Author: xuchen.zhang

Case 4: Quarter 3, 2021

Clinical History

A 2-year-old-baby presented as a transfer from an outside hospital (OSH) due to concerns for possible acute cholecystitis. The patient has a history of abdominal pain for the last 2 weeks. The laboratory tests from the OSH were notable for leukocytosis. An abdominal CT scan showed a thickened gallbladder wall with numerous polypoid, non-mobile lesions. Eventually, the patient underwent laparoscopic cholecystectomy.

Macroscopic Description
On gross examination, the gallbladder measured 8.8 x 1.5 x 1.2 cm, with multiple, scattered polypoid mucosal lesions mainly in the body and fundus. The largest lesion measured 2 cm in the greatest dimension (arrows) (Figure 1). No cholelithiasis was present.

Figure 1. Gross photograph of the gallbladder showing polypoid exophytic lesions on the mucosa.

Histologic/Cytologic Features 

Microscopic pictures of the gallbladder lesions are shown in Figures 2-4. As shown in Figure 2, The lesions had an intraluminal exophytic (mass-forming) growth pattern and papillary architecture (black arrows). Adjacent mucosa (white arrows) is also involved by papillary overgrowth of epithelium. Figure 3 showed that the neoplastic epithelial lining is composed of a combination of biliary (black arrow), gastric foveolar-type (white arrow), and intestinal-type epithelium with goblet cells (blue arrow). No high grade cytologic atypia or architectural abnormalities were identified. A higher-power image is shown in Figure 4 and highlights a collection of the lamina propria macrophages (black arrows).

Figure 2. Low-power view of the exophytic lesion, H&E stain.
Figure 3. Medium-power view of the exophytic lesion, H&E stain.
Figure 4. High-power view of the lamina propria of the lesion, H&E stain.

[line]

Please select your diagnosis in the poll, then see the answer and the discussion in the links below.

[line]

What is the diagnosis of the lesion?

View Results

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[line]

Answer: Intracholecystic papillary neoplasm

Final diagnosis:  

Intracholecystic papillary neoplasm

Educational Objectives and Discussion:

Educational Objectives

  1. To understand the definition of intracholecystic papillary neoplasm
    (ICPN) of the gallbladder by 2019 WHO Digestive System Tumours.
  2. To recognize the gallbladder lesions associated with metachromatic
    leukodystrophy (MLD), an unusual neurologic disease in pediatric patients.
  3. To discuss the differential diagnosis of ICPN.

Discussion

Intracholecystic papillary neoplasm (ICPN) is a precancerous lesion of the gallbladder. Per the 2019 WHO Digestive System Tumours [1], ICPN encompasses/replaces the previous terminologies, including biliary
adenoma, tubulopapillary adenoma, intracystic papillary neoplasm, and papillomatosis. Grossly, these tumors form distinct polypoid/exophytic intraluminal masses that are grossly visible. Microscopically, these tumors show papillary and/or tubular configuration with varying degrees of epithelial dysplasia. There are four morphologic patterns recognized: biliary, intestinal, gastric, oncocytic, or combination of these. These morphologic patterns contrast with classifications of intraductal papillary mucinous neoplasms (IPMN) of the pancreas in which oncocytic lesions (intraductal oncocytic papillary neoplasms (IOPN)) have been separated from IPMN due to distinct molecular findings. Mucosa surrounding ICPN may demonstrate dysplasia as well. About 50% of ICPNs are associated with invasive adenocarcinoma, but they have a better clinical outcome than conventional gallbladder adenocarcinomas [1, 2].

Our case exhibited low-grade ICPN with combined biliary, gastric, and intestinal differentiation. Adjacent mucosa also showed diffuse low-grade dysplasia. No high-grade dysplasia or invasive carcinoma was identified in extensively submitted sections. The aforementioned unusual findings in the gallbladder from a 2-year-old baby triggered further work-up since there is a well-known association between ICPN (previously called gallbladder papillomatosis) and metachromatic leukodystrophy (MLD) [3-5]. Genetic analysis was performed and the results revealed homozygous deletion of pathogenic variant c.1283C>T (p.Pro428Leu) in ARSA gene, which is associated with MLD. Brain MRI findings were non-specific and she has no history of developmental delay, neurologic symptoms, or regression.

MLD is a lysosomal storage disease caused by a deficiency of arylsulfatase A (ASA) with autosomal recessive inheritance in most cases. The ASA deficiency leads to the accumulation of sulfatides in the central and peripheral nervous system, which results in the destruction of the myelin sheath and eventually leads to neurologic symptoms such as seizures, loss of motor functions, and peripheral neuropathy [6]. Sufatide accumulation is also detected in other organs, e.g., the gallbladder, kidney, lymph nodes, liver, and bone marrow. The gallbladder epithelial cells and macrophages contain cytoplasmic inclusions on electron microscopic examination, consistent with sulfatide accumulation [3, 7]. Almost all case reports described the presence of collections of the lamina propria macrophages in the gallbladder [3, 4, 7, 8], as seen in our case (Figure 4). This accumulation of macrophages could show histologic overlap with cholesterolosis, a more common finding in the gallbladder. In MLD, Giemsa and toluidine blue stains will show metachromasia of the cytoplasm of macrophages, consistent with the accumulation of sulfatide deposits. In contrast, the accumulation of cholesterol esters and triglycerides can be highlighted on frozen tissue with Oil red O or Sudan black stains.

According to the age of disease onset, there are three clinical subtypes of MLD, including late infantile-onset, juvenile-onset, and adult-onset. Our patient showed no neurologic symptoms but was homozygous for mutation of the ARSA gene, which encodes ASA. Numerous mutations in the ARSA gene have been identified, and c.1283C_T mutation in our case is usually seen in juvenile or adult-onset phenotype [6]. That may explain the neurologic symptom-free status of our patient. A possible treatment for MLD so far is hematopoietic stem cell transplantation for selected cases [4]. MLD-associated gallbladder abnormalities occasionally appear before the onset of neurologic symptoms or an MLD diagnosis [3]. One case series with 34 patients reported that 76% of MLD patients showed gallbladder involvement [4]. The gallbladder abnormalities consist of benign and malignant conditions, e.g., cholecystitis, cholelithiasis, mucosal hyperplasia, polypoid lesions (now most lesions are under the category of ICPN), and adenocarcinoma [3-5]. In conclusion, gallbladder abnormalities, in particular polypoid lesions, are rare during childhood. This condition can be seen in cases with MLD, Peutz-Jeghers’ syndrome, and pancreaticobiliary malunion [8]. Pathologists should pay close attention to unusual gallbladder abnormalities in pediatric and adolescent patients to consider the above-mentioned possibilities and associated risk of malignancy.

Differential diagnosis:

Pyloric gland adenoma is composed of lobules of small, tightly packed, bland-looking glands that are morphologically similar to pyloric or Brunner glands. The uninvolved gallbladder mucosa is mostly devoid of dysplasia or pyloric gland metaplasia. Of note, pyloric gland nodules <0.5 cm arising in a background of pyloric gland metaplasia should not be designated as pyloric gland adenoma [9].
Reactive epithelial hyperplasia, commonly due to secondary causes (e.g., cholelithiasis, chronic cholecystitis, inflammatory bowel disease, primary sclerosing cholangitis), shows focal or diffuse papillary-shaped and elongated mucosal folds lined by bland epithelial cells with or without metaplastic changes. The presence of significant inflammation and no discrete, grossly visible mass-forming lesion, may help distinguish reactive hyperplasia from ICPN [1,10].
Invasive adenocarcinoma is present in about 50% of the ICPN cases at the time of diagnosis [2]. Gallbladder adenocarcinoma arising in ICPN is more commonly associated with papillary growth patterns, biliary epithelial lineage, and high-grade dysplasia. The invasive component is often a tubular adenocarcinoma, although other types, such as mucinous, adenosquamous, or neuroendocrine carcinoma, have also been reported. Extensive sampling is warranted because approximately 60% of ICPN with carcinoma showed ≤ 5mm of invasive focus, and the carcinoma may also occur away from the main ICPN lesion. Some patients with non-invasive ICPN can also die of new primary carcinoma in the biliary tract, typically long after the diagnosis of ICPN, possibly due to the field cancerization phenomenon. This observation supports long-term surveillance of these patients with ICPN even after resection [1, 2].

