A Case of Lacrimal Gland Ductal Carcinoma: Clinical, Morphological and Genetic Characterization

doi:10.21203/rs.3.rs-4984062/v1

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Case Report

A Case of Lacrimal Gland Ductal Carcinoma: Clinical, Morphological and Genetic Characterization

https://doi.org/10.21203/rs.3.rs-4984062/v1

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Lacrimal gland ductal carcinoma is a rare, highly invasive tumor associated with a poor prognosis, arising from the lacrimal gland ductal epithelium. This study presents a rare case of lacrimal gland ductal carcinoma, analyzed through histopathology, immunohistochemistry (IHC) staining, fluorescence in situ hybridization (FISH), and whole-exome sequencing (WES) following surgical excision. Pathological examination confirmed a lacrimal gland ductal carcinoma with different structure features, including a solid pattern with comedo necrosis, cribriform pattern, and trabecular pattern. IHC assays demonstrated negative expression for P63, Calponin, CK5/6, SMA, S100, CK14, CD117, and GCDFP-15 in the tumor cells, while CK (Pan), EMA, and mammaglobin were positively expressed. Additionally, AR, GATA3, and HER-2 showed focal weak positivity. FISH analysis revealed a positive PLAG1 rearrangement and a negative HMAG1 rearrangement. WES revealed mutations in BAX, RB1, USP48, SDHB, COL17A1, COL6A6, PIK3CG, PIK3C2B, POLE, and APOBEC3G, suggesting these as potential driver genes in lacrimal gland ductal carcinoma. The patient remained alive at the time of this report.

ductal adenocarcinoma

ductal carcinoma

lacrimal gland

NGS

RB1 mutation

Lacrimal gland ductal carcinoma represents one of the most aggressive subtypes of lacrimal gland tumors. This carcinoma may manifest either as a de novo lesion or as a high-grade transformation of a pre-existing benign neoplasm of the lacrimal gland [1]. Morphologically and phenotypically, lacrimal gland ductal carcinoma closely resembles ductal carcinoma of the salivary gland and breast, characterized by intraductal and infiltrative components of cords [2–5]. Notably, some lacrimal gland ductal carcinomas express HER2 and AR, suggesting that patients with lacrimal gland ductal carcinoma may benefit from HER2-targeted and endocrine therapies [4, 6]. The protein molecular expression patterns of lacrimal gland ductal carcinoma compared to salivary and breast ductal carcinomas remain to be clarified with larger sample sizes. Presently, there are limited studies on the molecular characteristics of lacrimal gland ductal carcinoma. Some reports indicate mutations in the HRAS and PTEN genes and transcoding mutations in CDKN2A [7]. Therefore, understanding the histologic morphology, protein expression, and molecular features of lacrimal gland ductal carcinoma is crucial for early diagnosis and treatment. In this study, we present the clinicopathologic parameters, histology, immunohistochemistry, and molecular characteristics of a case of lacrimal gland ductal carcinoma.

Clinical history

Clinical data from this patient were collected, encompassing the chief complaint, ophthalmologic examination, and imaging studies including Computed Tomography (CT) and Positron Emission Tomography/Computed Tomography (PET/CT). The study was ethically approved by Zhejiang Provincial People's Hospital.

Histopathology and immunohistochemistry

Formalin-fixed surgical specimens were sent to the Department of Pathology for sampling and paraffin embedding. Hematoxylin and eosin (HE) staining and immunohistochemical staining were performed for diagnostic purposes. HER-2 and CD117 were from Roche, CK5/6, S100, CK (Pan), EMA, Ki67, P53, AR, GATA3, mammaglobin, and GCDFP-15 were from Zhongshan Jinqiao Co (Beijing, China).

Fluorescence in situ hybridization

The paraffin sections were subjected to FISH analysis using break-apart probes for PLAG1 and HMGA2, following the manufacturers’ protocol (Anbiping Pharmaceutical Technology Co., Ltd.). After hybridization, the nuclei were counterstained with DAPI. A total of one hundred nuclei were counted, prioritizing those with an observable complete nuclear membrane. A rearrangement was considered present when split signals were detected in at least 10% of the nuclei.

