Upload
sonel
View
31
Download
1
Embed Size (px)
DESCRIPTION
CHALLENGING DIAGNOSIS IN SURGICAL PATHOLOGY ANNUAL SYMPOSIUM 2014 ACADEMY OF PATHOLOGY AND LABORATORY MEDICINE OF PUERTO RICO. JOSE LUIS MIRA-HERNANDEZ, MD SURGICAL PATHOLOGIST CSI LABORATORIES, ALPHARETTA, GA USA. Case 1. - PowerPoint PPT Presentation
Citation preview
CHALLENGING DIAGNOSIS IN SURGICAL PATHOLOGY
ANNUAL SYMPOSIUM 2014ACADEMY OF PATHOLOGY AND LABORATORY
MEDICINE OF PUERTO RICO
JOSE LUIS MIRA-HERNANDEZ, MDSURGICAL PATHOLOGIST
CSI LABORATORIES, ALPHARETTA, GAUSA
Case 1
72-year-old female underwent Whipple resection for a pancreatic head mass
D-PAS
D-PAS
CD10
CD56
B-CATENIN
B-CATENIN
PR
VIMENTIN
CD99
CD99
Additional pertinent markers• Few positive cells:
– CAM 5.2– CK 19
• Rare positive cells: – Chromogranin– Synaptophysin
• Negative– CK 7 CK 20– EMA S100– CEA CA 19.9– Trypsin Chymotrypsin– α1-AT α1-ACT– ER
DIAGNOSIS
PANCREATIC SOLID PSEUDOPAPILLARY NEOPLASM
Solid neoplasms of the pancreas
• Adenocarcinoma• Pancreatoblastoma• Acinar cell carcinoma• Pancreatic neuroendocrine neoplasm• Solid pseudopapillary neoplasm• Mixed tumors: each component should
comprise at least 25% of the entire tumor: – Acinar-ductal– Acinar-endocrine– Acinar-endocrine-ductal
Solid pseudopapillary neoplasia
• First described by Frantz in 1959 (AFIP Atlas of tumor pathology, fascicles 27 and 28); solid and cystic tumor of the pancreas, Frantz’s tumor.
• Solid pseudopapillary neoplasm, WHO Classification of tumors, 2010
• Uncertain cell differentiation• Uncommon, 2-5% of pancreatic malignancies
Solid pseudopapillary neoplasia• Affects females predominantly (89%), 9.8:1 female
to male ratio• Mean age 28 years, range 7-79 years• Males, mean age 5-10 years older than females• No hormonal, clinical syndrome or genetic disease
association has been demonstrate• Frequently reported during pregnancy or
postpartum, possibly explained by the high incidence during child-bearing age
• Non specific symptoms, palpable abdominal mass• Asymptomatic, incidental radiographic finding
Solid pseudopapillary neoplasm• Gross
– Anywhere within the pancreas– Large tumors, mean diameter 10
cm– Asymptomatic incidental tumors
<5 cm– Well circumscribed, partially
encapsulated– Red/tan, hemorrhagic, soft, friable
solid areas– Cystic degeneration
• Near complete cystic change may simulate a pseudocyst
– True necrosis may occur but is rare– Firm consistency reflects abundant
fibrous hyalinazed stroma
Solid pseudopapillary neoplasm
• Microscopic – Solid sheets of
uniform polygonal cells are separated into nests by abundant capillary sized blood vessels
– No true acinar lumen formation
Solid pseudopapillary neoplasm
• Microscopic – Solid sheets of
uniform polygonal cells are separated into nests by abundant capillary sized blood vessels
– No true acinar lumen formation
Solid pseudopapillary neoplasm
• Microscopic – Ischemic degenerative
changes with discohesive cell and cell drop leaving a ragged cuff of neoplastic cells clinging to blood vessels
– pseudopapillary architecture
– Microcystic and macrocystic architecture, pseudocysts
Solid pseudopapillary neoplasm
• Microscopic – Ischemic degenerative
changes with discohesive cell and cell drop leaving a ragged cuff of neoplastic cells clinging to blood vessels
– pseudopapillary architecture
– Microcystic and macrocystic architecture, pseudocysts
Solid pseudopapillary neoplasm
• Microscopic – Tumor cells
with foamy cytoplasm and aggregates of foamy macrophages
Solid pseudopapillary neoplasm
• Microscopic – Intracytoplas
mic and extracellular PAS and D-PAS positive hyaline globules
Solid pseudopapillary neoplasm
• Microscopic – Intracytoplas
mic and extracellular PAS and D-PAS positive hyaline globules
D-PAS
Solid pseudopapillary neoplasm
