patoloji-ders-notlari

Title

Serdar Balcı

Neoplasms of Exocrine and Endocrine Pancreas

Serdar BALCI, MD

PANCREATOBLASTOMA

Pancreatoblastoma showing a predominantly solid pattern of growth but also small rosette-like glandular formations

Rosai and Ackerman’s Surgical Pathology

PANCREATIC EXOCRINE NEOPLASMS

Pancreatic Exocrine Neoplasms

Cystic
Solid
Benign
Malignant
- most lethal

Cystic Neoplasms

5-15% of all pancreatic cysts are neoplastic

<5% of all pancreatic neoplasms

Serous Cystadenoma

Robbins Basic Pathology

25% of all pancreatic cystic neoplasms

Small cysts containing clear, yellowish fluid

Robbins Basic Pathology

Serous Cystadenoma

Glycogen-rich cuboidal cells

Robbins Basic Pathology

Seventh decade of life
Nonspecific symptoms
- abdominal pain
F:M=2:1
Almost uniformly benign
Surgical resection is curative
Most carry somatic mutations von Hippel-Lindau ( VHL ) tumor suppressor gene

Robbins Basic Pathology

Mucinous Cystic Neoplasm

Robbins Basic Pathology

Mucinous Cystic Neoplasm

95% of mucinous cystic neoplasms arise in women

Usually in the body or tail of the pancreas

Painless, slow-growing masses

Cystic spaces are filled with thick, tenacious mucin

Robbins Basic Pathology

Mucinous Cystic Neoplasm

The cysts are lined by columnar mucinous epithelium, with a densely cellular “ovarian” stroma.

Robbins Basic Pathology

Mucinous Cystic Neoplasm

Degree of cytologic and architectural atypia in the lining epithelium
- low-grade, moderate, or severe dysplasia
1/3 associated with an invasive adenocarcinoma

The cysts are lined by columnar mucinous epithelium, with a densely cellular “ovarian” stroma.

Robbins Basic Pathology

Mucinous Cystic Neoplasm

Distal pancreatectomy for noninvasive cysts typically is curative
- even in the setting of severe dysplasia

Intraductal Papillary Mucinous Neoplasms (IPMNs)

Cross-section through the head of the pancreas showing a prominent papillary neoplasm distending the main pancreatic duct.

Robbins Basic Pathology

Intraductal Papillary Mucinous Neoplasms (IPMNs)

Mucin-producing intraductal neoplasms

More frequently in men than in women

More frequently involve the head of the pancreas

Arise in the main pancreatic ducts, or one of its major branch ducts

Robbins Basic Pathology

Intraductal Papillary Mucinous Neoplasms (IPMNs)

The papillary mucinous neoplasm involved the main pancreatic duct (left) and is extending down into the smaller ducts and ductules (right).

Robbins Basic Pathology

Intraductal Papillary Mucinous Neoplasms (IPMNs)

No cellular stroma seen in mucinous cystic neoplasms

Grades of dysplasia

Associated with an invasive adenocarcinoma component

Up to two thirds of IPMNs harbor oncogenic mutations of GNAS on chromosome 20q13, which encodes the alpha subunit of a stimulatory G-protein

Robbins Basic Pathology

Ankara Atatürk Eğitim ve Araştırma Hastanesi Arşivi

Pancreatic Carcinoma

Infiltrating ductal adenocarcinoma of the pancreas
Fourth leading cause of cancer death
5-year survival rate is less than 5%
80% of cases 60-80 years of age
Smoking, doubles the risk
Chronic pancreatitis and diabetes mellitus are also both associated with an increased risk of pancreatic cancer
- chronic pancreatitis; cause of pancreatic cancer? effect of it?
- diabetes can occur as a consequence?, new-onset diabetes in an elderly patient may be the first sign of this malignancy?
Familial clustering of pancreatic cancer
Germline mutations of the familial breast/ovarian cancer gene BRCA2
- 10% of cases arising in persons of Ashkenazi Jewish heritage

Precursor lesions

Intraductal papillary mucinous neoplasms

Mucinous cystic neoplasms

Pancreatic intraepithelial neoplasias (PanINs)

Accumulation of multiple mutations is more important than their occurrence in a specific order

KRAS

point mutation

most frequently altered oncogene

80-90%

SMAD4 TSG

inactivated 55%

TP53 TSG

50-70%

P16

most frequently inactivated TSG

turned off in 95%

Mutations of VHL or GNAS

Not been described in ductal adenocarcinomas

Robbins Basic Pathology

Pancreatic intraepithelial neoplasia grade 3 (PanIN-3) involving a small pancreatic duct.