References:

  1. Basturk O, Aishima S, Esoposito I. World Health Organization Classification of Tumours. Intracholecystic papillary neoplasm. In: Digestive System Tumours. 2019, IARC, Lyon.
  2. Adsay V, Jang KT, Roa JC, Dursun N, Ohike N, Bagci P, Basturk O, Bandyopadhyay S, Cheng JD, Sarmiento JM, Escalona OT, Goodman M, Kong SY, Terry P. Intracholecystic papillary-tubular neoplasms (ICPN) of
    the gallbladder (neoplastic polyps, adenomas, and papillary neoplasms that are ≥1.0 cm): clinicopathologic and immunohistochemical analysis of 123 cases. Am J Surg Pathol. 2012 Sep;36(9):1279-301.
  3. McFadden K, Ranganathan S. Pathology of the gallbladder in a child with metachromatic leukodystrophy. Pediatr Dev Pathol. 2015 May-Jun;18(3):228-30.
  4. van Rappard DF, Bugiani M, Boelens JJ, van der Steeg AF, Daams F, de Meij TG, van Doorn MM, van Hasselt PM, Gouma DJ, Verbeke JI, Hollak CE, van Hecke W, Salomons GS, van der Knaap MS, Wolf NI. Gallbladder
    and the risk of polyps and carcinoma in metachromatic leukodystrophy. Neurology. 2016 Jul 5;87(1):103-11.
  5. Kim J, Sun Z, Ezekian B, Schooler GR, Prasad VK, Kurtzberg J, Rice HE, Tracy ET. Gallbladder abnormalities in children with metachromatic leukodystrophy. J Surg Res. 2017 Feb;208:187-191.
  6. Cesani M, Lorioli L, Grossi S, Amico G, Fumagalli F, Spiga I, Filocamo M, Biffi A. Mutation Update of ARSA and PSAP Genes Causing Metachromatic Leukodystrophy. Hum Mutat. 2016 Jan;37(1):16-27.
  7. Rodriguez-Waitkus PM, Byrd R, Hicks J. Metachromatic leukodystrophy and its effects on the gallbladder: a case report. Ultrastruct Pathol. 2011 Dec;35(6):271-6.
  8. Garavelli L, Rosato S, Mele A, Wischmeijer A, Rivieri F, Gelmini C, Sandonà F, Sassatelli R, Carlinfante G, Giovanardi F, Gemmi M, Della Giustina E, Amarri S, Banchini G, Bedogni G. Massive hemobilia and
    papillomatosis of the gallbladder in metachromatic leukodystrophy: a life-threatening condition. Neuropediatrics. 2009 Dec;40(6):284-6.
  9.  Basturk O, Aishima S, Esoposito I. World Health Organization Classification of Tumours. Pyloric gland adenoma of the gallbladder. In: Digestive System Tumours. 2019, IARC, Lyon.
  10. Umudum H, Gunbatili E, Sanal M, Ceyhan K. Primary diffuse papillary hyperplasia of the gallbladder. Pathology. 2006 Dec;38(6):591-2.

[line] 

Case contributed by:

Goo Lee, MD, PhD. University of Alabama at Birmingham

Rong Li, MD, PhD. Children’s of Alabama Benjamin Russell Hospital For Children

Conflict of Interest: NO

Case 4: Quarter 3, 2021

Case 4: Quarter 3, 2021

Clinical History

A 2-year-old-baby presented as a transfer from an outside hospital (OSH) due to concerns for possible acute cholecystitis. The patient has a history of abdominal pain for the last 2 weeks. The laboratory tests from the OSH were notable for leukocytosis. An abdominal CT scan showed a thickened gallbladder wall with numerous polypoid, non-mobile lesions. Eventually, the patient underwent laparoscopic cholecystectomy.

Macroscopic Description
On gross examination, the gallbladder measured 8.8 x 1.5 x 1.2 cm, with multiple, scattered polypoid mucosal lesions mainly in the body and fundus. The largest lesion measured 2 cm in the greatest dimension (arrows) (Figure 1). No cholelithiasis was present.

Figure 1. Gross photograph of the gallbladder showing polypoid exophytic lesions on the mucosa.

Histologic/Cytologic Features 

Microscopic pictures of the gallbladder lesions are shown in Figures 2-4. As shown in Figure 2, The lesions had an intraluminal exophytic (mass-forming) growth pattern and papillary architecture (black arrows). Adjacent mucosa (white arrows) is also involved by papillary overgrowth of epithelium. Figure 3 showed that the neoplastic epithelial lining is composed of a combination of biliary (black arrow), gastric foveolar-type (white arrow), and intestinal-type epithelium with goblet cells (blue arrow). No high grade cytologic atypia or architectural abnormalities were identified. A higher-power image is shown in Figure 4 and highlights a collection of the lamina propria macrophages (black arrows).

Figure 2. Low-power view of the exophytic lesion, H&E stain.
Figure 3. Medium-power view of the exophytic lesion, H&E stain.
Figure 4. High-power view of the lamina propria of the lesion, H&E stain.

[line]

Please select your diagnosis in the poll, then see the answer and the discussion in the links below.

[line]

What is the diagnosis of the lesion?

View Results

Loading ... Loading ...

[line]

Click Here To See The Answer

Answer: Intracholecystic papillary neoplasm

 

[line]

Click Here To See The Discussion

Final diagnosis:  

Intracholecystic papillary neoplasm

Educational Objectives and Discussion:

Educational Objectives

  1. To understand the definition of intracholecystic papillary neoplasm
    (ICPN) of the gallbladder by 2019 WHO Digestive System Tumours.
  2. To recognize the gallbladder lesions associated with metachromatic
    leukodystrophy (MLD), an unusual neurologic disease in pediatric patients.
  3. To discuss the differential diagnosis of ICPN.

Discussion

Intracholecystic papillary neoplasm (ICPN) is a precancerous lesion of the gallbladder. Per the 2019 WHO Digestive System Tumours [1], ICPN encompasses/replaces the previous terminologies, including biliary
adenoma, tubulopapillary adenoma, intracystic papillary neoplasm, and papillomatosis. Grossly, these tumors form distinct polypoid/exophytic intraluminal masses that are grossly visible. Microscopically, these tumors show papillary and/or tubular configuration with varying degrees of epithelial dysplasia. There are four morphologic patterns recognized: biliary, intestinal, gastric, oncocytic, or combination of these. These morphologic patterns contrast with classifications of intraductal papillary mucinous neoplasms (IPMN) of the pancreas in which oncocytic lesions (intraductal oncocytic papillary neoplasms (IOPN)) have been separated from IPMN due to distinct molecular findings. Mucosa surrounding ICPN may demonstrate dysplasia as well. About 50% of ICPNs are associated with invasive adenocarcinoma, but they have a better clinical outcome than conventional gallbladder adenocarcinomas [1, 2].

Our case exhibited low-grade ICPN with combined biliary, gastric, and intestinal differentiation. Adjacent mucosa also showed diffuse low-grade dysplasia. No high-grade dysplasia or invasive carcinoma was identified in extensively submitted sections. The aforementioned unusual findings in the gallbladder from a 2-year-old baby triggered further work-up since there is a well-known association between ICPN (previously called gallbladder papillomatosis) and metachromatic leukodystrophy (MLD) [3-5]. Genetic analysis was performed and the results revealed homozygous deletion of pathogenic variant c.1283C>T (p.Pro428Leu) in ARSA gene, which is associated with MLD. Brain MRI findings were non-specific and she has no history of developmental delay, neurologic symptoms, or regression.

