renal tumors in infancy and childhood

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Pathology of renal tumors in infancy and childhood

Dr Sangeeta Desa

Pathology of Renal Tumors

Gaya Prasad Memorial Pathology Symposium

APCON 2005, Indore; 2nd December, 2005 1

Pathology of Renal Tumors in Infancy and Childhood

Dr. Tanuja ShetDr Sangeeta Desai

Pathologists, Tata Memorial Hospital, Mumbai

The renal neoplasms in childhood are infrequent, often undifferentiated, have unusuavariants, mimic several other renal and extrarenal tumours and due to these reasons,yield themselves to clinically significant diagnostic errors.Significant advances in therapy & histology have led to parallel development ofprotocols & various trials resulting in improved survival of children and young adultswith renal tumours. The role of pathologist in the total management of childhood renaltumors cannot be overemphasized. Therapy is based on stage and histology!

Steps in grossing of renal tumors

Specimen must be submitted intact. Avoid frozen section & bivalving. Weighing the specimen is mandatory. Stage I tumors weighing < 550mgs do not

require additional treatment. Never strip capsule. Ink the external surface. Locate vessels & ureter & take cut margins. From the freshly cut surface, use tissue to molecular/ cytogenetics/ EM Always sample the periphery of specimen and obviously uninvolved rena

parenchyma. Submit nodes before tumor is cut to avoid floater.

Bisect the specimen such that tumor is seen well. Serially slice the specimen 2 cm apart, incisions parallel to the initial one should

be made at the intervals of 2 cm avoiding sites of capsular infiltration. Refrigerate in formalin & fix overnight Grid the central slice and submit for histology entirely.Why grid? - Essential for☺ Evaluating anaplasia☺ Evaluating post chemotherapy tumor (% necrosis)☺ Recognition of renal sinus☺ Detection of capsular invasion

Important anatomic considerations while grossingRenal sinus is the concave region on the medial aspect of the kidney which containsmajor renal vessels and portions of pelvicalyceal system. Medial sinus margin isragged connective tissue surrounding the resected renal vessels.


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Renal vein usually retracts and may give false impression of margin involvement, if thetumour is in close proximity.

Essential features that must be documented in a histology report Tumor type, favorable/ unfavorable histology Extent of invasion, capsular invasion, status of renal sinus

Vascular / lymphatic emboli Tumor kidney interface, nephrogenic rests Margins Lymph nodes – number, metastasis +/-

Wilms tumour Accurate staging and histology are very important since the therapeutic protocols arestage related. Hence clinical stage determined by imaging and the operating surgeon

and pathologic stage determined by systematic gross and histologic examination are ofutmost importance.

GrossThere is nothing distinctive about gross features of WT. However, bilateralitymulticentricity and renal vein thrombosis are more common in WT than in other renaltumours.

Microscopy Histology of WT is a recapitulation of nephrogenesis and aberrant epithelial and /ormesenchymal differentiation. Depending on the predominance of the blastemalepithelial and mesenchymal elements, WT is characteristically described as tri-, bi- ormono- phasic. Subtypes are classical triphasic (59%), blastemal predominant (25%),epithelial predominant (8%) and mesenchymal predominant (8%). The predominantpattern is the one which is noted in > 80% tumor. In pre-chemothrapy era, thesesubtypes were important as the blastemal tumors fared badly; however in today’schemotherapy era blastema is chemo sensitive while epithelial dominant tumors areresistant to treatmentThe reporting pathologist should be aware of nuclear details of blastema, since this

knowledge helps distinguish blastemal WT from the other NWT particularly onaspiration cytology and biopsy. In blastemal cells, the ratio of length of the nucleus toits width is 3.


