Interesting Cases of Pancreatic Masses Martha Bishop Pitman, MD Professor of Pathology Harvard Medical School Director of Cytopathology Massachusetts General Hospital Boston, MA MASSACHUSETTS GENERAL PHYSICIANS ORGANIZATION HARVARD MEDICAL SCHOOL Case 1 A 76 year old asymptomatic man was found to have a multiloculated cyst in the pancreatic tail. Approximately 1mL of slightly thin, slightly bloody fluid was removed. A cystospin was made of the cells and the supernatant was sent for CEA and amylase. Case 1: EUS Report A 3.5 cm well defined multiloculated, lobulated cystic mass was noted in the pancreatic tail. The cyst wall was not well visualized and the septations were thick. 1
Case 1 Case 1 Case 1 2
Case 1 Case 1: Cyst Fluid Analysis Amylase = 20 U/L CEA = 0.5 ng/ml. Case 1 Cytology Diagnosis: Satisfactory for Evaluation Neoplastic: Benign Nonmucinous cyst fluid with low amylase (20 U/L) and CEA (0.5 ng/ml.) consistent with serous cystadenoma. 3
Serous Cystadenoma Shark Core Biopsy Moray Microforceps Biopsy 4
Serous Cystadenoma PAS dpas Case 1: Teaching Points SCA produce nonmucinous fluid Usually bloody or clear Hemosiderin-laden macrophages act as a surrogate marker to suggest the diagnosisi Epithelium is fragile and may not survive processing by smearing SCA have low amylase and CEA Case 2 A 64 year old woman being worked up for esophageal stricture is noted to have a cystic mass in the uncinate process. An EUS-FNA is scheduled. 5
Case 2: EUS Report The body and tail of the pancreas is very atrophic. In the uncinate process, there is a fairly well circumscribed round cystic mass with thick cyst wall measuring about 30 X 20 mm. Aspirates are productive of yellow cyst fluid; cyst fluid CEA and amylase are assessed. Case 2 Case 2 6
Case 2 Case 2: Cyst Fluid Analysis CEA = 6 mg/ml Amylase = 65 U/L Case 2: Molecular Analysis KRAS wild type GNAS wild type 7
Case 2: CB Case 2: chromogranin Case 2: synaptophysin 8
Case 2 Cytological Diagnosis Satisfactory for Evaluation Neoplastic: Other Cystic neuroendocrine tumor Case 2: Teaching Points cpannets mimic primary pancreatic cysts The cells of PanNET fall into the HGA category due to the small cell size and the abnormal chromatin Usually the endocrine features of the cells are apparent Cytology is THE test to diagnose cpannets: CEA and amylase are low and molecular analysis is negative Morales-Oyarvide V, Yoon WJ, Ingkakul T, Forcione DG, Casey BW, Brugge WR, Fernández-Del Castillo C, Pitman MB. Cystic pancreatic neuroendocrine tumors: The value of cytology in preoperative diagnosis. Cancer Cytopathol. 2014 Case 2: Teaching Points If the diagnosis is indeterminate use the ATYPICAL category, not the SUSPICIOUS category Atypical is to Neoplastic as Suspicious is to Positive Similar for other neoplasms in the Other category 9
Case 3 A 54 year old woman was found to have a cyst in the pancreatic body following resolution of a bout of pancreatitis that brought her to the ER. Case 3: EUS Report A 25 mm cyst was identified in the pancreatic body. There was a single compartment without septae. The outer wall of the lesion was thick. There was a small mural nodule. Case 3 10
Case 3 Case 3: Cyst Fluid Analysis Amylase = 409 U/L CEA = 5165 ng/ml. Case 3: Molecular Analysis KRAS mutant GNAS mutant 11
Case 3 Cytological Diagnosis Satisfactory for Evaluation Neoplastic: Other Mucinous cyst with high-grade grade atypia consistent with IPMN with at least high-grade dysplasia. See note. Case 3: IPMN-branch duct type with high-grade dysplasia Case 3: Teaching Points Cytology is the best test for determining cyst grade Distinguishing between low and high-grade is sufficient for patient management Intermediate-grade dysplasia is best placed with low-grade but features overlap with HGD. HGD cells are smaller than a 12 duodenal enterocyte, have abnormal chromatin and high N/C ratio; necrosis is often present 12
Case 4 An 84 year old female was found to have a 2.6 cm cyst in the body/tail of the pancreas during evaluation of her Barrett s esophagus. An FNA was performed. 1 ml of thin, clear fluid was submitted for cytology and biochemical testing. Case 4: EUS Report A 2.6 cm anechoic cyst was noted in the body-tail of the pancreas. There were no septations and the wall was thin. There was no associated mass lesion. A connection to the main pancreatic duct was visualized. Case 4: Cyst Fluid Analysis Amylase = 111,153 U/L y, CEA = 56 ng/ml. 13
Case 4 Case 4 Case 4 14
