014(17)
46/M/L
18
Kubota, 2013(10)
75/M/R
19
Kubota, 2013(10)
67/M/L
20
Kubota, 2013(10)
53/M/R
21
Kubota, 2013(10)
39/M/L
22
Kubota, 2013(10)
46/F/R
23
Damasceno, 2012(4)
78/M/R
24
**Ishida, 2009(7)
70/F/L
25
Lee, 2009(15)
50/M/R
26
(4)
Weis, 2009
N/A
headache, blurring of vision and proptosis Progressive, painless swelling upper lid Painless, palpable mass, double vision and epiphora Lumbar pain and exophthalmo s Exophthalmo s and blurred vision
resection + RT + lapatinib
T2N0M0
2.8
1 year
N/A
N/A
N/A
N/A
T1N0M0
1.1
6 months
+
+
-
T2NxM1
2.3
3 years
+
+
T4bN0M0
3.0
2 months
N/A
N/A
cerebellum
TR
2
none
AOD
-
ET + RT
9
none
AOD
-
-
ET + RT + androgen blockade
19
Lumbar spine 1
AWD
N/A
N/A
TR + RT
5
none
AOD
24
Cervical LN and lung
DWD
T4bN1M0
2.8
3 months
+
+
-
-
RT + resection of submandi bular LN
T2N0M0
4
6 months
-
+
-
-
ET + bone removal
16
Submandibular LN, bone and liver
DWD
T4aN0M0
3.7
18 months
-
+
-
-
ET + RT
52
Spine, brain and liver
DWD
Upper eyelid swelling
T4bN0M0
2.5
6 months
+
+
-
-
120
Lung and brain
AWD
Upper eyelid swelling
T2N0M0
2.5
1 month
+
+
-
-
66
none
AOD
T2N0M0
2.4
6 months
+
N/A
N/A
N/A
24
Ipsilateral parotid and cervical LN
DWD
T2NxMx
2.5
N/A
-
-
-
-
8
none
AWD
T2N0M0
4.0
2 years
-
N/A
-
-
10
none
AOD
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
Upper eyelid swelling Upper eyelid swelling and ptosis Upper eyelid swelling and ptosis
Diplopia, painless, palpable mass and restricted abduction Painful exophthalmo s Exophthalmo s N/A
ET + bone removal + RT Globe sparing TR
ET
TR (2x) for recurrence + RT Globe sparing TR TR + RT
27
Kim, 2008(9)
47/M/L
28
**Takahira, 2007(22)
48/F/L
29
Milman, (16) 2005
59/M/R
30
Kurisu, 2005(12)
Lacrimal gland mass
Progressive exophthalmo s Orbital mass and blepharoptos is
67/M/R
Visual disturbance
31
Krishnakumar, 2003(11)
46/M/L
Firm irregular mass with progressive ptosis in the orbit
32
Paulino, 1999(25)
52/F/R
N/A
ET + RT + CT
204
Chest skin, lymphatics, ilium, rib, femur, spine, orbit, postnasal region and cerebellum
-
TR + RT
N/A
none
N/A
ET + RT
6
Parotid and cervical LN
AWD
DWD
N/A
N/A
N/A
N/A
N/A
N/A
N/A
T2N0M0
3.8
3 years
+
+
-
T1N1M1
1.5
15 years
-
N/A
-
DWD
N/A
T2N0M0
3.0
N/A
N/A
N/A
N/A
N/A
TR + RT
34
Local recurrence, brain, lungs, liver, pancreas, common bile duct
N/A
N/A
2 years
N/A
N/A
N/A
N/A
ET + RT
19
None Neurofibroma
AOD
N/A
N/A
N/A
N/A
N/A
N/A
N/A
ET + RT
72
Neck LN
AOD
TR + Sella turcica to the Small nodule frontal subdural spaces (18) 33 Nasu, 1998 67/M/R in the upper N/A 2.5 N/A N/A N/A N/A 24 craniotom of the right eyelid y + RT temporal lobe TR + Lump in the Frontotem 34 Katz, 1995(8) 68/M/R upper outer N/A 4 6 months N/A N/A N/A N/A poral 10 none eyelid crainiotom y, + RT *This study; ** Malignant component of carcinoma ex pleomorphic adenoma; *** Her 2 nu gene amplified; IHC: Immunohistochemistry; AR: Androgen receptor; ER: Estrogen receptor; PR: Progesterone receptor; ET: Exenteration; TR: Tumor resection; RT: Radiation Therapy; CT: Chemotherapy; LN: Lymph node; AOD: Alive without disease; AWD: Alive with disease; DOC: Dead of other cause; DWD: PDA-related death.
