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Disclosure of Relevant Financial Relationships
USCAP requires that all planners (Education Committee) in a position to influence or control the content of CME disclose any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their spouse/partner have, or have had, within the past 12 months, which relates to the content of this educational activity and creates a conflict of interest.
Disclosure of Relevant Salivary Duct Carcinoma: Financial Relationships Its Apocrine Nature, Mimics, and
USCAP requires that all faculty in a position to Androgen Receptor influence or control the content of CME disclose any relevant financial Immunohistochemistry relationship WITH COMMERCIAL INTERESTS which they or their spouse/partner have, or have had, within the past 12 months, which relates to the content of this educational activity and creates a conflict of interest. S. Chiosea Dr. S. Chiosea declares he has no conflict of interest University of Pittsburgh Medical Center to disclose.
Salivary Duct Carcinoma (SDC): its Apocrine Nature and Salivary Duct Carcinoma (SDC): its Apocrine Nature and Androgen Receptor (AR) Expression Androgen Receptor (AR) Expression 1998, 2000, Dr. Barnes and colleagues reported on AR expression in SDC: 1968: SDC was first described by Kleinsasser et al. 1991: SDC was recognized as a distinct entity by the World Health Organization (WHO) 1998, 2000: Dr. Barnes and colleagues reported several novel findings regarding the morphology of and AR expression in SDC
2015: Multi-institutional study of SDC on predominance of apocrine morphology, histologic variants, and AR expression.
Kapadia SB, et al., Mod Pathol. 1998; Fan CY, et al., Am J Surg Pathol. 2000; Williams L., et al., Am J Surg Pathol. 2015 Fan CY, et al., Am J Surg Pathol. 2000
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Salivary Duct Carcinoma (SDC): its Apocrine Nature and Salivary Duct Carcinoma: its Apocrine Nature and Androgen Receptor (AR) Expression Androgen Receptor Expression
1998, 2000, Dr. Barnes and colleagues : 1998, 2000, Dr. Barnes and colleagues: #1: “.. apocrine appearance,… and diffuse, strong immunoreactivity … for AR… are characteristic of SDC.” #1: “Papillary-cribriform areas, necrosis, pleomorphism, apocrine appearance,… and diffuse, strong nuclear immunoreactivity … for #2: “The … magnitude of the AR expression in SDC approaches that seen in prostate androgen receptor… are characteristic of salivary duct carcinoma.” carcinoma. By contrast, AR expression in breast carcinoma remains sporadic, except for apocrine breast carcinoma”.
#3: “… hormonal profile (i.e., ER-/PR-/AR +) suggests that SDC… is immunophenotypically related to prostatic carcinoma. The … expression of AR in SDC raises the possibility that anti-androgen therapy might have a role in the management of patients with disseminated disease”. Kapadia SB, et al., Mod Pathol. 1998; Fan CY, et al., Am J Surg Pathol. 2000; Williams L., et al., Am J Surg Pathol. 2015
SDC: An Apocrine High Grade Adenocarcinoma The Knowledge Of Nearly Uniform AR ‘+” in SDC Has Affected UPMC Practice: • High skepticism about cases of non-apocrine AR “-” “salivary duct carcinoma”
• Intraductal carcinoma (Low grade cribriform cystadenocarcinoma, LGCCA) is unrelated to SDC • All SDC are high grade • Avoid the use of “low grade SDC” (as a synonym to LGCCA) Apocrine Phenotype AR Expression
Is there a Non-Apocrine/ Androgen Receptor Mimics of SDC: Adenoid Cystic Carcinoma Negative SDC? with High Grade Transformation (HGT)
HER2 ER (α)PRAR Study AR+ Locati 2009 44% SDC 17- 44% 0-8% 0-4% 44‐97% Williams 2007 67% Young female; Non‐apocrine, AR‐negative; Masubuchi 2014 72%
Di Palma 2012 86% pulmonary metastasis with What is the morphology of an unequivocal AR‐negative SDC? Kapadia 1998 92% morphology of adenoid cystic Fan 2000 92% carcinoma; no MYB/NFIB translocation by FISH Griffith 2013 97%