Case 4 Cytological Diagnosis Satisfactory for Evaluation Negative for Malignancy Mucoid cyst fluid; no high-grade g epithelial cells present. See note. Note: There appears to be extracellular mucin but its source is unclear and CEA is not elevated above our cut off level of 192 ng/ml to support a neoplastic mucinous cyst. Benign appearing mucinous epithelium is present, the distinction from gastric contamination is not possible. Case 4: Follow-up -In this elderly, asymptomatic woman with low-risk imaging that supports the diagnosis of an IPMN and low-risk cytology, conservative e observation was recommended -Follow-up at one year showed no growth Case 4: Teaching Points Aspiration of pancreatic cysts serves two main purposes: Determining if the cyst is mucinous Definitive criteria may not be present- choice between ND and negative, and correlation with clinical and imaging helps to determine which is best for the patient Determining if the cyst is high-risk by cytology, e.g. if there is HGA present HGA = HGD or adenocarcinoma No HGA + low-risk imaging = 99% NPV Wu RI, Yoon WJ, Brugge WR, Mino-Kenudson M, Pitman MB. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) contributes to a triple-negative test in preoperative screening of pancreatic cysts. Cancer Cytopathol. 2014; 122:412-419. 15
Case 5 A 62 year old female is worked up for acute onset of abdominal pain. Ultrasound shows a markedly dilated pancreatic duct with sharp tapering in the pancreatic head where a 2 cm round cystic mass is identified. EUS with FNA was performed. Case 5: EUS Report A round hypoechoic, calcified and cystic mass is identified in the pancreatic head measuring 16 mm by 20 mm The endosonographic borders are welldefined. An intact interface is seen between the mass at the adjacent structures suggesting a lack of invasion. Diagnostic needle aspiration for fluid is performed into the cystic component of the mass and into the mass itself. The amount of brown-yellow fluid collected is 4 ml. The fluid is sent for biochemical and molecular analysis. Case 5: Cyst Fluid Analysis CEA = 35 mg/ml Amylase = 65,549 U/L KRAS mutant GNAS mutant 16
Case 5:cyst Case 5:cyst Case 5: mass TP 17
Case 5:mass TP Case 5:mass CB Case 5:mass CB 18
Case 5:mass CB-ki-67 Case 5:mass CB-SMAD4 Case 5 Diagnosis: Satisfactory for Evaluation Positive for Malignancy Adenocarcinoma consistent with IPMN with invasive carcinoma. See note. Note: The cyst is mucinous by CEA elevation and KRAS/GNAS mutations, the GNAS mutation supporting an IPMN. The cyst epithelium is low-grade but the associated mass is diagnostic of adenocarcinoma, supported by a brisk ki-67 positivity and loss of nuclear SMAD4 staining. 19
PDAC Case 5: Teaching Points Aspiration of both the cyst and associated mass is required for accurate diagnosis. A cyst may not show significant atypia whereas the mass will show adenocarcinoma Although these components of a single mass lesion may have discordant results, the overall result of the FNA is what counts This type of case should be considered a TP in studies A low CEA does not exclude a mucinous cyst GNAS mutations support the diagnosis of IPMN Cytology is the best test for grading the cyst/mass PDAC may be deceptively bland- the cytoplasm is the biggest clue to diagnosis!! Case 6 A 45 year old male was found to have a mass in the pancreatic tail during workup for non-specific abdominal pain. 20
Case 6: EUS Report EUS showed a 1.5 cm round, well-defined solid and cystic mass with a heterogenous echotexture in the pancreatic tail; 3cc of thick cyst fluid obtained Case 6: Cyst Fluid Analysis CEA = 235 mg/ml Amylase = 237 U/L Case 6: Molecular Analysis KRAS WT GNAS WT 21
Case 6 Case 6 Case 6 22
Case 6 Keratinous debris mimicking desiccated mucin Case 6 Cytological Diagnosis: Evaluation limited by scant cellularity Evaluation limited by scant cellularity Negative for Malignancy Lymphoepithelial Cyst 23
Case 6: Teaching Points Rare; 4:1 M:F; mean 56 years thick cheesy keratinous debris may cause the cyst to appear solid on imaging Recognition of keratinous debris is the key to diagnosis Elevated CEA a pitfall! Case 7 A 68 year old female presented to the emergency room for acute abdominal pain about 1 week following a dental procedure. A CT scan showed a ~3cm cyst in the pancreatic head. The patient was referred to a gastroenterologist. MASSACHUSETTS GENERAL PHYSICIANS ORGANIZATION HARVARD MEDICAL SCHOOL Case 7: Clinical History No history of alcohol abuse No history of pancreatitis Sudden onset of abdominal pain MASSACHUSETTS GENERAL PHYSICIANS ORGANIZATION HARVARD MEDICAL SCHOOL 24
