38 th Annual Seminar PATHOLOGY REVIEW: Pulmonary, Neuro, and Hepatic Pathology for the General Pathologist
Thursday, February 16, 2017 The Westin Snowmass Resort • Snowmass Village, CO
Educational Symposia TABLE OF CONTENTS
Thursday, February 16, 2017
Update of Adenocarcinoma of the Lung - Case Based (Kevin O. Leslie, M.D.)...... 241
An Approach to Hepatic Fibrosis - Case Based (Maxwell L. Smith, M.D.)...... 257
Peripheral Nerve Sheath Tumors (Arie Perry, M.D.)...... 271
Drug Induced Liver Injury - Case Based (Maxwell L. Smith, M.D.)...... 289
Neoplastic Lung Disease - Case Based (Kevin O. Leslie, M.D.)...... 303
SAVE THE DATES: 2017 & 2018 Pathology Symposia 241 242 Leslie Case 5 Supplemental History Molecular Pathology of Lung Caucasian Cancer 30 pack year history of smoking No asbestosis exposure 67 y/o male with 4 cm lung mass Pleural nodules identified by imaging VATS biopsy performed
243 What do we do with this specimen?
1990s and Before = Meso vs. Non-Small Cell Keratin Positive, Meso Markers Negative
2000s = Lung Adeno vs. Squamous TTF-1 Positive, p40 Negative
2010s = EGFR vs. ALK vs. KRAS vs. ROS-1
Are there markers that can predict response or survival benefit in the context of treatment intervention? • " • " Can we selectively apply beneficial • " therapies to those most likely to • " benefit? Can we avoid toxic interventions in those unlikely to benefit? # The Holy Grail of Therapeutic Intervention
Need All Three for Effective Therapy Mutations that are integral to tumor growth
AND
Mutations the are testable
AND
Agents that target the mutations and thus tumor
growth From M. Ledanyi MD
244 gefitinib Present Day Potentially Significant Lung Cancer Mutations (% 84>$ $ $ &)%! ;6>1# !& 2 !( #/ 56> %+#!$ $ :5>1& 2 / ! 0 ($ $ %!#$12 $ ! #$/ 1# !& % 2 !#$"#! !$ $ * %#%* % (% 54>$ $ $ $% %! 409> $/$ ! #$/ 74> ( !($ ($ $ !%#% !1 2 %#" $) (% 60:>1 !# $ &)%! 99> !( #/ ! 0 $" %+2 %!#$1# ,!& 2 $ ! #$ $ $% %%!
From M. Ledanyi MD 05 (% 6> $ &)%! . !( #/ ! 0 !$$ + !# %!# $ ! #$
Modified after: Chirieac L, Dacic S. Targeted therapies in lung cancer. Surg Pathol Clin.2010; 3(1):73. Transmembrane EGF Ligand Directed Tx EGFR --Monoclonal antibodies receptor EGF-Cetuximab VEGF- Bevacizumab A transmembrane TK receptor that Plasma membrane binds EGF and TGF-alpha ligands. Tyrosine kinase inhibitors for EGFR- gefitinib, erlotinib, etc. Actions: activates cell proliferation and for VEGFR- AZD2171, vandetanib, etc. angiogenesis, and inhibits apoptosis. Tipifamib, Signaling RAS PI3K LY294002 Ionafamib pathways Tyrosine kinase inhibitors block Sorafamib BRAF PDK1 these intracellular pathways with downstream effects on proliferation. CI-1040 MEK AKT PTEN ERK TSG mTOR Sirolimus, et al Overall only ~10% patients with lung p53 Therapy Vornostat cancer show a response to TKIs despeptide HDAC
Slide courtesy SA Yousem MD Nucleus
EGFR Mutations
• Mutations of EGFR that confer therapeutic KRAS responsiveness to TKI are largely restricted Oncogene Prevalence Therapeutic Response Clinical to two exons: Results Rates Associations KRAS Mut 10% Asians Resistance to EGFR 0-5% Males, • #19 – 50%; deletion 30% TKI smokers, All Caucasians No targeted mucinous • #21 – 40%; point mutation therapies available adeno • Mutations of EGFR initially thought to be Most common mutation in lung adenocarcinoma in the US mutually exclusive to mutations of K-RAS, (~30%)
BRAF, Her2. Mutually exclusive with EGFR (usually) • Mutations of EGFR are progressive resulting in resistance to TKI over long term Nearly ALL mucinous adenocarcinomas will be KRAS mut
No targeted therapies available = not worth testing for
