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Mixed and embryonal renal tumours in adults
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Mixed and embryonal renal tumours in adults
S. Fleming
adult Wilm's tumour, cystic nephroma, mesoblastic nephroma, nephrogenic adenofibroma, mesonephroid blastoma, rhabdoid renal tumour, clear cell sarcoma and angiomyolipoma. In establishing the diagnosis of such tumours adequate tissue sampling is essential.
Introduction
The classification of renal turnouts has recently been revised and is shown in the Table. A feature of this classification is the separation of groups according to their phenotype and genotype. These tumours are frequently encountered in paediatric pathology practice but rarely occur in the adult patient, where they may present diagnostic difficulty. The tumours selected for discussion because of their diagnostic difficulty are: sarcomatoid renal carcinoma,
Sarcomatoid renal carcinoma
The classification of renal carcinoma has been re-examined in the light of cytogenetic advances? .2 The majority of renal carcinomas are composed entirely of epithelial cells, however, some renal carcinomas contain both neoplastic epithelial and mesenchymal elements. For individual patient m,'magement, clinical trials and survival statistics and for tumour research these tumours are best separately classified as sarcomatoid renal carcinoma. They constitute 1 - 6 % of malignant renal neoplasms in the adult. Sarcomatoid carcinomas occur in a similar age to other forms of renal carcinoma, mainly from fourth to eight decades with a median age of 56264 in different series? The tumour is slightly more common in men than women. The usual presenting features are the common triad of haematuria, loin pain and abdominal mass. At least one of these being found in two thirds of cases. 3 0 - 4 0 % of patients have metastatic disease at the time of presentation, manifest either symptomatically or on clinical evaluation. There are radiological features which, although not diagnostic, raise the possibility that a renal tumour is a sarcomatoid carcinoma. On plain abdominal radiographs calcification is more frequently seen (34%) than in other renal carcinomas (6%). The tumours tend to be larger with more extensive retroperitoneal involvement and anatomical distortion of the urinary tract and adjacent structures. Compared to other renal carcinomas the sarcomatoid component of these tumours is markedly hypovascular on arteriographic investigation. 4
Table Nephroblastic Wilms' tumour/nephroblastoma Mesoblastic nephroma Atypical mesoblastic nephroma Multilocular cystic nephroma Cystic partially differentiated nephroblastoma Mesonephroid blastoma/mcsonephric adenosarcoma Nephrogenic adenofibroma Clear cell sarcoma/bone metastasising renal tumour of childhood Rhabdoid renal tumour Epithelial Adenoma Renal carcinoma (no special type) Papillary renal carcinoma Chromophobe renal carcinoma Renal oncocytoma Collecting duct carcinoma Sarcomatoid renal carcinoma Mese~zchymal Angiomyolipoma Juxtaglomerular cell tumour Renal medullary inlgrstitial cell tumour Prim_aryrenal sarcomas (various types)
Stewar! Fleming, Department of Pathology, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK CurrentDiagnosticPathology(994) I, 32-.10 © 1994LongmanGroupLtd
32
EMBRYONAL RENALTUMOURS
33
Diagr~ostic features The diagnostic features are: malignant neoplasm of kidney, neoplastic epithelial and mesenchymal components, and no blastemal elements• The morbid anatomy which is often strongly suggestive of this form of renal carcinoma varies according to the relative proportion of epithelial and mesenchymal conaponents. The epithelial component has the usual yellow/grey soft haemorrhagic appearance seen in renal carcinoma of no special type. The sarcomatoid element has a finn, sometimes hard, grey/white appearance and is characteristically more infiltrative than the other forms of renal carcinoma. These tumours are usually large with a mean maximum diameter of over 10 cm. Retroperitoheal spread and direct involvement of adjacent organs is common, indeed a significant number of sarcomatoid renal carcinomas cannot be completely excised at nephrectomy. Regional lymph node, vascular and pelviureteric invasion and distant metastases are seen in up to 50% of patients at the time of initial presentation. Histologically there are obviously two essential components - epithelial and mesenchymal. In the majority of cases the epithelial areas have the morphology of renal carcinoma of no special type. It is less common for the epithelial cells to have the" features of papillary renal carcinoma or chromophobe carcinoma. Sarcomatoid forms of collecting duct carcinoma have recently been reported: These appear to behave in a manner similar to that observed for other groups of sarcomatoid renal carcinoma. A range of nuclear grades have been described but at least some areas of high grade nuclear morphology are usually found in the epithelial component. The mesenchymal areas may mimic any sarcoma: fibrosarcoma, leiomyosarcoma, haemangiopericytoma, chondrosarcoma, osteosarcoma, malignant fibrous histiocytoma and rhabdomyosarcoma have all been described. The most frequent appearance is of an infiltrating poorly differentiated spindle cell tumour with necrosis and haemorrhage. The sarcomatous component is usually high grade with mitotic activity, including abnormal mitoses and nuclear pleomorphism. There are often areas of transition between the epithelial and spindle cell components. This component is extensively infiltrative, surrounding and invading structures in the adjacent renal parenchyma or retroperitoneum (Fig. 1). Whereas most renal carcinomas invade as a cohesive 'pushing' edge sarcomatoid carcinomas show a more infiltrative pattern.
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Fig. 1--Sarcomatoid renal carcinoma. There is a mixture of neoplastic epithelial and mesenchyal elements merging into each other in this field. The epithelial component is of clear cell type and the mesenchymal a poorly differentiated spindle cell.
In the absence of epithelial elements identified by conventional microscopy the surgical pathologist should investigate the case by immunocytochemistry and electron microscopy• In sarcomatoid carcinoma even some spindle cell areas may be positive with antibodies to cytokeratins. I use CAM 5.2 and PKK1 in the investigation of these tumours. Epithelial membrane antigen (EMA) and CD 15 will rarely be positive except in areas which are morphologically epithelial• Sarcomatoid collecting duct carcinomas also express some epithelial markers in the spindle cell component. Some caution must be observed in interpreting cytokeratin staining some sarcomas such as leiomyosarcoma may demonstrate cytokeratin reactivity• Electron microscopy can be used and of particular value is the finding of desmosomes which confirms the diagnosis of sarcomatoid renal carcinoma. In this situation it is important to distinguish desmosomes from the adherens junctions found in some smooth muscle cells and their tumours (Fig. 2). Desmosomes are usually sparse in spindle cell areas but would be a most unusual feature in a primary sarcoma. The spindle cell element of sarcomatoid renal carcinoma may express differentiated mesenchymal features. This "•ll•'•"
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diagnosis
Spindle cell tumours of the kidney can present diagnostic difficulty. The most common problem is the histopathological classification of a tumour in which an epithelial component is not-seen. In the majority of cases extensive sampling guided by morbid anatomical observation will reveal areas of renal carcinoma and confirm the diagnosis of sarcomatoid carcinoma. It is important to remember that sarcomatoid renal carcinoma is more common than any of the primary renal sarcomas•
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34
CURRENT DIAGNOSTIC PATHOLOGY
is seen morphologically by chondroid or osteoid production but may also become apparent on immunocytochemical or ultrastructural investigation. This is important since the presence of smooth muscle actin, desmin, myoglobin on immunocytochemistry or myofilaments on electron microscopy do not confirm the diagnosis of a primary sarcoma unless, after full investigation, the absence of epithelial elements is confirmed. Finally the diagnosis of a primary renal sarcoma must be considered in the absence of morphological, immunocytochemical and ultrastructural evidence of epithelial differentiation. These tumours should be classified by histopathological criteria applicable to soft tissue tumours in other sites. Most types of soft tissue tumours have been described in the kidney. The presence of blastemal areas or embryonal elements place the tumour within the adult Wilms' tumour group and should be classified accordingly.
in sarcomatoid renal carcinoma may reflect altered activity of transcription factor-regulated activity of a promoter region common to cadherin and keratin genes as described in some breast carcinomas. 7 Sarcomatoid carcinomas certainly show evidence of accumulated genomic abnormalities, aneuploidy and a more aggressive biological course suggesting a later stage in tumour progression. Most authorities now accept that these represent an undifferentiated progression of other forms of renal carcinoma.
