JOSE LUIS MIRA-HERNANDEZ, MD SURGICAL PATHOLOGIST CSI LABORATORIES, ALPHARETTA, GA USA

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

B-CATENIN

VIMENTIN

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

• Microscopic – Solid sheets of

uniform polygonal cells are separated into nests by abundant capillary sized blood vessels

– No true acinar lumen formation

• 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

• 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

• Microscopic – Tumor cells

with foamy cytoplasm and aggregates of foamy macrophages

• Microscopic – Intracytoplas

mic and extracellular PAS and D-PAS positive hyaline globules

• Microscopic – Intracytoplas

mic and extracellular PAS and D-PAS positive hyaline globules

• 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

• Microscopic– Stromal

fibrosis and hyalinization may be present

– Mixoid change

• Microscopic – Well

circumscribed tumor but often there is tumor invasion within associated non neoplastic pancreatic parenchyma

• Microscopic – Well circumscribed

tumor but often there is tumor invasion within associated non neoplastic pancreatic parenchyma

– Peripheral “blood lakes” suggesting blood vessel invasion

• 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

• 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

• 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

• Gross:– Large (10 cm),

well circumscribed

– Red, soft and fleshy

• 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

• 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: minute lumina, basal nuclei, eosinophilic granular apical cytoplasm

• Solid: lacks acinar lumina, basal palisading of nuclei

• 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

• 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

• 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.

• 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

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

• 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

• 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

• 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

• Cytologically malignant

• By definition >20MF/10HPF, Ki67 >20%, but most cases have >40-50MF/10HPF

• Lymphovascular invasion

• Blood vessel invasion

• 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

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

CHROMOGRANIN

SYNAPTOPHYSIN

E-CADHERIN

VIMENTIN

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

JOSE LUIS MIRA-HERNANDEZ, MD SURGICAL PATHOLOGIST CSI LABORATORIES, ALPHARETTA, GA USA

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