245 Modified after: Chirieac L, Dacic S. Targeted therapies in lung cancer. Surg Pathol Clin.2010; 3(1):73. Transmembrane EGF Ligand Directed Tx --Monoclonal antibodies receptor EGF-Cetuximab VEGF- Bevacizumab ALK and ROS1 Plasma membrane Tyrosine kinase inhibitors for EGFR- gefitinib, erlotinib, etc. Rearrangements of the ALK and ROS1 for VEGFR- AZD2171, vandetanib, etc. gene result in changes to the
Tipifamib, Signaling RAS PI3K LY294002 cytoplasmic side of the TKR Ionafamib RAS pathways Sorafamib BRAF PDK1 Result is constitutive activation
CI-1040 MEK AKT PTEN Results in cell proliferation and anti- apoptosis along the RAS (and PI3K for ERK TSG mTOR Sirolimus, et al p53 Therapy ROS) pathway
Vornostat despeptide HDAC Can be inhibited with crizotinib Nucleus
Modified after: Chirieac L, Dacic S. Targeted therapies in lung cancer. Surg Pathol Clin.2010; 3(1):73. Transmembrane EGF Ligand Directed Tx --Monoclonal antibodies receptor EGF-Cetuximab VEGF- Bevacizumab Plasma membrane • ALK Mutations ROS1 Mutations # " % Crizotinib Crizotinib • % • " % Tipifamib, Signaling Ionafamib RASRAS PI3K LY294002 pathways • ! % Sorafamib BRAF PDK1
CI-1040 MEK AKT PTEN ! ERK TSG mTOR Sirolimus, et al # p53 Therapy # & # Vornostat despeptide HDAC Nucleus
()# ' "
246
• • "" • • • !
247
• • • •
248 Do IHC on this core!
Save for potential molecular studies, ";7 98A >=A depending on IHC results 38 =:A p40 $%! !,& (#$ %) !#$%!$%/ • %#$&! 1 • %# ) ##$!# #& -&! B • ,$% %) !#+% • $0 ) 0 ! % $B !# ! ! "! %! !# ! – !#"! ! , • ! !%!*0!38 ";7 – , 4385 – $$";7"!$&* 38! " % , • !+#$%%$& &*0%$%!# 4" ! !)# $% ,!)#! ! !,"#!%!! $5 • %!"$,2,%! !,1 – !)# ! ) &! +% ! ! !,% 249 $!+!&')# # +# #& $"%& '$#$')# $! )' • .('(#$&- ((& ('0 • ((+"$&'($('(0 "$+#($+"$& 4:!!' :6!!' 966!!' ?7""9 • $-($('(0 &7:1666 !!' • (&$'(),'(&( '0 !!+!& (. #2 #2 ?86> ?;6> )$$"! ##( !!'($#$# #2 #2 ?:6> ?86> & ,'$ ( $!$ .# $&($&. #1&!. $#! #&!' ''&#$& $!+!& 3723 7 &%.$& +()$#' " # '(&)$#$ !$ # ($!&#($( (+"$&' • # %&$+(', !! #'$ • #+$!+ #!!' *!) $# • #$('#' ),$&!!$( &#( • -%'((.) +)""$'.#' *!)$'.!! "+()$#' • $,#' *!)(7.)$)$- 8!!(. # # )$4 :5 ; • – & !&'+!(''$#( ,#$& –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ow to Test for EGFR? $ ! ! #! PCR for all mutations occurring in at ) " ! ! ! ! least 1% of lung adenocarcinoma & ! Formalin fixed tissue or cell block $ ! & & cytology $ ' Adequacy – depends on the specimen, % ) 300 cells is general guideline IHC for EGFR has no role at this time &! ( $ " $ # (' &# # (' &# # (' (*&% &%' # (' (#- $)% 1.2 mm Length of tumor necessary for 300 cells = 0.5/% cellularity 0.8 mm 0.5/0.2 = 2.5mm 0.2 mm 0.5 mm # ( &## . # ( - # ( (.$ = 2.7 mm 251 1st H&E for diagnosis 2nd H&E for diagnosis Molecular Lab H&E Examples of QNS for EGFR Molecular lab according to Lab #1 PCR QNS! BLACK BOX #*&%@^# Viable Tumor Cell Necrotic Tumor Cell Benign Cell Examples of Acceptable Specimens for EGFR according to Lab #1 252 Examples of Acceptable Specimens for EGFR according to Lab #2 How to Test for ALK and ROS1? Formalin fixed tissue or cell block from cytology Adequacy – less important than EGFR as the test is FISH based (50 minimum cells) Must demonstrate fusion product in 15% of 50 cells counted at minimum 253 Telomere 2p23 region Centromere t(2;5) ALK gene • + " breakpoint region ALK 3’ 5’ EML4 • # ")40 """# !! ~250 kb ~300 kb • !"$! ! , ")! " "% 4 3! ! " " "% ! " ! , ! "3! . ! ! &/ • !"$! )9148 ."!"40/"# ! ' &! "(! "! '"* 2013(136)727+750* #'"* 2012(16.11/)1341+1364* "% ! !'!#!" ! & (%$# !! ! " " %',*+) ( !! !% #" "!" - # "!" !&" &! !! & " "$ "! $ "!" !) >1 microgram DNA , +!""