# Renal Adenomas: Pathological Differential Diagnosis with Malignant Tumors

Authors: F. Algaba
Journal: Advances in Urology
 (2008)

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## Abstract

The renal adenomas can be confused by imaging diagnosis with malignant renal tumors, but there
are also real biological dilemmas to determine their behavior.
The consensus decisions are the following. (1) The adenoma of clear cells is not accepted, instead
it is considered that all the clear-cell tumors are carcinomas, with greater or lesser aggressiveness. (2)
Among the papillary neoplasms the WHO 2004 renal cell tumors classification are considered as papillary
adenomas tumors with a maximum diameter of 5 mm and may represent a continuum biological process to
papillary renal cell carcinoma. The papillary adenomas associated with End-kidney and/or acquired cystic
disease may have a different pathogenesis. (3) To consider a tumor as an oncocytoma the size is not important,
only the cytological features, microscopic, ultrastructural, and immunohistochemically can help, but some
chromosomal observations introduce some questions about its relation with the chromophobe renal cell carcinoma.
(4) Finally, the metanephric adenoma, a tumor with some morphological similarity with the nephroblastoma must be
considered in the renal adenomas diagnosis.


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## Body

## 1. Introduction

Before sonographic  studies, 85% to 90% of renal masses were malignant, with the majority being renal-cell carcinoma. However, with the increasing frequency of incidentally discovered renal masses, only 70% to 85% of lesions are found to be malignant [1].When we take on the subject
of benign neoplasias of the kidney, we must make two large groups, the benign
mesenchymal neoplasias and the benign epithelial neoplasias or adenomas.The benign mesenchymal
tumors, with the exception of the angiomyolypoma, are usually subclinical and
rarely give the pathologist diagnostic problems, although they can be confused
with malignant neoplasias for imaging diagnosis [2].The adenomas are a true
clinical-pathological dilemma, not only because they can be confused by imaging
diagnosis, but because there  are biological dilemmas to determine and therefore
different questions emerge: firstly, do the
renal adenomas really exist?, and secondly, in case they do exist, are
they precursor lesions of renal carcinomas?, and if they were, do we have the
possibility of differentiating the benign neoplasias from the malignant ones?The current classifications
of renal carcinomas have managed to integrate the genetic and molecular
findings with the cytological characteristics [3]. This conjunction has made it
possible to correlate the histological subtypes with the prognostic and
therapeutic ones. For this reason, we can approach the renal adenomas according
they are of clear cells, of eosinophilic cells (oncocytes), with papillary growth,
or have a metanephric blastema appearance.


## 2. Results

### 2.1. Adenomas with Clear Cells?

The most frequent renal
neoplasia of the adult is the clear cell renal cell carcinoma. When the pieces
from the nephrectomy are studied with this type of carcinoma, around 10% of the
cases are multifocal and small tumor nodes with clear cells can be found. This
same finding can be made more frequently in kidneys of patients with von
Hipel-Lindau disease. These nodes could have been considered adenomas of clear
cells, but since Bell's
descriptions [4] it is well known that some of the small clear-cell tumors have
metastasis capacity and therefore currently the existence of an adenoma of
clear cells is not accepted, instead it is considered that all the clear-cell
tumors are carcinomas, with greater or lesser aggressiveness.Having established this
axiomatic attitude, there is no problem of differential diagnosis; however,
from the morphological point of view, thecystic
nephroma (Figure 1), formed by multiple separate cysts (which are also known
as multilocular cyst) covered by epithelium without nuclear atypia, monolayer,
with eosinophilic cytoplasma, can occasionally be covered by cells of clear
cytoplasma, without nuclear atypia. In this case, clear cells must not be found
in the walls and the intercystic stroma. The cystic nephroma does not have any
relation to the multilocular clear cell carcinoma (despite certain similarity
with it) [5]. Currently, it is being related to other benign neoplasias such as
the mixed epithelial and stromal tumor of the kidney, all of them are much more
frequent in women and with estrogen and progesterone receptors in the stromal
component [6].Cystic nephroma: cystic neoplasm with fibrous stroma an flat epithelium covering
the wall.
(a)(b)