Embryonal renal tumours in the adult Rarely renal tumours which have the morphological and behavioural characteristics of embryonal tumours of childhood are encountered in adults. Although they are classified as for the childhood forms when, encountered in the adult patient they may present diagnostic difficulty to the surgical pathologists and his clinical colleagues.
Clinical behaviour Adult Wilms' tumour
Most sarcomatoid renal carcinomas are large, advanced turnouts, many unresectable, at the time of initial presentation. The recognition of this entity separate from renal carcinoma of no special type is necessary not only because of its morphological features but more importantly because of its markedly aggressive clinical behaviour. In my own series of 16 patients none were alive at 12 months from initial presentation. Experience from other centres is similar. The mean survival of patients with sarcomatoid renal carcinoma is about 4-6 months. The large size and infiltrative behaviour results in operative difficulties and patients with these tumours have a high peri-operative mortality. The remainder succumb to the consequences of metastatic sarcomatoid renal carcinoma. This is undoubtedly a most aggressive renal malignancy requiring separate identification.
Wilms' tumours have been described in over 200 adult and adolescent patients. The documentation in many of these patients is incomplete. Particularly deficient is adequate morbid anatomical and histopathological description and photomicrographs to support the diagnosis. Indeed some of these diagnoses have been challenged. 8 Nevertheless it is clear that many of the cases described are Wilms' tumours and that though they can occur in any age group, including the elderly, they are more common in patients under 40 years. As in childhood cases abdominal mass and flank pain are particularly prominent presenting symptoms. Other symptoms, including those related to extra-renal spread of disease, are encountered. In the adult patient the symptoms are often of prolonged duration of up to 2 years.
Origin
Diagnostic criteria
In the past there has been considerable debate concerning the presumed histogenesis of these tumours. Are the two tumours synchronous in development? Are they a form of embryonal tumour, the epithelium coming from the poorly differentiated mesenchyme? Are they carcj.nomas which lose the capacity for epithelial differentiation as genomic damage accumulates? Although there is no conclusive evidence the author firmly believes this last option to be the most likely. Loss of differentiated phenotype is a common feature of neoplastic progression of many tumour types. The loss of epithelial morphology will occur if there is loss of the cell adhesion and cytoskeletal properties of epithelial cells. 6 In sarcomatoid renal carcinomas stained with antibodies to desmosomal components and cytokeratins there is usually simultaneous loss of these molecules. The prediction of cell biology experiments is that loss of these components, essential for the maintainence of the epithelial phenotype, will result in a poorly differentiated infiltrative spindle cell tumour. This loss of adhesion and cytoskeleton molecules
Tile diagnostic criteria are: primary renal neoplasm, blastematous component, embryonal tubules or glomeruloid structures, no evidence of renal carcinoma, and age more than 15 years. Diagnostic criteria for the acceptance of a tumour as an adult Wilms' tumour must be strict. The author would expect all of the above criteria to be met. The one exception considered acceptable would be a lack of embryonal nelllaron components in a monophasic blastematous Wilms' tumour, provided that in such cases other small blue cell tumours such as carcinoid, neuroendocrine carcinoma or rhabdomyosarcoma have been carefully excluded. The surgical pathologist has an important role in assessing size and stage of the adult Wilms' tumour. The tumours are staged by a combined surgical and pathological staging in which completeness of excision must be jointly assessed. Stage 1 is limited to the kidney and the tumour is completely excised; stage 2 tumour extends beyond the kidney but is completely excised, stage 3 represents residual non-haematogenous spread of disease
EMBRYONAL RENALTUMOURS 35
in abdomen; stage 4 denotes metastatic tumour at presentation; stage 5 is reserved for bilateral Wilms' tumour. Using this staging procedure it is clear that adults with Wilms' tumour often have tumours at an advanced stage at the time of presentation. Grossly adult Wilms' tumour is large, often greater than 10 cm, with a Iobulated appearance and pseudoencapsulation. It has a grey colour with areas of necrosis, haemorrhage and cyst formation or mucinous change. Local invasion, vascular invasion, regional lymph node involvement and completeness of excision are all important features in the morbid anatomical assessment. Occasional tumours are multifocal and areas of nephroblastomatosis may be seen in the adjacent kidney. Microscopically, adult Wilms' tumour has the same appearances as the childhood form. The typical triphasic pattern of blastema, stroma and immature epithelial elements is most frequently encountered (Fig. 3). The presence of blastema is required to be certain of the diagnosis. This consists of sheets of ovoid cells with scant, indistinct cytoplasm and hyperchromatic oval nuclei. Mitotic figures, apoptosis and necrosis are frequently seen. They are usually arranged in solid
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sheets but on occasion adopt trabecular or nesting arrangements and may form poor pseudorosettes around a central capillary. The epithelium can form tubules, glomemloid bodies, microcysts, cysts or trabeculae. The epithelial cells are usually columnar with elongated hyperchromatic nuclei again showing mitotic activity or evidence of programmed cell death. Epithelium of ciliated, squamous, mucinous, neuroendocrine or other types are seen but these are thought to be direct ingrowths from collecting ducts in the adjacent kidney. Mesenchyme is mostly immature spindle shaped or stellate fibroblasts surrounded by a pale staining extra cellular matrix (Fig. 3). Heterologous elements such as skeletal muscle, cartilage and bone may be seen. The identification of anaplasia (Fig. 3) is an important part of the surgical pathology evaluation in Wilms' tumour. Anaplasia is present if all three of the following criteria are met;9 nuclear enlargement of at least three times the diameter of adjacent tumour cells, nuclear hyperchromasia, multipolar mitoses. Anaplasia may be diffuse or focal, the prognostic implications are similar for these two. Adequate sampling is required to ensure its detection. Some tumours may be entirely composed of immature mesenchyme. However in the adult these are more accurately designated as primary renal sarcomas.