• Microscopic – Uniform round to oval
nuclei, nuclear groves– Tumor cell nuclei oriented
away from capillary wall resulting in a zone of cytoplasm separating the nuclei from the capillaries
– Rare mitoses, 0-10 MF/50HPF
– Nuclear pleomorphism is rare but may be present
Solid pseudopapillary neoplasm
• Microscopic– Stromal
fibrosis and hyalinization may be present
– Mixoid change
Solid pseudopapillary neoplasm
• Microscopic – Well
circumscribed tumor but often there is tumor invasion within associated non neoplastic pancreatic parenchyma
Solid pseudopapillary neoplasm
• Microscopic – Well circumscribed
tumor but often there is tumor invasion within associated non neoplastic pancreatic parenchyma
– Peripheral “blood lakes” suggesting blood vessel invasion
Solid pseudopapillary neoplasm
• Microscopic – Well circumscribed
tumor but often there is tumor invasion within associated non neoplastic pancreatic parenchyma
– Peripheral “blood lakes” suggesting blood vessel invasion
Solid pseudopapillary neoplasm
• Microscopic – Well circumscribed
tumor but often there is tumor invasion within associated non neoplastic pancreatic parenchyma
– Peripheral “blood lakes” suggesting blood vessel invasion
Solid pseudopapillary neoplasia
• Genetics– Somatic point mutations in exon 3 of the β-catenin gene
(same as in acinar cell carcinoma and pancreatoblastoma)• Β- catenin and Cyclin D1 overexpression
– Chromosomal gains in 13q, 17q, 1q and 8q– Chromosomal losses in 11q– No ductal adenocarcinoma associated mutations: KRAS,
p16, p53,DPC4– No E-cadherin gene mutations– No KIT/PDGFRA mutations
Solid pseudopapillary neoplasm
• Prognosis:– Low grade malignant neoplasm/low malignant potential
• Indolent behavior• Potential for local invasion and metastatic disease
– 95% cured by complete surgical excision when confined to the pancreas
– 19.5% present with or develop local invasion and/or metastatic spread• Metastasis usually limited to liver and peritoneum• Lymph node metastasis are exceptional
– Long-term survival even in patients with metastasis or unresectable disease
– Rupture with potential life-threatening hemoperitoneum
Solid pseudopapillary neoplasia
• Malignant transformation: solid pseudopapillary carcinoma– Residual areas of conventional solid pseudopapillary neoplasia– Diffuse sheets of markedly atypical cells – True tumor necrosis– High mitotic activity– Perineural and blood vessel invasion– Aneuploidy
• No reliable criteria• Rare tumor deaths associated to dedifferentiated or
sarcomatoid carcinoma
Acinar cell carcinoma
• Acinar differentiation is defined as the production of pancreatic enzymes, packaged in zymogen granules, by neoplastic cells
• 1-2% of adult and 15% of pediatric pancreatic neoplasms • Most common in males in the 6th decade of life• Abdominal pain, nausea, vomiting, weight loss• 10-15% present with lipase hypersecretion syndrome:
– Massive serum lipase elevation– Subcutaneous fat necrosis– Polyarthralgia
Acinar cell carcinoma
• Gross:– Large (10 cm),
well circumscribed
– Red, soft and fleshy
Acinar cell carcinoma
• Microscopic:– High cellularity, stroma-
poor tumors, with sheets of uniform cells organized in various architectural patterns• Solid: lacks acinar
lumina, basal palisading of nuclei
• Acinar: minute lumina, basal nuclei, eosinophilic granular apical cytoplasm
• Glandular• Trabecular • Mixed
Acinar cell carcinoma
• Microscopic:– High cellularity, stroma-
poor tumors, with sheets of uniform cells organized in various architectural patterns• Solid: lacks acinar lumina,
basal palisading of nuclei • Acinar: minute lumina,
basal nuclei, eosinophilic granular apical cytoplasm
• Glandular• Trabecular • Mixed
Acinar cell carcinoma