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Anaplasia in WT Anaplasia is rare in WT cases


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Gross MN is usually large relative to the infant's kidney. Externally, the surface of the tumorand kidney is smooth and the renal capsule and calyceal systems are stretched overthe tumor. The surface may be bosselated. The cut surface resembles that of aleiomyoma: firm, whorled or trabeculated, and light colored. The tumor isunencapsulated, typically interdigitates with the surrounding kidney, and may extend

into surrounding tissues. Renal vein invasion also occurs occasionally. Cystshemorrhage, and necrosis are present in a minority of cases, particularly those that arecellular on microscopic examination.

Microscopy The classical pattern of MN is a moderately cellular proliferation of thick interlacingbundles of spindle cells with elongate nuclei which usually infiltrate renal and perirenatissues. Entrapment of glomeruli and renal tubules is common. Mitotic figures areusually in the range of 0 to 1 per 10 high power fields. Islands of cartilage and foci of

extramedullary hematopoiesis are present in some tumors.

Another, more common, pattern consists of a densely cellular proliferation of polygonacells with mitotic figures in the range of 8-30 per 10 high power fields, and oftenpushing borders. This pattern has been called cellular MN. Cysts are common in thispattern. The classical and cellular patterns often are mixed in the same tumor. Age andcompleteness of resection are the primary risk factors for adverse outcome of MN, andnot histopathologic pattern.

There are cases which display overlap of cellular variant of MN and spindled variant of

CCSK, which suggests pathogenetic relationship between the two.

Differential diagnosis MN usually is easily diagnosed when the histology and patient’s age are consideredPreoperatively treated WT with stromal predominance may be confused withcongenital mesoblastic nephroma. This problem can usually be resolved by theproviding attention to the age, bilaterality, identification of blastema, nephrogenic restsand tumour border.

CCSKOriginally called "bone-metastasizing renal tumor of childhood", CCSK is responsiblefor maximum diagnostic discrepancies due to overlapping and variant patterns and is ahighly malignant neoplasm resistant to conventional therapy for WT, but oftenresponsive to doxorubicin-containing regimens. Thus, it is of considerable therapeuticimportance that CCSK be correctly diagnosed.


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Occurring in the same general age range as WT, CCSK comprises approximately 6%of pediatric renal tumors. Most are diagnosed in patients between 12 and 36 months ofage. Approximately 66% of the patients are male. The propensity for metastasis tobone and unusual sites is marked.

Gross

The appearance of the cut surfaces of this tumor is variable: it may be homogeneous,gray and lobular or variegated, including firm gray whorled tissue and light pink softareas. Occasionally, the tumor may produce abundant mucin which gives a slimyglistening appearance. Most appear well-circumscribed. Cysts ranging from a fewmillimeters to centimeters in diameter are present in approximately a third of cases.Often, the tumor weighs more than 500 g. Bilaterality has not been reported.

Microscopic At low magnification, CCSK usually consists of a monotonous sheet of cells with lightly

staining cytoplasm. At higher magnification, the cells are arranged in cords separatedby septa composed of spindle cells with dark nuclei and a distinctive branching patternof small blood vessels. The cells in the cords have pale or vacuolated cytoplasm andindistinct borders. Despite the name, the cytoplasm of CCSK is usually much less clearthan that of clear cell RCC and cytoplasmic clarity should not be relied upon toestablish the diagnosis. The nuclei contain finely dispersed chromatin and the nucleolare small. A characteristic feature is the infiltrative border between the CCSK and thesurrounding renal parenchyma.Confusing variant patterns occur, including epithelioid, spindle cell, myxoid, cystic,hyaline sclerosis, palisading and monstrocellular. The tumor should be sampled

generously to find “classical” areas.

Differential diagnosis The distinctive vascular pattern and nuclear features of CCSK are often helpful indistinguishing it from WT. However, in addition, some important points are as followsCCSK is unilateral and unicentric with infiltrative borders, unassociated with syndromesand precursor lesions, blastema and nonrenal elements such as cartilage or muscleare not found in CCSK and sclerotic stroma is uncommon in WT before therapy.Exceptionally, CCSK may contain foci in which the cells have prominent nucleoli,

similar to those of RTK; other areas with “classic” pattern and lack of extremeinvasiveness, typical of CCSK usually will clarify the diagnosis.