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The cystic group of embryonal tumours merits further attention. There are two lesions within this group, multilocular cystic nephroma (MCN) and cystic partially differentiated nephroblastoma (CPDN). Despite many morphological similarities, the distinction between these two is important because of differing clinical behaviour. Both may be encountered in adults but the former is the more frequent in this age group. They have similar presenting features. The most common is the identification of a large abdominal mass. These are usually painless but on occasion loin pain and haematuria may be present. In a few cases there has been systemic hypertension on presentation but the relationship to the cystic nephroma is uncertain. Cystic nephroma requires thorough and careful examination for accurate diagnosis and management advice. They are large and composed of multilocular cysts which do not communicate with the calyces or renal pelvis (Fig. 4). Despite their size there is at most minor distortiot~of the adjacent renal parenchyma. The lesion is often greater than 10 cm in diameter. Between cysts is a firm white fibrous stroma. Any solid areas •should be examined and sampled for histology. Histological examination shows the cysts lined by a single layer of flattened or cuboidal epithelium. The epithelium may adopt a hob-nail morphology (Fig. 4). The epithelial cells have eosinophilic, sometimes granular cytoplasm and round or ovoid nuclei. Nuclear pleomorphism is not a feature and mitoses are rare. It is in the stroma that the feature distinguishing MCN and CPDN is found. The stroma of both types is composed of
36 CURRENTDIAGNOSTICPATHOLOGY
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area of solid tissue examined in histological sections the tumour should be classified as CPDN grade 2. The distinction between the grades is necessary because tumours composed of > 50% immature elements may metastasise while metastatic spread has not been recorded in tumours fulfilling the diagnostic criteria for grade 1 CPDN, nor in MCN. Surgical excision is curative for MCN and CPDN grade 1. However, CPDN grade 2 may require follow-up and further therapy if metastases develop. Other non-Wilms' childhood renal tumours may be encountered in the adult patient.
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Mesoblastic n e p h r o m a This is a rare, usually congenital tumour of infancy. Usually discovered in the first few months of life it is unusual beyond 1 year of age. Eight cases have been described in adults although the accuracy of the diagnosis has been challenged in one case) ° The ages at presentation range from 19-66 with presenting features similar to those in other renal tumours. Although imaging techniques are of value in demonstrating the'presence of a renal tumour there were no features specific to mesoblastic nephroma. There are some differences in the pathology of adult and childhood mesoblastic nephroma - at least some of which may be related to the age of the tumour. Adult, unlike childhood, cases are often encapsulated or nodular with surrounding fibrous tissue. They are grey-yellow or tan coloured and up to 3 cm in diameter. Polypoid growth and an intrapelvic component have been described in adult cases. ~° The tumours are composed of sheets or interlacing bundles of eosinophilic spindle or cigar shaped cells with uniform elongated nuclei (Fig. 5). Adult cases appear to have a lower cell density than childhood cases with increased periceilular fibrosis and areas of hyalinisation. The turnouts may be highly vascular• Nuclear pleomorphism is not seen; and although prominent nucleoli may be present there are no mitoses. A feature particularly prominent in adult cases is the presence of cystic or
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hyalinised connective tissue without heterologous elements and with prominent mast cells. If immature blastemal elements are found in the stroma, the lesion is a CPE)N (Fig. 4); if they are not present it is a MCN, In most instances, particularly in adults, the proportion of blastema is small and the tumour is a grade 1 CPDN. In a few cases the blastema is marked, if immature and blastemal components occupy greater than 50% of the
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EMBRYONALRENALTUMOURS 37 dysplastic tubules, some with papillary growth patterns, and immature glomeruli. The atypical form described in childhood has not been recorded in an adult. Of value in the diagnosis of these tumours is the immunocytochemical and ultrastructural evidence of smooth muscle differentiation of the spindle cell component. These cells stain with antibodies to desmin, or-smooth muscle actin and vimentin. On electron microscopy the basal plasmalemmal densities, cytoplasmic filaments and pinocytosis of smooth muscle cells are evident. These tumours usually behave in a benign manner. In one series, recurrence in a scar of an incompletely resected tumour was seen 21 years after resection in one adult. Nephrectomy should be regarded as a curative procedure.
Nephrogenic adenofibroma This is a very rare, recently described tumour occurring in adolescents and young adults. Five cases were identified from 7000 submitted over 20_years to the NWTS Pathology Centre. n Its recent identification and small number of cases, with a complex morphology mean that the recognition of the full ronge of features of this entity will require further development. The tumours presented in patients from 3.5-23 years (mean 13.3). One obvious and potentially important finding was the frequent occurrence of polycythaemia, hypertension or haematuria resolving after nephrectomy. All of these tumours had previously been diagnosed as Wilms' tumour or mesoblastic nephroma. They are non-encapsulated, firm, irregular tumours variably coloured tan, grey or yellow. Extension into adjacent renal parenchyma and beyond the kidney into perinephric soft tissue or renal sinus may be seen. There is a complex and presumably evolving histopathological picture, and the diagnosis may present considerable difficulty. The characteristic histology is of morphologically benign mesenchymal cells surrounding discrete nodules of embryonal epithelium and blastema. The mesenchyme consists of sheets or bundles of spindle shaped cells with a vascularised stroma showing focal hyalinisation or myxoid change. The cellular density is lower than that of mesoblastic nephroma. These ceils lack mitotic figures and significant atypia. The nodules of embryonal tissue are well circumscribed with areas of epithelial differentiation. The epithelium is mostly of tubules lined by immature cuboidal or columnar cells with indistinct cell borders. The nuclei, often overlapping, show hyperchromasia but lack pleomorphism or mitotic activity. Papillary areas are prominent and these "frequently contain psammoma bodies. In three of the five cases there were papillary areas morphologically distinct from the-embryonal epithelium. These areas of the-turnour are described as resembling foci of low grade collecting duct carcinoma. The cells have abundant eosinophilic cytoplasm, large nuclei and prominent single nucleoli. There is mild atypia but mitoses remain rare.
The epithelial cells all stain with cytokeratin antibodies but only the collecting duct carcinoma-like areas stain for EMA. The stromal component stains for vimentin and fibronectin but not for cytokeratin, smooth muscle actin or desmin. These immunocytochemical features clearly distinguish this from mesoblastic nephroma. Although the follow-up of cases is limited there was no evidence of recurrence or metastatic disease in the cases 2 years after surgery. Mesonephroid blastoma/mesonephric adenosarcoma These two terms have been used to describe two unusual renal tumours similar in morphology and in clinical features, teA3 One of these occurred in an adult patient. The turnout is characterised by a sarcomatous mesenchymal element coupled with well differentiated tubules and nests of epithelium. The mesenchyme is loose immature connective tissue with extensive rhabdomyoblastic and some fat cell differentiation. In the rhabdomyoblastic areas some ceils with cytoplasmic cross striations may be seen. The sarcomatous area shows pleomorphism and mitotic activity. The epithelial component consist~ of solid nests of tubules lined frequently by a double layered epithelium. The inner layer of cuboidal or columnar cells with distinct cell borders and small uniform nuclei lacking mitotic activity, but the basaloid layer is more flattened or cuboidal. Both cell types frequently have clear cytoplasm. It has been noted that these tubules resemble immature collecting ducts, urothelium or yon Brunn's nests. These tumours have adopted an aggressive course with early metastases and death.
Rhabdoid renal tumour I am aware of only one case of this tumour in an adult patient. These tumours are lobulated but infiltrating and non-encapsulated, yellow-grey masses within the kidney. The tumour is highly cellular and in its typical form relatively hypovascular. The polygonal cells contain large prominent eosinophilic fibriilar cytoplasmic inclusions (Fig. 6). Equally characteristic and helpful is the vesicular nucleus with one, occasionally two, large cen"tral eo~ginophilic nucleoli? 4 The inclusions are weakly PAS positive and stain with antibodies to vimentin and cytokeratin in half of cases. Electron microscopy reveals that the inclusions are composed of whorls of intermediate filaments. ,90me variant forms may be seen but most tumours contain some areas with this classical appearance. These are aggressive tumours with a tendency to early invasion and metastases.
