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Here is a complete explanation of all three topics from the image, sourced directly from Robbins, Cotran & Kumar - Pathologic Basis of Disease.

Pancreatic Neuroendocrine Neoplasms (PanNENs)

What are they? PanNENs are tumors arising from the hormone-secreting islet cells of the pancreas (formerly called "islet cell tumors"). They are rare, accounting for only about 2% of all pancreatic neoplasms. They can arise anywhere in the pancreas or adjacent peripancreatic tissue, and may be single or multiple. Some produce hormones and cause distinct clinical syndromes ("functional"), while others are silent ("nonfunctional").

Grading: PanNENs are graded by their proliferative index (Ki-67 marker) and mitotic activity. Poorly differentiated ones (Ki-67 >20%) behave as carcinomas.

Key genetic mutations in sporadic PanNENs:

MEN1 gene mutations (also seen in familial MEN-1 syndrome)
PTEN / TSC2 loss-of-function mutations → activate mTOR signaling pathway
ATRX / DAXX inactivating mutations → allow "alternative lengthening of telomeres" (ALT); nearly half of PanNENs carry one of these

1. Hyperinsulinism (Insulinoma)

The most common PanNEN. These are β-cell tumors that produce excess insulin.

Pathology:

Usually solitary, small (<2 cm), encapsulated, benign (only ~10% are malignant)
Located anywhere in the pancreas
Histologically resemble enlarged islets - monotonous cells in regular cords
Characteristic finding: amyloid deposition within the tumor (see histology image below)

Insulinoma histology showing monotonous neoplastic cells with abundant pink amyloid deposition

Histology of an insulinoma: monotonous neoplastic islet cells with characteristic pink amyloid deposits. The patient had episodic hypoglycemia.

Clinical features:

Hypoglycemic episodes when blood glucose falls below 50 mg/dL
Symptoms: confusion, stupor, loss of consciousness
Triggered by fasting or exercise; relieved immediately by glucose
Key lab finding: inappropriately elevated insulin + low blood glucose + elevated C-peptide (confirms endogenous source)
Treatment: surgical removal - usually curative

Important DDx of hypoglycemia: adrenal insufficiency, liver disease, glycogen storage disorders, ectopic insulin production, sulfonylurea use, factitious insulin injection.

2. Zollinger-Ellison Syndrome (Gastrinoma)

G-cell tumors (gastrinomas) that hypersecrete gastrin, driving excessive gastric acid production.

Location: These arise in the "gastrinoma triangle" - spanning the duodenum, pancreas, and peripancreatic soft tissues. They are as likely to arise in the duodenum as in the pancreas.

Pathology:

Over 50% are already locally invasive or metastatic at diagnosis (more aggressive than insulinomas)
~25% arise as part of MEN-1 syndrome (typically multifocal); sporadic ones are usually single
Histologically bland, minimal anaplasia

Clinical features (Zollinger-Ellison Syndrome):

Hypergastrinemia → excess gastric acid → peptic ulceration
Ulcers are often multiple, recurrent, and in unusual locations (including the jejunum)
Ulcers are resistant to standard therapy
Present in 90-95% of patients with gastrinoma

Treatment:

Suppress acid: H⁺/K⁺-ATPase inhibitors (PPIs)
Surgical excision of the tumor when possible (curative)
Hepatic metastases carry a poor prognosis (liver failure typically within 10 years)

3. Other Rare Pancreatic Endocrine Neoplasms

Tumor	Cell of Origin	Hormone	Clinical Syndrome
Glucagonoma	α-cells	Glucagon	Mild diabetes, necrolytic migratory erythema (skin rash), anemia; mainly in peri/postmenopausal women
Somatostatinoma	δ-cells	Somatostatin	Diabetes, gallstones (cholelithiasis), steatorrhea, achlorhydria (hypochlorhydria); hard to localize preoperatively
VIPoma	-	VIP (Vasoactive Intestinal Peptide)	WDHA syndrome: Watery Diarrhea, Hypokalemia, Achlorhydria; can metastasize
Pancreatic carcinoid	-	Serotonin	Atypical carcinoid syndrome; exceedingly rare
PPoma	-	Pancreatic polypeptide	Presents as a mass lesion only (no symptoms even with high hormone levels)

Some PanNENs are multihormonal, secreting two or more hormones simultaneously (e.g., insulin + glucagon, or ACTH + ADH). These must be distinguished from MEN syndromes, where separate tumors arise in multiple endocrine glands independently.

Summary table:

Feature	Insulinoma	Gastrinoma	Others
Frequency	Most common PanNEN	2nd most common	Rare
Malignancy rate	~10%	>50%	Variable
Key hormone	Insulin	Gastrin	Glucagon/VIP/somatostatin
Key syndrome	Hypoglycemia	Peptic ulcers (ZES)	See table above
Treatment	Surgery	PPIs + surgery	Surgery

Source: Robbins, Cotran & Kumar - Pathologic Basis of Disease, pp. 1027-1029

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