MLD is a lysosomal storage disease caused by a deficiency of arylsulfatase A (ASA) with autosomal recessive inheritance in most cases. The ASA deficiency leads to the accumulation of sulfatides in the central and peripheral nervous system, which results in the destruction of the myelin sheath and eventually leads to neurologic symptoms such as seizures, loss of motor functions, and peripheral neuropathy [6]. Sufatide accumulation is also detected in other organs, e.g., the gallbladder, kidney, lymph nodes, liver, and bone marrow. The gallbladder epithelial cells and macrophages contain cytoplasmic inclusions on electron microscopic examination, consistent with sulfatide accumulation [3, 7]. Almost all case reports described the presence of collections of the lamina propria macrophages in the gallbladder [3, 4, 7, 8], as seen in our case (Figure 4). This accumulation of macrophages could show histologic overlap with cholesterolosis, a more common finding in the gallbladder. In MLD, Giemsa and toluidine blue stains will show metachromasia of the cytoplasm of macrophages, consistent with the accumulation of sulfatide deposits. In contrast, the accumulation of cholesterol esters and triglycerides can be highlighted on frozen tissue with Oil red O or Sudan black stains.

According to the age of disease onset, there are three clinical subtypes of MLD, including late infantile-onset, juvenile-onset, and adult-onset. Our patient showed no neurologic symptoms but was homozygous for mutation of the ARSA gene, which encodes ASA. Numerous mutations in the ARSA gene have been identified, and c.1283C_T mutation in our case is usually seen in juvenile or adult-onset phenotype [6]. That may explain the neurologic symptom-free status of our patient. A possible treatment for MLD so far is hematopoietic stem cell transplantation for selected cases [4]. MLD-associated gallbladder abnormalities occasionally appear before the onset of neurologic symptoms or an MLD diagnosis [3]. One case series with 34 patients reported that 76% of MLD patients showed gallbladder involvement [4]. The gallbladder abnormalities consist of benign and malignant conditions, e.g., cholecystitis, cholelithiasis, mucosal hyperplasia, polypoid lesions (now most lesions are under the category of ICPN), and adenocarcinoma [3-5]. In conclusion, gallbladder abnormalities, in particular polypoid lesions, are rare during childhood. This condition can be seen in cases with MLD, Peutz-Jeghers’ syndrome, and pancreaticobiliary malunion [8]. Pathologists should pay close attention to unusual gallbladder abnormalities in pediatric and adolescent patients to consider the above-mentioned possibilities and associated risk of malignancy.

Differential diagnosis:

Pyloric gland adenoma is composed of lobules of small, tightly packed, bland-looking glands that are morphologically similar to pyloric or Brunner glands. The uninvolved gallbladder mucosa is mostly devoid of dysplasia or pyloric gland metaplasia. Of note, pyloric gland nodules <0.5 cm arising in a background of pyloric gland metaplasia should not be designated as pyloric gland adenoma [9].
Reactive epithelial hyperplasia, commonly due to secondary causes (e.g., cholelithiasis, chronic cholecystitis, inflammatory bowel disease, primary sclerosing cholangitis), shows focal or diffuse papillary-shaped and elongated mucosal folds lined by bland epithelial cells with or without metaplastic changes. The presence of significant inflammation and no discrete, grossly visible mass-forming lesion, may help distinguish reactive hyperplasia from ICPN [1,10].
Invasive adenocarcinoma is present in about 50% of the ICPN cases at the time of diagnosis [2]. Gallbladder adenocarcinoma arising in ICPN is more commonly associated with papillary growth patterns, biliary epithelial lineage, and high-grade dysplasia. The invasive component is often a tubular adenocarcinoma, although other types, such as mucinous, adenosquamous, or neuroendocrine carcinoma, have also been reported. Extensive sampling is warranted because approximately 60% of ICPN with carcinoma showed ≤ 5mm of invasive focus, and the carcinoma may also occur away from the main ICPN lesion. Some patients with non-invasive ICPN can also die of new primary carcinoma in the biliary tract, typically long after the diagnosis of ICPN, possibly due to the field cancerization phenomenon. This observation supports long-term surveillance of these patients with ICPN even after resection [1, 2].

References:

  1. Basturk O, Aishima S, Esoposito I. World Health Organization Classification of Tumours. Intracholecystic papillary neoplasm. In: Digestive System Tumours. 2019, IARC, Lyon.
  2. Adsay V, Jang KT, Roa JC, Dursun N, Ohike N, Bagci P, Basturk O, Bandyopadhyay S, Cheng JD, Sarmiento JM, Escalona OT, Goodman M, Kong SY, Terry P. Intracholecystic papillary-tubular neoplasms (ICPN) of
    the gallbladder (neoplastic polyps, adenomas, and papillary neoplasms that are ≥1.0 cm): clinicopathologic and immunohistochemical analysis of 123 cases. Am J Surg Pathol. 2012 Sep;36(9):1279-301.
  3. McFadden K, Ranganathan S. Pathology of the gallbladder in a child with metachromatic leukodystrophy. Pediatr Dev Pathol. 2015 May-Jun;18(3):228-30.
  4. van Rappard DF, Bugiani M, Boelens JJ, van der Steeg AF, Daams F, de Meij TG, van Doorn MM, van Hasselt PM, Gouma DJ, Verbeke JI, Hollak CE, van Hecke W, Salomons GS, van der Knaap MS, Wolf NI. Gallbladder
    and the risk of polyps and carcinoma in metachromatic leukodystrophy. Neurology. 2016 Jul 5;87(1):103-11.
  5. Kim J, Sun Z, Ezekian B, Schooler GR, Prasad VK, Kurtzberg J, Rice HE, Tracy ET. Gallbladder abnormalities in children with metachromatic leukodystrophy. J Surg Res. 2017 Feb;208:187-191.
  6. Cesani M, Lorioli L, Grossi S, Amico G, Fumagalli F, Spiga I, Filocamo M, Biffi A. Mutation Update of ARSA and PSAP Genes Causing Metachromatic Leukodystrophy. Hum Mutat. 2016 Jan;37(1):16-27.
  7. Rodriguez-Waitkus PM, Byrd R, Hicks J. Metachromatic leukodystrophy and its effects on the gallbladder: a case report. Ultrastruct Pathol. 2011 Dec;35(6):271-6.
  8. Garavelli L, Rosato S, Mele A, Wischmeijer A, Rivieri F, Gelmini C, Sandonà F, Sassatelli R, Carlinfante G, Giovanardi F, Gemmi M, Della Giustina E, Amarri S, Banchini G, Bedogni G. Massive hemobilia and
    papillomatosis of the gallbladder in metachromatic leukodystrophy: a life-threatening condition. Neuropediatrics. 2009 Dec;40(6):284-6.
  9.  Basturk O, Aishima S, Esoposito I. World Health Organization Classification of Tumours. Pyloric gland adenoma of the gallbladder. In: Digestive System Tumours. 2019, IARC, Lyon.
  10. Umudum H, Gunbatili E, Sanal M, Ceyhan K. Primary diffuse papillary hyperplasia of the gallbladder. Pathology. 2006 Dec;38(6):591-2.

[line] 

Case contributed by:

Goo Lee, MD, PhD. University of Alabama at Birmingham

Rong Li, MD, PhD. Children’s of Alabama Benjamin Russell Hospital For Children

Conflict of Interest: NO

Case 3: Quarter 2, 2021

Case 3: Quarter 2, 2021

Clinical History

A 50-year-old woman with no significant past medical history presented with abdominal pain and a syncopal episode. Abdominal MRI showed a multicystic mass with a significant solid component in the pancreatic tail, measuring 2.2 cm in the greatest dimension. A fine-needle biopsy of the lesion was performed.

Histologic/Cytologic Features 

Microscopic pictures of the biopsy are shown in Figures 1-5. The histologic examination revealed a spindle cell lesion. The cells had relatively uniform and elongated nuclei, and some had vesicular chromatin with conspicuous nucleoli; others appeared wavy and hyperchromatic. No significant nuclear atypia or mitotic activity was present. Background normal pancreatic parenchyma was also identified.