AOD
AOD
Table 2. Summary of 34 cases of PDA of the lacrimal gland. Feature Age at presentation (years) Sex, n (%) M F Size range (cm) Average duration of symptoms (months) Perineural invasion, n Vascular invasion, n Local recurrence, n Lymph node metastasis, n Distant metastases, n PDA-related death, n Dead of other cause, n Alive with disease, n Alive without disease, n
34-78 (SD 11.48) 25 (76%) 8 (24%) 1.1-5.0 (SD 0.90) 32 (SD 41.28) 8 (26%) 7 (23%) 1 (3%) 8 (24%) 16 (50%) 11 (34%) 1 (3%) 8 (25%) 12 (38%)
Table 3. Summary of Immunohistochemical studies of the 32 cases. Marker Cell growth and proliferation
Immunohistochemical stain
Her-2/neu Ki-67 EGFR Metaplasia p53 Cyclin D1 Apocrine differentiation GCDFP-15 Mammaglobin AR Epithelial differentiation AE1/AE3 CK7 CK19 CK17 CK18 CK10 HMWK LMWK CK5 P63 CK20 EMA CEA Myoepithelial cells α-SMA Calponin Hormone receptors ER PR Prostate PSA Thyroid and lung TTF-1 Gastrointestinal DOG1 CDX2 Melanocytes S-100 HMB45 Melan A SOX-10 Neuroendocrine NSE Chromogranin
Number of (+) Cases/ Number Tested 14/21 12/12 4/4 10/13 3/3 13/14 1/1 16/18 7/7 18/18 5/5 4/4 2/2 1/1 1/1 2/2 2/5 0/4 3/12 10/10 5/8 0/7 0/2 0/18 0/16 0/11 0/6 1/4 0/1 1/14 0/2 0/1 0/1 0/1 0/2
S0039-6257(19)30289-9
DOI:
https://doi.org/10.1016/j.survophthal.2019.11.002
Reference:
SOP 6912
To appear in:
Survey of Ophthalmology
Received Date: 1 August 2019 Revised Date:
11 November 2019
Accepted Date: 18 November 2019
Please cite this article as: See TRO, Stålhammar G, Tang T, Manusow JS, Jordan DR, Nerad JA, Kersten RC, Yonkers M, Syed NA, Brownstein S, Grossniklaus HE, Primary ductal adenocarcinoma of the lacrimal gland: A review and report of five cases, Survey of Ophthalmology (2020), doi: https:// doi.org/10.1016/j.survophthal.2019.11.002. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.
1
Primary ductal adenocarcinoma of the lacrimal gland: A review and report of five
2
cases.
3
Thonnie Rose O. See1, Gustav Stålhammar2, Tina Tang3, Joshua S. Manusow3, David
4
R. Jordan3, Jeffrey A. Nerad , Robert C. Kersten6, Marc Yonkers7, Nasreen A. Syed4,
5
Seymour Brownstein3, Hans E. Grossniklaus1
5
6 7
1
8
Atlanta, Georgia, USA.
9
2
Departments of Ophthalmology and Pathology, Emory University School of Medicine,
Oncology and Pathology Service, St. Erik Eye Hospital and Department of Clinical
10
Neuroscience, Karolinska Institutet, Stockholm, Sweden.
11
3
12
Ottawa, Ottawa, Ontario, Canada.
13
4
14
5
15
6
16
California, U.S.A.
17
7
Departments of Ophthalmology and Pathology, The Ottawa Hospital, University of
F.C. Blodi Eye Pathology Laboratory, University of Iowa, Iowa City, IA, USA. Cincinnati Eye Institute, Cincinnati, Ohio, USA.
Department of Ophthalmology, University of California San Francisco, San Francisco,
Kaiser Permanente, South San Francisco, California, U.S.A
18 19
Corresponding author
20
Hans E. Grossniklaus MD
21
BT 428 Emory Eye Center, 1365 Clifton Rd, Atlanta, GA 30322
22
Email: [email protected]
23
ABSTRACT
24
Primary ductal adenocarcinoma (PDA) is a rare epithelial tumor of the lacrimal gland.
25
Herein we report 5 cases and reviewed 29 published cases of PDA of the lacrimal
26
gland. Among these 5 cases, the most common clinical presentation was painless
27
swelling and/or proptosis of their eye. The size of the lesions ranged from 1.6 to 2.5 cm.
28
Histopathologic examination revealed proliferations of ductal or gland-like cells with
29
vesiculated pleomorphic nuclei and prominent nucleoli. Tumor cells stained positive for
30
epithelial and apocrine differentiation markers. Immunohistochemistry for human
31
epidermal growth factor 2 (HER- 2/neu) were positive in 2 of the 4 cases. Four of the
32
five patients were alive at last follow-up. One died with bone metastases, which were
33
diagnosed 25 months post exenteration, and then survived an additional 51 months. On
34
reviewing of twenty-nine previously published cases of PDA, the mean age of diagnosis
35
was 58 years, with a male predominance (75%). Fifteen patients (54%) had distant
36
metastases, 1 (4%) had local recurrence, and 10 (37%) suffered from a PDA-related
37
death. PDA is a high-grade aggressive epithelial tumor of the lacrimal gland. Though
38
rare, awareness and recognition of this malignancy is important in order to help
39
determine prognosis and treatment options.
40 41
Keywords: primary ductal adenocarcinoma, lacrimal gland, immunohistochemistry,
42
metastases.
