Mixed epithelial and stromal tumour and cystic nephroma

• MEST: generally benign biphasic renal neoplasm of epithelial tubules, glands or cysts admixed with a distinctive spindle-cell stroma.
• Adult cystic nephroma (adult CN): the predominantly cystic end of the MEST family in current WHO classification.
• Shared age, marked female predominance, morphology and ovarian-type stromal immunophenotype.
• MEST: variable solid stroma with tubular, glandular, cystic or papillary epithelium. Adult CN: mostly noncommunicating cysts with thin septa, often with ovarian-type stroma.
• Stroma typically ER, PR and smooth muscle marker positive, with variable distribution.
• Epithelium bland: flat, cuboidal, columnar, often hobnail; mucinous, ciliated, endometrioid-like or intestinal types may occur.
• Most behave benignly after complete excision.
• Paediatric cystic nephroma is a separate, DICER1-associated entity, not the same biology as adult CN.

Diagnostic pearl: MEST and adult CN are overlapping phenotypes of one family; paediatric CN needs separate biological consideration.

• The distinction rests on the relative amounts of epithelium and stroma; intermediate tumours exist.
• MEST often has thick stromal nodules or complex glands; adult CN lacks expansile solid nodules.
• The name reflects dominant morphology rather than different molecular identities.

Diagnostic pearl: substantial solid stroma supports MEST; an almost entirely cystic lesion with bland ovarian-type septal stroma supports adult CN.

Clinical

• Mostly middle-aged or perimenopausal women; less often men, some with prior hormonal therapy.
• Often incidental; flank pain, haematuria or a mass; tumours near the pelvis can obstruct or cause hydronephrosis.

MEST gross

• Well circumscribed, mixed solid and cystic; tan-white fibrous solid areas; cysts with clear, serous or haemorrhagic fluid; thick septa and mural nodules; sometimes a polypoid component protruding into the pelvis.

Adult CN gross

• Well-defined multilocular mass of noncommunicating cysts with fibrous septa, clear fluid and little or no solid tissue; radiologically can match cystic RCC.

Sample more if you see

• Irregular enhancing mural nodules, necrosis, friable or overtly malignant solid tissue, markedly thick irregular walls, infiltrative borders.

Diagnostic pearl: a solid nodule may be pure bland ovarian-type stroma, but every unusual mural nodule must be checked for epithelial malignancy or malignant stromal transformation.

Biphasic architecture

• Variable mixture of tubules, cysts, glands and spindle stroma; either may predominate; solid areas are mostly stroma, not confluent carcinoma.

Epithelium

• Round or elongated tubules, dilated cysts, branching glands, short papillae, occasional complex proliferations.

Stroma

• Bland spindle cells; hypocellular fibrous and cellular ovarian-type areas; smooth muscle fascicles; focal fat, oedema or myxoid change.

Cytology

• Both components bland with few mitoses; no infiltrative malignant epithelium in conventional MEST.
• Marked atypia, high mitotic activity or coagulative necrosis requires reassessment.

Diagnostic pearl: bland epithelium within heterogeneous ovarian-type and smooth muscle-rich stroma is more informative than renal cysts alone.

• Simple tubular: round or elongated tubules, cuboidal to low columnar, scattered or grouped.
• Branching glandular: interconnected tubules, nephrogenic adenoma-like, still bland.
• Thyroid follicle-like: round spaces with dense eosinophilic material.
• Papillary / phyllodes-like: broad leaf-like stromal projections into epithelial spaces.
• Complex papillary: may resemble PRCC; atypia or destructive infiltration is not benign MEST.
• Cribriform / crowded glands: usually without malignant cytology; deceptive on biopsy.

53-case series (Caliò, AJSP 2016): small crowded branching glands in 60%; more than four epithelial patterns in 64%.

Diagnostic pearl: considerable epithelial heterogeneity is part of benign MEST.

