Malignant salivary gland tumor; Adenoid cystic carcinoma. Category: VI (Milan System for Reporting Salivary Gland Cytopathology)
Cytopathology:
- Thin layered as well as crowded clusters of basaloid cells with easily appreciable hyaline globules.
- Background also numerous naked basaloid cells.
- Basaloid cells are rounded, ovoid and elongated with angulated nuclei and minimal cytoplasm.
- Additional findings of intranuclear grooves/folding of nuclear membrane are seen.
- Few atypical mitoses are also seen.
- Multiple hyaline globules surrounded by basaloid cells with coarse chromatin and scanty cytoplasm.
- Many clusters of small basaloid cells surround the well-defined rounded dense hyaline globules, giving a cribriform and tubular architecture.
- Most hyaline globules are sharply surrounded by basaloid cells while few hyaline cylinders show irregular and haphazard arrangement of basaloid cells, some cells inside the hyaline material.
- Magenta colored round dense homogenous well defined hyaline globules are seen on Giemsa stain while hyaline globules are pale pink on hematoxylin and eosin stain. These globules do not show ill-defined borders and fibrillary architectures.
Practical Points of Pathoclinics:
- Adenoid cystic carcinoma accounts for 5-10% of all salivary gland tumors, with little female preponderance. It is common in middle and old aged individual. Though it can occur in both the minor and major salivary glands, it is the most common malignant tumor in minor salivary glands. Adenoid cystic carcinoma can be seen in upper respiratory tract, lung, nasal cavity, breast, external auditory canal and lacrimal gland.
- Adenoid cystic carcinoma is a slow-growing malignant tumor with more tendency to invade the local nerves, led to localized tenderness (pain during FNAC procedure) and palsy (commonly facial nerve involvement). In few cases, patient may be asymptomatic. Rare cases may present with ulcerated growth.
- The classic histologic picture of adenoid cystic carcinoma is composed of small uniform round-ovoid basaloid cells (with myoepithelial differentiation) in a cribriform and/or tubular pattern. Cribriform structures appear as round to ovoid lumen-like space, which is filled with dense pink homogeneous hyaline material (not fibrillary material, which is seen in pleomorphic adenoma), produced by the tumor cells. Tubular pattern presented as duct-like structures, line with outer myoepithelial cells and inner epithelial cells. Mixture of cribriform and tubular pattern is common. Isolated and predominant solid pattern of basaloid cells are uncommon. When such solid pattern encountered in small specimen, diagnosis is difficult and challenging, due to absence of stromal hyaline balls and cribriform architecture. Adequate and sometimes extensive sampling revealed classic cribriform and tubular pattern, which help to sort out the diagnostic difficulties.
- In most cases with classic cytologic features, diagnosis of adenoid cystic carcinoma is not difficult. Cytologic features are:
- Usually, smears are cellular or hypercellular
- Variable number and size of clusters, aggregates, rosette-like areas, vague papillary areas and solid sheets of basaloid cells
- Discrete naked basaloid cells are also seen
- Basaloid cells are small round cells with scanty/narrow rim of cytoplasm and hyperchromatic nuclei. Nucleoli are often angulated. Nucleoli are inconspicuous. Mild degree of anisonucleosis can be seen.
- In most cases, basaloid cells are arranged around rounded cylinders or punched out spaces. These spaces are filled with dense homogeneous hyaline globules.
- Commonly basaloid cells are not seen inside the hyaline globules. However, sometimes border of cribriform architecture may be fuzzy and cells may be seen inside the hyaline globules.
- Hyaline globules appear as magenta coloured, well-defined, non-fibrillar homogenous on May–Grünwald–Giemsa stain. These structures are difficult to identify in a Pap-stained smears as globules appears pale.
- Solid variant of adenoid cystic carcinoma may not show classical features of adenoid cystic carcinoma The solid variant contains less matrix material and more basaloid cells in crowded clusters and groups.
- The hyaline globules and cribriform structures on cytology smears along with clinical evidence of regional pain (also during FNAC procedure) are best indicator of adenoid cystic carcinoma.