• Acinar: minute lumina, basal nuclei, eosinophilic granular apical cytoplasm
Acinar cell carcinoma
• Solid: lacks acinar lumina, basal palisading of nuclei
Acinar cell carcinoma
• Fine granular eosinophilic cytoplasm, abundant PAS and D-PAS positive zymogen granules (95% of tumors). 5% zymogen deficient tumors
• Uniform, large, central nuclei with prominent single nucleoli
• Frequent mitoses
Acinar cell carcinoma
• Immunohistochemistry: – pancreatic enzymes: trypsin and chymotrypsin
positive in 95% of tumors. Amylase rare– Endocrine differentiation in 35-54% of cases:
scattered cells positive for chromogranin and/or synaptophysin
– Some AFP positive tumors with or without elevated serum AFP
Acinar cell carcinoma
• Genetics: – Losses on chromosome 11p in 50% of cases– 24% of cases have abnormalities in the APC/B-
catenin pathway: activating mutations of the B-catenin gene or truncating mutations of the of the APC gene
– Lack the more common ductal carcinoma associated abnormalities: KRAS mutations, p53, DPC4 and p16 abnormalities.
Acinar cell carcinoma
• Highly aggressive tumors:– 50 % of patients have metastatic disease at
presentation and more than 50% of the remaining patients develop metastasis subsequently, more frequently in regional lymph nodes and liver.
– Very poor survival: 6% at five years– Median survival time: 18-19 months. Not as rapidly
lethal as conventional ductal carcinoma, some patients with distant metastasis survive for 2-3 years
– Pediatric patients have better prognosis than adults
Pancreatic neuroendocrine neoplasia
• Pancreatic neoplasms with predominant neuroendocrine line of differentiation
• 1-2% of pancreatic neoplasms, 1/100000 in the general population
• Can occur at any age (20-80), mean age 50 years; rare in children
• Male to female ratio 1: 1.15• Occur throughout the pancreas, 60% in the
tail
Pancreatic neuroendocrine neoplasia• Most are sporadic but can occur in association to
genetic syndromes – MEN-1
• Multiple PNEN– Microadenomas– NETs, at least one functional
» gastrinoma, more common» Insulinoma» VIPoma» Glucagonoma» GH NET
– pituitary and parathyroid adenomas
– von Hippel-Lindau disease, 5-10 % of patients, multiple, most non-functional
– Neurofibromatosis
Pancreatic neuroendocrine neoplasia (PNEN). 2010 WHO Classification
– Neuroendocrine microadenoma • <0.5 cm• Non-functional (non-syndromic)
– Well differentiated pancreatic neuroendocrine neoplasm , regardless of biological behavior• Neuroendocrine tumor Grade 1 (NET G1), Ki67 <2%• Neuroendocrine tumor Grade 2 (NET G2), Ki67 2-20%
– Poorly differentiated neuroendocrine neoplasms• Neuroendocrine carcinoma Grade 3 (NEC G3), Ki67 >20%
– Large cell NEC G3– Small cell NEC G3– Mixed adenoneuroendocrine carcinoma (MANEC), at least 30% non-neuroendocrine
tumor component
• Further tumor prognosis and treatment stratified by TNM stage classification
2004 vs. 2010 WHO classificationsWHO 2004 WHO 2010
Well differentiated neuroendocrine tumor: confined to the pancreas; lack high grade malignant featuresa) Neoplasms of predicted benign behavior: <2.0
cm. and <2 MF/10HPFb) Neoplasms of uncertain behavior: display one or
more of the following features: >2.0 cm., >2MF/10HPF, vascular or perineural invasion
Neuroendocrine tumora) NET GI: Ki67 <2% (5%?)B) NET G2: Ki67 2-20 %
Well differentiated neuroendocrine carcinoma: gross local invasion or metastasis, lack high grade malignant features
Poorly differentiated neuroendocrine carcinoma: high grade malignant features, small cell type, large cell type
Neuroendocrine carcinoma (NEC) G3: Ki67>20%
Mixed exocrine-endocrine carcinoma (MEEC) Mixed adenoneuroendocrine carcinoma (MANEC): at least 30% non-neuroendocrine tumor component
Definitions ENETS TNM UICC/AJCC/WHO 2010 TNM