Figure. 1-3. 1. H&E stain of the tumor, 4X; 2. H&E stain of the tumor, 10X; 3. H&E stain of the tumor, 10X
Figure. 4-5. 4. H&E stain of the tumor, 20X; 5. H&E stain of the tumor, 20X

[line]

Please select your diagnosis in the poll, then see the answer and the discussion in the links below.

[line]

What is the diagnosis of the lesion?

View Results

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[line]

Click Here To See The Answer

Answer: Mucinous cystic neoplasm

 

[line]

Click Here To See The Discussion

Final diagnosis:  

Mucinous cystic neoplasm

Educational Objectives and Discussion:

Educational Objectives

  1. Discuss spindle cell lesions of the pancreas.
  2. Review the clinicopathological characteristics of mucinous cystic neoplasms of the pancreas.
  3. Identify an unusual presentation of mucinous cystic neoplasms with stromal overgrowth.

Discussion

Immunohistochemistry stains were performed, and the spindle cells were positive for estrogen and progesterone receptors (Figures 6-7) and focally positive for inhibin. The spindle cells were negative for CD117, DOG1, S100, pan-cytokeratin, and beta-catenin. The proliferation index assessed with Ki-67 was approximately 1%. Based on the lesion’s morphology and immunoprofile, the case was diagnosed as mucinous/non-mucinous cystic neoplasm with ovarian-type stroma.

Figure. 6-7. 6. Immunohistochemical stain for estrogen receptor, 20X; 7. Immunohistochemical stain for progesterone receptor, 20X

After the diagnosis, distal pancreatectomy and splenectomy were performed. Grossly, there was a 2.2 x 1.6 x 1.6 cm partially cystic well-circumscribed mass in the pancreatic tail containing thick clear fluid (Figure 8). Serial sections showed a 60% cystic and a 40% solid component. The mass showed no communication with the pancreatic ductal system.

Figure. 8. Gross photograph of the cystic lesion at the tail of the pancreas

Microscopic pictures of the resection are shown in Figures 9 – 11. The histologic examination revealed multiple cysts lined by a single layer of cuboidal cells that lacked mucin and had abundant eosinophilic cytoplasm. A prominent densely packed spindle cell-rich stroma was identified. The spindle cells had elongated nuclei with fine chromatin and inconspicuous nucleoli. No malignant features were present.

9-11. 9. H&E stain of the tumor in resection specimen, 10X; 10. H&E stain of the tumor in resection specimen, 10X; 11. H&E stain of the tumor in resection specimen,

Pancreatic mucinous/non-mucinous cystic neoplasm (MCN) is an epithelial tumor typically associated with ovarian-type stroma. The majority of these lesions are found in the body or tail of the pancreas, occur in women, and have a mean age at diagnosis of 48 years old (1). Clinically, patients with MCN present with abdominal discomfort or epigastric pain, while others may be asymptomatic, and the tumor is found incidentally (2).

The histogenesis of these lesions is still in debate. Some proposed hypotheses suggest that the mesenchymal component derives from ectopic ovarian stroma incorporated during embryogenesis in the pancreas or represents persistent fetal periductal mesenchyme under hormonal stimulation (1).

Grossly, MCN usually presents with large unilocular or multilocular cysts, filled with thick gelatinous material, and lacks communication between the cyst and the pancreatic ductal system (3). Microscopically, the cysts are lined by mucin-producing columnar cells with varying degrees of cytologic and architectural atypia. However, cuboidal cells with no mucin can also occur. Based on the level of atypia, MCNs are further categorized as MCN with low- or high-grade dysplasia. The stromal component, called “ovarian-type stroma,” forms bands of densely packed spindle cells amongst the cysts, and its presence is required for the diagnosis. Typically, the stroma represents a smaller constituent of the lesion, and in some cases, it is difficult to identify as it can become hypocellular and replaced by hyalinized tissue (3). The epithelial cells stain positive with CK7 and MUC5AC. The ovarian-type stroma expresses PR (60-90%), ER (30%), SMA, and desmin. Luteinized cells can stain for inhibin and calretinin (1).

Molecularly, most MCN epitheliums carry activating mutations in codon 12 of KRAS (50-66%), some can carry loss-of-function mutations in RNF43 (1).

The case reported here has a very unusual presentation, given the fact that the stroma represents the predominant component of the lesion. The subepithelial stroma in this lesion was cellular and composed of cytologically bland spindle cells mimicking ovarian-type stroma without any malignant features. To our knowledge, this rare presentation of MCN has only been reported twice in the literature (4-5).

Molecular studies have shown frequent mutations in ID3, ARID1A, APC, and CDKN2A tumor suppressor genes in ACC (5-7). TP53 mutation or deletion has been identified in 12-24% of ACC (5,6). About 23% of ACC harbor gene fusion involving BRAF and RAF1 with the most common fusions being SND1-BRAF and HERPUD1-BRAF (5). These tumors are more sensitive to MEK inhibitors. In addition, microsatellite instability has been found in 8-14% of ACC (8,9).

Differential diagnosis:

The specimen was composed predominantly of bland-looking stroma on the initial biopsy, lacking a prominent epithelial component. Hence the initial differential diagnosis of this case comprises MCNs with sarcomatous stroma, carcinosarcoma, and benign mesenchymal tumors.

MCNs with sarcomatous stroma are infrequent and have been reported more frequently in the tail of the pancreas (6). The sarcomatous component is hypercellular, contains mitotic figures, and shows atypia and pleomorphism, in contrast with the bland looking stroma of the typical MCN.

Carcinosarcoma of the pancreas is a neoplasm composed of malignant mixed epithelial and mesenchymal elements (7). The sarcomatous component is composed of highly cellular areas with pleomorphic spindle cells containing abundant cytoplasm, hyperchromatic nuclei, and prominent nucleoli. Occasional bizarre cells can be identified. The histogenesis of this tumor remains unclear.

Benign mesenchymal tumors of the pancreas are extremely rare; some examples include inflammatory myofibroblastic tumor, extra gastrointestinal stromal tumor (GIST), schwannoma, and solitary fibrous tumor (SFT). Very few cases of pancreatic SFT have been reported in the literature. In the present case, the stroma did not show prominent staghorn-like vascularization, or a short storiform arrangement of the spindle cells, characteristics of SFT (8). Inflammatory myofibroblastic tumors could also be excluded based on the absence of a significant chronic inflammatory cell component. Primary GIST of the pancreas has been reported, showing the typical morphologic characteristics of the uniform spindle or epithelioid cells arranged in short fascicles or whorls (9). Differential diagnosis between MCN stroma and these mesenchymal tumors is based on histology and immunohistochemistry findings. The immunoprofile of the ovarian-type stroma of MCNs, showing positivity for inhibin, calretinin, estrogen and progesterone receptors, is not shared by these benign mesenchymal lesions. GIST is positive for c-kit and DOG1, schwannoma for S100, and SFT for STAT6 and CD34.

Finally, in the resection specimen, intraductal papillary mucinous neoplasms (IPMNs) should be considered in the differential diagnosis. IPMNs are characterized by cystic dilatation of pancreatic ducts in which an intraductal proliferation of neoplastic mucin-producing cells is arranged in a papillary pattern. IPMNs do not contain the ovarian-type stroma that characterizes the MCN (10).