Clear cell sarcoma/bone melastasising renal i u m o u r
of childhood This tumour which constitutes about 4% of childhood renal tumours has been described rarely in the adult patient. The morphology is similar to the tumour seen in
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children./5 It is a grey firm tumour in which haemorrhage is common but necrosis infrequent. Clear cell sarcoma is composed of sheets of u_niform polygonal pale staining or clear cells supported by a rich capillary vasculature (Fig. 7). There is at most a minor degree of pleomorphism and mitoses are usually infrequent. Nuclei are round and vesicular lacking conspicuous nucleoli. Occasional trabecular areas may be seen. Hyaline sclerosis can occur in a perivascular distribution and may dominate the morphology presenting diagnostic difficulty. It is often an aggressive tumour with early blood borne metastases particularly to bone but also to lungs and liver. Immunocytochemistry is of little value in the diagnostic assessment of these tumours.
Angiomyolipoma These are benign tumours arising most commonly in the kidney although they can be found in other sites. They may be sporadic or occur as part of the tuberous sclero-
sis syndrome. Sporadic cases constitute between 5 0 % 80% of angiomyolipomas, are usually present in the fifth decade, are single and are four times more common in women than men. In tuberous sclerosis the presentation is two decades earlier, the tumours are often multifocal and bilateral at presentation and have a female: male ratio of 2:1. The presence of symptoms at presentation correlates closely with tumour size. Tumours of a size greater than 4 cm are symptomatic in 82% of cases whereas only 23% of patients with tumours smaller than 4 cm experience symptoms. Sporadic single tumours tend to be larger than the multifocal, usually smaller tumours, of tuberous sclerosis. The most common symptoms are acute flank or abdominal pain (53%), palpable mass (47%), haematuria (26%) and anaemia (2%). Occasional patients present as acute catastrophic illness with haemorrhage and shock. Less common presenting features include pyrexia of unknown origin or hypercalcemia and shock. Asymptomatic angiomyolipomas are discovered during medical examinations, management of tuberous sclerosis or as incidental autopsy or surgical findings.
Diagnostic criteria The diagnostic criteria are: thick walled blood vessels, smooth muscle cells, mature adipose tissue, and pleomorphism and normal mitoses acceptable. Grossly these are usually well circumscribed nonencapsulated tumours, although some permeation around adjacent structures may be present. The cut surface has a yellow or grey whorled appearance. Areas of haemorrhage are frequent but necrosis is uncommon. In addition to multifocality cases involving regional lymph nodes have been described. There has also been a case report describing direct extension of the tumour along the renal vein into the inferior vena cava. The relative proportions of the three major compo., nents is variable. The blood vessels are thick walled with
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EMBRYONAL RENALTUMOURS 39 " ,
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a normal endothelial lining. There is eccentric subendothelial fibrosis and the elastic lamina of these arteries is multi-layered and incomplete (F!g. 8). These arteries are often surrounded by smooth muscle cells in a pin wheel arrangement. Elsewhere in the tumour smooth muscle cells may be randomly scattered or present in interlacing well formed fascicles. In some tumours the smooth muscle cells may show epithelioid features resembling granular cell tumour (myoblastoma) or more rarely granular cell renal carcinoma. The mature adipose tissue is haphazardly arranged throughout the tumour. In a few cases this component may be relatively sparse but following adequate sampling will usually be found. Lipoblasts are not a usual feature but can be found. There may be a moderate degree of pleomorphism especially in the myoid element but only morphologically normal mitoses are encountered and these are usually infrequent. Abnormal mitoses are not acceptable in the diagnosis of angiomyolipoma. Rarely other tissue elements such as cartilage or bone are encountered in otherwise typical examples of angiomyolipoma. Trapped, non-neoplastic tubules may be seen at the tumour periphery. It has recently been demonstrated that the spindle cells of angiomyolipomas express the melanocyte marker HMB 45 and have premelanosome like structures in their cytoplasm. The biological significance of this rather suprising finding remains to be determined. ~6 Lymph node or intravascular extension of the lesion shows the same morphological features although the adipose tissue may be less well represented. Clinical behaviour
I am unaware of any cases of metastatic spread of angiomyolipoma. Lymph node involvement and intravascular spread were originally considered to be evidence of malignant potential. The lymph node disease is now considered to represent multifocality rather than metastasis. The case of intravascular spread was direct extension of a tumour of which vascular elements are an essential component and was not associated with the
There is rarely any difficulty or confusion for the surgical pathologist in diagnosing renal angiomyolipoma. However in the presence of significant mitotic ac.tivity and abnormal mitoses a diagnosis of leiomyosarcoma must seriously be considered. It should also be noted that patients with the tuberous sclerosis syndrome have a slightly increased risk of development of renal carcinoma. A renal mass in the tuberous sclerosis patient is therefore not always an angiomyolipoma. The one significant area of controversy remaining is whether angiomyolipoma is a true neoplasm or a hamartoma. Although various arguments have been presented there is no really satisfactory evidence to resolve this issue. Sampling
It is clear from much of the above that adequate sampling and surgical pathology assessment of renal tumours, particularly unusual variants, is essential. My recommendations are that nephrectomy specimens should be received unfixed immediately following removal. Appropriate samples can then be taken for histology, immunocytochemistry, flow cytometry and cytogenetics. It is important to record any multifocality, tumour size, invasion beyond the renal capsule into Gerotta's perirenal fascia and invasion of the renal pelvis, renal vein or renal sinus. Adequacy of excision should be assessed by blocks from specimen margins, if necessary following consultation with the surgeon. Difficulty may be encountered in assessing the renal or tumour capsule because of compression and fibrous pseudocapsule formation around the tumour, surgical damage to the capsule and, in the case of tumours such as angiomyolipoma, the separate identification of tumour fat as opposed to normal perirenal fat. Lymph nodes contained within the resection should be carefully examined for metastatic spread• Some abnormalities which may create the appearance of metastatic tumour in lymph nodes l~ave been described. ]7 With any complex or unusual renal tumour, as a minimum the author samples one block for every cm of maximum tumour diameter. This level of sampling should allow the detection of most cases of anaplaga, and identify any minor tumour components which may be helpful in the histopathological classification•
Acknowledgement Thanks to Mrs Helena Black for her secretarial support.
References
1• Fleming S. The impactof genetics on the classificationof renal carcinoma. Histopathology1993; 22: 89-92.
40
CURRENT DIAGNOSTIC PATHOLOGY
2. Kovacs G. Molecular differential pathology of renal cell tumours. ttistopathology 1993; 22: !-8. 3. Medeiros L J, Weiss L M. Renal adenocarcinoma. In: Eble J N, ed. Tumors and tumor-like conditions of the kidney and ureters. New York: Churchill Livingstone, 1990: 35-70. 4. Mucci B, Lewi H J E, Fleming S. The radiology of sarcomas and sarcomatoid carcinomas of the kidney. Clin Radiol 1987; 38: 249-254. 5. Baer S C, Ro J Y, Ordonez N G, et al. Sarcomatoid collecting duct carcinoma; a clinicopathologic and immunohistochemical study of five cases. Hum Pathol 1993; 24: 1017-1022. 6. Fleming S. Cell adhesion and epithelial differentiation. J Pathol 1991; I64: 95-100. 7. Behrens J, Lowerick O, Klein-Hitglass L, Birchmeier W. The Ecadherin promotor; functional analysis of a G-C rich region and an epithelial cell specific palindromic regulatory element. Proc Natl Acad Science USA 1991; 88:11495-11499. 8. Reinfuss M, Kociolek D, Sholyszewski J. Adult Wilms' tumour. Eur J Cancer 1991; 27:1186 9. Zuppan C, Beckwith J B, Luckey D W. Anaplasia in Wilms' tumor: report from the national Wilms" tumor study pathology center. Hum Pathol 1988; 19:1199-1206. I0. Durham J R, Bostwick D G, Farrow G M, Ohorodnik J M.
