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CANCER
161
CYTOPATHOLOGY
Fine-Needle Aspiration Biopsy of Chromophobe Renal
Cell Carcinoma and Oncocytoma
Comparison of Cytomorphologic Features
Beata A. Wiatrowska, M.D.
Maureen F. Zakowski, M.D.
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York.
BACKGROUND. Chromophobe renal cell carcinoma (ChRCC) is a distinct tumor
with a prognosis intermediate between renal oncocytoma (RO) and clear cell renal
cell carcinoma. To our knowledge the cytologic features of only a limited number
of ChRCC have been described to date. A retrospective review of the cytomorphologic features of ChRCC and a comparison with RO was performed.
METHODS. Fine-needle aspiration biopsies (FNABs) of six cases of histopathologically proven ChRCC were reviewed. The material examined was comprised of
smears, cytospins, Thin Prept Pap Test™ preparations, and cell block sections
stained with Diff-Quikt, Papanicolaou, and hematoxylin and eosin. Six FNABs of
ROs were examined similarly. The cytomorphology of each tumor was studied and
particular attention was paid to features differentiating the two entities.
RESULTS. The characteristic cytomorphologic features of ChRCC (present in all
cases) included round/oval, occasionally polygonal, moderately pleomorphic large
cells present singly and in small clusters. The abundant cytoplasm was variegated,
ranging from dense to flocculent to vacuolated, with prominent cytoplasmic membranes. The nuclei were large and hyperchromatic, with nuclear membrane irregularities and grooves present at least focally. Frequent binucleation was observed.
Small nucleoli were present in many cells, but rarely prominent. In contrast, RO
showed large cells with homogenous granular cytoplasm. The nuclei showed
minimal to no nuclear membrane irregularities, tiny nucleoli, mild pleomorphism,
and only an occasional large, more hyperchromatic nucleus was observed.
CONCLUSIONS. ChRCC has a distinct combination of cytomorphologic features.
Careful attention to cytoplasmic and nuclear features allows for the distinction
between ChRCC and RO in cytologic preparations. Cancer (Cancer Cytopathol)
1999;87:161–7. © 1999 American Cancer Society.
KEYWORDS: chromophobe, renal cell carcinoma, oncocytoma, cytology, differentiating features.
Presented in abstract form at the American Society
of Cytopathology Annual Meeting, Nashville, Tennessee, November 3–7, 1998.
Address for reprints: Maureen F. Zakowski, M.D.,
Cytology Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY
10021.
Received August 26, 1998; revision received December 28, 1998; accepted January 6, 1999.
© 1999 American Cancer Society
C
hromophobe renal cell carcinoma (ChRCC) is a tumor with distinct morphologic, histochemical, ultrastructural, and genetic features. The lesions are well circumscribed and solitary, with a graybrown homogeneous cut surface. The tumor cells are large and
polygonal with well defined borders and abundant cytoplasm that is
pale (typical) or granular and strongly acidophilic (eosinophilic variant). The nuclei show slight pleomorphism and hyperchromasia with
coarsely granular chromatin, irregular nuclear membranes, and occasional binucleation. There is diffuse cytoplasmic positivity of tumor
cells for colloidal iron. The cells express cytokeratins but are vimentin
negative. The characteristic ultrastructural feature is the presence of
162
CANCER (CANCER CYTOPATHOLOGY) June 25, 1999 / Volume 87 / Number 3
FIGURE 1. Cluster of cells of chromophobe renal cell carcinoma showing
large round to oval cells with well defined cytoplasmic membranes. (DiffQuikT, 3200)
round to oval cytoplasmic vesicles varying in size from
150 –300 nanometers that are concentrated around the
nucleus.1
The distinct genetic features of ChRCC include
allelic losses at chromosomes 1p, 2p, 6p, 10p, 13q, 17p,
and 21q.2 The prognosis for ChRCC is intermediate
between renal oncocytoma (RO) and clear cell renal
carcinoma.3-5 The cancer staging system used for renal tumors including RO and ChRCC carcinoma is that
of the American Joint Committee on Cancer.6 To our
knowledge the cytologic features of only a limited
number of cases of ChRCC have been described to
date.7-9
A retrospective review of the cytomorphologic features of ChRCC and comparison with RO was performed in our laboratory.