Next-generation sequencing

Genomic DNA from paraffin-embedded tissue was extracted using the GeneRead DNA FFPE Kit (QIAGEN). The concentration of genomic DNA was determined with Qubit 4.0, and its integrity was assessed via agarose gel electrophoresis. Genomic DNA was fragmented using the Bioruptor ultrasonic fragmentation apparatus, and a conventional DNA library was constructed with the AHTS Universal DNA Library Prep Kit for Illumina V3. Human whole exome hybridization capture and elution were performed using the SureSelect XT Human All Exon V6 and SureSelect XT Reagent Kit. Sequencing was conducted on the Illumina NovaSeq 6000 platform at Nanjing Jiangbei Science Co. Ltd (Nanjing, China).

Case report

A 58-year-old man presented with a 3-month history of swelling in the left eye of unknown etiology, accompanied by numbness and occasional pain in the left side of the head and face, as well as tearing. Ophthalmologic examination revealed that the left eye exhibited a swollen eyelid, difficulty in opening the eye, noticeable eyeball protrusion, and a palpable mass measuring approximately 3×2.5 cm under the orbit. The mass was firm and had indistinct margins. Enhanced CT revealed a soft tissue mass of about 3.9× 3.4 cm in the left orbit, with a patchy dense shadow inside. Following the enhanced scan, the lesion showed continuous mild to moderate enhancement, and the mass in the left orbit was accompanied by internal calcification (Fig. 1a).

Histopathology

Gross examination revealed a soft tissue specimen from the eyeball and periorbital region, measuring 5×4×4 cm³. A greyish-white mass of tumor tissue, measuring 3.5×3.2×2 cm³, was observed in the periorbital area, lacking a clear capsule. The cut surface of the tumor was firm and grey-white (Fig. 1b). Histopathological examination showed the tumor displayed infiltrative growth pattern, the tumor cells showed different structure features, including solid pattern with comedo-necrosis (Fig. 1c, d), cribriform pattern (Fig. 1e, f), and trabecular pattern (Fig. 1g, h). Tumor cells presented with abundant eosinophilic cytoplasm, prominent nucleoli, and significant heteromorphosis, pathological mitotic figures were also common. Tumor cells infiltrated into surrounding adipose and striated muscle tissues, as well as perineural and vascular.

Immunohistochemistry

Combined with the patient's history and microscopic pathomorphology, a diagnosis of lacrimal ductal carcinoma was considered. The possible differential diagnoses included adenoid cystic carcinoma, pleomorphic adenoma, pleomorphic adenoma with high-grade transformation, and mucoepidermoid carcinoma. Immunohistochemical results showed that tumor cells were negative for P63, Calponin, CK5/6, SMA, S100, CK14, CD117, and GCDFP-15, but positive for CK (Pan), EMA, and mammaglobin. AR, GATA3, and HER-2 exhibited focal weak positivity (Fig. 2). To further exclude pleomorphic adenoma with high-grade transformation, the tumor tissues were thoroughly sampled, revealing no other low-grade tumor areas. The final diagnosis of ductal carcinoma was made based on the rapid tumor growth, histologic pattern, and immunohistochemical findings.

Fluorescence in situ hybridization

Rearrangements of Pleiomorphic adenoma gene 1 protein (PLAG1) and High mobility group AT-hook protein 2 (HMGA2) are frequent and specific findings in pleomorphic adenoma (PA) [7]. To enhance diagnostic precision, we conducted FISH analysis to detect PLAG1 and HMGA2 gene rearrangement in the tumor tissue. The results revealed the sample had a positive PLAG1 rearrangement, and a negative HMGA2 rearrangement (Fig. 3a,b).

Next-generation sequencing

To further investigate the molecular features of lacrimal gland ductal carcinoma, we conducted a comprehensive molecular examination of tumor tissues using whole exome sequencing (WES). The results showed that missense mutation was the most common variant classification, SNP was the most common variant type, and C > T ranked top SNV class (Fig. 4a). Additionally, we identified several notable mutations, including a BAX mutation at c.281G > A resulting in p.(Arg94Gln), an RB1 mutation at c.2206C > T resulting in p.(Gln736*), a USP48 mutation at c.2083C > T resulting in p.(Pro695Ser), and an SDHB mutation at c.307A > G resulting in p.(Met103Val) (Table 1). In comparison to other tumors in the TCGA database, our analysis revealed that this sample exhibited a significantly higher tumor mutation burden (TMB) of 12.2368 mutations per megabase (Mb) (Fig. 4b).