References:

  1. Basturk O, Esposito I, Fukushima N et al. Pancreatic mucinous cystic neoplasm. In: Board WCoTE, ed. WHO Classification of Tumours: Digestive System Tumours. 5th ed. Lyon, France: IARC Press; 2019:319-321.
  2. Fukushima N, Fukayama M. Mucinous cystic neoplasms of the pancreas: pathology and molecular genetics. J Hepatobiliary Pancreat Surg. 2007;14(3):238-42.
  3. Jang KT, Park SM, Basturk O, Bagci P, Bandyopadhyay S, Stelow EB, Walters DM, Choi DW, Choi SH, Heo JS, Sarmiento JM, Reid MD, Adsay V. Clinicopathologic characteristics of 29 invasive carcinomas arising in 178 pancreatic mucinous cystic neoplasms with ovarian-type stroma: implications for management and prognosis. Am J Surg Pathol. 2015;39(2):179-87.
  4. Handra-Luca A, Couvelard A, Sauvanet A, Fléjou JF, Degott C. Mucinous cystadenoma with mesenchymal over-growth: a new variant among pancreatic mucinous cystadenomas? Virchows Arch. 2004;445(2):203-
  5. Lee WA. Mucinous cystadenoma of the pancreas with predominant stroma creating a solid tumor. World J Surg Oncol. 2005; 3:59.
  6. Van den Berg W, Tascilar M, Offerhaus GJ, Albores-Saavedra J, Wenig BM, Hruban RH, Gabrielson E. Pancreatic mucinous cystic neoplasms with sarcomatous stroma: molecular evidence for monoclonal origin with subsequent divergence of the epithelial and sarcomatous components. Mod Pathol. 2000;13(1):86-91.
  7. Farbod Darvishian, James Sullivan, Saul Teichberg, Kevin Basham; Carcinosarcoma of the Pancreas: A Case Report and Review of the Literature. Arch Pathol Lab Med. 2002; 126 (9):1114–1117.
  8. Baxter AR, Newman E, Hajdu CH. Solitary fibrous tumor of the pancreas. J Surg Case Rep. 2015; (12): rjv144.
  9. Trabelsi A, Yacoub-Abid LB, Mtimet A, et al. Gastrointestinal stromal tumor of the pancreas: A case report and review of the literature. N Am J Med Sci. 2009;1(6):324-326.
  10. Basturk O, Esposito I, Fukushima N et al. Pancreatic intraductal papillary mucinous neoplasm. In: Board WCoTE, ed. WHO Classification of Tumours: Digestive System Tumours. Lyon, France: IARC Press; 2019:310-314.

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Case contributed by:

Julia A. Gallardo, M.D.

Sadhna Dhingra, M.D.

Department of Pathology and Immunology, Baylor College of Medicine

Conflict of Interest: NO

2021 PBPath Business Meeting agenda/minutes

Pancreatobiliary Pathology Society Members,

Alas, we will not be able to meet in person this year, therefore please find attached the 2021 Pancreatobiliary Pathology Society (PBPS) Annual Business meeting agenda/minutes for your review to learn what PBPS has accomplished: PBPath Business Meeting 2021

Two requests:
1. Listen to our PBPS Companion meeting speakers, submit your questions and attend the LIVE Question and Answer on Tuesday March 16, 2021 11-11:30 AM PST
2. Vote for our new member before March 20, 2021 (will only take 1 minute) https://www.surveymonkey.com/r/7PWVKV5

Can’t wait to see all of you in person next year!

Most appreciatively,
Grace E. Kim
Pancreatobiliary Pathology Society Secretary/Treasurer

USCAP 2021 Companion Society Program

Pancreatobiliary Pathology Society Companion Meeting USCAP 2021

Rondell Graham, MBBS, Mayo Clinic (Moderator)
Michelle D. Reid, MD, MSc, Emory University Hospital (Moderator)
Barbara A. Centeno, MD, H. Lee Moffitt Cancer Center & Research Institute
Vikram Deshpande, MBBS, MD, Massachusetts General Hospital, Harvard Medical School
Günter Klöppel, MD, PhD, Technical University of Munich
Giuseppe Zamboni, MD, University of Verona

Inflammatory Conditions of the Pancreatobiliary Tree 

This session includes 1.5 hours of on-demand educational content. This content can be viewed starting March 1. There will also be a live 30-minute Q&A session with the faculty on Tuesday, March 16, from 11:00 AM – 11:30 AM Pacific Time.

Chronic pancreatitis is a complex inflammatory process with rising incidence and prevalence, and no curative treatment for frequently intractable chronic pain. Despite advances in the field, challenges remain in the radiologic, endoscopic and histologic diagnosis, and the distinction of pancreatitis from cancer. Although some specific pathologic subtypes of pancreatitis have been described and characterized in the past decade, many pathologists are still unaware of their existence, clinicopathologic characteristics, management and genetic implications. Pathologists also struggle with formulating diagnoses, reporting terminology, and determining etiology, particularly on small biopsies, fine needle aspirations and bile duct brushings. In the past year alone numerous multidisciplinary international, consensus guideline manuscripts have made new recommendations regarding risk factors, etiology, management (endoscopic, surgical/non-surgical), and histopathology of chronic pancreatitis. The latter was aimed at clarifying the pathologist’s role in diagnosis, histopathologic criteria, standardizing reports, and limiting confusion in reporting and the literature. The Pancreatobiliary Pathology Society executive committee determined the theme, titles, content and speakers for this year’s companion meeting, with a mission to educate surgical and Cytopathologists on recent advances in inflammatory conditions of the pancreatobiliary tree. This year’s meeting will provide a 360-degree expert analysis and update on acute and chronic inflammatory conditions of pancreatobiliary tree, including specific entities acute/alcoholic pancreatitis (Dr. Günter Klöppel), paraduodenal pancreatitis (Dr. Giuseppe Zamboni), IgG4-related (autoimmune) pancreatitis (Dr. Vikram Deshpande), and the cytopathology of inflammatory lesions of the pancreatobiliary tree (Dr. Barbara Centeno).

 The program can be accessed by USCAP attendees here:

USCAP 2021 Annual Meeting

 Continuing Medical Education

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of The United States and Canadian Academy of Pathology and the Pancreatobiliary Pathology Society. The United States and Canadian Academy of Pathology is accredited by the ACCME to provide continuing medical education for physicians.

The United States and Canadian Academy of Pathology designates this Other activity (enduring materials and internet live activity) for a maximum of 2 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Live Q&A Session: Tue, March 16, 11:00 AM – 11:30 AM PT

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Case 2: Quarter 2, 2021

Case 2: Quarter 2, 2021

Clinical History

A 63-year-old man with a history of mixed hyperlipidemia and gallstones underwent cholecystectomy for recurrent episodes of pancreatitis. A follow-up computed tomography (CT) scan revealed an interval increase in the size of an ill-defined, mass-like lesion in the pancreatic head with peripheral enhancement and central necrosis, concerning for malignancy (Figure 1). Endoscopic ultrasound with fine needle aspiration documented a solid/cystic mass and acinar cells on cytology. He underwent pancreaticoduodenectomy.

Figure-1. CT demonstrating a mass in the head of the pancreas

Macroscopic Description

Grossly, the resection specimen was remarkable for a 10 cm, well-circumscribed, tumor in the head of the pancreas, which had yellow and pink cut surfaces and areas of hemorrhage (Figure 2).

Figure-2. Gross photograph of the pancreaticoduodenectomy specimen showing a large mass in the head of the pancreas)

Histologic/Cytologic Features 

Microscopic pictures of the tumor are shown in Figures 3-6. Sections revealed a highly cellular tumor with a delicate vascular network, scant intervening stroma, and foci of tumor necrosis. Neoplastic cells exhibited a prominent acinar pattern of growth with basally located nuclei. Some acini showed minute lumina. Individual tumor cells had moderate amounts of granular eosinophilic cytoplasm and uniform nuclei. Some neoplastic cells exhibited prominent nucleoli. There were scattered mitotic figures but no cellular pleomorphism. Tumor cells were immunoreactive for pancytokeratin AE1/AE3. Rare cells showed weak reactivity for synaptophysin. They were negative for chromogranin and nuclear β-catenin.

Figure-3. Interface between pancreas (upper left) and tumor (right), H&E stain (4x)
Figure-4. Tumor, H&E stain (10x)
Figure-5. Tumor necrosis, H&E stain (10x)
Figure-6. Tumor, H&E stain (40x)

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Please select your diagnosis in the poll, then see the answer and the discussion in the links below.

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What is the diagnosis of the lesion?