Case 7:EUS Performed 36 x 26 mm cyst in the pancreatic head ~10 cc of thin purulent fluid was obtained. Cultures sent; no other CFA performed. Cytology = neutrophils only. A gram stain showed gram positive cocci in pairs and chains. and culture grew abundant Rothia Dentocariosa. 1 month of antibiotics was prescribed. Repeat EUS persistent cyst 30 x 25mm 12 cc of opaque, thin, yellow fluid obtained. Cytospin of cyst fluid- whole mount image 25
Case 7 Case 7 Case 7 26
Case 7 Case 7 Case 7: Diagnosis Neoplastic: Other Mucinous cyst with high-grade epithelial atypia consistent with branch-duct intraductal papillary mucinous neoplasm with at least high-grade dysplasia. 27
. IPMN, branch-duct type, with focal high-grade dysplasia. No invasion identified Case 7 Case 7: Teaching Points Clinical presentation Benign appearing BD-IPMN infected from dental procedure No high risk imaging features Small, no mural nodule, no associated dilated MPD CFA: Biochemical very elevated CEA supporting a mucinous etiology Cytology HGA (suspicious) Resect Case 8 A 56 year old man presents with abdominal pain. CT shows an 8 cm solid, partially cystic mass in the pancreatic head. An FNA is performed- smears and cellblock are made. 28
Case 8 Case 8 Case 8 29
Case 8 Case 8 Case 8 30
Case 8 Case 8 Beta-catenin 31
Beta-catenin CD10 CD56 32
Case 8:Diagnosis Satisfactory for Evaluation Neoplastic: Other Solid-pseudopapillary Neoplasm Case 8: Teaching Points SPN do occur in males (4-7%) with the same age mean and range as females- Mean age 30-35; Range 8-85 Frequent pseudopapillary pattern Formed by separation of vascular cores with adherent cells Typically thin walled vessels in cores >95% cured by resection Most recurrences or metastases associated with atypical features Rare non-atypical cases may metastasize May occur years later Most common metastatic sites Liver Peritoneum / omentum Local lymph nodes involved rarely Neoplastic: Other interpretation category rather than Malignant in the PSC PB terminology system Case 9 A 72 year old female is found incidentally to have a vague, questionable mass in the pancreatic body. The pancreas otherwise was normal. An EUS-FNA of the mass is performed. Direct smears fixed in alcohol are stained with a Papanicolaou stain. No EUS report was available as the case was sent to me in consultation. 33
Case 9 Case 9 Case 9 34
Case 9 Case 9 Case 9 35
Case 9 Cytological Diagnosis: Satisfactory for Evaluation Negative for Malignancy Benign pancreatic tissue. Acinar Tissue is often confused with NET Case 9: Teaching Points negative is an appropriate interpretation category when imaging does not indicate a definitive mass lesion nondiagnostic is the more appropriate category when imaging clearly defines a mass lesion Misdiagnosis of normal acinar tissue as NET is a significant pitfall. Mixture of ductal epithelium and?acinar/lesional? tissue is a clue to it being pancreatic acinar epithelium If uncertain, and NET is a possibility, use atypical category 36
Case 10 A 50 year old asymptomatic man is found to have a 1.5 cm round mass in the tail of the pancreas. Case 10: EUS 1.5 cm round well-circumscribed solid mass consistent with a neuroendocrine tumor Case 10 37
Case 10 Case 10 Case 10 38
Case 10 Case 10 Case 10: synaptophysin 39
Case 10: chromogranin Case 10: CD8 Diagnosis Negative Splenule (Accessory spleen) 40
Non-viscous and CEA c and -KRAS/GNAS Serous Cystadenoma Lymphoepithelial cyst GI contaminate in Pseudocyst Cystic neuroendocrine tumor Solid-pseudopapillary tumor Cystic acinar cell carcinoma Viscous or CEA c or +KRAS/GNAS Mucinous cystic neoplasm with lowintermediate grade dysplasia Intraductal papillary mucinous neoplasm with low-intermediate grade dysplasia Colloid carcinoma Mucinous cystic neoplasm with highgrade dysplasia or invasive carcinoma Intraductal papillary mucinous neoplasm with high-grade dysplasia or invasive carcinoma Colloid carcinoma Cystic ductal adenocarcinoma a small cell with high nuclear to cytoplasmic ratio and abnormal chromatin and/or nuclear membranes b large cells with low nuclear to cytoplasmic ratio and moderate to abundant cytoplasm, often mucinous c Cut off value of 192 ng/ml has an accuracy of ~80% for detecting a mucinous cyst 5/1/2017 Case 10: Teaching Points Splenule mimic NETs on images Cytologically, splenules mimic NETs or lymph node CD8 is diagnostic IHC stain along with negative endocrine markers Helpful Resources Chapter 3: Tissue handling and processing, including cellblock technique (collodian bag) Chapter 4: Ancillary Studies Chapter 7: Cystic Lesions Algorithm for interpretation Helpful Resources Appendix A: Template for signing out pancreatic cysts Appendix B: Mucinous Etiology Epithelium High grade a Low g grade b Absent Present 41