Definition/General
Introduction:
Ovarian neuroendocrine carcinoma is a rare malignant tumor with neuroendocrine differentiation
It constitutes less than 1% of all ovarian malignancies
Can be primary or metastatic from other sites (GI tract, lung, pancreas)
Shows expression of neuroendocrine markers (chromogranin, synaptophysin)
Most cases are high-grade with poor prognosis.
Origin:
Primary ovarian neuroendocrine tumors arise from ovarian surface epithelium or inclusion cysts
May develop through neuroendocrine differentiation of conventional epithelial tumors
Can arise from mature teratoma (teratoma-associated)
The pathogenesis involves activation of neuroendocrine pathways
Most commonly metastatic from gastrointestinal tract.
Classification:
WHO 2020 classifies as neuroendocrine carcinoma
Graded as well-differentiated (Grade 1), moderately differentiated (Grade 2), or poorly differentiated (Grade 3)
Based on mitotic count and Ki-67 index
Primary versus metastatic determined by clinical and pathological correlation
Staged according to FIGO staging system.
Epidemiology:
Peak incidence in 5th-6th decades (45-60 years)
Can occur at any age including young women
Most cases are metastatic (80-90%)
Primary ovarian cases are extremely rare
Risk factors include family history of neuroendocrine tumors
Associated with MEN syndromes rarely.
Clinical Features
Presentation:
Most patients present with advanced stage disease
Palpable adnexal mass (80-90% cases)
Carcinoid syndrome (10-15% cases) with flushing, diarrhea, bronchospasm
Abdominal distension and ascites (60%)
Carcinoid heart disease in advanced metastatic cases
May present with bowel obstruction (metastatic cases).
Symptoms:
Abdominal pain (70-80% cases)
Carcinoid syndrome symptoms: flushing, diarrhea, wheezing
Pelvic pressure and urinary frequency
Weight loss and fatigue (50%)
Hormonal symptoms (rare): Cushing syndrome, ACTH syndrome
Right heart failure (carcinoid heart disease).
Risk Factors:
Family history of neuroendocrine tumors (5-10%)
MEN-1 syndrome (rare association)
Previous history of carcinoid tumor elsewhere
Age >40 years
Genetic syndromes (von Hippel-Lindau, tuberous sclerosis)
Primary GI tract neuroendocrine tumor (metastatic risk).
Screening:
No routine screening available
High-risk patients: chromogranin A and 5-HIAA levels
Octreotide scintigraphy for detection
68Ga-DOTATATE PET/CT (gold standard imaging)
CT chest/abdomen/pelvis to rule out primary elsewhere
Echocardiography for carcinoid heart disease.
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Gross Description
Appearance:
Solid or solid-cystic mass with smooth or bosselated surface
Cut surface shows tan to yellow-brown color
Fleshy, firm consistency
May show areas of necrosis in high-grade tumors
Primary tumors often well-circumscribed
Metastatic deposits show multiple nodules on ovarian surface.
Characteristics:
Size ranges from 2-20 cm (median 8-10 cm)
Solid consistency predominates
Cut surface shows homogeneous tan appearance
May contain cystic areas with serous fluid
Hemorrhage and necrosis in high-grade tumors
Surface may show nodular deposits (metastatic cases).
Size Location:
Primary tumors: usually unilateral (70-80%)
Size varies from 5-15 cm typically
Metastatic tumors: often bilateral (60-70%)
Multiple surface nodules common
May involve entire ovarian surface
Can be microscopic deposits in some cases.
Multifocality:
Bilateral involvement common in metastatic cases (60-70%)
Multiple peritoneal implants frequent
Omental involvement (omental cake)
Primary site evaluation needed for GI tract, lung, and pancreas
Liver metastases common
Lymph node involvement frequent.
Microscopic Description
Histological Features:
Tumor cells arranged in nests, trabeculae, or ribbons
Uniform small to medium-sized cells with round to oval nuclei
Salt-and-pepper chromatin pattern characteristic
Scanty to moderate cytoplasm
Rosette formation may be present
Crush artifact common due to fragile nature.
Cellular Characteristics:
Cells show monomorphic appearance
Round to oval nuclei with fine chromatin
Inconspicuous nucleoli
Scant eosinophilic cytoplasm
Indistinct cell borders
Mitotic activity varies by grade (Grade 1: <2/10 HPF, Grade 2: 2-20/10 HPF, Grade 3: >20/10 HPF).
Architectural Patterns:
Organoid or trabecular pattern most common
Solid nests with peripheral palisading
Rosette-like structures (perivascular or true rosettes)
Ribbon pattern in well-differentiated tumors
Sheet-like growth in poorly differentiated cases
Invasive growth pattern with desmoplastic stroma.
Grading Criteria:
WHO grading system based on mitotic count and Ki-67 index
Grade 1: <2 mitoses/10 HPF, Ki-67 <3%
Grade 2: 2-20 mitoses/10 HPF, Ki-67 3-20%
Grade 3: >20 mitoses/10 HPF, Ki-67 >20%
Presence of necrosis upgrades to Grade 3.
Immunohistochemistry
Positive Markers:
Chromogranin A positive (90-95% cases)
Synaptophysin positive (95-100% cases)
CD56/NCAM positive (85-90% cases)
Neuron-specific enolase (NSE) positive (80-85%)
CK7 positive (ovarian primary)
TTF-1 positive (lung primary)
CDX2 positive (GI primary).