View Results

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Click Here To See The Answer

Answer: Acinar cell carcinoma

 

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Click Here To See The Discussion

Final diagnosis:  

Acinar cell carcinoma

Educational Objectives and Discussion:

Educational Objectives

  1.  Know the key histologic and immunohistochemical findings required for a diagnosis of acinar cell carcinoma.
  2.  Recognize the most common gross findings and clinical presentation of acinar cell carcinoma.
  3. Review the differential diagnosis and necessary workup to exclude histologically similar tumors.

Discussion

Acinar cell carcinoma (ACC) accounts for about 1-2 % of adult pancreatic neoplasms. The average age of adult patients is approximately 60 years. Some patients develop lipase hypersecretion and associated paraneoplastic syndrome. These tumors are generally well-circumscribed, at least partially encapsulated, solid, and large (average diameter 8-10 cm) with a homogenous pink to tan cut surface. They can arise in any part of the pancreas and are more common in the head region.

Microscopically, these tumors are typically denselycellular with minimal stroma. They may have different architectural patterns, solid and acinar patterns being the most prevalent. Less common patterns include a glandular and trabecular pattern. Individual tumor cells have striking eosinophilic cytoplasm, uniform nuclei, and a characteristic large central nucleolus. The mitotic rate is variable, ranging from 5 to 20 (mean 14) per 10 high power fields. Vascular invasion within the capsule of the neoplasm is common. The eosinophilic cytoplasm reflects the presence of cytoplasmic zymogen granules. However, in some cases, the cytoplasmic granularity is not well developed, and special stains are required to document their presence.

A cystic variant of ACC has been described as typically large, circumscribed tumors with cysts lined by single or multiple layers of neoplastic acinar cells. In these cystic lesions, there are areas of solid nests of acinar cells, areas of necrosis, and mitotic figures, which support a malignant process.

The finding of granular Periodic Acid-Schiff (PAS)/diastase positivity in the apical cytoplasm may be enough to confirm a diagnosis of acinar cell carcinoma (Figure 7). The butyrate esterase stain detects the presence of enzymatically active lipase in the neoplastic cells and is highly specific for acinar differentiation. Trypsin (Figure 8), chymotrypsin, and BCL10 (clone 331.1) (Figure 9) antibodies are the most sensitive, and simultaneous use of any two of them allows the detection of nearly 100% of acinar cell carcinomas. Of these, BCL10 is the most sensitive and specific. They have a favorable prognosis compared to the more common pancreatic ductal adenocarcinoma. (1-4)

Figure-7. Tumor, PAS/diastase stain (40x)
Figure-8. Tumor, immunohistochemical stain for trypsin (20x)
Figure-9. Tumor, immunohistochemical stain for BCL 10 (20x)

 

Molecular studies have shown frequent mutations in ID3, ARID1A, APC, and CDKN2A tumor suppressor genes in ACC (5-7). TP53 mutation or deletion has been identified in 12-24% of ACC (5,6). About 23% of ACC harbor gene fusion involving BRAF and RAF1 with the most common fusions being SND1-BRAF and HERPUD1-BRAF (5). These tumors are more sensitive to MEK inhibitors. In addition, microsatellite instability has been found in 8-14% of ACC (8,9).

Differential diagnosis:

Well-differentiated pancreatic neuroendocrine tumor, previously called islet cell tumors/islet cell carcinomas, are the pancreatic counterparts of APUDomas (Amine Precursor Uptake and Decarboxylation tumors) or carcinoids. They can be functional or non-functional (more common), are composed of monotonous cells with typical coarse nuclear chromatin, and express general markers of neuroendocrine differentiation (diffuse/intense synaptophysin and usually also chromogranin staining). They are the most important differential diagnosis of acinar cell carcinoma. Similarities between the two include a solid, acinar, or glandular architecture, relatively minimal stroma, and nuclear uniformity. Features favoring the diagnosis of well-differentiated pancreatic neuroendocrine tumor include hyalinized or amyloid-like stroma between nests of neoplastic cells (indicative of insulinoma), trabecular or gyriform growth patterns (particularly when arranged in single cell-thick cords), central nuclear localization, a coarsely clumped “salt and pepper” chromatin pattern, paler cytoplasm with less granularity and diffuse rather than focal positivity for synaptophysin and chromogranin. (1,10)

Mixed acinar-neuroendocrine carcinomas are malignant epithelial neoplasms with both acinar and neuroendocrine differentiation. They are defined as having > 30% of each line of differentiation by immunohistochemistry. They are best regarded as a subtype of acinar cell carcinoma because they share its clinical behavior and genomic features. (1,10)

Mixed acinar-ductal carcinomas are malignant epithelial neoplasms with both acinar and ductal differentiation. They are defined as having > 30% of each line by immunohistochemistry. These tumors may present with extensive extracellular colloid-like pools of mucin or nests of columnar or signet ring cells with cytoplasmic mucin or individual gland pattern of infiltration with an associated desmoplastic stromal response. Ductal differentiation is based on immunohistochemical reactivity for glycoproteins such as CEA (using monoclonal antibodies), CA19-9, or B72.3. Treatment is like that of ACC. (1,11)

Pancreatoblastomas are malignant epithelial neoplasms of the pancreas, principally affecting children in the first decade of life. However, it can rarely occur in adults. These are very cellular tumors and typically have more prominent lobules separated by cellular stromal bands. They are predominantly composed of solid sheets and acini of uniform cells with characteristic squamoid nests or corpuscles. Lesser amounts of a neuroendocrine component, ductal component, and/or primitive round blue cell component may be seen. Though acinar differentiation is the most common and predominant pattern in most cases, careful microscopic examination and additional sampling may help reveal ductal and/or neuroendocrine components as well as squamoid nests and cellular stromal bands. The age of the patient helps suggest the right diagnosis as pancreatoblastoma. (1)

Solid pseudopapillary neoplasm (SPN) are low grade malignant pancreatic tumors composed of poorly cohesive epithelial cells forming solid and pseudopapillary structures that lack a specific line of pancreatic epithelial differentiation. SPN displaying a predominantly solid growth pattern without foamy cells or eosinophilic globules could be confused with ACC. However, SPN never exhibits true lumen formation, so the presence of an acinar or glandular pattern would
exclude this entity. In contrast to ACC, SPN does not label with specific acinar markers (trypsin and chymotrypsin) and consistently shows diffuse nuclear β-catenin staining. (1,12)

References:

  1. International Agency for Research on Cancer. (2019). WHO Classification of Tumours of the Digestive System. Lyon: International Agency for Research on Cancer.
  2. Klimstra DS, Heffess CS, Oertel JE, Rosai J. Acinar Cell Carcinoma of the Pancreas. Am J Surg Pathol. 1992;16(9):815-837.
  3. Wood LD, Klimstra DS. Pathology and Genetics of Pancreatic Neoplasms with Acinar Differentiation. Semin Diagn Pathol. 2014;31(6):491-497.
  4. Matos JM, Schmidt CM, Turrini O, Agaram NP, Niedergethmann M, Saeger HD, Merchant N, Johnson CS, Lillemoe KD, Grützmann R. Pancreatic Acinar Cell Carcinoma: A Multi-institutional Study. J Gastrointest Surg. 2009;13(8):1495-502.
  5. Chmielecki J, Hutchinson KE, Frampton GM, Chalmers ZR, Johnson A, Shi C, Elvin J, Ali SM, Ross JS, Basturk O, Balasubramanian S, Lipson D, Yelensky R, Pao W, Miller VA, Klimstra DS, Stephens PJ. Comprehensive genomic profiling of pancreatic acinar cell carcinomas identifies recurrent RAF fusions and frequent inactivation of DNA repair genes. Cancer Discov. 2014;4(12):1398-405.
  6. Jiao Y, Yonescu R, Offerhaus GJ, Klimstra DS, Maitra A, Eshleman JR, Herman JG, Poh W, Pelosof L, Wolfgang CL, Vogelstein B, Kinzler KW, Hruban RH, Papadopoulos N, Wood LD. Whole-exome sequencing of pancreatic neoplasms with acinar differentiation. J Pathol. 2014;232(4):428-35.
  7. Jäkel C, Bergmann F, Toth R, Assenov Y, van der Duin D, Strobel O, Hank T, Klöppel G, Dorrell C, Grompe M, Moss J, Dor Y, Schirmacher P, Plass C, Popanda O, Schmezer P. Genome-wide genetic and epigenetic analyses of pancreatic acinar cell carcinomas reveal aberrations in genome stability. Nat Commun. 2017;8(1):1323.
  8. Liu W, Shia J, Gönen M, Lowery MA, O’Reilly EM, Klimstra DS. DNA mismatch repair abnormalities in acinar cell carcinoma of the pancreas: frequency and clinical significance. Pancreas. 2014;43(8):1264-70.
  9. La Rosa S, Sessa F, Capella C. Acinar Cell Carcinoma of the Pancreas: Overview of Clinicopathologic Features and Insights into the Molecular Pathology. Front Med (Lausanne). 2015;2:41.
  10. Ulich T, Cheng L, Lewin KJ. Acinar-endocrine cell tumor of the pancreas. Report of a pancreatic tumor containing both zymogen and neuroendocrine granules. Cancer. 1982;50(10):2099-105.
  11. Stelow EB, Shaco-Levy R, Bao F, Garcia J, Klimstra DS. Pancreatic Acinar Cell Carcinomas with Prominent Ductal Differentiation: Mixed Acinar Ductal Carcinoma and Mixed Acinar Endocrine Ductal Carcinoma. Am J Surg Pathol. 2010;34(4):510-8.
  12. Notohara, Kenji, Hamazaki, Shuji, Tsukayama, Choutatsu, et al. Solid-Pseudopapillary Tumor of the Pancreas: Immunohistochemical Localization of Neuroendocrine Markers and CD10. Am J Surg Pathol. 2000;24(10):1361-1371.

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Case contributed by:

Pragya Jain, MD

Saryn Doucette, MD

Department of Pathology and Laboratory Medicine
Medical College of Wisconsin

Conflict of Interest: NO

Message from the President

Message from the President

 

Pancreatobiliary Pathology Society (PBPS) Members,

We will all remember 2020 as a year filled with challenges and new ways of doing things, and many of our modified processes are spilling into 2021 as well.  With the upcoming USCAP meeting being virtual, we have been working to prepare a compelling agenda for our PBPS Companion Meeting, and I am pleased to report that we have a very fine program devoted to the topic of pancreatitis.  Our speakers will include Dr. Barbara Centeno (Cytopathology of inflammatory lesions of the pancreatobiliary tree), Dr. Vikram Deshpande (IgG4-related (autoimmune) pancreatitis), Dr. Günter Klöppel (Acute/alcoholic pancreatitis) and Dr. Giuseppe Zamboni (Paraduodenal pancreatitis).  The lectures will be prerecorded, so you can listen to them any time after they go live on March 1.  Because of the modified format, the session will only be 90 minutes this year.  Please access the talks via the USCAP website.  There will be a 30 minute live question and answer session, hosted by Michelle Reid, PBPS Education Committee Chair, on Tuesday, March 16 at 2:00 PM Eastern time.  You can enter your questions on-line as well, and Michelle will review them with the speakers.  We hope this will be a highly interactive Q&A session, and that the virtual format will allow even more participants to hear these lectures.

I also want to remind everyone about the PBPS Abstract Award competition. Our PBPS Education Committee will select the winning abstract for 2021, and the first author will receive a $500 prize.  All applications should be submitted no later than 2/15/2021.  Please see the PBPS website for details.

In other news, we have recently revamped our Journal Watch feature, kindly edited by Daniela Allende, PBPS Chair of Journal Watch Subcommittee – please keep an eye on our website for updates about excellent publications related to pancreatobiliary pathology.

We truly regret that we cannot gather in person this year – one of the hardest things about the pandemic of course is the restriction on seeing family, friends, and colleagues – but there is a light at the end of the tunnel, and we will look forward to future meetings when we can gather again to share our interests and catch up on our professional lives!

David Klimstra,  Pancreatobiliary Pathology Society President

 

 

Abstract Award in USCAP 2021

Pancreatobiliary Pathology Society Abstract Award

Dear members of the PBPS,

Happy new year! 

The PBPS is now accepting applications for this year’s PBPS Abstract Award. This award will go to a pathology trainee with an abstract (poster/platform) in pancreatobiliary pathology presented at the 2021 annual USCAP meeting. Submitted abstracts will be evaluated for originality, scientific merit and presentation, and the winner will receive a $500 prize. At least one author should be a PBPS member. Trainees are strongly encouraged to apply.

The deadline for submission of Award applications is February 15, 2021.

Please email your completed abstract in Word format along with the information below to the education committee chair Dr. Michelle Reid (michelle.reid@emory.edu).

Name:
Training Institution:
Position:
PGY Year:
Date/Time of Presentation:
Abstract Name:
Poster Number (if applicable):

Comments:

Pancreatic Cancer Awareness Month

 

This month, with so many global issues in front of us, I want to remind everyone that November is Pancreatic Cancer Awareness Month.  Pancreatic cancer has been in the national consciousness this year, in part due to well-known figures who have been affected, but we also draw greater awareness to the disease through Pancreatic Cancer Awareness Month, to urge private and public agencies to extend more funding to study this disease and help researchers search for a cure and improve the lives of those affected.  This year, over 56,000 people in the United States will be diagnosed with pancreatic cancer, and many more around the world will be affected.  Recognition of the growing prevalence of pancreatic cancer, with the help of foundations and organizations like the Pancreatobiliary Pathology Society, can help direct resources towards research and clinical care efforts.  Thursday, November 19 is World Pancreatic Cancer Day – an even more focused opportunity to recognize this disease and the numerous efforts to improve the care of those affected.  Please remember to “wear purple” and spread the word that we are redoubling our efforts, so that the impetus to address pancreatic cancer is also felt throughout the year and reflected in renewed energy and enthusiasm for research collaboration and knowledge sharing.  Pancreatobiliary pathologists are charged with establishing the diagnosis of pancreatic cancer, and surely we should be leading advocacy efforts as well!

David Klimstra, President 

Pancreatobiliary Pathology Society

 

Case 4: Quarter 4, 2020

Case 4: Quarter 4, 2020

Clinical History

A 58-year-old woman with no significant past medical history developed left abdominal pain. An abdominal MRI showed an irregular enhancing 4.5 x 4.0 cm pancreatic tail mass that was inseparable from vessels in the splenic hilum. Endoscopic ultrasound-guided fine-needle aspiration showed rare malignant cells, favoring adenocarcinoma. The patient subsequently underwent neoadjuvant therapy with Gemcitabine/Abraxane followed by a distal pancreatectomy, splenectomy, partial omentectomy and removal of surrounding lymph nodes.

Histologic/Cytologic Features 

Figures 1-4 are representative photomicrographs of the tumor. The histologic examination revealed a small component of invasive ductal adenocarcinoma involving pancreatic parenchyma. Malignant glands were admixed with prominent nests of cells with cribriform/microcystic architecture containing intermingled epidermoid cells, mucin secreting cells, and intermediate/clear cells (the latter features resemble mucoepidermoid carcinoma of the salivary gland). The proportion of different cell types and microcystic architecture varied in different areas. Focal high grade pancreatic intraepithelial neoplasia (formerly PanIN-3) and pancreatic atrophy were also noted.

Figure-1. H&E stain of the tumor, 2X
Figure-2. H&E stain of the tumor, 4X
Figure-3. H&E stain of the tumor, 20X
Figure-4. H&E stain of the tumor, 20X

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Please Select Your Diagnosis in the Poll, Then See the Answer and the Discussion in the Links Below

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What is the diagnosis of the lesion?