!!!! " #&. %" / - !" & $ ! #" , ! .1 ! !% " " 1 %" ! "" "!":&/ 50ng DNA , !" "# + # ". !" & !! +$#" #"!/ Courtesy of Dr. A. John Iafrate &# "#$'#!# " • *#"# !(##!#", • )"$ ( # !"#- (* • ##& !"# #"#, • /.* • (# #"#, • & "! ( # • #! "#$'"#!# ", ! '" # * !# !* -! * ! " 254 What we do (currently) Test ALL non-small cell lung cancer except for PURE squamous cell carcinoma (morphology or by p40/ p63 IHC) EGFR and ALK simultaneously Considering NGS Test for others at clinician request Back to our Case! Liquid Biopsy Bulk of tumor was in the lung, Non-invasive TTF-1 + Performed on peripheral blood samples Testing for EGFR and ALK was negative Tests for cell free DNA fragments shed by tumor Possibly KRAS mutated (older male smoker) Potential to avoid sample bias Allow for serial monitoring No targeted therapy available for this patient Suggested Reading SPECIAL SECTION—2012 NEW FRONTIERS IN PATHOLOGY Lung Cancer Biomarkers: Present Status and Future Developments Philip T. Cagle , MD; Timothy Craig Allen , MD, JD; Randall J. Olsen , MD, PhD Archives of Pathology & Laboratory Medicine: ! September 2013, Vol. 137, No. 9, pp. 1191-1198 Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors Neal I. Lindeman, MD, Philip T. Cagle, MD, Mary Beth Beasley, MD, Dhananjay Arun Chitale, MD, Sanja Dacic, MD, PhD, Giuseppe Giaccone, MD, PhD, Robert Brian Jenkins, MD, PhD, David J. Kwiatkowski, MD, PhD, Juan-Sebastian Saldivar, MD, Jeremy Squire, PhD, Erik Thunnissen, MD, PhD, and Marc Ladanyi, MD J Thorac Oncol. 2013 Jul;8(7):823-59. 255 256 257 258 +-,/ ' • • 3 "$ • . " $$ #" ( & • $ ! $ % * • ) 259 260 ! !!+ • 401 • 43. • 40- • "4-)3 • " "' !! • 4-)- * " #" # • # 4/), "" ! ! • ""!432 " " !! • ( "(#" ! * !!$! • !! "%"#" ! !!$ &&!" & !! • & ! "! "& " ! # " "!( &!& " " • & !!" $ # • " ! "" ! "" !$ !& " " "& " ! !& ""&!# " "#"' !! "" 261 ! "##$" #& ! " $ ## # #&#! %! "" % "#" $ ! %#!# # #"" # !! # % ) ". # "#* ! &" !" # $ #% "#" (! # %!"""# #!+# "# ' ! %# !$"$ #$#$!- ! " ! # #! # %! # '#$'! $ 6456+579,8/: "# """"0#1 %!"" • "'"""" # • %!$ # #"#"% $# !"' ## '"$ # • # $" !""$!! #2 3 • ! " # "# ! ' • !$ !!" • $ $ #% ! '"# "2 3 ! " ! # #! # %! # '#$'! $ 6456+579,8/: 262 263 ! ! ! ! 264 ! ! , ! $ ! ! , ! % ! ! ! # ' • !% • • !, ! , • $ % ' • " ( % " % ) ) • + " % & "! 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School of Medicine PNST PERSPECTIVE Neuropathologist Dermatopathologist Soft tissue GI pathologist pathologist UPDATE OF “COMMON” MOST USEFUL STAINS PROBLEMS • Neurofibroma vs. Schwannoma • H&E • CD34 • Leu-7 (CD57) − Plexiform NF vs. plexiform schwannoma • Reticulin • Cytokeratin • Cellular schwannoma vs. MPNST • Alcian Blue • S-100 • Ki-67 • Atypical NF vs. MPNST • SOX10 • p53 • Low-grade MPNST in NF1 patient • GFAP • p16 • Melanotic schwannoma vs. • Collagen IV • INI-1 melanocytoma or melanoma • Neurofilament • Calretinin? • High-grade MPNST vs. various • EMA • H3K27me3 sarcomas • Neurofibromin School of Medicine School of Medicine • Claudin or GLUT-1 273 PERINEURIOMA PERINEURIOMA (Intraneural v ST) NFP S-100 PERINEURIOMA TUMOR PREDISPOSITION SYNDROMES Schwann Cell From: Rodriguez FJ, Stratakis CA, Evans DG, Acta Neuropathol 2012 EMA SCHWANNOMA, WHO GRADE I MRI IN AN NF2 PATIENT • CPA = “acoustic neuroma” or vestibular schwannoma • Spinal cases are intradural extramedullary or dumbbell-shaped extending through foramina • Arises in single fascicle and grows eccentric to parent nerve allowing for some functional preservation • NF2 gene implicated in both sporadic and familial cases • Schwannomatosis defined by multiple non- School of Medicine