T1 Limited to the pancreas, <2 cm Limited to the pancreas, <=2 cm
T2 Limited to the pancreas, 2-4 cm Limited to the pancreas, >2 cm
T3 Limited to the pancreas, >4 cm or invading duodenum or bile duct
Beyond the pancreas but without involvement of the superior mesenteric artery
T4 Tumor invading adjacent organs: stomach, spleen, colon, adrenal gland, the wall of large vessels (celiac axis, sup. mesent. artery)
Involvement of celiac axis or the superior mesenteric artery (unresectable tumor)
Stage I T1, N0, M0 N/A
Stage IIa T2, N0, M0 N/A
Stage IIb T3, N0, M0 N/A
Stage IIIa T4, N0, M0 N/A
Stage IIIb Any T, N1, M0 N/A
Stage IV Any T, Any N, M1 N/A
Stage IA N/A T1, N0, M0
Stage IB N/A T2, N0, M0
Stage IIA N/A T3, N0, M0
Stage IIB N/A T1-T3, N1, M0
Stage III N/A T4, Any N, M0
Stage IV N/A Any T, Any N, M1
Neuroendocrine tumors• Functioning (syndromic): associated with clinical syndromes caused by
hypersecretion of hormones– Pancreatic
• Insulinomas, 42%• Glucagonomas, 14%• Somatostatinomas, 6%. Although somatostatin producing tumors do occur, the
associated somatostatin syndrome has recently been questioned• PPoma: exception to the rule. Traditionally classified as “functioning”, elevated serum
PP and positive PP by immunohistochemistry, however no specific syndrome
– Ectopic• Gastrinomas, 24%• Vasoactive intestinal peptide/VIPomas, 10%• ACTH NET (Cushing’s syndrome)• GH NET(Acromegaly)• Calcitonin NET(Diarrhea)• Serotonin NET (Carcinoid syndrome)
Neuroendocrine tumors
• Nonfunctioning (non-syndromic)– Not associated with a clinical syndrome– Hormone production may be demonstrated by
immunohistochemistry– May present with elevated serum hormone levels– Represent at least 60% of all PNET– Non specific abdominal mass associated symptoms including
pain, nausea, jaundice due to compression of bile ducts– 15% incidental finding on imaging studies for other reasons – Symptoms related to metastatic disease at presentation,
usually within the liver, and/or local invasion
Neuroendocrine tumorsGross features
• Well demarcated, solitary, white –yellow or pink-brown• Soft and fleshy or densely fibrotic• Hemorrhage and necrosis can occur, usually larger tumors• Functioning tumors usually <2 cm. Insulinomas usually
smaller than most other functioning tumor• Syndrome severity not related to tumor size• Non functioning tumors 2-5 cm or larger• Larger tumors may be multinodular with gross evidence
of invasion• Rarely cystic with a central single locule surrounded by a
thin rim of neoplastic tissue
• By definition well differentiated• Well circumscribed, partially or completely encapsulated• Organoid histological patterns: nesting, trabecular,
glandular, gyriform, tubuloacinar, pseudorosette cellular arrangements
• Different patterns may be present in different areas of the same tumor
• Histological pattern does not indicate functional status or type of produced hormone. Exceptions:– Amyloid deposits typical in insulinomas– Glandular pattern with psammoma bodies in
somatostatinomas of the periampullary duodenum
Neuroendocrine tumorsMicroscopic features
Neuroendocrine tumorsMicroscopic features
• Relatively uniform cells with finely granular eosinophilic to amphophilic cytoplasm
• Centrally located round to oval nuclei with coarse clumped (salt and pepper) chromatin, sometimes distinct nucleoli
• Often the nucleus is peripherally locate resulting in plasmacytoid appearance
• Occasionally clear cells, vacuolated lipid-rich cells, oncocytes, rhabdoid cells may be observed
Neuroendocrine tumorsMicroscopic features
• Marked nuclear pleomorphism (pleomorphic NET) may occur
• By definition <20 MF/10HPF, most have <10MF/10HPF
• Variable stromal amount and degree of fibrosis
• Prominent vascular background with variable perivascular fibrosis encircle the tumor nests
