Microsecretory adenocarcinoma of the external ear canal

Abstract

Microsecretory adenocarcinoma (MSA) is a recently described salivary gland tumor characterized by unique histomorphologic and immunohistochemical features as well as recurrent MEF2C::SS18 gene fusion. Since 2019, 24 cases have been reported in the literature, primarily arising in the oral cavity, with a single reported case arising in the parotid gland. Here, we present a case of MSA that arose in the external ear canal in an 89‐year‐old woman and was discovered during management of vertigo symptoms. Excisional biopsy of the lesion showed multiple fragments of squamous epithelium with hyperplastic changes and a distinct subepithelial infiltrating neoplasm composed of bland cells forming tubules and cords. Neoplastic cells expressed keratin, S100 protein, p63, and TLE1 and did not express p40, mammaglobin, pan‐TRK, synaptophysin, or chromogranin by immunohistochemistry. SS18 gene rearrangement was shown with break‐apart fluorescent in situ hybridization. Overall, the histomorphologic, immunohistochemical, and cytogenetic findings confirm a diagnosis of MSA arising in a unique extraoral location.

Microsecretory adenocarcinoma is a recently described salivary gland tumor characterized by unique histormorphologic and immunohistochemical features as well as recurrent MEF2C::SS18 gene fusion. Here, we describe the first reported case presenting in the external ear.

1. INTRODUCTION

Microsecretory adenocarcinoma (MSA) is a recently described salivary gland tumor characterized by a unique set of histomorphologic and immunohistochemical features and a recurrent MEF2C::SS18 translocation, which was first described in 2019. ¹ Since its description, 24 definitive cases of MSA have been reported. ¹ , ² , ³

MSA most often arises as a painless mass in the oral cavity, especially within the palate and buccal mucosa, with only one reported extraoral case arising in the parotid gland. Tumors show a characteristic histomorphology and are well‐circumscribed with subtle infiltration of the surrounding tissue. They are composed of intercalated duct‐like cells with regular, hyperchromatic ovoid nuclei. Tumors grow in a microcystic tubular pattern with abundant basophilic luminal secretions and a variably cellular fibromyxoid stroma. Immunohistochemical staining of these tumors reliably shows expression of S100 protein, p63, and SOX10 with lack of expression of p40, calponin, and mammaglobin and variable smooth muscle actin (SMA) expression. ¹ , ² , ³ , ⁴

Here, we report a case of MSA of the external ear canal in an 89‐year‐old woman, which showed characteristic histopathologic and immunohistochemical findings along with an SS18 rearrangement but arose in a unique extraoral location.

1.1. Case report

An 89‐year‐old woman with medical history significant for prior lumpectomy for unspecified breast cancer presented for treatment of benign paroxysmal positional vertigo. She was noted to have a painless mass of the right external ear canal. Further examination showed an obstructing, friable lesion causing cerumen impaction. The patient underwent excisional biopsy of the mass, and her short‐term postoperative course was uneventful. No long‐term follow‐up data are available at this time.

Slides as well as a formalin‐fixed paraffin‐embedded tissue block from the patient's excisional biopsy were sent to our institution for consultation. On H&E staining, the specimen was composed of several fragments of skin showing acanthosis and pseudohorn cysts, reminiscent of a seborrheic keratosis (Figure 1). Distinct from the overlying epithelial process, the underlying soft tissue showed diffuse involvement by an infiltrative lesion composed of tubules and cords with bland cells having a small to moderate amount of eosinophilic cytoplasm and uniform, small round to oval nuclei (Figure 1). Atypia and mitotic activity were absent. The tubules contained prominent pale basophilic intraluminal secretions and were embedded in a paucicellular fibromyxoid stroma. Tumor necrosis, lymphovascular space invasion, and perineural invasion were not seen.

FIGURE 1.