vestibular schwannomas School of Medicine 274 SCHWANNOMA SCHWANNOMA SCHWANNOMA NF2 OR SCHWANNOMATOSIS Schwannomatosis defined by multiple non- vestibular schwannomas and no meningiomas (rare exceptions now reported) INI-1 S-100 C-IV SOX10 School of Medicine School of Medicine Patil et al., Brain Pathol 2008:517-19 CELLULAR SCHWANNOMA FOUR (OR 3) HIT HYPOTHESIS • Schwannomas in schwannomatosis inactivate 2 genes • Familial cases have germline INI1 mutations • Somatic NF2 inactivation • Monosomy 22 event deletes both genes at once (“3 hit” model) School of Medicine 275 CELLULAR SCHWANNOMA PLEXIFORM SCHWANNOMA MMST MMST MMST 276 MMST MMST S-100 Melan-A HMB-45 MMST MELANOMA/CYTOMA Col-IV Col-IV PRKAR1A NEUROFIBROMAS • Cutaneous − Localized − Diffuse (Plaque-like; NF1 in ~10%) • Intraneural − Localized − Plexiform (mostly NF1) − Centrally entrapped axons • Massive soft tissue (‘elephantiasis’) − Often has plexiform component − NF1 • Atypical Neurofibroma School of Medicine 277 DIFFUSE CUTANEOUS NEUROFIBROMA PARASPINAL INTRANEURAL NEUROFIBROMAS IN NF1 INTRANEURAL NEUROFIBROMA PLEXIFORM NEUROFIBROMA NFP PLEXIFORM NEUROFIBROMA PLEXIFORM NEUROFIBROMA Alcian Blue 278 PLEXIFORM NEUROFIBROMA PLEXIFORM NEUROFIBROMA S-100 EMA CD34 SOX10 ATYPICAL NEUROFIBROMA ATYPICAL NEUROFIBROMA p16 MPNST ETIOLOGY • Synonyms: neurofibrosarcoma, malignant schwannoma, neurogenic sarcoma MPNSTs • WHO 2016 Definition: “A malignant tumour with evidence of Schwann cell or perineurial cell Rad differentiation, commonly arising in a peripheral (10%) NF1 Associated nerve or in extraneural soft tissue. MPNSTs NF1 primarily affect young to middle-aged adults, but (~45%); Sporadic also affect adolescents; about 50% of MPNSTs are mostly in associated with NF1, in which they often arise Radiation Induced from a pre-existing plexiform or intraneural Sporadic PNFs (~45%) neurofibroma and affect younger patients. In Schwannoma, contrast, most sporadic cases arise from large GNB, GN, Pheo peripheral nerves without an associated benign precursor. Most MPNSTs show combined inactivation of NF1, CDKN2A, and PRC2 School of Medicine component genes.” School of Medicine 279 Low-grade MPNST MPNST GRADING • WHO 2016: “Clinically validated and reproducible grading systems for MPNST are generally lacking. One approach to MPNST grading is to divide the tumours into low-grade (~15% of cases) and high- grade (~85% of cases), but robust and validated criteria are lacking. Low-grade MPNSTs are well- differentiated tumours most often arising in transition from neurofibroma. An increased mitotic rate is often seen but is not required for the diagnosis. Conventional monomorphous spindle cell MPNSTs, highly pleomorphic MPNSTs, and MPNSTs with divergent differentiation (e.g. malignant triton tumour; glandular MPNST; and osteosarcomatous, chondrosarcomatous, and angiosarcomatous differentiation) are all School of Medicine considered high-grade.” Low-grade MPNST Low-grade MPNST S100 Low-grade MPNST Low-grade MPNST (but only rarely like this!) Ki-67 p53 EGFR 280 FDG-PET MPNST arising in a Neurofibroma MPNST arising in a Neurofibroma MPNST arising in a Neurofibroma Col-IV S-100 281 H3K27me3 Beware mosaic pattern! HG MPNST H3K27me3 HG MPNST HG MPNST 282 HG MPNST HG MPNST HG MPNST HG MPNST HG MPNST Intraneural Spread 283 HG MPNST HG MPNST S100 SOX10 p16 HG MPNST HG MPNST Ki-67 Neurofibromin 284 COMMON DIAGNOSTIC ERRORS • Mistaking a cellular schwannoma for a low-grade MPNST • Overcalling degenerative atypia in a neurofibroma as MPNST • Dx of all malignancies involving nerve as MPNST (e.g. synovial sarcoma) • Dx of MPNST