• Limited tumor necrosis, usually comedo type
Neuroendocrine tumorsMicroscopic features
• Marked nuclear pleomorphism (pleomorphic NET) may occur
• By definition <20 MF/10HPF, most have <10MF/10HPF
• Variable stromal amount and degree of fibrosis
• Prominent vascular background with variable perivascular fibrosis encircle the tumor nests
• Limited tumor necrosis, usually comedo type
Neuroendocrine carcinoma
• 2-3 % of all pancreatic neuroendocrine neoplasms• Most commonly in adults with a male predominance• Cytologically malignant, extensive necrosis often geographic• Large and small cell types similar to lung criteria• Large cell more common than small cell• By definition >20MF/10HPF, Ki67 >20%, but most cases
have >40-50MF/10HPF• Tumors histologically similar to NET low to intermediate
grade with >20MF/10HPF/Ki67>20% are currently classified as NEC
Neuroendocrine carcinoma
• Cytologically malignant
Neuroendocrine carcinoma
• Cytologically malignant
Neuroendocrine carcinoma
• By definition >20MF/10HPF, Ki67 >20%, but most cases have >40-50MF/10HPF
Neuroendocrine carcinoma
• Cytologically malignant
• Lymphovascular invasion
Neuroendocrine carcinoma
• Cytologically malignant
• Blood vessel invasion
Neuroendocrine carcinoma
• Cytologically malignant, extensive necrosis often geographic
PNEN Immunohistochemistry
• Positive markers:– LMWCK: CAM5.2, CK8/18, CK19– Synaptophysin, Chromogranin, CD56– Peptide hormones in functioning NET– Peptide hormone immunohistochemical evaluation
in nonfunctioning NET has no clinical significance– Microadenomas usually express one single peptide
most often glucagon or PP– Glycoproteins: CEA, CA19-9– Ki67: evaluation of cellular proliferation rate– Lack of neuroendocrine markers in small cell NEC
does not preclude the diagnosis– p53 may be positive in NEC but not expressed in
NET
Genetics• Susceptibility: Germline mutations in the MEN1 and VHL genes in
patients with MEN1 and VHL syndromes play a role in the development of PNET in those patients
• MEN1: germ line mutations on chromosome 11q13 and somatic loss of the second allele– 60-70% of MEN1 patients have pancreatic NETs usually in the background
of multiple microadenomas, islets hypertrophy and/or hyperplasia– At least one functioning NET
• Gastrinoma, almost all are duodenal, is the more frequent functioning GEP NET in MEN1 patients
• Insulinoma, second most common• MEN1 associated NEC are rare
• VHL– 12-17% develop NETs, most are nonfunctioning
• NF1– Somatotastinomas, almost all duodenal– Insulinomas, rare
Genetics
• The molecular basis for sporadic PNET is not well known• Somatic mutations in the MEN1 gene are present in
20% of sporadic PNET• 68-70% harbor loses of 11q13 or more distal parts of
the long arm of chromosome 11 suggesting another unknown tumor suppressor gene might be involved
• Point mutations in the VHL gene are rare (1-3%)• The gene mutations involved in pancreatic ductal
adenocarcinoma (TP53, KRAS, CDKN2A/p16, SMAD4/DPC4) are not found in PNET
Pancreatic neuroendocrine tumor
32-year-old female underwent Whipple resection for a pancreatic
head tumor. Gross: 2.5 cm mass in the head of
the pancreas with apparent invasion of peripancreatic soft tissues and
metastatic disease in 2/18 regional lymph nodes
CAM 5.2
CK19
NSE
CHROMOGRANIN
SYNAPTOPHYSIN
A1-AT
E-CADHERIN
CD56
CD99
Ki-67
BCL-1
EMA
VIMENTIN
PR
CD10
B-CATENIN
Immunostain SPN PNET ACC PB
Pancytokeratin +/- (focal) + + +
Vimentin + +/- +/- +
Progesterone + +/- - -
Synaptophysin +/- + +/- -
Chromogranin - + +/- +/-
A-1 antitrypsin + +/- + +
Trypsin +/- - + +
CD56 + + (weak) - + (focal)
B-catenin + (nuclear) - + +/-
CD99 + (paranuclear dotlike)
+ (membranous) - +/- (rare and faint)
E-cadherin - +/- ? ?