### 2.2. Papillary Adenomas

In about 35% of the cases the
renal carcinomas with a papillary pattern have multiple lesions of diverse
sizes (from millimeters to centimeters), especially those associated with
family syndromes. This fact again poses the existence of adenomas and their
possible relation with carcinomas.The small papillary tumors are
characterized by a growth of cells with scant cytoplasma (chromophilic cells),
occasionally somewhat eosinophilic, with tubular-papillary patterns, well
delimited and not encapsulated (Figure2). In chromosomal studies, trisomies in
chromosomes 7 and 17 were confirmed in the small tumors. Additionally, other chromosomes presented tri-tetrasomies when the in size of the tumor increase. From
these findings it was considered that there is a series of small benign lesions
and that the increase in size is associated with greater amount of chromosomal
alterations and therefore the possible transformation in papillary carcinomas.
For this reason, the WHO 2004 renal cell tumors classification considered tumors
with a maximum diameter of 5 mm as papillary adenomas [3]. In a practical manner, many pathologists consider
that the tumors over 5 mm and up to 10 mm are of low aggressiveness [7].Papillary adenomas: different types of basophilic cell adenomas.
(a)(b)(c)(d)It should be underscored that
although the majority of the papillary
adenomas are associated with papillary renal
cell carcinoma (47%), they can also be found associated with other variants
(16% with clear cell RCC, 8% with chromophobe RCC and 2.5% with oncocytoma)
[8].It should be highlighted that
5% of the papillary adenomas are found in sclerosed kidneys (end-kidneys) and
18% in patients with acquired cystic disease (with or without dialysis). Their
morphological characteristics are identical to those associated with carcinomas
but curiously they differ from the latter by not expressing alpha-methylacyl-CoA
racemase (AMACR) [8].In conclusion, papillary
adenoma and papillary renal cell carcinoma may represent a continuum of the
same biological process. Unfortunately, it is not possible to define an
unequivocally benign papillary renal adenoma, for this reason the WHO used the size
(arbitrarily) as a marker.The papillary adenomas
associated with end-kidney and/or acquired cystic disease may have a different
pathogenesis.


### 2.3. Oncocytoma

The clinically most important
renal cortical adenoma is the oncocytoma, since despite the fact that it is not
usually associated with the carcinoma, in the imaging diagnosis it is usually
considered as renal cell carcinoma.The cytological
characteristics of the oncocytoma are defined by the oncocytic cells (tumor
cells arranged in nests, cords, or tubules, with eosinophilic cytoplasm and no
mitosis). They are usually solid, homogeneous, with occasional sclerosed
central areas, which can also present in other tumors, and are of a diameter
from millimeters up to 12–15 or more centimeters. Therefore, in this tumor type,
the criterion of size does not exist [9].The problem originates in the
cytological characteristics that at times are difficult to distinguish from
other neoplasias of eosinophilic cells, such as the clear-cell renal carcinomas
eosinophilic variant and especially the chromophobe eosinophilic carcinomas
(Figure3).(a) Oncocitomas, (b) eosinophilic chromophobe renal cell carcinoma variant.
Notice the similar aspect that both lesions can present.
(a)(b)To distinguish them, the
electronic microscope, histochemistry (colloidal iron), and
immunohistochemistry can help (Figure4).Colloidal iron to distinguish oncocytoma (negative) and chromophobe renal
cell carcinoma (positive).
(a)(b)It is interesting to point
out that the chromosomal studies have demonstrated different types of
alterations, and therefore while some tumors do not have any chromosomal
alteration, others show translocation
11q13 and (−) 1p, 14q, Y [10]. The latter chromosomal alteration is similar to
that of the chromophobe carcinomas (−1p, Y), which together with the finding of
hybrid carcinomas (oncocytoma + chromophobe renal cell carcinoma) especially in
the Birt-Hogg-Dubé syndrome [11] it has suggested that certain cases of
oncocytomas could evolve into chromophobe renal cell carcinoma.