Mesoblastic nephroma of adulthood. Am J Surg Pathol 1993; 17: 1029-1038. 11. Hennigar R D, Beckwith J B. Nephrogenic adenofibroma. Am J Surg Pathol 1992; 16: 325-334. 12. Gonzalez-Crussi F, Hsueh W, Pang L C H, Lin J N, Kuo T T. Mesonephroid blastoma; a previously undeseribed renal tumor of childhood. Am J Surg Pathol 1983; 7: 707-712. 13. Marco V, Forcada P. Mesonephric adenosarcoma of the renal pelvis with heterologous elements. Am J Surg Pathol 1985; 9: 610-614. 14. Weeks D A, Beckwith J B, Mierau G N, Luckey D W. Rhabdoid tumour of the kidney. A report of 111 cases from the National Wilms" tumour pathology study center. Am J Surg Pathol 1989; 13: 438-458. 15. Sotela-Avila C, Gonzalez-Crussi F, Sadowinski S et al. Clear cell sarcoma of the kidney; a clinicopathologic study of 21 cases with long-term follow-up evaluation, tlum Pathol 1985; 16: 1219-1226. 16. Ashfag R, Weinberg A G, Albores-Saavedra J. Renal angiomyolipomas and ttMB-45 reactivity. Cancer 1993; 71: 3091-3097. 17. Weeks D A, Beckwith J B, Mierau G W. Benign nodal lesions mimicking metastases from pediatric renal neoplasms. Hum Pathol 1990; 21" 1239-1244.
Mixed and embryonal renal tumours in adults
S. Fleming
adult Wilm's tumour, cystic nephroma, mesoblastic nephroma, nephrogenic adenofibroma, mesonephroid blastoma, rhabdoid renal tumour, clear cell sarcoma and angiomyolipoma. In establishing the diagnosis of such tumours adequate tissue sampling is essential.
Introduction
The classification of renal turnouts has recently been revised and is shown in the Table. A feature of this classification is the separation of groups according to their phenotype and genotype. These tumours are frequently encountered in paediatric pathology practice but rarely occur in the adult patient, where they may present diagnostic difficulty. The tumours selected for discussion because of their diagnostic difficulty are: sarcomatoid renal carcinoma,
Sarcomatoid renal carcinoma
The classification of renal carcinoma has been re-examined in the light of cytogenetic advances? .2 The majority of renal carcinomas are composed entirely of epithelial cells, however, some renal carcinomas contain both neoplastic epithelial and mesenchymal elements. For individual patient m,'magement, clinical trials and survival statistics and for tumour research these tumours are best separately classified as sarcomatoid renal carcinoma. They constitute 1 - 6 % of malignant renal neoplasms in the adult. Sarcomatoid carcinomas occur in a similar age to other forms of renal carcinoma, mainly from fourth to eight decades with a median age of 56264 in different series? The tumour is slightly more common in men than women. The usual presenting features are the common triad of haematuria, loin pain and abdominal mass. At least one of these being found in two thirds of cases. 3 0 - 4 0 % of patients have metastatic disease at the time of presentation, manifest either symptomatically or on clinical evaluation. There are radiological features which, although not diagnostic, raise the possibility that a renal tumour is a sarcomatoid carcinoma. On plain abdominal radiographs calcification is more frequently seen (34%) than in other renal carcinomas (6%). The tumours tend to be larger with more extensive retroperitoneal involvement and anatomical distortion of the urinary tract and adjacent structures. Compared to other renal carcinomas the sarcomatoid component of these tumours is markedly hypovascular on arteriographic investigation. 4
Table Nephroblastic Wilms' tumour/nephroblastoma Mesoblastic nephroma Atypical mesoblastic nephroma Multilocular cystic nephroma Cystic partially differentiated nephroblastoma Mesonephroid blastoma/mcsonephric adenosarcoma Nephrogenic adenofibroma Clear cell sarcoma/bone metastasising renal tumour of childhood Rhabdoid renal tumour Epithelial Adenoma Renal carcinoma (no special type) Papillary renal carcinoma Chromophobe renal carcinoma Renal oncocytoma Collecting duct carcinoma Sarcomatoid renal carcinoma Mese~zchymal Angiomyolipoma Juxtaglomerular cell tumour Renal medullary inlgrstitial cell tumour Prim_aryrenal sarcomas (various types)
Stewar! Fleming, Department of Pathology, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK CurrentDiagnosticPathology(994) I, 32-.10 © 1994LongmanGroupLtd
32
EMBRYONAL RENALTUMOURS
33
Diagr~ostic features The diagnostic features are: malignant neoplasm of kidney, neoplastic epithelial and mesenchymal components, and no blastemal elements• The morbid anatomy which is often strongly suggestive of this form of renal carcinoma varies according to the relative proportion of epithelial and mesenchymal conaponents. The epithelial component has the usual yellow/grey soft haemorrhagic appearance seen in renal carcinoma of no special type. The sarcomatoid element has a finn, sometimes hard, grey/white appearance and is characteristically more infiltrative than the other forms of renal carcinoma. These tumours are usually large with a mean maximum diameter of over 10 cm. Retroperitoheal spread and direct involvement of adjacent organs is common, indeed a significant number of sarcomatoid renal carcinomas cannot be completely excised at nephrectomy. Regional lymph node, vascular and pelviureteric invasion and distant metastases are seen in up to 50% of patients at the time of initial presentation. Histologically there are obviously two essential components - epithelial and mesenchymal. In the majority of cases the epithelial areas have the morphology of renal carcinoma of no special type. It is less common for the epithelial cells to have the" features of papillary renal carcinoma or chromophobe carcinoma. Sarcomatoid forms of collecting duct carcinoma have recently been reported: These appear to behave in a manner similar to that observed for other groups of sarcomatoid renal carcinoma. A range of nuclear grades have been described but at least some areas of high grade nuclear morphology are usually found in the epithelial component. The mesenchymal areas may mimic any sarcoma: fibrosarcoma, leiomyosarcoma, haemangiopericytoma, chondrosarcoma, osteosarcoma, malignant fibrous histiocytoma and rhabdomyosarcoma have all been described. The most frequent appearance is of an infiltrating poorly differentiated spindle cell tumour with necrosis and haemorrhage. The sarcomatous component is usually high grade with mitotic activity, including abnormal mitoses and nuclear pleomorphism. There are often areas of transition between the epithelial and spindle cell components. This component is extensively infiltrative, surrounding and invading structures in the adjacent renal parenchyma or retroperitoneum (Fig. 1). Whereas most renal carcinomas invade as a cohesive 'pushing' edge sarcomatoid carcinomas show a more infiltrative pattern.