Histomorphologic findings of microsecretory adenocarcinoma (H&E). (A) An infiltrating tubular neoplasm with overlying pseudohorn cysts (×20). (B–D) The tubules are uniform in size with basophilic luminal contents (B and C) and bland cytology (D) (×40, ×100, and ×200, respectively)

The histomorphologic findings raised the differential of a salivary gland‐type neoplasm and included ceruminous carcinoma, secretory carcinoma, polymorphous adenocarcinoma, mucoepidermoid carcinoma, and MSA. Immunohistochemical staining was performed to help differentiate amongst these diagnoses. The infiltrating cells showed strong, diffuse expression of pan‐keratin (Leica BOND III, clone CAM5.2 [Becton and Dickinson]; clone OSCAR [BioLegend]; clone K902 [ENZO]; clone MNF116 [Agilent]; clone AE1/AE3 [Agilent]) and S100 protein (Leica BOND III, clone EP32 [Leica]) (Figure 2). Expression of p63 and TLE1 (both nuclear and cytoplasmic) were also seen (Leica BOND III, clones A4A [Biocare] and F4 [Santa Cruz], respectively) (Figure 2). The infiltrating cells completely lacked expression of p40 (Leica BOND III, clone BC28 [Leica]), mammaglobin and pan‐TRK (Leica BOND III, clones 31A5 [Cell Marque]; Ventana Benchmark ULTRA, clone EPR17341 [Ventana], respectively), as well as synaptophysin and chromogranin (Leica BOND III, clones 27G12 [Leica] and 5H7 [Leica], respectively) (Figure 2). Break‐apart fluorescent in situ hybridization (FISH) was performed for MAML2 (Empire Genomics Dual Color Break‐apart DNA probe) and SS18 genes (Vysis LSI SYT Dual Color Break‐apart DNA probe) using a count of at least 100 cells and a threshold of 10% disruption for a diagnosis of gene rearrangement. FISH showed an intact MAML2 gene (100% intact); however, SS18 rearrangement was identified (60% disrupted), confirming a diagnosis of MSA (Figure 3). At the time of writing, the tissue block was unavailable for further molecular evaluation of the tumor.

FIGURE 2.

Immunohistochemical findings of microsecretory adenocarcinoma. (A) Expression of p63 (×200). (B) Lack of p40 expression (×200). (C and D) Expression of TLE1 (×200)

FIGURE 3.

Fluorescent in situ hybridization (FISH) Dual Color Break‐apart SYT probe, which showed disruption of the SS18 gene (arrow) in 60% of counted cells (×1000)

2. DISCUSSION

MSA is a recently described salivary gland carcinoma characterized by MEF2C::SS18 translocation and a distinct set of histomorphologic and immunohistochemical features (summarized in Tables 1 and 2), which was first reported in 2019. ¹ These tumors usually arise in the oral cavity, with one reported extraoral case in the parotid gland. Clinically, these lesions typically present as painless masses. ¹ , ² , ³ While prognostic information regarding this entity is limited, the current literature reports this low‐grade carcinoma is sometimes associated with local tissue infiltration but has no reported cases of metastasis or recurrence following surgical resection. ²

TABLE 1.

Microscopic findings of microsecretory adenocarcinoma

Microscopic findings of MSA
Tumor:	well‐circumscribed
	unencapsulated
	± microscopic surrounding tissue infiltration
Cells:	bland intercalated duct‐like cells
	variable amounts of eosinophilic cytoplasm
	uniform, small round to oval nuclei
Architecture:	anastomosing microcysts, tubules, cords
	abundant intraluminal basophilic secretions
Stroma:	variably cellular
	fibrous to myxohyaline
	± central sclerosis
Absent:	lymphovascular space invasion
	tumor necrosis

Abbreviation: MSA, microsecretory adenocarcinoma.

TABLE 2.

Immunohistochemical profile of microsecretory adenocarcinoma

Immunohistochemical profile of MSA
Positive	Negative
S100	p40
p63	calponin
SOX10	mammaglobin
smooth muscle actin (variable)

Abbreviation: MSA, microsecretory adenocarcinoma.

