Definition/General
Introduction:
Ovarian minimal deviation adenocarcinoma (adenoma malignum) is an extremely rare, well-differentiated variant of mucinous adenocarcinoma that closely mimics benign glands histologically
Represents less than 0.5% of all ovarian carcinomas
Originally described in cervical location
Shows deceptively bland morphology despite malignant behavior
Associated with Peutz-Jeghers syndrome in some cases.
Origin:
Arises from ovarian surface epithelium or inclusion cysts with mucinous differentiation
May develop from mucinous cystadenoma through malignant transformation
Shows minimal cytological atypia despite invasive nature
Gastric-type mucin production characteristic
Associated with STK11/LKB1 mutations (Peutz-Jeghers syndrome).
Classification:
WHO 2020 classifies as variant of mucinous adenocarcinoma
Also termed adenoma malignum of ovary
FIGO staging system applies (Stage I-IV)
Grading typically Grade 1 (well-differentiated) by definition
Distinguished from conventional mucinous carcinoma by extreme bland morphology.
Epidemiology:
Extremely rare with fewer than 100 cases reported worldwide
Peak incidence in 4th-5th decades (mean age 40-50 years)
Strong association with Peutz-Jeghers syndrome (30-40% cases)
STK11/LKB1 germline mutations in PJS patients
Indian population data extremely limited
May be associated with sex cord tumors in PJS patients.
Clinical Features
Presentation:
Large pelvic mass (80-90% cases) often unilateral and mobile
Abdominal distension due to large cystic mass (70-80%)
Pelvic discomfort or pressure (60-70%)
Asymptomatic in early cases (30-40%)
Family history of Peutz-Jeghers syndrome
Associated polyps (gastrointestinal, if PJS).
Symptoms:
Abdominal bloating and fullness (70-80% cases)
Pelvic pressure sensation (60-70%)
Urinary frequency (50-60% cases)
Constipation or bowel changes (40-50%)
Menstrual irregularities (30-40%)
Early satiety if large mass
Back pain in advanced cases.
Risk Factors:
Peutz-Jeghers syndrome (30-40% cases) - major risk factor
STK11/LKB1 germline mutations
Family history of PJS or related cancers
Multiple GI polyps (hamartomatous)
Mucocutaneous pigmentation (lips, oral mucosa)
Personal history of other PJS-associated tumors.
Screening:
CA-125 levels usually normal or mildly elevated (<50 U/mL)
CEA levels may be elevated (mucinous component)
CA 19-9 occasionally elevated
Transvaginal ultrasound shows large cystic mass with thin septations
MRI demonstrates low T1, high T2 signal (mucin)
CT shows low-density cystic lesion.
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Gross Description
Appearance:
Large, multilocular cystic masses with smooth internal surface
Thin-walled cysts containing thick, viscous mucin
Minimal solid areas or papillary projections
Yellow to green mucinous content
Smooth capsular surface without external nodularity
Resembles benign cystadenoma grossly.
Characteristics:
Multilocular cystic architecture predominant
Thick, tenacious mucin (gastric-type)
Thin septations between cysts
Minimal solid component (<10% of tumor)
Smooth internal surface with rare papillary areas
No obvious necrosis or hemorrhage.
Size Location:
Mean size 15-20 cm at presentation (range 10-30 cm)
Unilateral involvement in 90-95% cases
May reach enormous size before detection
Surface involvement uncommon
Bilateral involvement rare (5-10% cases).
Multifocality:
Usually unifocal within affected ovary
Bilateral synchronous occurrence very rare (<5%)
Peritoneal seeding uncommon at presentation
Nodal involvement rare (10-15% cases)
Pseudomyxoma peritonei may develop if ruptured.
Microscopic Description
Histological Features:
Well-formed glands with minimal cytological atypia
Tall columnar epithelium with abundant gastric-type mucin
Basally located nuclei with minimal pleomorphism
Rare mitotic figures (<2 per 10 HPF)
Stromal invasion present but subtle
Desmoplastic reaction minimal or absent.
Cellular Characteristics:
Tall columnar cells with abundant apical mucin
Minimal nuclear atypia (bland, uniform nuclei)
Basally located nuclei pushed by mucin
Prominent goblet cells with gastric-type mucin
Rare mitoses (malignancy marker)
Apical mucin caps characteristic.
Architectural Patterns:
Simple to complex glands infiltrating stroma
Angulated glands in desmoplastic stroma (invasion sign)
Back-to-back glands without intervening stroma
Cystic spaces lined by mucinous epithelium
Minimal papillary architecture
Stromal infiltration despite bland cytology.
Grading Criteria:
Grade 1 (well-differentiated) by definition
Low mitotic rate (<2 mitoses per 10 HPF)
Minimal nuclear pleomorphism (score 1)
Glandular architecture preserved (score 1)
Well-differentiated morphology throughout
Ki-67 proliferation index typically <10%.
Immunohistochemistry
Positive Markers:
CK7 (90-95% positive)
CK20 (60-70% positive) - gastric phenotype
MUC6 (85-90% positive) - gastric mucin
CEA (70-80% positive)
CDX2 (40-50% positive)
HIK1083 (gastric mucin marker, 80-90%)
PAX8 (70-80% positive).
