Multilocular cystic renal neoplasm of low malignant potential

• An indolent renal epithelial neoplasm composed entirely of multiple cysts lined by low-grade clear cells and separated by fibrous septa.
• Part of the VHL-associated clear cell spectrum — shares morphology, immunophenotype and molecular features with ccRCC.
• Defining feature: exclusively cystic architecture with no expansile solid growth.
• Cyst-lining cells must be low grade — WHO/ISUP grade 1–2.
• Small, nonexpansile clear cell aggregates within septa do not exclude the diagnosis.
• True expansile solid nodules, tumour necrosis or high-grade nuclei exclude MCRNLMP.
• No recurrence, metastasis or tumour-related death has been documented in well-characterised, completely resected cases.

Architecture

• Well-circumscribed lesion of numerous noncommunicating or interconnected cysts of variable size.
• Thin, occasionally thick, fibrous septa.
• No expansile solid component anywhere.

Cyst lining

• Single layer of flattened, cuboidal or low columnar cells with clear cytoplasm and small, uniform nuclei.
• Focal stratification of a few layers may occur; denudation is common.

Septa

• Predominantly fibrous connective tissue.
• Small clusters of clear cells may sit within septa — limited and nonexpansile, not distorting the septal contour.
• Delicate capillaries may accompany these aggregates, echoing ccRCC.

Cytology

• Round to oval, uniform nuclei; nucleoli inconspicuous or mildly prominent (grade 1–2).
• Grade 3–4 nuclei, sarcomatoid or rhabdoid change are incompatible.

Cyst size

• Microscopic to several centimetres, often mixed; size alone does not determine classification.

Thickened septa

• Fibrosis or hyalinisation may look solid at low power or on imaging.
• The key distinction: sparsely cellular fibrous thickening versus an expansile epithelial nodule.

Focal multilayering

• Small areas of stratification do not by themselves establish ccRCC.

Intraseptal clear cell clusters

• Limited, nonexpansile nests that do not deform the septa are acceptable.
• Practical guide: an individual cluster should not exceed ~1 mm (one ×20 field).
• A discrete expansile nodule beyond this supports cystic ccRCC.

Cyst contents

• Serous, haemorrhagic or proteinaceous; haemorrhage is not necrosis.

Diagnostic pearl: a tumour may contain small epithelial aggregates and still qualify — what matters is whether they form expansile solid growth.

All of the following must be absent throughout the adequately sampled tumour:

• Expansile solid tumour nodule — excludes MCRNLMP.
• WHO/ISUP grade 3 or 4 nuclei — excludes.
• Tumour necrosis — excludes.
• Sarcomatoid or rhabdoid differentiation — excludes.
• Unequivocal invasive growth — incompatible.

Important distinctions

• Small nonexpansile septal clusters are permissible; expansile nodules are not.
• Thick fibrous septa do not on their own exclude the diagnosis.
• Haemorrhagic or proteinaceous material is not necrosis.
• A predominantly cystic ccRCC is not MCRNLMP, even if the solid component is very small.

Shares the ccRCC immunophenotype — IHC mainly excludes other cystic tumours rather than separating MCRNLMP from cystic ccRCC.

• PAX8 — positive · renal epithelial origin.
• CAIX — diffuse, complete, box-like membranous.
• CK7 — variable, often positive · not discriminatory alone.
• CD10 — frequently positive.

Key points

• CK7 may be more extensive in cystic clear cell tumours than in solid ccRCC.
• Diffuse CK7 does not establish clear cell papillary renal cell tumour.
• No routine marker separates MCRNLMP from cystic ccRCC — the distinction is morphologic.

VHL pathway

• Chromosome 3/3p loss in ~77%; inactivating VHL mutations in ~25–40%.
• Explains the CAIX expression and vascular phenotype.

Relationship with ccRCC

• Substantial genomic overlap, with a lower burden of recurrent somatic alterations than aggressive ccRCC.
• Supports a shared lineage rather than a separate origin.

Diagnostic implications

• 3p loss or VHL alteration does not distinguish MCRNLMP from ccRCC.
• Molecular testing is not routinely needed when strict morphologic criteria are met.
• In ambiguous cases it mainly helps exclude molecularly defined cystic mimics.

Cystic ccRCC

• The most important differential; even a small expansile solid nodule excludes MCRNLMP.
• Necrosis, high-grade nuclei or infiltrative growth favour ccRCC; CAIX, CK7 and CD10 overlap.
• Pitfall: a tiny solid nodule is easily missed without sampling thickened septa and mural regions.

Clear cell papillary renal cell tumour

• Cystic, tubular, branching and papillary growth with nuclei aligned away from the basement membrane.
• Diffuse CK7, cup-like CAIX, CD10 usually negative; no 3p/VHL alterations.

MED15::TFE3-rearranged RCC

• A recently recognised mimic — predominantly multilocular cystic with bland clear cells.
• Clues: small mass-forming septal aggregates and psammomatous calcifications; confirm with TFE3 IHC and molecular testing.

MEST / adult cystic nephroma

• Variable, often hobnail lining without widespread clear cells.
• Ovarian-type, ER/PR-positive stroma, sometimes with smooth muscle.

Resections

• Adequate examination is needed to exclude expansile nodules, high-grade areas and necrosis.
• Target thickened septa, mural irregularities and radiologically solid-appearing areas; submit entirely when feasible.
• A small conventional ccRCC component changes the classification.

Core biopsies

• MCRNLMP should not be diagnosed definitively on core biopsy.
• Absence of solid growth in a biopsy does not exclude unsampled ccRCC; cystic lesions yield scant tissue.
• Prefer a descriptive diagnosis — low-grade clear cell renal neoplasm with cystic features.

Diagnostic pearl: a classic-looking biopsy cannot prove an exclusively cystic architecture throughout the lesion.

• A biological continuum — MCRNLMP → predominantly cystic ccRCC → solid ccRCC; MCRNLMP is the most indolent end, but the distinction remains morphologic.
• Limited solid growth reconsidered — a 2024 review found extensively cystic ccRCC (>75% cystic) can have outcomes approaching MCRNLMP. An emerging idea, not a revised criterion: a true expansile solid component still excludes MCRNLMP.
• MED15::TFE3 RCC — strongly associated with multilocular cystic morphology; multilocular cysts with low-grade clear cells are not exclusive to VHL-associated neoplasia.
• Imaging can mislead — a 2025 case of MCRNLMP mimicked a solid mass because of dense septa and intracystic haemorrhage; radiologic–pathologic correlation matters.

• Entirely cystic — even a small genuine expansile nodule excludes MCRNLMP.
• Small nonexpansile septal clear cell clusters are permissible.
• The ~1 mm threshold is a practical guide; expansile growth is what matters.
• Only WHO/ISUP grade 1–2 nuclei are acceptable.
• Tumour necrosis excludes; intracystic haemorrhage does not.
• Thick fibrous septa are not solid tumour growth.
• CAIX diffuse box-like; CK7 often positive and non-discriminatory.
• 3p loss / VHL alterations support the ccRCC relationship but are not diagnostic alone.
• Think of MED15::TFE3 RCC when calcifications or septal nodules are present.
• Not reliably diagnosable on core biopsy; adequate sampling is crucial.