### 2.4. Metanephric Adenoma

A
relatively short time ago a tumor was introduced among the renal adenomas that
was comprised by small cells with scant cytoplasma, uniform, without mitosis,
embryonic-appearing, distributed in small round acini with a phenotype similar to
the nephroblastoma (Figure5). They represent 1% of localized tumors of less than 7 cm. The mean age is 41 years
(from 5 to 83 years). Fifty percent are incidental
and 10% have a polycythemia. Immunohistochemistry,
the WT1, CD 56, and CD 57 are positive and the AMACR is negative [12].Figure 5
Metanephric adenoma. microacinar structures of basophilic cells with a nephroblastic appearance.From
the genetic point of view, it is characterized by allelic loss in 2p13 (56% of the cases) and
is differentiated from the nephroblastoma
(with alterations 11p13) and from the papillary carcinoma (+7,  +17) [13].To distinguish the metanephric
adenoma from the nephroblastoma, strict diagnostic criteria have been used, and
only accepting the tumors without mitosis and nucleoli as metanephric adenoma.


## 2.1. Adenomas with Clear Cells?

The most frequent renal
neoplasia of the adult is the clear cell renal cell carcinoma. When the pieces
from the nephrectomy are studied with this type of carcinoma, around 10% of the
cases are multifocal and small tumor nodes with clear cells can be found. This
same finding can be made more frequently in kidneys of patients with von
Hipel-Lindau disease. These nodes could have been considered adenomas of clear
cells, but since Bell's
descriptions [4] it is well known that some of the small clear-cell tumors have
metastasis capacity and therefore currently the existence of an adenoma of
clear cells is not accepted, instead it is considered that all the clear-cell
tumors are carcinomas, with greater or lesser aggressiveness.Having established this
axiomatic attitude, there is no problem of differential diagnosis; however,
from the morphological point of view, thecystic
nephroma (Figure 1), formed by multiple separate cysts (which are also known
as multilocular cyst) covered by epithelium without nuclear atypia, monolayer,
with eosinophilic cytoplasma, can occasionally be covered by cells of clear
cytoplasma, without nuclear atypia. In this case, clear cells must not be found
in the walls and the intercystic stroma. The cystic nephroma does not have any
relation to the multilocular clear cell carcinoma (despite certain similarity
with it) [5]. Currently, it is being related to other benign neoplasias such as
the mixed epithelial and stromal tumor of the kidney, all of them are much more
frequent in women and with estrogen and progesterone receptors in the stromal
component [6].Cystic nephroma: cystic neoplasm with fibrous stroma an flat epithelium covering
the wall.
(a)(b)


## 2.2. Papillary Adenomas

In about 35% of the cases the
renal carcinomas with a papillary pattern have multiple lesions of diverse
sizes (from millimeters to centimeters), especially those associated with
family syndromes. This fact again poses the existence of adenomas and their
possible relation with carcinomas.The small papillary tumors are
characterized by a growth of cells with scant cytoplasma (chromophilic cells),
occasionally somewhat eosinophilic, with tubular-papillary patterns, well
delimited and not encapsulated (Figure2). In chromosomal studies, trisomies in
chromosomes 7 and 17 were confirmed in the small tumors. Additionally, other chromosomes presented tri-tetrasomies when the in size of the tumor increase. From
these findings it was considered that there is a series of small benign lesions
and that the increase in size is associated with greater amount of chromosomal
alterations and therefore the possible transformation in papillary carcinomas.
For this reason, the WHO 2004 renal cell tumors classification considered tumors
with a maximum diameter of 5 mm as papillary adenomas [3]. In a practical manner, many pathologists consider
that the tumors over 5 mm and up to 10 mm are of low aggressiveness [7].Papillary adenomas: different types of basophilic cell adenomas.
(a)(b)(c)(d)It should be underscored that
although the majority of the papillary
adenomas are associated with papillary renal
cell carcinoma (47%), they can also be found associated with other variants
(16% with clear cell RCC, 8% with chromophobe RCC and 2.5% with oncocytoma)
[8].It should be highlighted that
5% of the papillary adenomas are found in sclerosed kidneys (end-kidneys) and
18% in patients with acquired cystic disease (with or without dialysis). Their
morphological characteristics are identical to those associated with carcinomas
but curiously they differ from the latter by not expressing alpha-methylacyl-CoA
racemase (AMACR) [8].In conclusion, papillary
adenoma and papillary renal cell carcinoma may represent a continuum of the
same biological process. Unfortunately, it is not possible to define an
unequivocally benign papillary renal adenoma, for this reason the WHO used the size
(arbitrarily) as a marker.The papillary adenomas
associated with end-kidney and/or acquired cystic disease may have a different
pathogenesis.