43
I. Introduction:
44
Primary tumors of the lacrimal gland are rare, with an estimated incidence of
45
1.3/1,000,000 per year. (24) Malignant tumors account for 25% of all lacrimal gland
46
neoplasms. (24) A previous study by Andreoli and coworkers reviewing all cases of
47
malignant orbital tumors between 1973 and 2009 from the Surveillance, Epidemiology,
48
and End Results (SEER) database, demonstrated that the most common malignant
49
tumor of the lacrimal gland was lymphoma (58, followed by adenoid cystic carcinoma
50
(13.4%), adenocarcinoma (3.8%), and mucoepidermoid carcinoma (3.6%). (2) Primary
51
ductal
adenocarcinoma
(PDA)
is
currently
classified
under
52
adenocarcinoma of the lacrimal gland in the recent World Health Organization
53
Classification of Tumors (3). It is described as a malignant epithelial tumor forming
54
ductal and/or glandular structures. PDA makes up only 2% of all epithelial lacrimal gland
55
tumors. (25) It is a high-grade aggressive malignancy that resembles salivary duct
56
carcinoma and Invasive breast cancer (no special type, formerly known as ductal
57
carcinoma). (3,13,17,24) Previously, 29 cases have been reported in the English
58
language literature. Herein, we describe five new cases, and review the clinical,
59
histological, and immunohistochemical (IHC) characteristics of the previously reported
60
cases.
61
II. Methods
62
We collected clinical and histopathologic information on 5 new cases of PDA of
63
the lacrimal gland from 4 centers in USA (Cincinnati Eye Institute, Emory Eye Center,
64
University of California San Francisco and Gavin Herbert Eye Institute) and 1 in Canada
65
(University of Ottawa Eye Institute). The first three cases had been presented in the
66
Verhoeff-Zimmerman Society Meetings in the years 2010 (Sarasota, Florida), 2012 (Big
67
Island, Hawaii), and 2018 (Durham, North Carolina). Case studies do not require
68
approval by the institutional review board (i.e. have IRB exempt status) according to
69
each institution’s respective university and hospital standards. No animals were used.
70
Formalin-fixed and paraffin-embedded biopsies and surgical specimens were collected
71
by the authors and stained for hematoxylin-eosin and IHC at each respective center.
72
Histopathological features and electron microscopy findings were evaluated by
73
pathologists and discussed during the above-mentioned meetings.
74
III. Results
75
A. Case 1
76
A 64-year-old man presented with 8-months of painless left globe prominence
77
and diplopia on left gaze. Two months post biopsy, the patient underwent left
78
orbital exenteration, followed by radiotherapy. Twenty-five months later he
79
developed extensive bone metastases. Chemotherapy (cisplatin and navelbine)
80
was initiated, after which he survived for an additional 51 months.
81
B. Case 2
82
A 62-year- old man was evaluated for 6-months of painless progressive swelling
83
of his left upper eyelid. (Figure 1.A) He reported numbness of the lateral third of
84
his brow for three weeks. There was 3 mm proptosis and restricted motility in all
85
directions of his left eye. A trans-lid crease biopsy (Figure 1.C) revealed primary
86
ductal adenocarcinoma of the lacrimal gland. (Figure 2.A) Tumor cells were
87
positive for HER-2/nei, and he was started on Trastuzumab, in addition to
88
carboplatin and taxol. Currently, he is on his 4th cycle and has not developed
89
metastases during the 3 months since diagnosis.
90
C. Case 3
91
A 53-year-old man presented with 4-months of right ptosis, a sensation of right
92
eyelid fullness and dry eye. He underwent a right orbital incisional biopsy with
93
the original pathological diagnosis of “a poorly differentiated adenocarcinoma”. A
94
right orbital exenteration was done with burring of the bone, neck dissection, and
95
free flap, followed by external beam radiation. He is alive and well with no
96
evidence of disease at 6 months of follow-up.
97
D. Case 4
98
A 61-year-old man presented with 1-month of redness, pain and discharge
99
of the left upper eyelid. He was initially managed as a case of dacryoadenitis and
100
was started on cefalexin and difluprednate eye drops with no improvement. He
101
underwent lacrimal gland excisional biopsy via left anterior orbitotomy with
102
intralesional
103
adenocarcinoma with perivascular and perineural invasion. Few days after
104
biopsy, he was noted to have a palpable cervical lymph node. He underwent left
105
lateral orbitotomy with en bloc removal and cervical node core biopsy that
106
revealed ductal adenocarcinoma. He was advised to have neck dissection ,but
107
declined and opted to transfer care.
108
steroid injection.
Pathologic
diagnosis
was
primary ductal
E. Case 5
109
A 74-year- old woman presented with a 4-months of left proptosis with
110
restricted motility on up gaze. She underwent lacrimal gland excision via lateral
111
orbitotomy. After tumor excision, she underwent fractionated radiation therapy
112
with a total of 5,400 centigray (cGy). She is alive and well with no evidence of
113
disease on imaging at 12 months of follow-up.
114
IV. Discussion:
115
What is now known about the pathology of the epithelial neoplasms of the
116
lacrimal gland is largely derived from data regarding salivary duct carcinoma and
117
invasive breast cancer (no special type, formerly known as ductal carcinoma),
118
owing to their histological resemblance. (6) PDA was first described by Katz and
119
coworkers in 1996. (8) To date, there are 29 cases reported in the English
120
language literature. These cases, including our 5 new cases, are summarized in
121
Table 1.