Rhabdoid tumor of kidney (RTK) The most malignant renal neoplasm of childhood, RTK is usually diagnosed inadvanced stage and metastasizes widely and causes death within 1 year of diagnosis.The patients usually are very young at the time of diagnosis (NWTS median age 11


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months, and rare after 3 years) and there is a 1.5:1 predominance of boys to girls. Associations with embryonal tumors of the central nervous system, neurovascularhamartoma, paraneoplastic hypercalcemia and chromosome 22q11-12, 11p15.5abnormalities have been reported.

Gross

RTK lacks the appearance of encapsulation often seen in cases of WT or CCSK. Thetumors usually are located medially in the kidney and the renal sinus and pelvis arealmost always infiltrated. They are typically yellow-gray or light tan friable tumors withindistinct borders. Necrosis and hemorrhage are common.

Microscopy RTK is typically diffuse and monotonous with poorly defined border. It consists ofmedium or large polygonal cells with abundant eosinophilic cytoplasm, round nuclewith thick nuclear membranes and large nucleoli. It is the resemblance of the

cytoplasm of these cells to differentiating rhabdomyoblasts which gave the tumor itsname. However, the resemblance to skeletal muscle is merely superficial and if definiteevidence of differentiation toward skeletal muscle is present, the tumor is not arhabdoid tumor. Often, the cytoplasm contains a large eosinophilic globular inclusionwhich displaces the nucleus. Electron microscopy has shown that these consist ofaggregates of whorled filaments. As more cases have accrued to the NWTS, a widerange of patterns has been appreciated, including sclerosing, epithelioid, spindle cell,lymphomatoid, vascular, pseudopapillary, and cystic. Typically, these patterns aremixed with the common pattern and with each other. The characteristic nuclearfeatures of large centrally placed nucleoli and thick nuclear membranes are usually

retained.

Differential diagnosis A wide variety of renal and extrarenal tumors may mimic rhabdoid tumor in routinesections. Cases of WT, congenital MN, RCC, urothelial carcinoma, collecting ductcarcinoma, oncocytoma, rhabdomyosarcoma, neuroendocrine carcinoma, andlymphoma have been confused with RTK. Filamentous cytoplasmic inclusions orconspicuous macronucleoli are the misleading features in most cases. Conventionallight microscopy is able to clarify most cases, but electron microscopy and

immunohistochemistry are sometimes necessary to show the characteristic features ofthe mimics and exclude RTK. Occasionally, blastemal cells contain inclusionssuggestive of rhabdoid tumor, but the presence of characteristic aggregates ofblastema, such as nodules or serpentine groupings, clarifies the diagnosis.

RCC


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Conventional RCC is uncommon in children. Definite translocations associated withRCC in children have been documented

Translocations involving chromosome Xp11.2Renal carcinoma characterized by several different translocations involvingchromosome Xp11.2, all resulting in gene fusions involving the TFE3 gene

predominantly affect children and young adults. The most distinctive histopathologicappearance is that of a carcinoma with papillary or nested architecture and clear cellmorphology. In keeping with the chromosomal translocation, the most distinctivefeature on immunohistochemistry is nuclear reactivity for TFE3 protein.

ASPL-TFE3 gene fusion t(X;17)(p11.2;q25) The tumor cells in this tumor exhibit an organoid arrangement and pseudo

papillary pattern. They also show extensive psammomatous calcifications. Each cell has

voluminous granular cytoplasm with distinct cell borders.On EM – The tumors exhibit a combination of features of both alveolar soft partsarcoma and epithelial cells

t(6;11)(p21.1;q12) chromosome translocation Tumor shows nests of polygonal clear cells with well defined cell membrane A second population of smaller cells form clusters surrounded by nodules of pink

basement membrane like material stained with Periodic Acid Schiff D resistantreaction.