Robbins and Cotran Pathologic Basis of Disease

60% of pancreatic cancers arise in the head of the gland

15% in the body, and 5% in the tail

20% diffusely involves the entire organ

Ggray-white, stellate, poorly defined masses

Robbins Basic Pathology

Ductal adenocarcinoma

Highly invasive
- even “early” invasive pancreatic cancers invade peripancreatic tissues extensively
__ Desmoplastic response__
- Intense non-neoplastic host reaction composed of fibroblasts, lymphocytes, and extracellular matrix
Obstruct the distal common bile duct
- 50% of such cases, there is marked distention of the biliary tree
- jaundice
Carcinomas of the body and tail of the pancreas do not impinge on the biliary tract and hence remain silent
- quite large and widely disseminated by the time they are discovered
Extend through the retroperitoneal space
Entrap adjacent nerves
- pain
Invade the spleen, adrenals, vertebral column, transverse colon, and stomach
Peripancreatic, gastric, mesenteric, omental, and portahepatic lymph nodes
Liver often is enlarged as a consequence of metastatic deposits
Distant metastases to the lungs and bones

Robbins and Cotran Pathologic Basis of Diseases

Autopsy Pathology: A Manual and Atlas

Moderately to poorly differentiated adenocarcinoma

Abortive tubular structures or cell clusters

Aggressive, deeply infiltrative growth pattern

Dense stromal fibrosis

Perineural invasion within and beyond the organ

Lymphatic invasion also is commonly seen

Robbins Basic Pathology

Ankara Atatürk Eğitim ve Araştırma Hastanesi Arşivi

Less common variants of pancreatic cancer

Adenosquamous carcinomas
- focal squamous differentiation in addition to glandular differentiation
Undifferentiated carcinomas with osteoclast-like giant cells of monocytic lineage intermixed within the neoplasm

Clinical features of pancreas carcinoma

Pain
Obstructive jaundice
Weight loss, anorexia, and generalized malaise and weakness
Migratory thrombophlebitis ( Trousseau syndrome )
- 10% of patients
- elaboration of platelet-aggregating factors
- pro-coagulants from the tumor or its necrotic products
<20% of pancreatic cancers are resectable at the time of diagnosis

PANCREATIC NEUROENDOCRINE TUMORS

Pancreatic Neuroendocrine Tumors

Islet cell tumors
2% of all pancreatic neoplasms
Most common in adults
Single or multifocal
Liver is the most common site of organ metastases
Produce and secrete pancreatic hormones, but some are nonfunctional
Nonfunctional are larger lesions at diagnosis
- no symptoms related to excessive hormone production

Autopsy Pathology: A Manual and Atlas

Endocr Pathol. 2014 Mar;25(1):65-79

Ankara Atatürk Eğitim ve Araştırma Hastanesi Arşivi

All PanNETs are regarded as having malignant potential
Insulinomas are detected earlier and they are regardded as “benign”
65-80% of PanNETs manifest with overtly malignant features of biologic aggressiveness
- invasion into local tissues or distant metastases
Grade
- Mitosis
- proliferation marker Ki-67
Genetics:
- Familial MEN syndrome, type 1
  - MEN1
- Loss-of-function mutations in tumor suppressor genes
  - PTEN and TSC2
    - negative regulators of the oncogenic mammalian TOR (mTOR) signaling pathway
- Inactivating mutations
  - ATRX and DAXX

Endocr Pathol. 2014 Mar;25(1):65-79

Insulinomas

**Beta cell tumors **

Most common type of PanNET

Whipple triad

Low blood glucose

Symptoms and signs of hypoglycemia

Resolve with blood glucose elevation

Favorable biologic behavior
- Possibly because the vast majority are identified while they are small
  - <2 cm in diameter
- localized to the pancreas
Most are solitary lesions
- multifocal tumors or tumors ectopic to the pancreas may be encountered
Malignancy in insulinomas
- <10% of cases
- Local invasion or metastases

Look remarkably like giant islets

Preservation of the regular cords of monotonous cells and their orientation to the vasculature

Not even malignant lesions present much evidence of anaplasia, and they may be deceptively encapsulated

Deposition of amyloid in the extracellular tissue is a characteristic feature of many insulinomas

Robbins Basic Pathology

Under the electron microscope, neoplastic beta cells, like their normal counterparts, display distinctive round granules

Robbins Basic Pathology

Gastrinomas

**Marked hypersecretion of gastrin **
Likely to arise in the duodenum and peripancreatic soft tissues as in the pancreas
- gastrinoma triangle
Zollinger-Ellison syndrome
- Pancreatic islet cell lesions with hypersecretion of gastric acid and severe peptic ulceration
  - 90-95% of patients with gastrinomas
- Duodenal and gastric ulcers often are multiple
- Unusual locations such as the jejunum
  - intractable jejunal ulcers
More than half of the affected patients have diarrhea