5. Adenoid cystic carcinoma commonly falls in the Milan category VI: Malignant neoplasm when all or almost many of the above cytologic features are matched. In few cases, especially solid variant of adenoid cystic carcinoma shows only partial features, specifically presence of prominence of basaloid cells in cohesive group, crowded clusters without cribriform-tubular structures and in absence or very scanty hyaline matrix material. In such cases, it is not bad to place adenoid cystic carcinoma in Milan category V (Suspicious for malignancy) or category IV (Neoplasm: salivary gland neoplasm of uncertain malignant potential -SUMP), according to the level of quantitative and qualitative features.
6. The combination of strong and diffuse expression of MYB (nuclear staining) and c- kit (CD117) (membranous staining) are highly sensitive for the diagnosis of adenoid cystic carcinoma. Positive CD43 stain also indicates adenoid cystic carcinoma while CD43 is usually negative or rarely positive in other salivary gland tumors. High ki67 index is helpful to distinguish adenoid cystic carcinoma from pleomorphic adenoma and basal cell adenoma.
7. Almost half of all adenoid cystic carcinoma has characteristic chromosomal translocation t(6;9) (q22–23;p23–24) causing MYB-NFIB gene fusion.
8. Pleomorphic adenoma may mimic adenoid cystic carcinoma and vice versa. Commonly pleomorphic adenoma shows characteristic fibrillar myxoid-chondroid stroma, which is not seen in adenoid cystic carcinoma. Sometimes such matrix material of both tumor look like each other, which is a major diagnostic pitfall. Cellular pleomorphic adenomas may lack matrix material, also causing diagnostic difficulty with solid variant of adenoid cystic carcinoma. In such situation, repeat cytology sampling and attention to clinical presentation help for proper diagnosis. Attention to hyperchromatic nucleus, finding of mitotic activity, pain during FNAC procedure help to render a diagnosis of adenoid cystic carcinoma. Cell block section can be utilized for MYB, CD117, CD43 and Ki-67 immunostain. Up to 70% of pleomorphic adenomas have rearrangements of PLAG1 or HMGA2 genes. Also use of Milan system help to understand the diagnostic dilemmas to the treating surgeon.
9. In the absence of dense well-defined homogenous hyaline globules, the distinction between the solid type of adenoid cystic carcinoma and basal cell adenoma/carcinoma is difficult. In both, cellular smears have basaloid cells arranged in crowded cohesive clusters. Again, close evaluation of nuclear details is necessary. Basal cell adenoma has even chromatin distribution, whereas adenoid cystic carcinomas often have a marked hyperchromatic nucleus. Palisading arrangement of basaloid cells seen in basal cell adenoma in a cellular cluster, which is not seen in adenoid cystic carcinoma.
10. Polymorphous low-grade adenocarcinoma of the minor salivary gland can show papillary, cribriform or solid growth pattern. Tumor cells of polymorphous low-grade adenocarcinoma are small ovoid uniform with a thin rim of cytoplasm, while nuclei are hyperchromatic in case of adenoid cystic carcinoma. Finding of even a few mitoses are helpful to identify the adenoid cystic carcinoma.
11. Epithelial–myoepithelial carcinoma can show homogeneous matrix substance, which simulate adenoid cystic carcinoma. Careful search for spindle, clear and plasmacytoid cells indicate the epithelial–myoepithelial carcinoma. Least common other theoretical differentials are small-cell undifferentiated carcinoma, neuroendocrine carcinoma and lymphoma.
12. Surgical resection is primary treatment choice. Radiation therapy can be given in cases with residual/recurrent tumor, extensive local spread and neural invasion.
13. Adenoid cystic carcinoma has a high tendency for recurrence after surgical removal, owing to its infiltrative growth pattern. Solid growth pattern has worst survival, followed by cribriform and then tubular patterns. Distant metastases is common in the liver, lungs, soft tissue and bone, whereas lymph node metastases are very uncommon.