2015, Multi-institutional study of 199 cases of SDC Williams L., et al., Am J Surg Pathol. 2015
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Mimics of SDC: Mimics of SDC: Acinic Cell Carcinoma with Epithelial Myoepithelial Carcinoma, High Grade High Grade Transformation (HGT)
Dual cell population in conventional area (with p63/p40 “+”)
Myoepithelial overgrowth and Comedo‐necrosis in High grade area
Zymogen granules highlighted by PASD; Focal DOG1 positivity
Comedo-Type Necrosis ≠ Salivary Duct Carcinoma Mimics of SDC: Non‐Keratinizing Squamous Cell Carcinoma (AR “‐” & p63 “+”) Metastatic to Parotid
Adenoid cystic Acinic cell carcinoma carcinoma
Epithelial- Myoepithelial myoepithelial carcinoma carcinoma
Other types of salivary carcinomas with high grade transformation mimic SDC
SDC: An Apocrine High Grade Micropapillary SDC Adenocarcinoma
•The most common mimics of SDC are: Micropapillary: –SDC is mimicked by other types of salivary carcinomas with high grade transformation: Rare - 6/187 –Squamous cell carcinomas metastatic to parotid area All AR IHC “+” • 98% of SDC are apocrine and AR IHC+ • Variant morphologies are rare and are not found in “pure” form EMA, “inside-out” pattern seen in 1 of 6 cases Williams L., et al., Am J Surg Pathol. 2015
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Sarcomatoid SDC and AR Expression Mucinous SDC and AR Expression 3/187; all 3 cases AR “+” in conventional component Mucinous: 2/187
1 of 2 AR “-”
Williams L., et al., Am J Surg Pathol. 2015
Basal-Like SDC and AR Expression 98% of Salivary Duct Carcinomas are Apocrine/AR-positive
1/187 p63 SDC component AR within the pre-existing PA
Extensive sampling key to identifying apocrine component
Rare mucinous, basal-like, and sarcomatoid components/variants of SDC p63 are likelier to be AR-negative
No Relationship Between SDC & Intraductal Carcinoma (Low Grade Intraductal Carcinoma (Low Grade Cribriform Cystadenocarcinoma) Cribriform Cystadenocarcinoma)
p63 p63
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SDC vs. Intraductal Carcinoma (Low Grade SDC, Comparison to Breast Cribriform Cystadenocarcinoma ) Carcinoma
AR S100 SOX10 1998, 2001, Dr. Barnes and colleagues: Salivary duct carcinoma +- - #1: “Papillary-cribriform areas, necrosis, pleomorphism, apocrine appearance,… and Intraductal diffuse, strong nuclear immunoreactivity … for androgen receptor… are characteristic of carcinoma/LGCCA -+ + salivary duct carcinoma.” Mammary analogue secretory carcinoma -+ + #2: The scale and magnitude of the androgen receptor (AR) expression in salivary duct carcinoma approaches that seen in prostate carcinoma. By LGCCA, SOX-10 Adenoid cystic carcinoma -- + contrast, AR expression in breast carcinoma remains sporadic, except for apocrine breast carcinoma”. Acinic cell carcinoma -- +
A subset of LGCCA harbor RET rearrangement. I. Weinreb et al., USCAP 2016
SDC Resembles A Specific Type of SDC, Comparison to Prostate Breast Carcinoma: Luminal AR “+” Carcinoma
#2: The scale and magnitude of the AR expression in SDC approaches that 1998, 2001, Dr. Barnes and colleagues: seen in prostate carcinoma. By contrast, AR expression in breast carcinoma remains sporadic, except for apocrine breast carcinoma”: #1: .. apocrine appearance,… and diffuse, strong nuclear immunoreactivity … for AR… are characteristic of SDC.” Salivary Duct Luminal AR+ breast Carcinoma carcinoma ER/PR #2: “The scale and magnitude of the AR expression in SDC approaches that seen in prostate carcinoma. -- By contrast, AR expression in breast carcinoma remains sporadic, except for apocrine breast carcinoma”. AR ++ Prevalence of PIK3CA, #3: “The … expression of AR in SDC raises the possibility that anti-androgen Comparable TP53 mutations therapy might have a role in the management of patients with disseminated PLAG1, HMGA2 disease”. rearrangements +- Chiosea, et al, AJSP, 2015; Dalin et al., CCR, 2016; Chiosea et al, Cancer 2016
