Definition/General

Introduction:
-Cervical secretory carcinoma is an extremely rare variant characterized by abundant intracellular and extracellular secretions
-Shows ETV6-NTRK3 fusion in most cases
-Accounts for less than 0.1% of cervical carcinomas
-Morphologically identical to mammary analogue secretory carcinoma (MASC).
Origin:
-Arises from cervical glandular epithelium with secretory differentiation
-Shows unique molecular signature with ETV6-NTRK3 fusion
-May originate from reserve cells with secretory potential
-HPV-independent carcinogenesis pathway.
Classification:
-WHO classification recognizes as distinct entity with molecular definition
-Requires demonstration of ETV6-NTRK3 fusion or alternative NTRK fusions
-Pure secretory pattern most common
-Mixed secretory-mucinous variant exists.
Epidemiology:
-Extremely rare with fewer than 30 cases reported
-Age range 25-75 years with no peak
-HPV-independent pathway
-Better prognosis than conventional adenocarcinoma
-No racial predilection.

Clinical Features

Presentation:
-Abnormal vaginal bleeding (70%)
-Mucoid discharge (40%)
-Cervical polyp or mass
-Early-stage disease common (60%)
-Incidental finding possible.
Symptoms:
-Postcoital bleeding most common
-Intermenstrual bleeding
-Clear mucoid discharge characteristic
-Pelvic discomfort mild
-Constitutional symptoms rare.
Risk Factors:
-No HPV association
-No clear risk factors identified
-Sporadic occurrence
-No hereditary syndrome association
-Prior radiation not implicated.
Screening:
-Pap smear shows atypical glandular cells
-Vacuolated cytoplasm may be noted
-HPV testing negative
-Colposcopy shows glandular lesion
-Biopsy with molecular testing diagnostic.

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Gross Description

Appearance:
-Well-circumscribed nodule or polyp
-Tan to pink color
-Soft to rubbery consistency
-Mucoid or gelatinous cut surface
-Cystic areas common.
Characteristics:
-Size 1-4 cm typically
-Well-demarcated borders
-Minimal hemorrhage or necrosis
-Glistening cut surface from secretions
-May be pedunculated.
Size Location:
-Endocervical location predominant
-May present as polyp
-Limited stromal invasion typical
-Parametrial involvement rare
-Confined to cervix in most cases.
Multifocality:
-Usually solitary lesion
-Multifocal disease not reported
-Lymph node metastases rare (5%)
-Distant metastases exceptional
-Local recurrence uncommon.

Microscopic Description

Histological Features:
-Microcystic and tubular architecture
-Abundant eosinophilic secretions in lumina
-Intracytoplasmic vacuoles with secretory material
-Colloid-like secretions
-Low-grade nuclear features.
Cellular Characteristics:
-Cuboidal to columnar cells
-Vacuolated cytoplasm with bubbly appearance
-Small uniform nuclei
-Inconspicuous nucleoli
-Low mitotic activity (<5/10 HPF).
Architectural Patterns:
-Microcystic pattern predominant
-Tubular and solid areas
-Papillary architecture possible
-Cribriform arrangements
-Infiltrative but well-circumscribed.
Grading Criteria:
-Low-grade morphology typical
-Nuclear grade 1-2
-Architectural grade 1
-Minimal cytologic atypia
-Low proliferative index.

Immunohistochemistry

Positive Markers:
-S100 positive (90%)
-Mammaglobin positive (80%)
-SOX10 positive (85%)
-GATA3 positive (70%)
-CK7 positive (95%)
-Pan-TRK positive (with fusion).
Negative Markers:
-p16 negative (HPV-independent)
-p63 negative
-DOG1 negative
-ER/PR usually negative
-CK20 negative
-CDX2 negative.
Diagnostic Utility:
-S100/mammaglobin co-expression characteristic
-Pan-TRK confirms NTRK fusion
-SOX10 supports secretory phenotype
-Negative p16 excludes HPV association.
Molecular Subtypes:
-ETV6-NTRK3 fusion (90%)
-Alternative NTRK fusions (ETV6-NTRK1, ETV6-NTRK2)
-RET fusions rarely
-Fusion-negative cases exist.

Molecular/Genetic

Genetic Mutations:
-ETV6-NTRK3 fusion defining feature (90%)
-Alternative NTRK fusions (5%)
-RET rearrangements (rare)
-No TP53 mutations
-No PIK3CA mutations.
Molecular Markers:
-NTRK fusion detection by FISH or NGS
-HPV DNA negative
-Low Ki-67 index (5-10%)
-Wild-type p53 pattern
-Intact DNA mismatch repair.
Prognostic Significance:
-Excellent prognosis with appropriate treatment
-Low metastatic potential
-NTRK fusion predicts TRK inhibitor response
-Low-grade behavior typical.
Therapeutic Targets:
-TRK inhibitors (larotrectinib, entrectinib) highly effective
-Surgery often curative for localized disease
-Radiation therapy if needed
-Chemotherapy rarely required.

Differential Diagnosis

Similar Entities:
-Mucinous carcinoma: mucin-positive, lacks secretory pattern
-Clear cell carcinoma: glycogen-rich, hobnail cells
-Mesonephric carcinoma: GATA3+, lateral location
-Endometrioid carcinoma: ER+, squamous morules.
Distinguishing Features:
-Secretory carcinoma: S100+, mammaglobin+, NTRK fusion
-Mucinous: MUC5AC+, intracellular mucin
-Clear cell: Napsin A+, HNF1β+
-Unique molecular signature definitive.
Diagnostic Challenges:
-Rare entity often not considered
-Molecular testing essential
-Limited tissue in biopsy
-IHC panel critical
-FISH/NGS for confirmation.
Rare Variants:
-High-grade transformation (exceptional)
-Mixed secretory-mucinous carcinoma
-Secretory carcinoma with solid pattern
-Microinvasive secretory 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

Radical hysterectomy with bilateral salpingo-oophorectomy and pelvic lymph node dissection, received [fresh/in formalin]

Diagnosis

Cervical secretory carcinoma with ETV6-NTRK3 fusion

Histological Features

Microcystic and tubular architecture with abundant intraluminal eosinophilic secretions, vacuolated cells, and low-grade nuclear features

Tumor Size

Greatest dimension: [X] cm; Additional dimensions: [X] × [X] cm

Depth of Invasion

Depth of stromal invasion: [X] mm; Cervical wall thickness: [X] mm; Percentage of wall invasion: [X]%

Margins

Ectocervical margin: [Negative/Positive] ([X] mm); Endocervical margin: [Negative/Positive] ([X] mm); Deep stromal margin: [Negative/Positive] ([X] mm)

Lymphovascular Invasion

[Absent/Present]; If present: [focal/multifocal]

Parametrial Involvement

Right parametrium: [Not involved/Involved]; Left parametrium: [Not involved/Involved]

Lymph Nodes

Total nodes examined: [X]; Positive nodes: [X]

Immunohistochemistry

S100: Positive; Mammaglobin: Positive; SOX10: Positive; Pan-TRK: Positive; p16: Negative; CK7: Positive

Molecular Testing

ETV6-NTRK3 fusion: Detected by [FISH/RT-PCR/NGS]; HPV ISH: Negative

Pathological Stage

FIGO Stage (2018): [stage]; TNM Stage (8th edition): pT[X]N[X]M[X]

Additional Findings

[Background cervical changes/Other findings]