Adenoid cystic carcinoma (ACC) is a relatively rare salivary gland malignancy. Approximately 25-55% of patients with ACC develop distant metastases. We present the case of a 65-year-old female who was incidentally found to have a hepatic lesion while undergoing monitoring for an intraductal papillary mucinous neoplasm of the pancreas. Significant background history included a previously resected ACC of the right sublingual gland with adjuvant radiotherapy seven years prior and Hepatitis B positive serology. Radiology review at the hepatobiliary oncology multidisciplinary meeting favoured a cholangiocarcinoma and a hemi-hepatectomy was performed. Macroscopic examination of the left hemi-hepatectomy specimen demonstrated a well-defined firm pale lesion in segment 2/4a. The histologic examination of this area showed a relatively well-demarcated lesion comprising of tubules and cords with a biphasic basaloid appearance and basement membrane matrix production. Large areas with signet ring morphology were also seen. The morphologic features and the presence of myoepithelial cells as demonstrated by immunohistochemical staining for S100, p63 and SMMHC were suggestive of a metastatic salivary gland tumour. Cribriform architecture typical of adenoid cystic cell carcinoma was not present. The histologic sections of the primary sublingual lesion were reviewed. These demonstrated typical cribriform architecture of adenoid cystic carcinoma with focal signet ring morphology. Fluorescent in situ hybridization (FISH) studies performed on both the primary and the metastatic lesion demonstrated MYB translocation, confirming the diagnosis and thus further augmenting the diagnostic accuracy. This case highlights the value of recent advances in molecular testing and their role in diagnosis of cases with unusual morphologic features.

Kirkpatrick D, McKenzie C, Luk PP, Selinger CI, Joseph D, et al. (2016) Metastatic Adenoid Cystic Carcinoma with Signet Ring Morphology in the Liver: Detection of MYB Translocation in Adenoid Cystic Carcinoma. Ann Clin Pathol 4(1): 1058.

•    Adenoid cystic carcinoma
•    Metastases
•    Signet ring morphology
•    FISH
•    MYB

ACC: Adenoid Cystic Carcinoma

Adenoid cystic carcinoma (ACC), while rare, is the 2nd most common primary salivary gland neoplasm. Metastases of ACC are rarely present at initial presentation, however, over the course of the disease, they occur in 25-55% of patients [1,2]. While most ACCs retain their usual morphologic features at metastatic sites, occasional tumours may show unusual architectural and cytological features causing a diagnostic dilemma. Recent advances in adenoid cystic carcinoma have centered around the identification of reciprocal translocation t(6;9)(q22-23;p23-24) resulting in the formation of MYB-NFIB fusion oncogene in 49% of ACCs [3]. MYB a leucine zipper transcription factor regulates cell proliferation, differentiation and apoptosis. MYB-NFIB fusion leads to overexpression of MYB and acts as an oncogenic driver. Fluorescent in situ hybridization probes for MYB rearrangement have recently become commercially available and their diagnostic utility is under investigation [4].

We present the case of a 65-year-old female who was found to have a lesion in segment 2/4a of her liver while undergoing monitoring for intraductal papillary mucinous neoplasm of the pancreas. The patient was otherwise well. She ceased smoking ten years prior and consumed minimal alcohol. An initial FNA at another center did not show any evidence of malignancy but a repeat MRI scan showed an increase in size from 13mm to 24mm in diameter over a period of 13 months. The MRI showed a single T1 hypointense, mildly T2 hyperintense liver lesion with some delayed enhancement as well as capsular retraction (Figure 1 and 2). Differentials included a peripheral cholangiocarcinoma or hepatic haemangio-endothelioma.

Significant background history included an ACC of the right sublingual gland which was resected seven years prior. Following surgery, and noting the close excision margins and the presence of extensive perineural invasion, the patient proceeded to wide field ipsilateral adjuvant radiotherapy directed to the surgical bed and neck with the aim of decreasing her risk of locoregional recurrence. The patient received a total of 60Gy in 30 fractions using CT planned 3D conformal megavoltage radiotherapy over six weeks. She tolerated her treatment well and experienced only the expected mucocutaneous side effects, which resolved shortly after completion of treatment. At the last follow up she remained clinically disease free within the head and neck. 

A left hemihepatectomy was performed and the hepatic lesion was resected. Macroscopic examination of the specimen showed a well defined firm pale lesion 28 x 24 x 16mm in segment 2/4a (Figure 3). Sections showed a relatively well-demarcated lesion comprising of tubules and cords of epithelial cells with associated eosinophilic basement membrane like material (Figure 4). The nests and cords showed biphasic appearance in several areas. The central luminal cells showed scanty to moderate amounts of eosinophilic cytoplasm. Multiple large areas showed signet ring cell morphology both of the luminal cells of the tubules as well as in the cords (Figure 5). The abluminal cells appeared flattened and spindle shaped. Minimal typical cribriform architecture with intraluminal amphophilic material was observed at the periphery after extensive sampling of the specimen.

Immunohistochemistry with CK7, p63 and SMMHC highlighted the biphasic nature of the lesion (Figure 6 and 7). The morphologic features and the immunohistochemical profile were in keeping with a biphasic salivary gland. A differential diagnosis of an adenoid cystic carcinoma and an epithelial myoepithelial carcinoma were considered. The slides of the sublingual gland resection were retrieved for comparison and showed ACC with predominantly typical histologic features and minimal signet ring cell morphology (Figure 8).