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In the absence of epithelial elements identified by conventional microscopy the surgical pathologist should investigate the case by immunocytochemistry and electron microscopy• In sarcomatoid carcinoma even some spindle cell areas may be positive with antibodies to cytokeratins. I use CAM 5.2 and PKK1 in the investigation of these tumours. Epithelial membrane antigen (EMA) and CD 15 will rarely be positive except in areas which are morphologically epithelial• Sarcomatoid collecting duct carcinomas also express some epithelial markers in the spindle cell component. Some caution must be observed in interpreting cytokeratin staining some sarcomas such as leiomyosarcoma may demonstrate cytokeratin reactivity• Electron microscopy can be used and of particular value is the finding of desmosomes which confirms the diagnosis of sarcomatoid renal carcinoma. In this situation it is important to distinguish desmosomes from the adherens junctions found in some smooth muscle cells and their tumours (Fig. 2). Desmosomes are usually sparse in spindle cell areas but would be a most unusual feature in a primary sarcoma. The spindle cell element of sarcomatoid renal carcinoma may express differentiated mesenchymal features. This "•ll•'•"
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Spindle cell tumours of the kidney can present diagnostic difficulty. The most common problem is the histopathological classification of a tumour in which an epithelial component is not-seen. In the majority of cases extensive sampling guided by morbid anatomical observation will reveal areas of renal carcinoma and confirm the diagnosis of sarcomatoid carcinoma. It is important to remember that sarcomatoid renal carcinoma is more common than any of the primary renal sarcomas•
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34
CURRENT DIAGNOSTIC PATHOLOGY
is seen morphologically by chondroid or osteoid production but may also become apparent on immunocytochemical or ultrastructural investigation. This is important since the presence of smooth muscle actin, desmin, myoglobin on immunocytochemistry or myofilaments on electron microscopy do not confirm the diagnosis of a primary sarcoma unless, after full investigation, the absence of epithelial elements is confirmed. Finally the diagnosis of a primary renal sarcoma must be considered in the absence of morphological, immunocytochemical and ultrastructural evidence of epithelial differentiation. These tumours should be classified by histopathological criteria applicable to soft tissue tumours in other sites. Most types of soft tissue tumours have been described in the kidney. The presence of blastemal areas or embryonal elements place the tumour within the adult Wilms' tumour group and should be classified accordingly.
in sarcomatoid renal carcinoma may reflect altered activity of transcription factor-regulated activity of a promoter region common to cadherin and keratin genes as described in some breast carcinomas. 7 Sarcomatoid carcinomas certainly show evidence of accumulated genomic abnormalities, aneuploidy and a more aggressive biological course suggesting a later stage in tumour progression. Most authorities now accept that these represent an undifferentiated progression of other forms of renal carcinoma.
Embryonal renal tumours in the adult Rarely renal tumours which have the morphological and behavioural characteristics of embryonal tumours of childhood are encountered in adults. Although they are classified as for the childhood forms when, encountered in the adult patient they may present diagnostic difficulty to the surgical pathologists and his clinical colleagues.
Clinical behaviour Adult Wilms' tumour
Most sarcomatoid renal carcinomas are large, advanced turnouts, many unresectable, at the time of initial presentation. The recognition of this entity separate from renal carcinoma of no special type is necessary not only because of its morphological features but more importantly because of its markedly aggressive clinical behaviour. In my own series of 16 patients none were alive at 12 months from initial presentation. Experience from other centres is similar. The mean survival of patients with sarcomatoid renal carcinoma is about 4-6 months. The large size and infiltrative behaviour results in operative difficulties and patients with these tumours have a high peri-operative mortality. The remainder succumb to the consequences of metastatic sarcomatoid renal carcinoma. This is undoubtedly a most aggressive renal malignancy requiring separate identification.
Wilms' tumours have been described in over 200 adult and adolescent patients. The documentation in many of these patients is incomplete. Particularly deficient is adequate morbid anatomical and histopathological description and photomicrographs to support the diagnosis. Indeed some of these diagnoses have been challenged. 8 Nevertheless it is clear that many of the cases described are Wilms' tumours and that though they can occur in any age group, including the elderly, they are more common in patients under 40 years. As in childhood cases abdominal mass and flank pain are particularly prominent presenting symptoms. Other symptoms, including those related to extra-renal spread of disease, are encountered. In the adult patient the symptoms are often of prolonged duration of up to 2 years.
Origin
Diagnostic criteria
In the past there has been considerable debate concerning the presumed histogenesis of these tumours. Are the two tumours synchronous in development? Are they a form of embryonal tumour, the epithelium coming from the poorly differentiated mesenchyme? Are they carcj.nomas which lose the capacity for epithelial differentiation as genomic damage accumulates? Although there is no conclusive evidence the author firmly believes this last option to be the most likely. Loss of differentiated phenotype is a common feature of neoplastic progression of many tumour types. The loss of epithelial morphology will occur if there is loss of the cell adhesion and cytoskeletal properties of epithelial cells. 6 In sarcomatoid renal carcinomas stained with antibodies to desmosomal components and cytokeratins there is usually simultaneous loss of these molecules. The prediction of cell biology experiments is that loss of these components, essential for the maintainence of the epithelial phenotype, will result in a poorly differentiated infiltrative spindle cell tumour. This loss of adhesion and cytoskeleton molecules
Tile diagnostic criteria are: primary renal neoplasm, blastematous component, embryonal tubules or glomeruloid structures, no evidence of renal carcinoma, and age more than 15 years. Diagnostic criteria for the acceptance of a tumour as an adult Wilms' tumour must be strict. The author would expect all of the above criteria to be met. The one exception considered acceptable would be a lack of embryonal nelllaron components in a monophasic blastematous Wilms' tumour, provided that in such cases other small blue cell tumours such as carcinoid, neuroendocrine carcinoma or rhabdomyosarcoma have been carefully excluded. The surgical pathologist has an important role in assessing size and stage of the adult Wilms' tumour. The tumours are staged by a combined surgical and pathological staging in which completeness of excision must be jointly assessed. Stage 1 is limited to the kidney and the tumour is completely excised; stage 2 tumour extends beyond the kidney but is completely excised, stage 3 represents residual non-haematogenous spread of disease
EMBRYONAL RENALTUMOURS 35
in abdomen; stage 4 denotes metastatic tumour at presentation; stage 5 is reserved for bilateral Wilms' tumour. Using this staging procedure it is clear that adults with Wilms' tumour often have tumours at an advanced stage at the time of presentation. Grossly adult Wilms' tumour is large, often greater than 10 cm, with a Iobulated appearance and pseudoencapsulation. It has a grey colour with areas of necrosis, haemorrhage and cyst formation or mucinous change. Local invasion, vascular invasion, regional lymph node involvement and completeness of excision are all important features in the morbid anatomical assessment. Occasional tumours are multifocal and areas of nephroblastomatosis may be seen in the adjacent kidney. Microscopically, adult Wilms' tumour has the same appearances as the childhood form. The typical triphasic pattern of blastema, stroma and immature epithelial elements is most frequently encountered (Fig. 3). The presence of blastema is required to be certain of the diagnosis. This consists of sheets of ovoid cells with scant, indistinct cytoplasm and hyperchromatic oval nuclei. Mitotic figures, apoptosis and necrosis are frequently seen. They are usually arranged in solid
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sheets but on occasion adopt trabecular or nesting arrangements and may form poor pseudorosettes around a central capillary. The epithelium can form tubules, glomemloid bodies, microcysts, cysts or trabeculae. The epithelial cells are usually columnar with elongated hyperchromatic nuclei again showing mitotic activity or evidence of programmed cell death. Epithelium of ciliated, squamous, mucinous, neuroendocrine or other types are seen but these are thought to be direct ingrowths from collecting ducts in the adjacent kidney. Mesenchyme is mostly immature spindle shaped or stellate fibroblasts surrounded by a pale staining extra cellular matrix (Fig. 3). Heterologous elements such as skeletal muscle, cartilage and bone may be seen. The identification of anaplasia (Fig. 3) is an important part of the surgical pathology evaluation in Wilms' tumour. Anaplasia is present if all three of the following criteria are met;9 nuclear enlargement of at least three times the diameter of adjacent tumour cells, nuclear hyperchromasia, multipolar mitoses. Anaplasia may be diffuse or focal, the prognostic implications are similar for these two. Adequate sampling is required to ensure its detection. Some tumours may be entirely composed of immature mesenchyme. However in the adult these are more accurately designated as primary renal sarcomas.