122
PDA of the lacrimal gland is an aggressive tumor, with a 5-year disease-
123
specific survival rate of 44% in previous reports. (3, 10, 14) Treatments include
124
complete excision, lymph node dissection, orbital bone resection and
125
radiotherapy. (3, 14)
126
A. Clinical Features
127
A total of 34 cases of PDA of the lacrimal gland, including the 5 new cases
128
presented above, were included in the study. The demographic and clinical
129
features of the cases are shown in Tables 1 and 2. PDA appears to occur more
130
commonly in men than women (3:1), with an average age at diagnosis of 58
131
years (SD 11). Interestingly, this male predominance was greater than that seen
132
in the salivary counterpart. It remains unclear as to whether this is a true trend, or
133
whether females are underrepresented due to misdiagnosis of these tumors as
134
metastatic ductal adenocarcinoma of the breast. The average size of the tumors
135
measured from 1.1 to 5 cm, with a mean diameter of 3 cm. The most common
136
presenting symptoms were painless proptosis in 10 (31%) cases and palpable
137
mass in 8 (25%) cases. Other symptoms included swelling in 7 (22%) cases,
138
diplopia in 5 (16%) cases, mechanical ptosis in 5 (15%) cases, reduction of
139
vision in 4 (12%) cases and pain in 4 (13%) cases. The average duration of
140
symptoms was 25 months. Left and right lacrimal glands were equally affected.
141
The average follow-up was 3 years (SD 3.5), with a range of 2 months to 17
142
years. No bilateral tumors have been reported. Among 33 cases with available
143
metastatic status, 16 (50%) had distant metastasis and 1 (3%) had local
144
recurrence. The lacrimal gland cases overall do not seem to be quite as
145
aggressive, with 11 (34%) patients having suffered a PDA-related death (Table
146
2), compared to those occurring in the salivary gland with a mortality rate of 60-
147
80% at 5 years. (6) Note that we find a slightly better disease-specific survival
148
than previous reports. (3, 10, 14) This behavior may somewhat be due to a
149
relative lack of a lymphatic supply in the orbit and the physical barrier that the
150
orbital bones may pose compared with the soft tissue surrounding salivary
151
glands.
152
Orbital imaging (CT, MRI) was available in 22 cases. Imaging features
153
revealed irregular shaped, heterogenous, enhancing mass in contrast T1 MRI
154
(Figure 1.B and D). Bony erosions were present in 9 (41%), muscle involvement
155
in 4 (18%), and calcification in 2 (9%) of cases.
156 157
were equally
B. Histologic Features
158
Tumor cells from the 34 cases are described as polygonal cells with granular
159
eosinophilic cytoplasm, pleomorphic and vesicular nuclei, with prominent nucleoli
160
and mitoses. (Figure 2.C) These cells are arranged in ductal structures of varying
161
patterns (glandular, cribriform and solid) with frequent central comedonecrosis
162
(Figure 2.B) resembling intraductal adenocarcinoma of the breast and salivary
163
gland. (6) Extracellular mucin may also be present, as seen in 5 cases. (16)
164
Among 30 cases with available histopathologic findings, there was neural
165
invasion in 8 (26%) vascular invasion in 7 (23%), lymphatic invasion in 7 (23%),
166
and bone invasion in 8 (26%) of cases. Ultrastructural examination of the tumor
167
disclosed anaplastic and neoplastic cells containing pleomorphic nuclei,
168
prominent intracytoplasmic lumina with apical microvilli, whorls of rough surface
169
endoplasmic reticulum, scattered desmosomes, bundles of filaments, and
170
numerous vesicles. (Figure 3). (17)
171
C. Immunohistochemistry
172
Tumor cells of our 5 cases stained positive for markers for epithelium (AE1/AE3
173
in cases 1 and 3, CK7 in cases 2, 4 and 5, EMA in cases 1, 2 and 3), apocrine
174
differentiation (AR in cases 1, 2, 4 and 5, GCDFP-15 in cases 2 and 3), cell
175
growth (HER-2/neu in cases 2 and 5, and Ki-67 in cases 1 and 2). These staining
176
characteristics coincide with the previous literature, where it has been shown that
177
PDA of the lacrimal gland usually stains positive for AR, CK 7, GCDFP-15 and
178
EMA. PR, ER and PSA are usually negative, and the Ki-67 proliferation index
179
may reach 60%. (1, 3, 10, 27) Myoepithelial markers including SMA, p63 and
180
calponin
were
negative
in
most
of
the
cases.
A
181
immunohistochemical staining reactions is shown in Table 3.
summary
of
the
182
Among 19 cases tested for HER-2/neu, 13 (68%) stained positive. Poor
183
prognosis has been associated with overexpression of ERBB2 (HER2) and p53.
184
(8) GCDFP-15, AR and EBBR2 (HER2) have been proposed as biomarkers for
185
treatment guidelines and prognosis. (27)
186
D. Differential Diagnosis
187
Histologic differential diagnosis of PDA of the lacrimal gland includes
188
carcinoma ex-pleomorphic adenoma (Ca ex-PA), mucoepidermoid carcinoma
189
(MEC) polymorphous low-grade adenocarcinoma (PLGA), and adenoid cystic
190
carcinoma (ACC).
191
PDA may arise from acinar and/or ductal cells de novo or in relation to a
192
pleomorphic adenoma. (3, 12) It is one of the rare lacrimal gland neoplasms that
193
is immunopositive for AR. PDAs are usually Immunonegative for p63, S-100 and
194
SMA. Ca ex-PA exhibits mixed features of an adenocarcinoma NOS or poorly
195
differentiated carcinoma. Like PDA, it is immunopositive for p53 howevever it is
196
also immunopositive for S-100, p63 and negative for AR. PDA can be
197
differentiated from MEC in that the latter contains 4 types of cells namely
198
mucous,
199
immunopositive for p63 and rarely with SMA and S-100. PLGAs, similar to PDA,
200
are formed by cuboidal or columnar cells arranged in tubular, ductal or cribriform
201
pattern with perineural invasion; however, unlike PDA, necrosis and mitotic
202
figures are not seen in PLGA and they are immunopositive for SMA, p63 and S-
squamous,
columnar
and
transitional
cells.