Negative Markers:
CK20 negative (unless GI primary)
PAX8 negative (unless ovarian primary)
WT1 negative
Inhibin negative
Calretinin negative
Estrogen receptor negative
Progesterone receptor negative
AFP negative.
Diagnostic Utility:
Neuroendocrine markers confirm diagnosis (chromogranin + synaptophysin)
Site-specific markers help determine primary site
CK7+/CK20- suggests ovarian/lung primary
CK7-/CK20+ suggests GI primary
TTF-1 for lung primary
CDX2 for GI primary
Panel: Chromogranin, Synaptophysin, CK7, CK20, CDX2, TTF-1.
Molecular Subtypes:
Most cases are sporadic
MEN-1 associated tumors (5-10%)
Microsatellite stable in majority
p53 wild-type in most cases
DAXX/ATRX loss in pancreatic primaries
Chromothripsis in high-grade tumors.
Molecular/Genetic
Genetic Mutations:
MEN1 mutations (10-15% of cases)
DAXX/ATRX mutations (pancreatic primaries)
TP53 mutations (rare in low-grade)
RB1 mutations (high-grade tumors)
CDKN2A deletions
PIK3CA mutations (10-15%)
mTOR pathway alterations.
Molecular Markers:
Chromogranin A serum levels (diagnostic and monitoring)
5-HIAA urine levels (serotonin metabolite)
Ki-67 proliferation index (prognostic)
Somatostatin receptor expression (SSTR2, SSTR5)
MGMT methylation status
TERT promoter mutations.
Prognostic Significance:
Grade is most important prognostic factor
Grade 1: 5-year survival >90%
Grade 2: 5-year survival 60-80%
Grade 3: 5-year survival <30%
Stage at presentation crucial
Primary site affects prognosis (ovarian primary better than metastatic)
Functional status (carcinoid syndrome) indicates advanced disease.
Therapeutic Targets:
Somatostatin analogs: octreotide, lanreotide (SSTR-positive tumors)
Peptide receptor radionuclide therapy: 177Lu-DOTATATE
Everolimus (mTOR inhibitor) for advanced disease
Sunitinib (tyrosine kinase inhibitor)
Temozolomide for high-grade tumors
Capecitabine + temozolomide (CAPTEM regimen).
Differential Diagnosis
Similar Entities:
Metastatic neuroendocrine carcinoma from GI tract, lung, pancreas
Primary ovarian small cell carcinoma (hypercalcemic type)
Granulosa cell tumor (adult type)
Carcinoid tumor arising in mature teratoma
Poorly differentiated adenocarcinoma
Lymphoma (small cell type).
Distinguishing Features:
Metastatic vs primary: bilateral involvement suggests metastatic
Clinical history of primary elsewhere
Small size suggests metastatic
Small cell carcinoma: hypercalcemia, younger age, inhibin positive
Granulosa cell: Call-Exner bodies, inhibin positive, neuroendocrine markers negative
Teratoma: other teratomatous elements present.
Diagnostic Challenges:
Distinguishing primary versus metastatic neuroendocrine carcinoma
Determining grade accurately (mitotic count, Ki-67)
Recognizing crush artifacts in small biopsies
Differentiating from other small round cell tumors
Identifying primary site in metastatic cases.
Rare Variants:
Mixed neuroendocrine-adenocarcinoma
Neuroendocrine carcinoma with sarcomatoid features
Composite tumor with other ovarian neoplasms
Functioning tumors with hormone production (ACTH, growth hormone)
Large cell neuroendocrine carcinoma.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
Right/Left salpingo-oophorectomy specimen measuring [X x Y x Z] cm, weighing [X] grams
Gross Description
Ovary shows [solid/solid-cystic] mass measuring [X] cm. Cut surface is [tan/yellow-brown] with [firm/soft] consistency. [No/Areas of] necrosis identified. Surface is [smooth/nodular]
Diagnosis
Neuroendocrine Carcinoma, WHO Grade [1/2/3]
Microscopic Description
Tumor cells arranged in [organoid/trabecular/solid] pattern. Cells show uniform morphology with round nuclei and salt-and-pepper chromatin. Mitotic count: [X] per 10 HPF. [No/Focal/Extensive] necrosis present
Immunohistochemistry
Chromogranin A: Positive\nSynaptophysin: Positive\nKi-67: [X]%\nCK7: [Positive/Negative]\nCK20: [Positive/Negative]\nCDX2: [Positive/Negative]\nTTF-1: [Positive/Negative]
WHO Grading
Mitotic count: [X] per 10 HPF\nKi-67 proliferation index: [X]%\nNecrosis: [Present/Absent]\nWHO Grade: [1/2/3]
Staging Information
Tumor size: [X] cm\nLaterality: [Unilateral/Bilateral]\nSurface involvement: [Present/Absent]\nFIGO Stage: [Stage]
Comments
Recommend clinical correlation and imaging to exclude primary neuroendocrine tumor elsewhere (GI tract, lung, pancreas). Serum chromogranin A and 24-hour urine 5-HIAA levels recommended for monitoring
Final Diagnosis
Neuroendocrine Carcinoma, WHO Grade [X], [Primary/Metastatic - pending clinical correlation]