• Flat / cuboidal: uniform basal nuclei in dilated cysts.
• Hobnail: focal or widespread; not specific, many cystic renal tumours have it.
• Columnar: lines larger glands, bland nuclei.
• Clear cell change: rarely, focal clear cytoplasm in the lining; it should not by itself prompt MCRNLMP or cystic ccRCC when the ovarian-type stroma is present.
• Ciliated: shows broad differentiation; does not imply a Müllerian or metastatic gynaecological lesion.
• Mucinous / intestinal-type: goblet or mucin-secreting cells; extensive mucinous change → exclude another primary.
• Endometrioid-like / cervical-type: uncommon, often with prominent ovarian-type stroma.

Diagnostic pearl: complex glands, papillae, cilia and mucinous change can occur without carcinoma.

• Bland spindle or plump cells, oval nuclei, delicate chromatin, minimal atypia, inconspicuous nucleoli.
• Pericystic condensation: cellularity rises just beneath the lining, forming a subepithelial cuff, especially in adult CN; hypocellular further away.
• Ropy collagen: coarse wavy bundles with cellular stroma; helps separate adult CN from paediatric DICER1-associated CN.
• Luteinised cells: plump epithelioid cells with eosinophilic or vacuolated cytoplasm; inhibin may be positive, variably between series.

Diagnostic pearl: bland lining over cellular ER/PR-positive ovarian-type stroma strongly suggests adult CN/MEST.

• Smooth muscle: fascicles that can dominate solid areas, leiomyoma-like with cysts; SMA and desmin.
• Hypocellular fibrous: dense collagen between large cysts.
• Cellular spindle: compact fascicles or nodules, ovarian cellular fibroma-like, without marked atypia or mitoses.
• Oedematous / myxoid: loose matrix, microcystic look, delicate vessels.
• Fat: mature adipocytes can raise AML, especially with smooth muscle; check melanocytic markers.
• Thick-walled vessels: with smooth muscle-rich stroma; not the dysmorphic vessels of AML.

About half of MESTs in the 53-case series had more than four stromal patterns.

Low power

• Well-demarcated multilocular lesion of noncommunicating cysts with thin septa; no expansile solid epithelial nodules; compresses rather than infiltrates the kidney.

Lining

• Single layer of flat, cuboidal or hobnail cells, small uniform nuclei, occasional columnar cells.

Septa

• Hypocellular collagen with small cellular ovarian-type foci; subepithelial condensation; ropy collagen; focal luteinised cells.

Must be absent

• Malignant epithelial nests, blastema, destructive carcinoma, sarcomatous stroma.

Diagnostic pearl: ovarian-type stroma is more informative than cyst architecture, because cystic RCCs can look identical grossly.

Favours MEST

• Expansile stromal nodules, thick solid areas, many small tubules or glands, extensive smooth muscle, phyllodes-like papillae, elaborate epithelium.

Favours adult CN

• Almost entirely cystic, thin septa, simple lining, minimal solid stroma, little epithelial complexity.

Qualification

• No validated percentage of solid tissue separates them; intermediate tumours exist.
• Substantial stromal and epithelial complexity → MEST is more informative; purely multilocular cystic → adult CN.

Diagnostic pearl: a small cellular stromal focus does not turn adult CN into MEST, and an extensively cystic MEST does not need two diagnoses.

• ER and PR are among the most characteristic stromal markers; SMA frequent; desmin and h-caldesmon follow smooth muscle differentiation.

53-case series: stromal PR 85%, ER 73%, SMA positive in all but one, inhibin negative in all. A 12-case adult CN/MEST study: at least focal inhibin in 10/12.

Diagnostic pearl: inhibin is variable and never a standalone test.

Historical view

• No consistent subtype-defining alteration; grouping rested on morphology, immunophenotype and epidemiology.
• A hormonal role has been proposed, but receptor expression does not prove hormonal causation.

Recurrent chromosome 12 gain (AJSP 2026, 14 adult MESTs)

• Any copy-number alteration 6/14; whole-chromosome 12 gain 5/14 (about 36%); no recurrences in 13 followed patients.
• No consistent RCC driver, no actionable alteration, no DICER1 alterations.
• Chromosome 12 gain is neither sensitive nor specific enough to diagnose MEST on its own.