Also,
MEC
are
203
100. In ACC, tumor cells are composed of dual population of intercalated duct
204
cell and myoepithelial cells arranged most commonly in cribriform pattern. ACC
205
like PDA also has risk of perineural invasion and vascular extension. However,
206
unlike PDA, necrosis and mitosis are uncommon and ACC are immunopositive
207
for p63, S-100 and SMA.
208
summarized in Table 4.
209
E. Treatment
(3, 15, 17, 21, 25). These histologic features are
Currently there is still no guidelines for the treatment for this rare entity.
210 211
The most common treatment was exenteration with radiation therapy (ET +RT)
212
(n=10); 7 (70%) were still alive after treatment. Other treatments options includes:
213
total resection of the tumor with radiation therapy (TR+RT, n=8); total resection
214
only (TR); exenteration only (ET); total resection with chemotherapy (TR+CT)
215
and excenteration with chemotherapy and radiation therapy (ET+CT+RT).
216
Outcomes for each of the treatment modalities are summarized in Figure 5.
217
V. Conclusion:
218
PDA is a high-grade aggressive epithelial tumor of the lacrimal gland. Though rare,
219
there are an increasing numbers of reported cases. Awareness and recognition of
220
this malignancyis important in order to help determine prognosis and possible future
221
treatment options. Cumulative data are therefore necessary to better characterize
222
PDA of the lacrimal gland and develop evidence-based treatment strategies for our
223
patients.
224
VI. Method of Literature search
225
The literature review was conducted in a comprehensive PubMed search without
226
date restrictions at the end of April 2019, for references in English related to the
227
following key word: “ductal adenocarcinoma” OR “ductal carcinoma” AND lacrimal
228
gland”. Of the 22 results (abstracts), we reviewed every available full-length article
229
for specific clinical, histological and immunohistochemical reports of PDA of the
230
lacrimal gland. After this review, 3 articles were excluded due to the following: 1.)
231
two articles were metastatic lacrimal gland tumors, 2.) Chinese literature. Thereby,
232
19 articles reporting 29 patients were included in this study.
233
Funding: This work was supported in part by the National Institutes of Health [grant
234
number P30EY06360].
235
Conflict of interest: The authors declare no conflicts of interest to disclose.
236
Disclosures
237
The authors do not report any proprietary or commercial interest in the subject matter of
238
this article.
239
240
Abbreviations:
241
(α-SMA) alpha-smooth muscle actin
242
(AE1/AE3) pan-cytokeratin
243
(AR) androgen receptor
244
(CD117/cKit) tyrosine-protein kinase Kit
245
(CDX2) caudal-related homeobox gene
246
(CEA) carcinoembryonic antigen
247
(CK) cytokeratin
248
(DOG1) discovered on gastrointestinal stromal tumor 1
249
(EGFR) epidermal growth factor receptor
250
(EMA) epithelial membrane antigen
251
(ER) estrogen receptor
252
(GCDFP-15/ BRST-2) gross cystic disease fluid protein 15
253
(HER-2Nu) human epidermal growth factor receptor 2
254
(HMB45) human melanoma black
255
(HMWK) high molecular weight keratin
256
(IHC) immunohistochemical
257
(Ki-67/ MIB-1) antigen Ki-67
258
(LMWK/cam 5.2) low molecular weight cytokeratin
259
(Melan A) melanocytic antigen
260
(MMP) metalloproteinase
261
(PDA) primary ductal adenocarcinoma
262
(PSA) prostate specific antigen
263
(S-100) 100% soluble in ammonium sulfate
264
(TTF-1) Thyroid transcription factor
Legends: Table 1. Clinical features and receptor status of 29 published cases of primary ductal adenocarcinoma of the lacrimal gland. Table 2. Summary of 34 cases of primary ductal adenocarcinoma of the lacrimal gland. * Denominator for computing for the percentages are based on the number of cases with available data. Table 3. Summary of Immunohistochemical studies of the 34 cases. Table 4. Summary of histopathologic and immunohistochemical features of the differential diagnoses. Figure 1. Clinical presentation and imaging findings of case 2. A-D. A: 62-year- old man with progressive swelling of his left upper eyelid (arrow). B: trans-lid crease incisional biopsy showing gross appearance of the mass (arrow). C: Coronal MRI with contrast showed a large enhancing mass with irregular border of the left lacrimal gland (arrow). D: Axial MRI with contrast showed a large enhancing mass (arrow) extending to the posterior orbit. Figure 2. Histopathologic sections of case 2. A: Tumour cells displayed glandular configurations (arrow). (H.E, hematoxylin and eosin staining, 10x) B: areas with comedonecrosis (asterix). (H.E, hematoxylin and eosin staining, 200x) C: Tumour cells showed pleomorphic, vesiculated nuclei (arrow head), prominent nuclei, abundant eosinophilic cytoplasm and scattered mitotic figures. F. Nuclear expression of androgen receptor. (immunohistochemical staining, 400x).