References• Klimstra, David S. Nonductal neoplasms of the pancreas. Mod Pathol 2007;20:S94-S112• Kloppel, Gunter. Classification and pathology of gastroenteropancreatic
neuroendocrine neoplasms. Endocrine-Related Cancer 2011;18:S1-S16• Scarpa A, Mantovani W, Capelli P, Beghelli S, Boninsegna L, Bettini R, Panzuto F,
Pederzoli P, delle Fave G and Falconi M. Pancreatic endocrine tumors: improved TNM staging and histopathological grading permit a clinically efficient prognostic stratification of patients. Mod Pathol 2010;23:824-833
• Chakhachiro ZI and Zaatari G. Solid-pseudopapillary neoplasm. A pancreatic enigma. Arch Pathol Lab Med. 2009;133:1989-1993
• Notohara K, Hamazaki S, Tsukayama C, Nakamoto S, Kawabata K, Mizobuchi K, Sakamoto K and Okada S. Solid-pseudopapillary Tumor of the pancreas. Immunohistochemical localization of neuroendocrine markers and CD10. Am J Surg Pathol 2000;24(10):1361-1371
• Estrella JS, Li L, Rashid A, Wang H, Katz MH, Fleming JB, Abbruzzese JL and Wang H. Solid pseudopapillary neoplasm of the pancreas. Clinicopathologic and survival analysis of 64 cases from a single institution. Am J Surg Pathol 2014;38:147-157
References• Geers C, Pierre M, Jean-Francois G, Birgit W, Pierre D, Jacques R and Christine S. Solid and pseudopapillary
tumor of the pancreas. Review and new insights into pathogenesis. Am J Surg Pathol 2006;30:1243-1249• Guo Y, Yuan F, Deng H, Wang HF, Jin XL and Xiao JC. Paranuclear dot-like immunostaining for CD99: A
unique staining pattern for diagnosing solid-pseudopapillary neoplasm of the pancreas. Am J Surg Pathol 2011;35:799-806
• Tang LH, Aydin H, Brennan MF, and Klimstra DS. Clinically aggressive solid pseudopapillary tumors of the pancreas. A report of two cases with components of undifferentiated carcinoma and a comparative clinicopathologic analysis of 34 conventional cases. Am J Surg Pathol 2005;29:512-519
• El-Bahrawy MA, Rowan A, Horncastle D, Tomlinson I, Theis BA, Russell RCG and Stamp G. E-cadherin/catenin complex status in solid pseudopapillary tumor of the pancreas. Am J Surg Pathol 2008;32:1-7
• Meriden Z, Shi C, Edil BH, Ellison T, Wolfgang CL, Cornish TC, Schulick RD and Hruban RH. Hyaline globules in neuroendocrine and solid-pseudopapillary neoplasms of the pancreas. A clue to the diagnosis. Am J Surg Pathol 2011;35:981-988
• Basturk O, Tang L, Hruban RH, Adsay V, Yang Z, Krasinskas AM, Vakiani E, La Rosa S, Jang KT, Frankel WL, Liu X, Zhang L, Giordano TJ, Bellizzi AM, Chen JH, Shi C, Allen P, Reidy DL, Wolfgang CL, Saka B, Rezaee N, Deshpande V and Klimstra DS. Poorly differentiated neuroendocrine carcinomas of the pancreas. A clinicopathologic analysis of 44 cases. Am J Surg Pathol 2014;38:437-447
• Klimstra DS, Arnold R, Capella C, Hruban RH, Kloppel G, Komminoth P, Solcia E and Rindi G. Neuroendocrine neoplasms of the pancreas. WHO classification of tumors 2010;322-326