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The cystic group of embryonal tumours merits further attention. There are two lesions within this group, multilocular cystic nephroma (MCN) and cystic partially differentiated nephroblastoma (CPDN). Despite many morphological similarities, the distinction between these two is important because of differing clinical behaviour. Both may be encountered in adults but the former is the more frequent in this age group. They have similar presenting features. The most common is the identification of a large abdominal mass. These are usually painless but on occasion loin pain and haematuria may be present. In a few cases there has been systemic hypertension on presentation but the relationship to the cystic nephroma is uncertain. Cystic nephroma requires thorough and careful examination for accurate diagnosis and management advice. They are large and composed of multilocular cysts which do not communicate with the calyces or renal pelvis (Fig. 4). Despite their size there is at most minor distortiot~of the adjacent renal parenchyma. The lesion is often greater than 10 cm in diameter. Between cysts is a firm white fibrous stroma. Any solid areas •should be examined and sampled for histology. Histological examination shows the cysts lined by a single layer of flattened or cuboidal epithelium. The epithelium may adopt a hob-nail morphology (Fig. 4). The epithelial cells have eosinophilic, sometimes granular cytoplasm and round or ovoid nuclei. Nuclear pleomorphism is not a feature and mitoses are rare. It is in the stroma that the feature distinguishing MCN and CPDN is found. The stroma of both types is composed of
36 CURRENTDIAGNOSTICPATHOLOGY
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area of solid tissue examined in histological sections the tumour should be classified as CPDN grade 2. The distinction between the grades is necessary because tumours composed of > 50% immature elements may metastasise while metastatic spread has not been recorded in tumours fulfilling the diagnostic criteria for grade 1 CPDN, nor in MCN. Surgical excision is curative for MCN and CPDN grade 1. However, CPDN grade 2 may require follow-up and further therapy if metastases develop. Other non-Wilms' childhood renal tumours may be encountered in the adult patient.
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Mesoblastic n e p h r o m a This is a rare, usually congenital tumour of infancy. Usually discovered in the first few months of life it is unusual beyond 1 year of age. Eight cases have been described in adults although the accuracy of the diagnosis has been challenged in one case) ° The ages at presentation range from 19-66 with presenting features similar to those in other renal tumours. Although imaging techniques are of value in demonstrating the'presence of a renal tumour there were no features specific to mesoblastic nephroma. There are some differences in the pathology of adult and childhood mesoblastic nephroma - at least some of which may be related to the age of the tumour. Adult, unlike childhood, cases are often encapsulated or nodular with surrounding fibrous tissue. They are grey-yellow or tan coloured and up to 3 cm in diameter. Polypoid growth and an intrapelvic component have been described in adult cases. ~° The tumours are composed of sheets or interlacing bundles of eosinophilic spindle or cigar shaped cells with uniform elongated nuclei (Fig. 5). Adult cases appear to have a lower cell density than childhood cases with increased periceilular fibrosis and areas of hyalinisation. The turnouts may be highly vascular• Nuclear pleomorphism is not seen; and although prominent nucleoli may be present there are no mitoses. A feature particularly prominent in adult cases is the presence of cystic or
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Fig. 5--Mesoblastic nephroma. The t u m o u r is c o m p o s e d of bundles of well differentiated spindle cells lacking mitotic activity and p l e o m o r p h i s m .
EMBRYONALRENALTUMOURS 37 dysplastic tubules, some with papillary growth patterns, and immature glomeruli. The atypical form described in childhood has not been recorded in an adult. Of value in the diagnosis of these tumours is the immunocytochemical and ultrastructural evidence of smooth muscle differentiation of the spindle cell component. These cells stain with antibodies to desmin, or-smooth muscle actin and vimentin. On electron microscopy the basal plasmalemmal densities, cytoplasmic filaments and pinocytosis of smooth muscle cells are evident. These tumours usually behave in a benign manner. In one series, recurrence in a scar of an incompletely resected tumour was seen 21 years after resection in one adult. Nephrectomy should be regarded as a curative procedure.
Nephrogenic adenofibroma This is a very rare, recently described tumour occurring in adolescents and young adults. Five cases were identified from 7000 submitted over 20_years to the NWTS Pathology Centre. n Its recent identification and small number of cases, with a complex morphology mean that the recognition of the full ronge of features of this entity will require further development. The tumours presented in patients from 3.5-23 years (mean 13.3). One obvious and potentially important finding was the frequent occurrence of polycythaemia, hypertension or haematuria resolving after nephrectomy. All of these tumours had previously been diagnosed as Wilms' tumour or mesoblastic nephroma. They are non-encapsulated, firm, irregular tumours variably coloured tan, grey or yellow. Extension into adjacent renal parenchyma and beyond the kidney into perinephric soft tissue or renal sinus may be seen. There is a complex and presumably evolving histopathological picture, and the diagnosis may present considerable difficulty. The characteristic histology is of morphologically benign mesenchymal cells surrounding discrete nodules of embryonal epithelium and blastema. The mesenchyme consists of sheets or bundles of spindle shaped cells with a vascularised stroma showing focal hyalinisation or myxoid change. The cellular density is lower than that of mesoblastic nephroma. These ceils lack mitotic figures and significant atypia. The nodules of embryonal tissue are well circumscribed with areas of epithelial differentiation. The epithelium is mostly of tubules lined by immature cuboidal or columnar cells with indistinct cell borders. The nuclei, often overlapping, show hyperchromasia but lack pleomorphism or mitotic activity. Papillary areas are prominent and these "frequently contain psammoma bodies. In three of the five cases there were papillary areas morphologically distinct from the-embryonal epithelium. These areas of the-turnour are described as resembling foci of low grade collecting duct carcinoma. The cells have abundant eosinophilic cytoplasm, large nuclei and prominent single nucleoli. There is mild atypia but mitoses remain rare.
The epithelial cells all stain with cytokeratin antibodies but only the collecting duct carcinoma-like areas stain for EMA. The stromal component stains for vimentin and fibronectin but not for cytokeratin, smooth muscle actin or desmin. These immunocytochemical features clearly distinguish this from mesoblastic nephroma. Although the follow-up of cases is limited there was no evidence of recurrence or metastatic disease in the cases 2 years after surgery. Mesonephroid blastoma/mesonephric adenosarcoma These two terms have been used to describe two unusual renal tumours similar in morphology and in clinical features, teA3 One of these occurred in an adult patient. The turnout is characterised by a sarcomatous mesenchymal element coupled with well differentiated tubules and nests of epithelium. The mesenchyme is loose immature connective tissue with extensive rhabdomyoblastic and some fat cell differentiation. In the rhabdomyoblastic areas some ceils with cytoplasmic cross striations may be seen. The sarcomatous area shows pleomorphism and mitotic activity. The epithelial component consist~ of solid nests of tubules lined frequently by a double layered epithelium. The inner layer of cuboidal or columnar cells with distinct cell borders and small uniform nuclei lacking mitotic activity, but the basaloid layer is more flattened or cuboidal. Both cell types frequently have clear cytoplasm. It has been noted that these tubules resemble immature collecting ducts, urothelium or yon Brunn's nests. These tumours have adopted an aggressive course with early metastases and death.
