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Head & Neck/Endocrine Pathology
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Case 2 -
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Mammary Analogue Secretory Carcinoma of Salivary Gland Origin
Kenneth W. Berean, UBC Hospital, Vancouver, BC, Canada
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Clinical History
46 year old woman who noted a “pea-sized” lump on the left buccal mucosa. There had been some fluctuation in size over the previous few months. Examination showed no evidence of cervical lymphadenopathy. No other abnormalities were evident in the oral cavity or oropharynx. An excisional biopsy was undertaken.
Case 2 - Figure 1
Tumor partially filling macrocystic space lined by one to several layers of cells |
Case 2 - Figure 2
Tumor composed of cells arranged in microcystic pattern with luminal amphophilic secretion |
Case 2 - Figure 3
Well developed microcystic architecture |
Case 2 - Figure 4
Tumor cells have relatively uniform ovoid nuclei and moderate amounts of eosinophilic cytoplasm |
Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
The excised tumor was unencapsulated and minimally invasive. The majority of the tumor was growing
within and partially filling a macrocystic space lined by one to several layers of cells. The tumor was
composed of cells with uniform nuclei arranged in a predominantly microcystic architecture. The cells
had a moderate amount of pale pink or vacuolated cytoplasm. Periodic acid Schiff stain with diastase
highlighted the secretions within the microcystic lumina. No basophilic granules were identified on H
and E and no PAS positive granules were present. The tumor cells were strongly positive for S100, CK7
and vimentin. The proliferation rate as assessed using Ki67 immunohistochemical staining was low.
Differential Diagnoses:
Acinic cell carcinoma Low-grade intraductal carcinoma (low-grade cribriform cystadenocarcinoma)
Mammary analogue secretory carcinoma of salivary gland origin
Final Diagnosis:
Mammary Analogue Secretory Carcinoma of Salivary Gland Origin
Case Discussion:
A tumor with this morphology has a limited differential. Until recently, the identification of a
microcystic architecture within a primary salivary gland neoplasm would have been strong evidence in
support of a diagnosis of acinic cell carcinoma. Serous acinar granules within the cytoplasm of tumor
cells would be carefully searched for, and if not apparent on routine hematoxylin and eosin stains, a
Periodic acid Schiff plus diastase stain would be applied to aid in the search. Depending on the
findings elsewhere, and assuming no acinar granules identified, the tumor in the past might have been
termed low-grade adenocarcinoma (favor acinic cell carcinoma) or, if other features supported, simply
acinic cell carcinoma. Now, with the description of the entity known as mammary analogue secretory
carcinoma (MASC), further study to identify the presence of the ETV6- NTRK3 gene fusion in addition to
immunohistochemical stains for S100, CK7, vimentin, mammaglobin and gross cystic disease fluid protein
would be required to completely evaluate tumors of this type. In the current case, the latter studies
confirmed the diagnosis of MASC.
Review of the Literature/Treatment Options (if applicable):
Mammary analogue secretory carcinoma (MASC) was initially described in a series of 16 cases by Skálová
et al [1]. The authors had identified in their consultation practices a tumor that showed morphologic
overlap between acinic cell carcinoma and secretory carcinoma of the breast. They were able to
demonstrate the ETV6-NTRK2 fusion gene in 13 of 14 cases that were analyzed. Since the initial
description, there have been several additional reports
[2,
3,
4,
5,
6,
7,
8]
describing small series of cases
designated as MASC. The total number of cases described is 35 and the following description summarizes
those cases where sufficient information has been provided. The tumors affect patients over a wide age
range, from 14 to 77, with an average age of 44 years. Males have been affected more frequently
(21M:F14), and most presented with a slow growing mass. In 23 cases the parotid was the site of
involvement, while oral sites made up the bulk of the remainder (lip, palate and buccal mucosa). In 2
cases, the submandibular gland was involved. The tumors varied is size from 0.7-5.5 cm. Most patients
were treated with non-radical excision with or without radiotherapy. There is limited follow-up
information, but 2 patients in the original series died of disease after 2 and 6 years, while 4 patients
had local recurrences. Lymph node metastases have been identified in 3 patients- two at the time of
diagnosis, and in another 86 months after initial treatment.