Table 1

Genetic alterations of the case.
Chromosome		Transcript Variant	Protein Variant	Allele frequency (%)
chr19	BAX	c.281G > A	p.R94Q	61.1
chr13	RB1	c.2206C > T	p.Q736*	54.5
chr1	USP48	c.2083C > T	p.P695S	28.2
chr1	SDHB	c.307A > G	p.M103V	18.8
chr10	COL17A1	c.3677G > A	p.R1226Q	15.3
chr3	COL6A6	c.1114G > A	p.D372N	14.3
chr12	ERBB3	c.1157T > A	p.V386D	13
chr2	USP34	c.9073C > A	p.Q3025K	11.4
chr7	PIK3CG	c.1848C > A	p.V616V	7.7
chr1	PIK3C2B	c.1623C > T	p.N541N	5.5
chr12	POLE	c.2221G > T	p.E741*	4.6
chr22	APOBEC3G	c.436C > T	p.R146C	3.6
chr10	USP6NL	c.1533G > A	p.A511A	1.8

Lacrimal gland ductal carcinoma is a rare and aggressive cancer that is similar to salivary duct carcinoma and breast cancer [5, 8, 9], the patient was male with no history of breast cancer, and immunohistochemical analysis effectively ruled out the possibility of breast cancer metastasis. Milman et al. first reported the testing of GCDFP-15 in lacrimal ductal adenocarcinoma [10]. GCDFP-15, a biomarker indicative of mammary differentiation, is also present in the serous cells of the submandibular salivary and lacrimal glands [11]. However, in this case, GCDFP-15 expression was negative. Previous research has shown that lacrimal duct carcinoma can express androgen receptor (AR), with Kubota et al. suggesting AR as a diagnostic hallmark of this cancer [12]. In this case, AR expression in tumor cells indicates that androgen deprivation therapy may be beneficial. Some lacrimal duct carcinoma showed HER2 was highly expressed [13]. Trastuzumab (Herceptin) has been informally utilized for HER2-positive tumors in lacrimal gland adenocarcinoma based on histopathological similarities to ductal carcinoma of the breast, where HER2 positivity suggests potential responsiveness to trastuzumab [4]. However, in this case, HER2 expression was low, according to the breast ductal carcinoma HER2 interpretation standard, should be classified as HER2 (1+), indicating a negative status. Thus, this patient would not benefit from anti-HER2 treatment. Taken together, despite some cases lacking GCDFP-15 and HER2 expression, it is recommended to test for GCDFP-15, AR, and HER2 in lacrimal gland duct carcinoma samples to confirm diagnosis and predict prognosis.

Duct carcinoma of the lacrimal gland can manifest as either a primary neoplasm or a high-grade transformation in a pre-existing benign neoplasm, such as pleomorphic adenoma or adenoid cystic carcinoma. In cases where a low-grade polytypic adenoma undergoes high-grade transformation, the high-grade area may present as ductal carcinoma, which can be identified by the presence of typical pleomorphic adenoma areas [1, 14, 15].In this particular case, comprehensive sampling and immunohistochemical analysis revealed no areas indicative of polytypic adenoma. PLAG1 and HMGA2 rearrangement may occur in pleomorphic adenomas [16], but PLAG1 alteration can also occur in some salivary duct cancers[17]. This sample showed PLAG1 gene rearrangement with additional copies of green signal, but loss of red signal. Previous research reported PLAG1 shows a different rearrangement pattern in carcinoma ex pleomorphic adenoma, such as FISH for PLAG1 shows one pair of split signals indicative of PLAG1 rearrangement with a balanced translocation pattern, PLAG1 rearrangement with additional copies of red signal, one or more copies of rearranged PLAG1 with an unbalanced translocation pattern and a polysomy profile[18]. The role of PLAG1 gene rearrangement pattern in the development of lacrimal duct carcinoma needs further study.

High-grade transformation areas of adenoid cystic carcinoma can exhibit histological features similar to ductal carcinoma [19]. Adenoid cystic carcinoma is characterized by tumor components derived from glandular and myoepithelial origins. Glandular epithelial-derived tumor cells typically express CD117, CK and EMA, while myoepithelial tumor cells express markers such as Calponin, P63, SMA, and S100. In this case, some areas displayed cribriform structures, while others showed trabecular and nest-shaped structures with infiltrative growth. However, the tumor cells were of glandular epithelial origin with no myoepithelial components, and the rapid disease progression ruled out adenoid cystic carcinoma. Overall, the absence of polytypic adenoma areas and the specific immunohistochemical profile supported the diagnosis of primary duct carcinoma of the lacrimal gland.