Negative Markers:
ER/PR (typically negative)
WT1 (usually negative)
p53 (wild-type pattern)
p16 (negative to patchy)
TTF-1 (negative)
Inhibin (negative - excludes sex cord-stromal)
MUC5AC (variable).
Diagnostic Utility:
CK7/CK20 co-expression supports gastric-type mucin
MUC6 positivity confirms gastric differentiation
CEA positivity supports carcinoma diagnosis
p53 wild-type distinguishes from high-grade carcinomas
Low Ki-67 (<10%) confirms well-differentiated nature
PAX8 supports ovarian origin.
Molecular Subtypes:
Gastric-type mucinous subtype (MUC6+, HIK1083+)
STK11/LKB1-associated in PJS cases
p53 wild-type pattern
Microsatellite stable in most cases
Low-grade molecular profile
KRAS mutations common (40-50%).
Molecular/Genetic
Genetic Mutations:
STK11/LKB1 germline mutations (30-40% cases) - Peutz-Jeghers syndrome
KRAS mutations (40-50% cases)
GNAS mutations (20-30% cases)
PIK3CA mutations (15-25% cases)
TP53 mutations rare (<10% cases)
SMAD4 mutations in some cases.
Molecular Markers:
CEA elevated in 70-80% cases
CA 19-9 may be elevated (30-40%)
CA-125 usually normal (<35 U/mL)
STK11 protein loss in PJS-associated cases
p53 protein wild-type expression
Ki-67 proliferation index <10%.
Prognostic Significance:
Generally better prognosis than conventional ovarian carcinomas
5-year survival 70-80% (stage-dependent)
STK11 mutations may predict better response
Early stage most important prognostic factor
Well-differentiated morphology favorable
PJS association requires lifelong surveillance.
Therapeutic Targets:
Standard chemotherapy (carboplatin/paclitaxel) less effective
mTOR inhibitors for STK11-mutated cases (investigational)
MEK inhibitors for KRAS-mutated tumors
Surgery remains primary treatment
Targeted therapy options limited
Clinical trials recommended for recurrent disease.
Differential Diagnosis
Similar Entities:
Mucinous cystadenoma (benign counterpart)
Mucinous borderline tumor (atypical proliferating)
Conventional mucinous carcinoma (higher grade)
Metastatic adenocarcinoma (GI, pancreatic primaries)
Endocervical adenocarcinoma (minimal deviation type)
Clear cell carcinoma (hobnail variant).
Distinguishing Features:
Minimal deviation: stromal invasion despite bland cytology
Minimal deviation: gastric-type mucin (MUC6+)
Cystadenoma: no stromal invasion
Borderline: epithelial tufting, no invasion
Conventional mucinous: higher-grade nuclei
Metastatic GI: bilateral involvement, smaller size
Endocervical: cervical location, HPV-associated.
Diagnostic Challenges:
Distinguishing from benign cystadenoma requires demonstration of invasion
Frozen section diagnosis extremely challenging
Bland morphology may lead to underdiagnosis
Extensive sampling required for diagnosis
Rare entity unfamiliar to pathologists
Clinical correlation with PJS essential.
Rare Variants:
Minimal deviation adenocarcinoma with signet ring cells
Mixed minimal deviation and conventional mucinous carcinoma
Minimal deviation pattern in borderline tumor
Minimal deviation adenocarcinoma with clear cell features
Cystic variant with predominant cystic architecture.
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
[Unilateral/Bilateral] salpingo-oophorectomy specimen, [right/left] ovary measuring [X x Y x Z] cm, with attached fallopian tube
Gross Description
Large, multilocular cystic mass with smooth surface, thin septations, filled with thick viscous mucin, minimal solid areas
Diagnosis
Ovarian minimal deviation adenocarcinoma (adenoma malignum)
Histological Features
Well-formed glands with minimal cytological atypia, tall columnar epithelium with gastric-type mucin, subtle stromal invasion, rare mitoses
Histological Grading
Grade 1 (well-differentiated): minimal nuclear pleomorphism, low mitotic rate ([X] mitoses/10 HPF), preserved glandular architecture
Invasion and Extent
Stromal invasion present (angulated glands in desmoplastic stroma), depth: [X] mm, lymphovascular invasion: [present/absent]
Immunohistochemistry
CK7: Positive, CK20: Positive, MUC6: Positive (gastric mucin), CEA: Positive, p53: Wild-type pattern, Ki-67: <10%
Staging (FIGO 2014)
Stage [I/II/III/IV] - [detailed staging criteria based on extent of disease]
Peutz-Jeghers Syndrome Correlation
Clinical correlation for Peutz-Jeghers syndrome: [family history], [mucocutaneous pigmentation], [GI polyps]
Molecular Testing Recommendations
STK11/LKB1 germline testing recommended if PJS suspected, genetic counseling advised, family screening recommended
Prognostic Factors
Well-differentiated morphology (favorable), stage [X], [unilateral/bilateral] involvement, PJS association (requires surveillance)
Comments
Extremely rare variant with deceptively bland morphology. Strong association with Peutz-Jeghers syndrome. Genetic counseling and family screening recommended.
Final Diagnosis
[Unilateral/Bilateral] ovarian minimal deviation adenocarcinoma (adenoma malignum), FIGO Stage [X], Grade 1