View Results

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Click Here To See The Answer

Answer: Pancreatic adenosquamous carcinoma with mucoepidermoid carcinoma-like features

 

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Click Here To See The Discussion

Final diagnosis:  

Pancreatic adenosquamous carcinoma with mucoepidermoid carcinoma-like features

Educational Objectives and Discussion:

Educational Objectives

1. Review the clinicopathologic features of pancreatic adenosquamous carcinoma with mucoepidermoid carcinoma-like features
2. Understand the molecular alterations of pancreatic adenosquamous carcinoma with mucoepidermoid carcinoma-like features
3. Discuss pertinent differential diagnosis for pancreatic adenosquamous carcinoma with mucoepidermoid carcinoma-like features

Discussion

The current tumor demonstrated that tumor cells were positive for pan-cytokeratin. p40, p63, and CK5 highlighted epidermoid tumor cells. CDX2 and CK20 highlighted luminal cells and mucin-producing cells. Synaptophysin, chromogranin, and CD56 stains were negative. Intracytoplasmic and luminal mucinous secretions were highlighted by mucicarmine stain (Figures 5-7). Molecular study showed mutations in KRAS, CDKN2A, SF3B1, and TP53 genes.

Figure-5. P40 immunohistochemical stain, 40X
Figure-6. CDX2 immunohistochemical stain, 40X
Figure-7. Mucicarmine stain, 40X

Pancreatic mucoepidermoid carcinoma (PAN-MEC, more appropriately termed as pancreatic adenosquamous carcinoma with mucoepidermoid carcinoma-like features) has been proposed as one of the histologic subtypes of pancreatic adenosquamous carcinoma because of their
clinicopathologic and molecular similarities (1). To date, approximately 20 PAN-MEC cases have been documented (1-6). This tumor is more frequently located at the pancreatic body/tail and is significantly larger in size and more aggressive than those of the conventional pancreatic ductal adenocarcinomas (1). 

Similar to salivary gland MECs, three intermingled cell types, including mucin-producing cells, epidermoid cells, and intermediate cells, are usually present in varying proportions in PAN-MEC. Mucin-producing cells (mucocytes) produce mucin (and are positive for mucin stains such as mucicarmine). These cells may have a vacuolated, columnar, or goblet cell-like appearance (Figure 8). Mucocytes often form the lining of microcysts or duct-like structures.

Figure-8. H&E stain of the tumor, 20X

Epidermoid cells are polygonal and squamoid in appearance with dense eosinophilic cytoplasm, which can be highlighted by immunohistochemical stains such as p40, p63, or CK5/6. Epidermoid cells commonly have nested, or sheet-like growth pattern and are often located at the periphery of the nests or cribriform/microcystic structures. While intercellular bridges may be found, keratin pearl formation, overt keratinization, or dyskeratosis is not typically seen. Intermediate cells are less differentiated, and are morphologically not mucous or fully epidermoid cells. Their appearance may vary from small clear cells to small basaloid cells with scant basophilic cytoplasm or intermediate oval cells with pale eosinophilic cytoplasm. The intermediate cells are often admixed with epidermoid cells or mucocytes (Figure 9).

Figure-9. H&E stain of the tumor, 40X

Despite morphologic similarity, PAN-MEC appears not to be a counterpart of MEC of the salivary gland. In the salivary gland, a high proportion of MECs have been reported to harbor an oncogenic CRTC1/3MAML2 gene fusion; whereas in the pancreas, these gene fusions were not detected by PCR in a study involving 16 PAN-MEC cases (all cases were classified as high-grade based on the salivary gland MEC grading system) (1). In addition, PAN-MEC has been reported to harbor KRAS and TP53 mutation, which is similar to the most common molecular signature found in pancreatic ductal adenocarcinomas (4)

Differential diagnosis:

Due to morphologic similarity, metastatic mucoepidermoid carcinoma or clear cell carcinoma of the salivary gland should be one of the first differentials to consider. However, the lack of clinical history of a salivary gland tumor, the presence of a pancreatic precursor lesion (high grade pancreatic intraepithelial neoplasia), and a component of conventional  invasive ductal adenocarcinoma would support this tumor being a primary pancreatic carcinoma with MEC features as opposed to a metastasis from salivary gland. Goblet cells and microcystic structures are generally not seen in clear cell carcinoma of the salivary gland, although squamous differentiation and mucinproduction are not uncommon (7).

Conventional pancreatic adenosquamous carcinoma is also in the differential diagnosis. By definition, this tumor has at least a 30% squamous cell carcinoma component with coexisting ductal adenocarcinoma. Apparent keratinization and squamous pearl formation, as well as focal nuclear anaplasia, are often noted. Low-grade mucoepidermoid carcinoma-like features are generally absent.

Neoadjuvant therapy has been reported to induce squamous metaplasia of ductal columnar cells. However, there was no squamous metaplasia identified in the background pancreatic tissue of the present case. Although focal squamous transdifferentiation from the small ductal adenocarcinoma component induced by neoadjuvant therapy (8) cannot be completely excluded, the diffuse squamoid cells intermingled with other cell types and predominant cribriform/microcystic architecture are difficult to be explained by focal squamous transdifferentiation changes.

Pancreatoblastoma is an uncommon malignant epithelial neoplasm characterized by multilineage differentiation including at least prominent acinar differentiation and focal squamoid morules that exhibit nuclear beta-catenin immunopositivity. Tumors are commonly seen in children but can occur in adults. Ductal/glandular or neuroendocrine differentiation can also be seen but are generally focal (9-10).

References:

  1. Saeki K, Ohishi Y, Matsuda R, et al. “Pancreatic Mucoepidermoid Carcinoma” Is not a Pancreatic Counterpart of CRTC1/3-MAML2 Fusion Gene-related Mucoepidermoid Carcinoma of the Salivary Gland, and May More Appropriately be Termed Pancreatic Adenosquamous Carcinoma With Mucoepidermoid Carcinoma-like Features. Am J Surg Pathol. 2018;42:1419-1428.
  2. Onoda N, Kang SM, Sugano S, Yamashita Y, Chung YS, Sowa M. Mucoepidermoid carcinoma of the pancreas: report of a case. Surgery. 1995;25:843-847.
  3. Ma R, Yu YQ, Li JT, Peng SY. Mucoepidermoid carcinoma of the pancreas: a case report and a review of literature. Journal of research in medical sciences: the official journal of Isfahan University of Medical Sciences. 2012;17:886-889.
  4. Kardon DE, Thompson LD, Przygodzki RM, Heffess CS. Adenosquamous carcinoma of the pancreas: a clinicopathologic series of 25 cases. Mod Pathol. 2001;14:443-451.
  5. Hu HJ, Zhou RX, Liu F, Wang JK, Li FY. You cannot miss it: Pancreatic mucoepidermoid carcinoma: A case report and literature. Medicine. 2018;97:e9990.
  6. Boecker J, Feyerabend B, Tiemann K, et al. Adenosquamous Carcinoma of the Pancreas Comprise a Heterogeneous Group of Tumors With the Worst Outcome: A Clinicopathological Analysis of 25 Cases Identified in 562 Pancreatic Carcinomas Resected With Curative Intent. Pancreas. 2020;49:683-691.
  7. Hsieh MS, Wang H, Lee YH, Ko JY, Chang YL. Reevaluation of MAML2 fusion-negative mucoepidermoid carcinoma: a subgroup being actually hyalinizing clear cell carcinoma of the salivary gland with EWSR1. Hum Pathol. 2017;61:9-18.
  8. Marcus R, Maitra A, Roszik J. Recent advances in genomic profiling of adenosquamous carcinoma of the pancreas. The Journal of pathology. 2017;243:271-272.
  9. Klimstra DS, Wenig BM, Adair CF, Heffess CS. Pancreatoblastoma. A clinicopathologic study and review of the literature. Am J Surg. 1995;19:1371-1389.
  10. Tanaka Y, Kato K, Notohara K, et al. Significance of aberrant (cytoplasmic/nuclear) expression of beta-catenin in pancreatoblastoma. The Journal of pathology. 2003;199:185-190.

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Case contributed by:

Wei Zheng, Assistant Professor

Alyssa M. Krasinskas, Professor

Department of Pathology and Laboratory Medicine

Emory School of Medicine

Conflict of Interest: NO