Rhabdoid renal tumour I am aware of only one case of this tumour in an adult patient. These tumours are lobulated but infiltrating and non-encapsulated, yellow-grey masses within the kidney. The tumour is highly cellular and in its typical form relatively hypovascular. The polygonal cells contain large prominent eosinophilic fibriilar cytoplasmic inclusions (Fig. 6). Equally characteristic and helpful is the vesicular nucleus with one, occasionally two, large cen"tral eo~ginophilic nucleoli? 4 The inclusions are weakly PAS positive and stain with antibodies to vimentin and cytokeratin in half of cases. Electron microscopy reveals that the inclusions are composed of whorls of intermediate filaments. ,90me variant forms may be seen but most tumours contain some areas with this classical appearance. These are aggressive tumours with a tendency to early invasion and metastases.
Clear cell sarcoma/bone melastasising renal i u m o u r
of childhood This tumour which constitutes about 4% of childhood renal tumours has been described rarely in the adult patient. The morphology is similar to the tumour seen in
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children./5 It is a grey firm tumour in which haemorrhage is common but necrosis infrequent. Clear cell sarcoma is composed of sheets of u_niform polygonal pale staining or clear cells supported by a rich capillary vasculature (Fig. 7). There is at most a minor degree of pleomorphism and mitoses are usually infrequent. Nuclei are round and vesicular lacking conspicuous nucleoli. Occasional trabecular areas may be seen. Hyaline sclerosis can occur in a perivascular distribution and may dominate the morphology presenting diagnostic difficulty. It is often an aggressive tumour with early blood borne metastases particularly to bone but also to lungs and liver. Immunocytochemistry is of little value in the diagnostic assessment of these tumours.
Angiomyolipoma These are benign tumours arising most commonly in the kidney although they can be found in other sites. They may be sporadic or occur as part of the tuberous sclero-
sis syndrome. Sporadic cases constitute between 5 0 % 80% of angiomyolipomas, are usually present in the fifth decade, are single and are four times more common in women than men. In tuberous sclerosis the presentation is two decades earlier, the tumours are often multifocal and bilateral at presentation and have a female: male ratio of 2:1. The presence of symptoms at presentation correlates closely with tumour size. Tumours of a size greater than 4 cm are symptomatic in 82% of cases whereas only 23% of patients with tumours smaller than 4 cm experience symptoms. Sporadic single tumours tend to be larger than the multifocal, usually smaller tumours, of tuberous sclerosis. The most common symptoms are acute flank or abdominal pain (53%), palpable mass (47%), haematuria (26%) and anaemia (2%). Occasional patients present as acute catastrophic illness with haemorrhage and shock. Less common presenting features include pyrexia of unknown origin or hypercalcemia and shock. Asymptomatic angiomyolipomas are discovered during medical examinations, management of tuberous sclerosis or as incidental autopsy or surgical findings.
Diagnostic criteria The diagnostic criteria are: thick walled blood vessels, smooth muscle cells, mature adipose tissue, and pleomorphism and normal mitoses acceptable. Grossly these are usually well circumscribed nonencapsulated tumours, although some permeation around adjacent structures may be present. The cut surface has a yellow or grey whorled appearance. Areas of haemorrhage are frequent but necrosis is uncommon. In addition to multifocality cases involving regional lymph nodes have been described. There has also been a case report describing direct extension of the tumour along the renal vein into the inferior vena cava. The relative proportions of the three major compo., nents is variable. The blood vessels are thick walled with
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EMBRYONAL RENALTUMOURS 39 " ,
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a normal endothelial lining. There is eccentric subendothelial fibrosis and the elastic lamina of these arteries is multi-layered and incomplete (F!g. 8). These arteries are often surrounded by smooth muscle cells in a pin wheel arrangement. Elsewhere in the tumour smooth muscle cells may be randomly scattered or present in interlacing well formed fascicles. In some tumours the smooth muscle cells may show epithelioid features resembling granular cell tumour (myoblastoma) or more rarely granular cell renal carcinoma. The mature adipose tissue is haphazardly arranged throughout the tumour. In a few cases this component may be relatively sparse but following adequate sampling will usually be found. Lipoblasts are not a usual feature but can be found. There may be a moderate degree of pleomorphism especially in the myoid element but only morphologically normal mitoses are encountered and these are usually infrequent. Abnormal mitoses are not acceptable in the diagnosis of angiomyolipoma. Rarely other tissue elements such as cartilage or bone are encountered in otherwise typical examples of angiomyolipoma. Trapped, non-neoplastic tubules may be seen at the tumour periphery. It has recently been demonstrated that the spindle cells of angiomyolipomas express the melanocyte marker HMB 45 and have premelanosome like structures in their cytoplasm. The biological significance of this rather suprising finding remains to be determined. ~6 Lymph node or intravascular extension of the lesion shows the same morphological features although the adipose tissue may be less well represented. Clinical behaviour
I am unaware of any cases of metastatic spread of angiomyolipoma. Lymph node involvement and intravascular spread were originally considered to be evidence of malignant potential. The lymph node disease is now considered to represent multifocality rather than metastasis. The case of intravascular spread was direct extension of a tumour of which vascular elements are an essential component and was not associated with the
There is rarely any difficulty or confusion for the surgical pathologist in diagnosing renal angiomyolipoma. However in the presence of significant mitotic ac.tivity and abnormal mitoses a diagnosis of leiomyosarcoma must seriously be considered. It should also be noted that patients with the tuberous sclerosis syndrome have a slightly increased risk of development of renal carcinoma. A renal mass in the tuberous sclerosis patient is therefore not always an angiomyolipoma. The one significant area of controversy remaining is whether angiomyolipoma is a true neoplasm or a hamartoma. Although various arguments have been presented there is no really satisfactory evidence to resolve this issue. Sampling
It is clear from much of the above that adequate sampling and surgical pathology assessment of renal tumours, particularly unusual variants, is essential. My recommendations are that nephrectomy specimens should be received unfixed immediately following removal. Appropriate samples can then be taken for histology, immunocytochemistry, flow cytometry and cytogenetics. It is important to record any multifocality, tumour size, invasion beyond the renal capsule into Gerotta's perirenal fascia and invasion of the renal pelvis, renal vein or renal sinus. Adequacy of excision should be assessed by blocks from specimen margins, if necessary following consultation with the surgeon. Difficulty may be encountered in assessing the renal or tumour capsule because of compression and fibrous pseudocapsule formation around the tumour, surgical damage to the capsule and, in the case of tumours such as angiomyolipoma, the separate identification of tumour fat as opposed to normal perirenal fat. Lymph nodes contained within the resection should be carefully examined for metastatic spread• Some abnormalities which may create the appearance of metastatic tumour in lymph nodes l~ave been described. ]7 With any complex or unusual renal tumour, as a minimum the author samples one block for every cm of maximum tumour diameter. This level of sampling should allow the detection of most cases of anaplaga, and identify any minor tumour components which may be helpful in the histopathological classification•
Acknowledgement Thanks to Mrs Helena Black for her secretarial support.
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40
CURRENT DIAGNOSTIC PATHOLOGY
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