On EM -The polygonal tumor cells contain abundant mitochondria and

membrane bound granules. The cytoplasm is rich in glycogen. Localized pools ofduplicated basement membrane material are prominent

Metanephric stromal tumorMST is a recently recognized benign tumor which occurs in children (neonatal to 11years old, mean age 24 months) and is equally prevalent in boys and girls. The mostcommon presentation is an abdominal mass, but hematuria or hypertension were thepresenting problem in some cases.

GrossThese are usually tan, lobulated, solid, and cystic (50%) tumors in the renal medulla.Multifocal MST is present in more than 10% of cases, but bilaterality has not beenreported. The tumors appear well-circumscribed and were confined to the kidney. Thetumors ranged from 30 mm to 100 mm in diameter.

Microscopic pathology


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MST is unencapsulated and superficially infiltrates among renal structures. They tendto infiltrate beneath the urothelium of the renal calices or pelvis. The generalappearance is of a variably cellular proliferation of spindle cells with tapered nuclei anddelicate cytoplasmic processes. The cells surround blood vessels or entrapped renaltubules, forming hypocellular myxoid onion skin nodules. Entrapped renal tubules showcystic change, epithelial hyperplasia; entrapped glomeruli show juxtaglomerular

hyperplasia; and entrapped arterioles may show angiodysplasia. Heterologousdifferentiation toward glia, cartilage, and neuroectoderm may also be present.MST is typically immunoreactive to CD34.Molecular data have revealed that metanephric stromal tumor may represent thebiphasic middle portion of the spectrum of tumors with purely mesenchymalmesoblastic nephroma at one end and completely epithelial tumor, metanephricadenoma at the other end.

Suggested References

1. Charles AK, Vujanic GM, Berry PJ. Renal tumours of childhood. Histopathology1998; 32: 293-309.

2. Argani P, Perlman EJ, Breslow NE, Browning NG, Green DM, D'Angio GJBeckwith JB. Clear cell sarcoma of the kidney: a review of 351 cases from theNational Wilms Tumor Study Group Pathology Center. Am J Surg Pathol 200024: 4-18.

3. Argani P, Antonescu CR, Illei PB, Lui MY, Timmons CF, Newbury R, Reuter VEGarvin AJ, Perez-Atayde AR, Fletcher JA, Beckwith JB, Bridge JA, Ladanyi M.Primary renal neoplasms with the ASPL-TFE3 gene fusion of alveolar soft partsarcoma: a distinctive tumor entity previously included among renal cel

carcinomas of children and adolescents. Am J Pathol 2001;159:179-92.4. Argani P, Hawkins A, Griffin CA, Goldstein JD, Haas M, Beckwith JB, Mankinen

CB, Perlman EJ. A distinctive pediatric renal neoplasm characterized byepithelioid morphology, basement membrane production, focal HMB45immunoreactivity, and t(6;11)(p21.1;q12) chromosome translocation. Am J Patho2001;158:2089-96.

5. Beckwith JB. National Wilms Tumor Study: an update for pathologists. PediatrDev Pathol 1998; 1:79-84.

6. Faria P, Beckwith JB, Mishra K, Zuppan C, Weeks DA, Breslow N, Green DM.

Focal versus diffuse anaplasia in Wilms tumor--new definitions with prognosticsignificance: a report from the National Wilms Tumor Study Group. Am J SurgPathol 1996; 20:909-20.


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Figure 1. Gross Specimen of Wilms Tumour

Fig 2. Triphasic Wilms tumour


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Fig 3. Anaplasia in Wilms tumour

Fig 4. Gross Specimen of Clear cell sarcoma


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Fig 5. Clear cell sarcoma

Fig 6. Mesoblastic_nephroma


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Fig 7. Mesoblastic nephroma

Fig 8. Rhabdoid Tumor


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renal tumors in infancy and childhood

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