## 2.3. Oncocytoma

The clinically most important
renal cortical adenoma is the oncocytoma, since despite the fact that it is not
usually associated with the carcinoma, in the imaging diagnosis it is usually
considered as renal cell carcinoma.The cytological
characteristics of the oncocytoma are defined by the oncocytic cells (tumor
cells arranged in nests, cords, or tubules, with eosinophilic cytoplasm and no
mitosis). They are usually solid, homogeneous, with occasional sclerosed
central areas, which can also present in other tumors, and are of a diameter
from millimeters up to 12–15 or more centimeters. Therefore, in this tumor type,
the criterion of size does not exist [9].The problem originates in the
cytological characteristics that at times are difficult to distinguish from
other neoplasias of eosinophilic cells, such as the clear-cell renal carcinomas
eosinophilic variant and especially the chromophobe eosinophilic carcinomas
(Figure3).(a) Oncocitomas, (b) eosinophilic chromophobe renal cell carcinoma variant.
Notice the similar aspect that both lesions can present.
(a)(b)To distinguish them, the
electronic microscope, histochemistry (colloidal iron), and
immunohistochemistry can help (Figure4).Colloidal iron to distinguish oncocytoma (negative) and chromophobe renal
cell carcinoma (positive).
(a)(b)It is interesting to point
out that the chromosomal studies have demonstrated different types of
alterations, and therefore while some tumors do not have any chromosomal
alteration, others show translocation
11q13 and (−) 1p, 14q, Y [10]. The latter chromosomal alteration is similar to
that of the chromophobe carcinomas (−1p, Y), which together with the finding of
hybrid carcinomas (oncocytoma + chromophobe renal cell carcinoma) especially in
the Birt-Hogg-Dubé syndrome [11] it has suggested that certain cases of
oncocytomas could evolve into chromophobe renal cell carcinoma.


## 2.4. Metanephric Adenoma

A
relatively short time ago a tumor was introduced among the renal adenomas that
was comprised by small cells with scant cytoplasma, uniform, without mitosis,
embryonic-appearing, distributed in small round acini with a phenotype similar to
the nephroblastoma (Figure5). They represent 1% of localized tumors of less than 7 cm. The mean age is 41 years
(from 5 to 83 years). Fifty percent are incidental
and 10% have a polycythemia. Immunohistochemistry,
the WT1, CD 56, and CD 57 are positive and the AMACR is negative [12].Figure 5
Metanephric adenoma. microacinar structures of basophilic cells with a nephroblastic appearance.From
the genetic point of view, it is characterized by allelic loss in 2p13 (56% of the cases) and
is differentiated from the nephroblastoma
(with alterations 11p13) and from the papillary carcinoma (+7,  +17) [13].To distinguish the metanephric
adenoma from the nephroblastoma, strict diagnostic criteria have been used, and
only accepting the tumors without mitosis and nucleoli as metanephric adenoma.


## 3. Conclusions

We see that the criteria used
to consider renal neoplasia as adenoma vary a great deal according to the
cellular type (never in the neoformations of clear cells, only in small
neoplasias of papillary pattern, and any size if we are sure that they are
oncocytic or metanephric cells). Therefore, it is fundamental to establish the
cellular type, and this determination is usually done with the usual
pathological anatomical methods with the help of the immunohistochemical
markers to which occasionally molecular methods can be added.



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*Source: 974848-2008-10-08.xml*