Diagnostic pearl: chromosome 12 gain supports clonality but is not yet a diagnostic molecular surrogate.

Clinical

• Infancy and early childhood; male predominance, especially under 2 years; abdominal mass.
• Frequent somatic or germline DICER1 alterations; part of DICER1 tumour predisposition syndrome.

Morphology

• Circumscribed multilocular cysts with thin septa; bland flat, cuboidal or hobnail lining; hypocellular septa with some subepithelial cellularity or inflammation; no immature nephroblastic elements.

Caution

• Stromal ER can be positive, so ER alone does not prove adult MEST-family biology.
• Inhibin and ropy collagen favour adult CN/MEST, though neither is absolute.
• A germline DICER1 variant means screening for associated tumours.

Diagnostic pearl: paediatric CN is a DICER1-associated tumour, not adult CN in a younger patient.

12 adult CN/MEST vs 7 paediatric CN: subepithelial cellularity 11/12 vs 6/7; ropy collagen 7/12 vs 0; inhibin 10/12 vs 0; DICER1 1/10 evaluable adult vs 6/7 paediatric.

• Age, morphology and molecular findings distinguish them best; an adult-type lesion does not need routine DICER1 testing.

Diagnostic pearl: always read “cystic nephroma” together with age and the stromal phenotype.

• MCRNLMP has clear-cell lining and small nonexpansile clear cell groups in the septa, with no expansile carcinoma and no ovarian-type stroma.
• MEST epithelium can rarely show focal clear cell change; the septal stroma (ER/PR+ ovarian-type) and the extent of clear cells decide.

Diagnostic pearl: clear cell lining with CAIX should prompt MCRNLMP, not adult CN.

Shared

• Epithelial-lined cysts, subepithelial cellular condensation, smooth muscle-rich stroma, ER and PR positivity, solid and cystic growth.

Favours AMLEC

• Dysmorphic thick-walled vessels; PEComa-like epithelioid or smooth muscle cells; HMB45 / Melan-A in the mesenchymal component; fat may be absent.

Favours MEST

• Bland ovarian-type stroma, diverse tubules and glands, no melanocytic marker expression, no PEComa component.

Diagnostic pearl: ER/PR cannot separate MEST from AMLEC; melanocytic markers in the stroma are the key discriminator.

• SMART (smooth muscle and adenoma-like renal tumour): bland glandular or tubulopapillary epithelium with smooth muscle-rich stroma; can mimic MEST on limited sections; check epithelial architecture and for true ovarian-type stroma.
• Leiomyoma with entrapped tubules: entrapped native tubules are not a neoplastic epithelial component; ER/PR distribution and architecture help.
• Adult CN/MEST: epithelium distributed throughout the lesion, not only at the periphery.

In the adult vs paediatric CN study, three cases first called adult CN/MEST were reclassified as SMART.

Diagnostic pearl: smooth muscle plus epithelium in one renal mass does not automatically mean MEST.

• Tubulocystic RCC: tightly packed tubules and cysts (sponge-like), eosinophilic hobnail cells, prominent nucleoli, no ER/PR-positive ovarian-type stroma; exclude FH-deficient RCC if atypical.
• Cystic ccRCC: expansile solid clear cell nodules favour ccRCC over MCRNLMP or adult CN; CAIX helps.
• Cystic TFE3/TFEB RCC: eosinophilic, clear or papillary cells; consider when morphology or IHC is discordant.
• Nephrogenic adenoma: small tubules and hobnail cells in the urinary tract including the pelvis; stroma, distribution and history matter.

Diagnostic pearl: a tubulocystic lesion with prominent nucleoli and no ovarian-type stroma is not cystic nephroma until proven otherwise.

• Cystic partially differentiated nephroblastoma shares multilocular cysts, thin septa, bland lining and childhood age.
• Defining difference: immature nephroblastic elements (blastema, primitive epithelium or stroma) in the septa; paediatric CN has none.
• Expansile solid malignant nodules suggest cystic Wilms tumour rather than CPDN.
• Sample septa extensively; nephroblastic foci can be minute and no grossly visible nodule does not exclude CPDN.