Figure 3. Electron microscopy of case 1. Ultrastructural examination of case 1 anaplastic
and
neoplastic
cells
containing
pleomorphic
nuclei,
prominent
intracytoplasmic lumina (L) and nucleoli (N) with apical microvilli (arrow heads) (4000x); whorls of rough surface endoplasmic reticulum (arrow) (17000x). Figure 4. Histopathologic differential diagnosis of primary ductal adenocarcinoma. Figure 5. Summary of treatment strategy and their outcome. Excenteration with radiation therapy (ET +RT); total resection of the tumor with radiation therapy (TR+RT) total resection only (TR); excenteration only (ET); total resection with chemotherapy (TR+CT) and excenteration with chemotherapy and radiation therapy (ET+CT+RT).
References: 1. Andreasen S, Grauslund M, Heegaard S. Lacrimal gland ductal carcinomas: Clinical, Morphological and Genetic characterization and implications for targeted treatment. Acta Ophthalmol. 2017;95(3):299-306. 2. Andreoli MT, Aakalu V, Setabutr P. Epidemiological trends in malignant lacrimal gland tumors. Otolaryngol Head Neck Surg. 2015;152(2):279-83. 3. Alkatan H, Roberts F, White VA. Adenocarcinoma of the lacrimal gland. In Grossniklaus HE, Eberhart CG, Kivelä TT. WHO Classification of Tumours of the Eye. WHO Press, Geneva, 2018. 4. Damasceno RW, Holbach LM. Primary ductal adenocarcinoma of the lacrimal gland: case report. Arq Bras Oftalmol. 2012;75(1):64-6. 5. Dennie T. Metastatic, her-2 amplified lacrimal gland carcinoma with response to lapatinib treatment. Case Rep Oncol Med. 2015;2015:262357. 6. Ellis GL, Auclair PL, American Registry of Pathology., Armed Forces Institute of Pathology (U.S.). Tumors of the salivary glands. Washington, DC: American Registry of Pathology in collaboration with the Armed Forces Institute of Pathology; 2008. 7. Ishida M, Iwai M, Yoshida K, et al. Primary ductal adenocarcinoma of the lacrimal sac: the first reported case. Int J Clin Exp Pathol. 2013;6(9):1929-34. 8. Katz SE, Rootman J, Dolman PJ, et al. Primary ductal adenocarcinoma of the lacrimal gland. Ophthalmology. 1996;103(1):157-62. 9. Kim MJ, Hanmantgad S, Holodny AI. Novel management and unique metastatic pattern of primary ductal adenocarcinoma of the lacrimal gland. Clin Exp Ophthalmol. 2008;36(2):194-6. 10. Kubota T, Moritani S, Ichihara S. Clinicopathologic and immunohistochemical features of primary ductal adenocarcinoma of lacrimal gland: five new cases and review of literature. Graefes Arch Clin Exp Ophthalmol. 2013;251(8):2071-6. 11. Krishnakumar S, Subramanian N, Mahesh L, et al. Primary ductal adenocarcinoma of the lacrimal gland in a patient with neurofibromatosis. Eye (Lond). 2003;17(7):843-5. 12. Kurisu Y, Shibayama Y, Tsuji M, et al. A case of primary ductal adenocarcinoma of the lacrimal gland: histopathological and immunohistochemical study. Pathol Res Pract. 2005;201(1):49-53. 13. Lakhani SR, Ellis IO, Schnitt SJ, et al. WHO Classification of Tumours of the Breast: Invasive carcinoma of no special type. WHO Press, Geneva, 2012. 14. Lau LL, Lung CK, Ahmad SS. A benign presentation of primary ductal adenocarcinoma of lacrimal gland: A rare malignancy. Indian J Ophthalmol. 2015;63(11):856-8. 15. Lee YJ, Oh YH. Primary ductal adenocarcinoma of the lacrimal gland. Jpn J Ophthalmol. 2009;53(3):268-70. 16. Milman T, Shields JA, Husson M, et al. Primary ductal adenocarcinoma of the lacrimal gland. Ophthalmology. 2005;112(11):2048-51. 17. Min KW, Park HK, Kim WY,et al. Primary ductal adenocarcinoma of the lacrimal gland, associated with abundant intracytoplasmic lumens containing some eosinophilic hyaline globules: cytological, histological and ultrastructural findings. Ultrastruct Pathol. 2014;38(5):363-6.
