updates of salivary gland tumours in cytopathology

1. Update in salivary gland cytopathology:
Recent molecular advances and
diagnostic applications
Pusztaszeri MP, Faquin WC. Seminars in
diagnostic pathology 2015 Jul 31 (Vol. 32,
No. 4, pp. 264-274)

2. Contents of the article
• Introduction
• Recent molecular advances in SGTs
• Uncommon and recently recognized
entities
• Conclusions

3. Introduction
• Fine needle aspiration biopsy of salivary
gland lesions
: high sensitivity - 86 to 100%
: high specificity – 90 to 100%
• Accuracy of FNAB in distinguishing
benign from malignant : 81 to 100%

4. • But , the accuracy of FNAB of salivary
gland in subtyping a neoplasm
: 48-94%

5. Why salivary gland FNAB is
challenging?
• 37 distinct epithelial neoplasms of salivary
gland (WHO 2005)
• Intratumoral heterogeneity
• Morphological overlapping among many
salivary gland tumours
Therefore, cytomorphology alone, without
the use of ancillary studies has limitations.

6. Translocations and fusion genes
• The translocation t(3;8) in Pleomorphic
adenoma, has been known for almost 2
decades, translocations in other SGTs have
been discussed in this article.
• In addition to their diagnostic role, they may
also represent prognostic markers and
possibly therapeutic targets in the near future

7. • The current treatment of patients with
SGT is mainly restricted to surgery and/or
radiation therapy, and only limited data is
available on the role of conventional
systemic and targeted therapies for
patients with advanced disease.

8. Pleomorphic adenoma
• Most common SGT of all sites in both adults
and children(60%).
• Cytological features
1) Epithelial cells, myoepithelial cells(spindle,
epithelioid, plasmacytoid, and clear cell),
2) fibrillary chondro-myxoid matrix (with
frayed edges and embedded myoepithelial
cells)

9. Fibrillary myxoid matrix
Myoepithelial
cells

10. • A subset of PAs may lack or have scant
chondro-myxoid matrix (i.e., cellular PA),
making it difficult to distinguish from other
myoepithelial and “basaloid” neoplasms.
• Metaplastic changes with squamous,
sebaceous, oncocytes or mucinous cells may
mimic ‘Mucoepidermoid Carcinoma ’

11. • Hyaline like globules may mimic adenoid
cystic carcinoma
Pleomorphic
adenoma with a
hyaline globule
Myoepithelial cells with bland round nuclei

12. Most common translocation t(3,8)(p21;q12)
Genes involved PLAG1, CTNNB1, LIFR
Prevalence 50-60%

13. • The translocation typically leads to
upregulation and overexpression of PLAG1.
• PAs (94%) are strongly immunoreactive for
PLAG1

14. • PLAG1 is negative in the most common
(SGCs), including AdCC, MEC, and acinic
cell carcinoma (ACC).
• In addition to PLAG1, HMGA2 gene are
found in a minor subset of PAs (10%).

15. • Cytologically, it can be difficult to
distinguish cellular PAs from other
basaloid neoplasms, including BCA, basal
cell adenocarcinoma, and AdCC.
Therefore, immunocytochemistry and/or
FISH for PLAG1 can be useful in this
setting

16. Carcinoma-ex-pleomorphic adenoma
• Carcinoma arising in a primary or
recurrent PA
• 12% of Salivary gland carcinomas
• Same genetic abnormality as in its benign
PA precursor including PLAG1 and
HMGA2.

17. cluster of malignant ductal cells in Ca-Ex-PA with dark
granular chromatin and high nuclear-to-cytoplasmic
ratio

18. • But also, accumulates additional aberrations
that presumably lead to the malignant
transformation
• Immunochemistry and/or FISH for PLAG1
may help to discriminate CA-ex-PA from
other high-grade SGCs arising de novo

19. Mucoepidermoid carcinoma
• Most common SGC in both adults and
children, representing approximately 30%
of SGCs
• Important to distinguish between low-
grade and high-grade MECs due to major
differences in prognosis, with 90% and
40% 5-year survival, respectively

20. • Cytomorphology of low grade MEC:
Mucous cells, epidermoid/squamoid cells,
and intermediate cells with extracellular
mucin.
• Cytomorphology of high grade MEC :
Same as low-grade plus overt cytologic
malignancy

21. Goblet type mucus cells
Intermediate
cells

22. Mucicarmine stain highlights the mucin content in
a goblet cell from a LGMEC

23. Mucoepidermoid carcinoma
most common translocation t(11;19)(q21-22;p13)
genes involved MAML2-CRTC1 gene
fusion
•The presence of the CRTC1–MAML2 fusion is
specific to MECs,
• It can also be used as a diagnostic tool to
differentiate high-grade MECs from other high-grade
SGCs or to distinguish oncocytic MECs from other
oncocytic neoplasms including Warthin tumor