Diagnostic pearl: in an infant’s cystic renal tumour, the key question is whether immature nephroblastic elements are present in the septa.

• Multiple dilated tubules in a localised segment, with native renal tissue between cysts; cysts may connect with nephrons; no pseudocapsule.
• Paediatric CN instead is a well-circumscribed mass displacing the kidney, without native nephrons spread through the septa; molecular findings can help.

Diagnostic pearl: native tubules and glomeruli throughout a cystic lesion point to a developmental cystic process, not a neoplasm.

1. Context: adult versus paediatric age is fundamental.
2. Architecture: predominantly multilocular cystic, or substantial stroma and complex glands?
3. Lining: flat, cuboidal, hobnail, columnar, clear or mucinous; search for atypia, papillary nodules or invasive carcinoma.
4. Stroma: ovarian-type cellularity, pericystic condensation, ropy collagen, smooth muscle, luteinised cells, PEComa features.
5. Targeted IHC: PAX8/CK7 for epithelium; ER/PR/SMA for stroma; add inhibin, HMB45/Melan-A or CAIX by differential.
6. Molecular: DICER1 for paediatric CN or suspected predisposition; not routine for classic adult MEST/CN.
7. Exclude malignancy: sample nodules, thick septa, atypical epithelium, necrosis and suspicious stroma.

• A core may show only bland lining and fibrous septa; ovarian-type stroma may be missed.
• A smooth muscle-rich core may be read as leiomyoma or AMLEC; entrapped tubules complicate the epithelial assessment.
• Malignant nodules, atypia or necrosis may not be sampled; MEST versus adult CN may be impossible but usually matters little in a classic lesion.

Suggested wording

• MEST: “Mixed epithelial and stromal tumour of the kidney. Bland renal epithelial tubules and cysts admixed with ovarian-type stroma.”
• Adult CN: “Adult cystic nephroma (MEST family). Predominantly multilocular cystic lesion with bland lining and ovarian-type stroma, no expansile malignant component in the examined sections.”
• Indeterminate core: “Biphasic renal epithelial and stromal lesion, favour MEST family. Limited sampling prevents exclusion of an unsampled solid component.”

• Conventional adult MEST and CN are generally benign; complete excision is usually curative; local recurrence is uncommon.
• Rare malignant transformation, mostly of the stroma, does not imply meaningful metastatic risk for conventional MEST.
• Paediatric CN is benign after excision, but a germline DICER1 variant matters beyond the kidney.
• RCC nuclear grading does not apply.

Diagnostic pearl: the key distinction is a conventional bland MEST-family tumour versus a lesion with a genuinely malignant epithelial or stromal component.

• Chromosome 12 gain in 5/14 adult MESTs (2026): first recurrent genomic alteration; supports clonality, not a routine criterion.
• Adult and paediatric CN stay separate: age, ovarian-type stroma and very different DICER1 frequencies.
• Morphological diversity: phyllodes-like projections, branching glands, thyroid follicle-like structures and complex papillae with many stromal types; complexity without malignant cytology is not carcinoma.
• Look at the septa: adult CN, paediatric CN, MCRNLMP and AMLEC can all have bland lining; stroma, cytology, age and focused IHC decide.

• MEST and adult CN are one family; adult CN is the cystic end; both mostly in middle-aged women.
• Ovarian-type stroma: ER/PR+, often SMA+, subepithelial condensation, ropy collagen, focal luteinised cells; inhibin variable and not required.
• Epithelium can be simple, branching, phyllodes-like, ciliated or mucinous.
• No validated quantitative cut-off separates MEST from adult CN.
• Paediatric CN is distinct and DICER1-associated; stromal ER does not separate adult from paediatric CN.
• MCRNLMP: clear cell lining, no ovarian-type stroma. AMLEC: melanocytic markers in the stroma. CPDN: immature nephroblastic elements in the septa.
• Chromosome 12 gain in a subset of adult MEST; most conventional tumours are benign.
• Sequence: epithelial architecture → septal stromal phenotype → compartment IHC → exclusion of malignancy.