18. Nasu M, Haisa T, Kondo T, et al. Primary ductal adenocarcinoma of the lacrimal gland. Pathol Int. 1998;48(12):981-4. 19. Patel SR, Cohen P, Barmettler A. Primary ductal adenocarcinoma of the lacrimal gland with changing genetic analysis mutations. Orbit. 2018;37(6):463-7. 20. Paulino AF, Huvos AG. Epithelial tumors of the lacrimal glands: a clinicopathologic study. Ann Diagn Pathol. 1999;3(4):199-204. 21. Ricci M, Amadori E, Chiesa F, et al. Single bone metastasis from adenocarcinoma of the lacrimal gland: a case report. Future Oncol. 2014;10(10):1735-9. 22. Takahira M, Minato H, Takahashi M, et al. Cystic carcinoma ex pleomorphic adenoma of the lacrimal gland. Ophthalmic Plast Reconstr Surg. 2007;23(5):407-9. 23. Touil A, El Abbassi S, Echchikhi Y, et al. Adenocarcinoma of the lacrimal gland: a case report. J Med Case Rep. 2017;11(1):257. 24. Von Holstein SL, Therkildsen MH, Prause JU, et al. Lacrimal gland lesions in Denmark between 1974 and 2007. Acta Ophthalmol. 2013;91(4):349-54. 25. Weis E, Rootman J, Joly TJ, et al. Epithelial lacrimal gland tumors: pathologic classification and current understanding. Arch Ophthalmol. 2009;127(8):1016-28. 26. Yang HY, Wu CH, Tsai CC, et al. Primary ductal adenocarcinoma of lacrimal gland: Two case reports and review of the literature. Taiwan J Ophthalmol. 2018;8(1):42-8. 27. Zhu MM, Cui HG, Teng XD. GCDFP-15, AR, and Her-2 as biomarkers for primary ductal adenocarcinoma of the lacrimal gland: a Chinese case and literature review. Onco Targets Ther. 2015;8:1017-24.
Table 1. Clinical features and receptor status of 29 published cases and 5 new cases of primary ductal adenocarcinoma of the lacrimal gland. Case
First author, year
Age/Sex/ Laterality
Complaint Prominence and diplopia Swelling of upper eyelid
IHC
TNM
Size (cm)
Duration
Her 2
AR
ER
PR
T2N0M0
2.5
8 months
-
+
-
-
ET+RT
76
Bone metastasis
DWD
T2N0M0
3.8
6 months
+
+
N/A
N/A
TR + CT
3
none
AWD
T1N0M0
1.6
4 months
-
N/A
-
-
ET + neck dissection and free flap +RT
6
none
AOD
T1aN1M0
1.9
1 month
+
+
N/A
N/A
ET + LN biopsy
2
Neck LN
AWD
1
See, 2019*
64/M/L
2
See, 2019*
62/M/L
3
See, 2019*
53/M/R
4
See, 2019*
61/M/L
5
See, 2019*
74/F/L
Pain, redness of upper lid Proptosis
T2N0M0
2.3
4 months
+
+
N/A
N/A
6
Yang, 2018(26)
64/M/L
Proptosis
T4N0M0
3.9
3 months
N/A
+
N/A
N/A
7
Yang, 2018(26)
64/M/R
Proptosis and diplopia
T4N0M0
5.0
3 weeks
N/A
+
N/A
N/A
8
Patel, 2018(19)
54/M/R
T2N1M1
3.4
3 years
+
+
N/A
N/A
9
Andreasen, 2017(1)
77/M/L
T4bN0M0
3.2
2 weeks
+
+
-
-
10
11
Andreasen, (1) 2017
Andreasen, 2017(1)
Ptosis, fullness and dry eye
Decreasing vision and proptosis Xerophthalmi a, diplopia and blepharitis
Treatment
TR +RT ET +CT + RT ET + bone removal + RT + CT
Follow-up (months)
Metastasis
Status
12
none
AOD
27
none
AOD
21
Neck LN, bilateral upper lobes of the lung
AWD
TR + bone flap +CT
10
Ipsilateral parotid gland and liver
AWD
ET + RT
19
none
DOC
DWD
53/M/L
Lumbar pain, severe headache and proptosis
T1N0M1
2.0
5 years
+
+
-
-
None
60
Lungs liver, suprarenal glands, vertebral column, cerebellum, LN of the neck, thorax, abdomen and groin
73/M/R
Progressive inferonasal globe displacement and proptosis
T4bN0M0
3.0
5 years
+
-
-
-
TR+RT
17
none
DWD
13
none
DWD
48
Vertebrae and
DWD
12
Touil, 2017(23)
55/M/R
Lower lid lesion
13
Dennie,
53/F/R
Progressive
N/A
4.0
7 years
N/A
N/A
N/A
N/A
T4cN0M0
3.0
2.5 years
+***
N/A
-
-
ET + LN dissection + ipsilateral parotidect omy Subtotal
2015(5)
14
Lau, 2015(14)
34/F/R
15
Zhu, 2015
(27)
49/F/L
16
Ricci, 2014(21)
71/M/R
17
**Min, 2014(17)
46/M/L
18
Kubota, 2013(10)
75/M/R
19
Kubota, 2013(10)
67/M/L
20
Kubota, 2013(10)
53/M/R
21
Kubota, 2013(10)
39/M/L
22
Kubota, 2013(10)
46/F/R
23
Damasceno, 2012(4)
78/M/R
24
**Ishida, 2009(7)
70/F/L
25
Lee, 2009(15)
50/M/R
26
(4)
Weis, 2009
N/A
headache, blurring of vision and proptosis Progressive, painless swelling upper lid Painless, palpable mass, double vision and epiphora Lumbar pain and exophthalmo s Exophthalmo s and blurred vision