Due to the rarity of ductal carcinoma of the lacrimal gland, its genetic molecular alterations remain largely unknown. Current molecular characterizations of ductal carcinoma of the salivary gland primarily include common gene alterations such as P53 and PTEN loss, PIK3CA and HRAS mutations, and ERBB2 amplification [20, 21]. One cohort study identified a mutational signature of BRCA and APOBEC/AID, along with a novel MYB-NHSL1 fusion gene [22]. For ductal carcinoma of the lacrimal gland, genetic analysis has identified a BRCA2 frameshift mutation, HER2 amplification, PTEN loss, BAP1 exon loss, and a TAF1 frameshift mutation [23]. The molecular characteristics of the presented case did not show the common gene mutations reported in previous studies but revealed a BAX mutation (c.281G > A: p. Arg94Gln), a RB1 mutation (c.2206C > T: p. Gln736*), a USP48 mutation (c.2083C > T: p. Pro695Ser), and a SDHB mutation (c.307A > G: p. Met103Val). BAX mutations, found in acute myeloid leukemia and gastric carcinoma, are associated with resistance to BH3-mimetics therapy and poor prognosis [24, 25]. RB1 has been regarded as a prototype tumor suppressor gene, and higher rates of RB1 mutations have been reported in East-Asian cohort samples in other cancer types, including prostate cancer, lung cancer, breast cancer and retinoblastoma [26, 27], consistent with our study, RB1 mutations are present in salivary duct carcinoma[22]. The mitochondrial gene Succinate dehydrogenase B (SDHB) plays a crucial role in the metabolic activities of cells. Mutations in SDHB have been identified in pheochromocytoma, paraganglioma, and other cancers including gastrointestinal mesenchymal stromal tumor and renal cell carcinoma, impacting the development and progression of these malignancies through its essential structural functions [28].The gene mutation mentioned above is expected to be a supplementary diagnostic basis and therapeutic target for lacrimal duct carcinoma.

Lacrimal adenocarcinoma has a high rate of bone destruction and distant metastasis, with a 5-year survival rate of 33.5% and poor prognosis associated with high Ki-67 expression [29], the Ki-67 expression of this case is about 70%, indicating the need for long-term follow-up. Presently, the primary treatment for ductal carcinoma of the lacrimal gland involves surgical intervention followed by adjuvant radiotherapy [30]. Traditional chemotherapy and radiation therapy have demonstrated limited effectiveness in treating recurrent or metastatic lacrimal gland duct carcinoma. Currently, targeted therapeutics approved for clinical use are not widely applicable, with only rare exceptions, highlighting the urgent need for the development of treatments specifically tailored to this distinct tumor type. Based on the fact that some lacrimal duct carcinomas express HER2 or AR, anti-HER2 therapy and androgen deprivation therapy may be beneficial [4, 31], but more research is needed to confirm their effectiveness. In conclusion, it is crucial to understand the characteristics of lacrimal duct carcinoma to differentiate between primary or low-grade tumors with high-grade transformations.

Author statement

Yanling Jin, Qinbo Wu, Lili Qian, Meihua Ye, Xianglei He: The study conception and design, material preparation, data analysis support and writing - original draft. Yanling Jin, Meihua Ye and Xianglei He: data collection, interpretation and critical revision of manuscript. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Declaration of competing interest

Authors declare no Conflict of Interests for this article.

Funding

This work was supported by the Basic Public Welfare Research Program of Zhejiang Province(LGF21H160031) and Medical Health Science and Technology Project of Zhejiang Provincial Health Commission(2022PY039).

Author Contribution

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No competing interests reported.

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A Case of Lacrimal Gland Ductal Carcinoma: Clinical, Morphological and Genetic Characterization

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Abstract

Figures

Introduction

Materials and methods

Clinical history

Histopathology and immunohistochemistry

Fluorescence in situ hybridization

Next-generation sequencing

Results

Case report

Histopathology

Immunohistochemistry

Fluorescence in situ hybridization

Next-generation sequencing

Discussion

Author statement

Declarations

Declaration of competing interest

Funding

Author Contribution

References

Additional Declarations

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