Microscopic descriptions of MASC have been generally uniform. The tumors are typically unencapsulated
and lobulated. They are composed of cells resembling intercalated duct cells arranged in microcystic,
papillary and tubular patterns, with microcystic architecture predominating in most cases. The lumina
contain abundant secretory material that stains with mucicarmine and PAS+D. Scant serous acinar granules
(identified by PASD stain) have been described by some authors
[2,
3],
though most have specifically noted
their absence. Recently, Connor et al also noted some intracytoplasmic mucin granules in some cases, as
well as apparent ductal involvement in 4 cases arising in the oral cavity [5]. Immunohistochemical
evaluation demonstrates positivity for S100, CK7, CK8, CK18 and vimentin in all cases, while EMA, gross
cystic disease fluid protein and mammaglobin the majority of cases. No basal/myoepithelial cell staining
is present. Most important, almost all cases (one exception) showed evidence of the fusion gene
ETV6-NTRK3, either by PCR or by FISH.
The ETV6-NTRK3 translocation was initially described in congenital fibrosarcoma, but has subsequently
been identified in cellular mesoblastic nephroma and acute myeloid leukemia. More recently, it has been
shown to be present in secretory carcinoma of the breast [9]. The ETV6- NTRK3 fusion product functions
as a protein kinase that results in activation of the Ras-MAP kinase and phosphatidyl inositol-3-kinase
pathways, leading to transformation.
The tumor most often considered in the differential diagnosis of MASC is acinic cell carcinoma
(AciCC). In fact, a number of the reported cases were pulled from consultation files where they had been
classified as AciCC. From a morphologic standpoint, the most important feature to allow distinction of
these two tumors is the presence of basophilic serous acinar granules. The latter are typically found in
AciCC, though they may not be readily identified in some variants, and are scant to absent in MASC. In
addition, many AciCC have a variety of patterns in addition to microcystic, such as papillary, cystic and
solid. In most cases, looking for the ETV6-NTRK3 fusion product by RT-PCR or FISH will be required to
absolutely establish the diagnosis. The other tumor that may be considered in the differential diagnosis
is low-grade intraductal carcinoma (LGIDC) (low-grade cribriform cystadenocarcinoma), as both are
characterized by a proliferation of cells with low-grade nuclear characteristics and monotonous
architecture that is dominated by the formation of multiple lumina and a cystic component. LGIDC is
characterized by the presence of a myoepithelial rim around the cell groups, which is absent in MASC.
Conclusion(s):
MASC is a recently described salivary gland neoplasm with characteristic immunoprofile and gene fusion
that has in the past been misclassified as acinic cell carcinoma in many instances. Though the number of
cases studied is small, the behavior of the tumor appears to parallel the low-grade histologic
appearance.
References:
- Skálová A, Vanecek T, Sima R, Laco J, Weinreb I, Perez-Ordonez B, et al. Mammary analogue secretory carcinoma of salivary glands, containing the ETV6-NTRK3 fusion gene: a hitherto undescribed salivary gland tumor entity. Am J Surg Pathol. 2010;34(5):599–608.
- Griffith C, Seethala R, Chiosea SI. Mammary analogue secretory carcinoma: a new twist to the diagnostic dilemma of zymogen granule poor acinic cell carcinoma. Virchows Archiv Int J Pathol. 2011;459(1):117–8.
- Petersson F, Lian D, Chau YP, Yan B. Mammary analogue secretory carcinoma: the first submandibular case reported including findings on fine needle aspiration cytology. Head Neck Pathol. 2011.
- Fehr A, Loning T, Stenman G. Mammary analogue secretory carcinoma of the salivary glands with ETV^-NTRK3 gene fusion. Am J Surg Pathol. 2011; 35(10): 1600-1602.
- Connor A, Perez-Ordonez B, Shago M, Skálová A, Weinreb I. Mammary analog secretory carcinoma of salivary gland origin with the ETV6 gene rearrangement by FISH: expanded morphologic and immunohistochemical spectrum of a recently described entity. Am J Surg Pathol. 2012; 36:27-34.
- Rastatter J, Jatana K, Jennings L, Melin-Aldana H. Mammary analogue secretory carcinoma of the parotid gland in a pediatric patient. Otolaryngol Head Neck Surg 2011 Aug 26. [Epub ahead of print]
- Lei Y, Chiosea SI. Re-evaluating historic cohort of salivary acinic cell carcinoma with new diagnostic tools. Head Neck Pathol 2011 Nov 30. [Epub ahead of print]
- Ito S, Ishida E, Skálová A, Matsuura K, Kumamoto H, Sato I. Case report of mammary analog secretory carcinoma of the parotid gland. Pathol Int. 2012; 62(2):149-52.
- Tognon C, Knezevich SR, Huntsman D, Roskelley CD, Melnyk N, Mathers JA, et al. Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell. 2002; 2(5):367–76
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