due to S100 positivity alone or excluding it if S100 negative • Still a need for more specific markers! School of Medicine Epithelioid MPNST Epithelioid MPNST S-100 INI-1 Epithelioid MPNST Epithelioid MPNST CD57 Col IV GFAP SOX10 285 Epithelioid MPNST EMA “Triton Tumor” “Triton Tumor” Desmin “Triton Tumor” “Glandular MPNST” S-100 Myoglobin 286 Perineurial MPNST/Malignant Perineurioma EMA Radiation-associated MPNST Schwannoma Lyrics and Music by Arie Perry, MD Schwannomas present in adult patients in their forties or their fifties They’re peripheral nerve tumors, often solitary, and they grow next to the nerve eccentrically Because of this feature, they can be excised, and still the nerve can be spared It’s mainly the compression of adjacent nerve, which makes the patient impaired (chorus) Ch: Schwannomas are no mystery; you look for Antoni A and Antoni B And Verocay bodies will clinch the diagnosis for me Hyalinized vessels is another clue, and good encapsulation is a key feature too To make the diagnosis when the surgeon’s leaning over you Acoustic neuromas are in the CP angle, and involve cranial nerve VIII In the spinal canal, nerve roots are involved, and can alter the patient’s gait Grossly, they’re firm, grey-white masses, on cut surface, they’re gelatinous Ancient neuromas have degenerative changes, cystic spaces and hemorrhage (chorus) Multiple tumors, and young age of onset, suggests hereditary disease Vestibular schwannomas, and meningiomas, meet NF2 criteria with ease The term schwannomatosis may be utilized, when multiple tumors are seen Non-vestibular involvement is a defining feature, so the head MRI should be clean (chorus) School of Medicine 287 288 289 290 ! & " " # " &) • -.& • # " &!& • # +$ ! & " (# ! 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"$ ! • ! % • * ) 300 301 302 303 304 A Pattern-Based Approach to Lung Disease A Pattern-Based Approach to Lung Disease Leslie Case 6 Clinical history A 70-year-old man presents with slowly progressive shortness of breath accompanied by non-productive cough. He is a prior smoker, but quit 10-years ago. The patient is a retired carpenter. A high resolution CT scan shows a 3.0 cm density in the peripheral right upper lobe. CT-guided needle biopsies are obtained. The histopathology shows 305 A Pattern-Based Approach to Lung Disease A distinctive characteristic of lepidic adenocarcinomas is the propensity to spread within the lung, in contrast to other lung adenocarcinomas that frequently spread to What is your “favored” diagnosis? extrapulmonary sites early in their development. Two histopathological forms exist: 1. Mucinous alveolar adenoma 2. Bronchioloalveolar adenocarcinoma Mucinous 3. Adenocarcinoma, in situ, mucinous type 4. Atypical adenomatous hyperplasia Nonmucinous 5. Mucinous adenocarcinoma, invasive (formerly “classical” BAC) Take home message Monotonous tall columnar mucinous cells in the lung are mucinous adenocarcinoma until proven otherwise. 306 307 308 Educational SAVE Symposia THE DATES 3rd Annual A Practical Approach to Surgical and Cytopathology April 6 - 8, 2017 Hotel del Coronado • Coronado, CA 2nd Annual Surgical Pathology Update: Diagnostic Pearls for the Practicing Pathologist September 14 - 15, 2017 The Venetian® | The Palazzo® • Las Vegas, NV 39th Annual Seminar Pathology Review February 11 - 16, 2018 The Westin Snowmass Resort • Snowmass Village, CO Date and Location Subject to Change. If you enjoyed this meeting and would like to share it with your colleagues, these lectures, and thousands more, are ONE available for streaming on-demand at FREE HOUR