Salivary Duct Carcinoma & Salivary Duct Carcinoma & Androgen Deprivation Therapy (ADT) Androgen Deprivation Therapy
1993 – first inadvertent attempt to 1993 – first inadvertent attempt of ADT for SDC: treat SDC with ADT: 66-year-old man with a 5 cm retro-auricular mass. A 1 cm biopsy revealed an adenocarcinoma positive for prostate specific antigen (PSA) and prostatic acid phosphatase (PAP). Van Krieken JH, Van der Hulst RW et PAS+/PAP+ immunoprofile was believed to be indicative of prostatic al., Lancet, 1994: adenocarcinoma. Although provided photomicrographs The patient was treated with an anti-testosterone (goserelin), without clinical and histologic description are most evidence of primary prostatic carcinoma (benign prostate biopsies, negative consistent with SDC, the authors did bone scan, and normal PSA serum level). not actually use the term “salivary duct carcinoma”, complicating the literature search. The retro-auricular tumor regressed. Literature search, 1990s… Van Krieken JH, Van der Hulst RW et al., Lancet, 1994
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Salivary Duct Carcinoma (SDC) or Salivary Duct Carcinoma & Prostate Adenocarcinoma? New markers Androgen Deprivation Therapy Dr. Barnes et al showed that PSA and PAP may be positive in a number of SDCs Similarities and differences between AR pathway activation in SDC and prostate cancer have been delineated:
Prostate SDC Adenocarcinoma Oncogenic AR splice variants (AR-V7) associated with ++ resistance to ADT
ERG Activating AR mutations -+ AR amplification -+ In the future, SDC patients may be selected for ADT clinical trials based on AR NKX3.1 isoforms. Mitani et al., CCR, 2014
Summary: Evolution Of Observations Made By Dr. Barnes and Colleagues References: 1. Kleinsasser O, et al., [Salivary duct carcinoma. A group of salivary gland tumors #1: .. apocrine appearance,… and diffuse, strong nuclear immunoreactivity analogous to mammary duct carcinoma]. Arch Klin Exp Ohren Nasen Kehlkopfheilkd. … for AR… are characteristic of SDC” : 1968;192(1):100-5. - 98% of SDC are apocrine & AR “+”. Before diagnosing an AR “-” SDC, 2. Fan CY, Wang J, Barnes EL. Expression of androgen receptor and prostatic specific consider: markers in salivary duct carcinoma: an immunohistochemical analysis of 13 cases and review of the literature. Am J Surg Pathol. 2000;24(4):579-86. - other salivary tumors with high grade transformation or 3. Kapadia SB, Barnes L. Expression of androgen receptor, gross cystic disease fluid - metastatic predominantly non-keratinizing squamous carcinoma protein, and CD44 in salivary duct carcinoma. Mod Pathol. 1998;11(11):1033-8. - there is no relationship between SDC and intraductal 4. Williams L, et al. Salivary duct carcinoma: the predominance of apocrine carcinoma/LGCCA morphology, prevalence of histologic variants, and androgen receptor expression. The American journal of surgical pathology. 2015;39(5):705-13 5. van der Hulst RW, et al., Partial remission of parotid gland carcinoma after goserelin. #2: SDC resembles one specific type of breast carcinoma – luminal AR “+” Lancet. 1994;344(8925):817. 6. van Krieken JH. Prostate marker immunoreactivity in salivary gland neoplasms. A rare pitfall in immunohistochemistry. Am J Surg Pathol. 1993;17(4):410-4. #3: ADT in patients with SDC is being actively studied and applied
Important Information Regarding CME/SAMs
The Online CME/Evaluations/SAMs claim process will only be available on the USCAP website until September 30, 2017.
No claims can be processed after that date!
After September 30, 2017 you will NOT be able to obtain any CME or SAMs credits for attending this meeting.
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Mimics of SDC: Mammary Analogue Secretory Carcinoma, High Grade
AR “‐”, S100 “+” IHC; positive for ETV6 translocation by FISH
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