resection + RT + lapatinib
T2N0M0
2.8
1 year
N/A
N/A
N/A
N/A
T1N0M0
1.1
6 months
+
+
-
T2NxM1
2.3
3 years
+
+
T4bN0M0
3.0
2 months
N/A
N/A
cerebellum
TR
2
none
AOD
-
ET + RT
9
none
AOD
-
-
ET + RT + androgen blockade
19
Lumbar spine 1
AWD
N/A
N/A
TR + RT
5
none
AOD
24
Cervical LN and lung
DWD
T4bN1M0
2.8
3 months
+
+
-
-
RT + resection of submandi bular LN
T2N0M0
4
6 months
-
+
-
-
ET + bone removal
16
Submandibular LN, bone and liver
DWD
T4aN0M0
3.7
18 months
-
+
-
-
ET + RT
52
Spine, brain and liver
DWD
Upper eyelid swelling
T4bN0M0
2.5
6 months
+
+
-
-
120
Lung and brain
AWD
Upper eyelid swelling
T2N0M0
2.5
1 month
+
+
-
-
66
none
AOD
T2N0M0
2.4
6 months
+
N/A
N/A
N/A
24
Ipsilateral parotid and cervical LN
DWD
T2NxMx
2.5
N/A
-
-
-
-
8
none
AWD
T2N0M0
4.0
2 years
-
N/A
-
-
10
none
AOD
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
Upper eyelid swelling Upper eyelid swelling and ptosis Upper eyelid swelling and ptosis
Diplopia, painless, palpable mass and restricted abduction Painful exophthalmo s Exophthalmo s N/A
ET + bone removal + RT Globe sparing TR
ET
TR (2x) for recurrence + RT Globe sparing TR TR + RT
27
Kim, 2008(9)
47/M/L
28
**Takahira, 2007(22)
48/F/L
29
Milman, (16) 2005
59/M/R
30
Kurisu, 2005(12)
Lacrimal gland mass
Progressive exophthalmo s Orbital mass and blepharoptos is
67/M/R
Visual disturbance
31
Krishnakumar, 2003(11)
46/M/L
Firm irregular mass with progressive ptosis in the orbit
32
Paulino, 1999(25)
52/F/R
N/A
ET + RT + CT
204
Chest skin, lymphatics, ilium, rib, femur, spine, orbit, postnasal region and cerebellum
-
TR + RT
N/A
none
N/A
ET + RT
6
Parotid and cervical LN
AWD
DWD
N/A
N/A
N/A
N/A
N/A
N/A
N/A
T2N0M0
3.8
3 years
+
+
-
T1N1M1
1.5
15 years
-
N/A
-
DWD
N/A
T2N0M0
3.0
N/A
N/A
N/A
N/A
N/A
TR + RT
34
Local recurrence, brain, lungs, liver, pancreas, common bile duct
N/A
N/A
2 years
N/A
N/A
N/A
N/A
ET + RT
19
None Neurofibroma
AOD
N/A
N/A
N/A
N/A
N/A
N/A
N/A
ET + RT
72
Neck LN
AOD
TR + Sella turcica to the Small nodule frontal subdural spaces (18) 33 Nasu, 1998 67/M/R in the upper N/A 2.5 N/A N/A N/A N/A 24 craniotom of the right eyelid y + RT temporal lobe TR + Lump in the Frontotem 34 Katz, 1995(8) 68/M/R upper outer N/A 4 6 months N/A N/A N/A N/A poral 10 none eyelid crainiotom y, + RT *This study; ** Malignant component of carcinoma ex pleomorphic adenoma; *** Her 2 nu gene amplified; IHC: Immunohistochemistry; AR: Androgen receptor; ER: Estrogen receptor; PR: Progesterone receptor; ET: Exenteration; TR: Tumor resection; RT: Radiation Therapy; CT: Chemotherapy; LN: Lymph node; AOD: Alive without disease; AWD: Alive with disease; DOC: Dead of other cause; DWD: PDA-related death.
AOD
AOD
Table 2. Summary of 34 cases of PDA of the lacrimal gland. Feature Age at presentation (years) Sex, n (%) M F Size range (cm) Average duration of symptoms (months) Perineural invasion, n Vascular invasion, n Local recurrence, n Lymph node metastasis, n Distant metastases, n PDA-related death, n Dead of other cause, n Alive with disease, n Alive without disease, n
34-78 (SD 11.48) 25 (76%) 8 (24%) 1.1-5.0 (SD 0.90) 32 (SD 41.28) 8 (26%) 7 (23%) 1 (3%) 8 (24%) 16 (50%) 11 (34%) 1 (3%) 8 (25%) 12 (38%)
Table 3. Summary of Immunohistochemical studies of the 32 cases. Marker Cell growth and proliferation
Immunohistochemical stain
Her-2/neu Ki-67 EGFR Metaplasia p53 Cyclin D1 Apocrine differentiation GCDFP-15 Mammaglobin AR Epithelial differentiation AE1/AE3 CK7 CK19 CK17 CK18 CK10 HMWK LMWK CK5 P63 CK20 EMA CEA Myoepithelial cells α-SMA Calponin Hormone receptors ER PR Prostate PSA Thyroid and lung TTF-1 Gastrointestinal DOG1 CDX2 Melanocytes S-100 HMB45 Melan A SOX-10 Neuroendocrine NSE Chromogranin
Number of (+) Cases/ Number Tested 14/21 12/12 4/4 10/13 3/3 13/14 1/1 16/18 7/7 18/18 5/5 4/4 2/2 1/1 1/1 2/2 2/5 0/4 3/12 10/10 5/8 0/7 0/2 0/18 0/16 0/11 0/6 1/4 0/1 1/14 0/2 0/1 0/1 0/1 0/2