Interphase FISH for ZytoLight SPEC MYB Dual Color Break Apart Probe (ZytoVision) were performed on both the primary sublingual lesion as well as the metastases (Figure 9). Both showed MYB rearrangement in 40% of tumour nuclei, thus supporting the diagnosis of metastatic adenoid cystic carcinoma.

A decision was made post surgery for review at six months with a PET scan, followed by a MRI at one-year post resection.

Adenoid cystic carcinomas have significant likelihood of late distant metastases, even when adequate primary locoregional surgery and radiotherapy has been performed. The presence of late metastasis often means that the patients require longterm follow up. It also means that the complete medical history is not readily available to the pathologist while examining the tissue from the metastatic site. An additional confounding factor, particular to this case, was the presence of signet ring morphology. Signet ring cell morphology is extremely rare in adenoid cystic carcinoma and was only first described in the literature in 2013 by Altemani et al [5]. They described four cases involving the sinonasal, lip and submandibular ACC and noted that although this rare cellular modification in ACC causes significant diagnostic problems it does not appear to change the biological behavior of the tumor [3].

Detection of MYB-NFIB translocation is gaining ground as an ancillary diagnostic test in adenoid cystic carcinomas [6]. The presence of MYB rearrangement is highly specific for adenoid cystic carcinomas as it has not been described in other primary salivary gland neoplasms such as epithelial myopeithelial carcinoma, polymorphous low grade adenocarcinoma and canalicular adenomas. However, the sensitivity is relatively low as it is present in only 49% of the cases [3]. Detection of MYB rearrangement can also be a useful prognostic tool as demonstrated by Mitani et al, who identified age greater than sixty, solid phenotype and high MYB expression as adverse prognostic factors in adenoid cystic carcinoma [7].

Currently there are limited treatment options for metastatic ACC. In patients with advanced disease, first-line therapy is still conventional chemotherapy. Combination chemotherapy such as cisplatin and 5-FU or CAP (cisplatin, doxorubicin, and cyclophosphamide) can be used, however these regimens typically show a low response rate and median survival time after distant metastasis is only 36 months [8,9]. Targeted therapies such as Sorafenib, an oral multikinase inhibitor, have also been investigated in clinical trials with limited success [10]. While the diagnostic and prognostic utility of MYB is being increasingly understood, currently drugs targeting the MYB pathway in ACC are not available.

In conclusion, we describe another case of adenoid cystic carcinoma with signet ring morphology, at a metastatic site. Awareness of this rare morphologic variation of an adenoid cystic carcinoma is essential to prevent misclassification as an epithelial-myoepithelial carcinoma, a low-grade carcinoma with an indolent biologic course. Detection of MYB rearrangement, a test with high specificity though low sensitivity, can augment diagnostic accuracy in problematic cases of adenoid cystic carcinoma with variant morphologic features or small specimens with procedural artifacts.

1. Bradley PJ. Adenoid cystic carcinoma of the head and neck: a review. Curr Opin Otolaryngol Head Neck Surg. 2004; 12: 127-132.

2. Barnes L, Eveson J.W, Reichart P, Sidransky D. World Health Organization Classification of Tumors. Pathology and Genetics of Head and Neck Tumors. Lyon 2005.

3. West RB, Kong C, Clarke N, Gilks T, Lipsick JS, CaoH, et al. MYB expression and translocation in adenoid cystic carcinomas and other salivary gland tumors with clinic pathologic correlation. Am J SurgPathol. 2011; 35: 92-99.

4. Gupta R, Balasubramanian D, Clark JR. Salivary gland lesions: recent advances and evolving concepts. Oral Surg Oral Med Oral Pathol Oral Radiol. 2015; 119: 661-674.

5. Altemani A, Costa AF, Montalli VA, Mosqueda-Taylor A, Paes de Almeida O, Leon JE, et al. Signet-ring cell change in adenoid cystic carcinoma: a clinic pathological and immuno histochemical study of four cases. Histopathology. 2013; 62: 531–542.

6. Bell D, Dianna Roberts, Matthew Karpowicz, Ehab Y. Hanna, Randal S. Weber, Adel K. El-Naggar. Clinical significance of Myb protein and downstream target genes in salivary adenoid cystic carcinoma. Cancer Biol Ther. 2011; 12: 569–573.

7. Mitani Y, Li J, Rao PH, Zhao YJ, Bell D, Lippman SM, et al. Comprehensive analysis of the MYB-NFIB gene fusion in salivary adenoid cystic carcinoma: Incidence, variability and clinicopathologic significance. Clin Cancer Res. 2010; 16: 4722-4731.

8. Gao M, Hao Y, Huang MX, Ma DQ, Luo HY, Gao Y, et al. Clinicopathological study of distant metastases of salivary adenoid cystic carcinoma. Int J Oral Maxillofac Surg. 2013; 42: 923-928.

9. Giorgos Papaspyrou M, Stephan Hoch M, Alessandra Rinaldo M, Juan P. Rodrigo, Robert P. Takes, Carla van Herpen, et al. Chemotherapy and targeted therapy in adenoid cystic carcinoma of the head and neck: a review. Head Neck. 2011; 33: 905–911.

10. Thomson DJ, Silva P, Denton K, Bonington S, Mak SK, Swindell R, et al. Phase II trial of sorafenib in advanced salivary adenoid cystic carcinoma of the head and neck. Head Neck. 2015; 37: 182-187.