24. Adenoid cystic carcinoma
• 10% of all SGTs
• Indolent growth pattern
• Frequent recurrences, marked
neurotropism, late onset of metastasis
• poor long-term survival (approximately 30–
40% at 10–20 years)

25. • Cytomorphology of adenoid cystic
carcinoma:
1) Basaloid cells with hyperchromatic and
often angulated nuclei
2) Acellular hyaline matrix forming globules
with sharp borders

26. Cibriform pattern in adenoid cystic carcinoma

27. Well demarcated Hyaline globiles with small basaloid
cells in adenoid cystic carcinoma

28. • Solid subtype, can be difficult to diagnose
on FNAB because of lack of the
characteristic matrix and overlapping
morphological features with PAs, BCA,
basal cell adenocarcinoma,
myoepithelioma, epithelial myoepithelial
carcinoma, and PLGAs

29. • MYB overexpression can be used as a
diagnostic marker for AdCC
Adenoid cystic carcinoma
most common translocation t(6;9)(q22-23;p23-24)
genes involved MYB-NFIB gene fusion

30. Basaloid cells in AdCC with bland nuclear features
and show strong nuclear immunostaining for MYB.

31. Mammary analog secretory carcinoma
• Rare SGT first described in 2010 by Skalova
et al
• Occurs more commonly in males and at
extraparotid sites.
• The morphology, immunohistochemical, and
molecular profiles of MASC are identical to
secretory carcinoma of the breast.

32. • Cytomorphology of mammary analog
secretory carcinoma:
1) Histiocytoid-like cells with abundant finely
vacuolated cytoplasm
2) Uniform round nuclei with open
chromatin and nucleoli
3) Background of pale-staining seromucinous
or cystic material

33. dyshesive large polygonal cells
with abundant vacuolated
cytoplasm, and round to ovoid
nuclei with small nucleoli
Background shows
seromucinous material

34. • It is the only primary salivary gland tumour
harbouring ETV6 rearrangement.
• Cytologically, MASCs can be confused with PA or
other oncocytic SGTs, including WT, ACC, and
MEC
• The most definitive marker of MASC is
identification of the ETV6 gene rearrangement,
usually by FISH

35. • Immunohistochemical positivity for
mammaglobin , GATA-3, 82 GCDFP-15, and
S-100 and negativity for DOG1 are useful.
strong cytoplasmic immunostaining for mammaglobin

36. Hyalinizing clear cell carcinoma
• Rare low-grade SGC
• It typically arises from the minor salivary
glands of the oral cavity of women
most common
translocation
t(12;22)(q13;p12)
genes involved EWSR1-ATF1 gene
fusion

37. • Cytomorphology of hyalinizing clear cell
carcinoma
1) Large and cohesive epithelial cell clusters
with nuclear uniformity
2) Clear cytoplasm, and distinct cell borders
3) scant homogenous fibrous stroma

39. • Being composed mainly of clear cells, the
cyto-histopathologic differential diagnosis of
HCCC is very broad and includes:
1) Clear cell oncocytoma,
2) Low-grade MEC,
3) Epithelial–myoepithelial carcinoma
4) Clear cell myoepithelioma/myoepithelial
carcinoma,
5) ACC,
6) Metastatic renal cell carcinoma,
7) Squamous cell carcinoma clear-cell variant,
8) Melanoma

40. • HCCC does not contain a myoepithelial
cell component or a myxohyaline stroma,
and lacks myoepithelial differentiation on
immunochemistry
• FISH for the EWSR-1 translocation can be
performed on smears or cell-block in order
to confirm a diagnosis of HCCC

41. Cribriform adenocarcinoma of
minor salivary gland
• Low-grade SGC, closely related to PLGA
• The most common reported location is the
base of the tongue (76%), followed by
palate (7%), tonsils (7%), retromolar
mucosa (5%), floor of mouth (2%), and
upper lip (2%)

42. • It may be confused with PLGA in minor
salivary gland sites and with papillary
thyroid carcinoma (PTC) in cervical lymph
node metastases.
• In contrast to PTC, however, TTF-1 and
thyroglobulin are consistently negative in
CAMSG.

43. Conclusions
• FNAB remains one of the mainstays of the
initial diagnosis of SGT
• Cell blocks and/or smears can provide
adequate material for ancillary studies such
as FISH or next-generation sequencing to
detect specific chromosomal translocation

44. • Immunocytochemistry can be used to
detect abnormal oncoproteins resulting
from these translocations, such as MYB or
PLAG1
• These ancillary studies may also provide
important prognostic and therapeutic
information for patients with SGT in the
future

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