Macroscopically, MSA is well‐circumscribed but unencapsulated and can show infiltration of the surrounding soft tissue microscopically. ¹ , ² , ³ , ⁴ Perineural invasion has been reported in a single case, but lymphovascular space invasion and tumor necrosis have not been documented. ² On histomorphology, the tumor is characterized by bland intercalated duct‐like cells that form anastomosing microcysts, tubules, and cords with rare single cells and abundant intraluminal basophilic secretions, embedded in a variably cellular fibrous to myxohyaline stroma which can show central sclerosis. ¹ , ² , ⁴ The epithelial lining cells are predominantly attenuated, but occasionally plump, with eosinophilic to clear cytoplasm, monomorphic hyperchromatic ovoid nuclei, and indistinct nucleoli. ¹ , ² , ³ , ⁴ Immunohistochemically, MSAs characteristically express S100 protein, SOX 10, and p63 and lack expression of p40, mammaglobin, and calponin, with variable expression of SMA. ¹ , ² , ³ , ⁴

MSA also demonstrates a unique gene fusion between MEF2C and SS18, which was originally identified via RNA sequencing. ¹ , ² , ³ , ⁴ , ⁵ Recent studies have also proven the utility of SS18 break‐apart FISH, ² , ⁶ the modality used for diagnosis of the present case. SS18 rearrangement by FISH is most often seen in synovial sarcoma, characterized by SS18::SSX fusions and expression of nuclear transducin‐like enhancer of split (TLE1) by immunohistochemistry. ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³ Interestingly, the present case of MSA also showed nuclear TLE1 positivity.

In non‐neoplastic tissue, TLE1 functions as a transcriptional corepressor involved in hematopoietic, neuronal, and terminal epithelial cellular differentiation. ⁷ , ⁸ TLE1 plays a role in Notch, NF‐κB, and Wnt/β‐catenin signaling pathways, the latter of which has been implicated in synovial sarcoma along with TLE1 overexpression. ⁹ , ¹⁰ Numerous studies have shown TLE1 immunohistochemistry is a sensitive but not entirely specific diagnostic biomarker of synovial sarcoma, as TLE1 expression has also been reported in schwannoma, neurofibroma, malignant peripheral nerve sheath tumors, spindle cell melanoma, and other cutaneous malignancies. ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³ TLE1 positivity has not been previously reported in MSA and raises questions about the molecular and diagnostic implications of this marker. However, further investigation and clarification are needed, as expression of TLE1 by immunohistochemistry is not entirely specific for SS18‐rearranged neoplasms.

Here, we present a case of MSA with characteristic histomorphologic, immunohistochemical, and cytogenetic findings arising in a unique extraoral location and setting. As with several prior reported cases, this case presented as a painless mass that was incidentally identified during routine care for an unrelated reason. ¹ , ² , ³ In addition, a single prior case of MSA is reported to have arisen in the parotid gland, with all remaining cases arising within the oral cavity ² , ³ ; occasional cases have been reported in association with pseudoepitheliomatous hyperplasia of the overlying oral squamous epithelium. ² In summary, the histomorphologic, immunohistochemical, and cytogenetic findings confirmed a diagnosis of MSA arising in a unique extraoral location.

AUTHOR CONTRIBUTIONS

Dr Megan E. Dibbern and Dr Edward B. Stelow each made substantial contributions to conception/design of this project, and all listed authors made substantial contributions to the acquisition/interpretation of data for this manuscript. Dr Megan E. Dibbern and Dr Edward B. Stelow were involved in drafting the manuscript; all listed authors have been involved in revising this manuscript critically for intellectual content and have given final approval of the submitted manuscript for publication. All authors agree to be accountable for all aspects of the work and in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

Dibbern ME, Gru AA, Stelow EB. Microsecretory adenocarcinoma of the external ear canal. J Cutan Pathol. 2023;50(2):106‐109. doi: 10.1111/cup.14277

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analyzed in this study.