MATERIALS AND METHODS
The files of the pathology department of Memorial
Hospital were searched for cases of histologically confirmed ChRCC for which there was previous or concomitant cytologic material. Seven fine-needle aspiration biopsies (FNABs) (five renal and two extrarenal)
were found. Material examined was comprised of
smears, cytospin, ThinPrept Pap Test™ (Cytyc Corporation, Boxborough, MA) preparations, and cell
block sections stained with Diff-Quikt, Papanicolaou,
and hematoxylin and eosin (H & E). The histologic
sections from nephrectomy specimens were prepared
in a standard fashion, cut 4-mm thick, and stained with
H & E and Hale’s colloidal iron. Six cases of RO were
similarly identified. The cytomorphology of each tu-
mor was studied, including the background, architecture, cell size and shape, cytoplasmic quantity and
quality, nuclear shape and size, binucleation chromatin pattern, and presence and prominence of nucleoli.
Particular attention was paid to features differentiating ChRCC from RO. No distinction was made between the typical and eosinophilic types of ChRCC.
RESULTS
FNABs from seven patients with ChRCC were reviewed. There were four females and three males, with
an age range of 41–75 years (mean, 54 years). FNAB
sites included the right kidney (five patients), the liver
(one patient), and a left supraclavicular mass (one
patient). In addition to the smears, two ThinPrept
preparations, one cytospin preparation, and two cell
block sections were available for review. FNABs from
six patients with RO were reviewed similarly. There
were two females and four males, with an age range of
63– 80 years (mean, 72 years). Four FNABs were from
the right kidney and two were from the left kidney. In
addition to air-dried, Diff-Quikt stained and alcohol
fixed, Papanicolaou, and/or H & E stained smears, one
ThinPrept and two cell block sections were available.
All ChRCCs originally were recognized as malignant, with four diagnosed as RCC not further classified, one as RCC chromophobe cell type, one adenocarcinoma of renal versus adrenal origin, and one
carcinoma favor transitional cell carcinoma.
The cytomorphologic features of ChRCC (Figs. 1,
2, and 3) are detailed in Table 1. The cellularity was
high with small clusters and single cells present in all
Cytology of Chromophobe Carcinoma and Oncocytoma/Wiatrowska and Zakowski
163
FIGURE 2.
Chromophobe renal cell
carcinoma showing (A) variegated cytoplasm ranging from granular to flocculent to vacuolated (3200). (B) Single
binucleate cell with vacuolated cytoplasm (DiffQuikT, 3400).
FIGURE 3.
Small cluster of chromophobe renal cell carcinoma demonstrating “raisinoid” nuclei, longitudinal nuclear grooves, and perinuclear halos
(Papanicolaou stain, 3400).
cases. The cells were large, round to oval, with abundant, variegated cytoplasm. A thick, prominent cytoplasmic membrane was observed in six of the seven
cases. The cytoplasm ranged from granular to flocculent to vacuolated in all cases. Perinuclear clearing or
halos were observed in three of seven cases in cyto-
logic preparations and was appreciated better in cell
block sections. There was moderate cellular pleomorphism, with greater variation in size than in shape of
the cells. Although the nuclei were large or moderate
to large in all cases the nuclear to cytoplasmic ratio
(N:C) remained low due to the abundance of cyto-
164
CANCER (CANCER CYTOPATHOLOGY) June 25, 1999 / Volume 87 / Number 3
TABLE 1
Predominant Cytomorphologic Features of Chromophobe Renal Cell
Carcinoma and Renal Oncocytoma
Cytoplasm
Cellular pleomorphism
Nuclear features
Nucleoli
Fuhrman nuclear
grade
Other
ChRCC
RO
Variegated, dense, granular,
flocculent, vacuolated
perinuclear clearing
Thick/prominent
cytoplasmic membrane
Moderate
Moderate pleomorphism
Mildly irregular nuclear
outline
Grooves
Intranuclear inclusions
Raisinoid nuclei
Rare
2–3
Uniform, granular, dense
Well defined
cytoplasmic
membrane
Subpopulation of larger cells
with large, irregular
hyperchromatic nuclei
and occasional nucleoli
Mild
Mild pleomorphism
Smooth contour
No grooves
Rare inclusions
No raisinoid nuclei
Occasional
1–2
Subpopulation of smaller
cells with a higher N:
C ratio
ChRCC: chromophobe renal cell carcinoma; RO: renal oncocytoma; N:C: nuclear:cytoplasmic.
plasm. Binucleation was frequent (present in five of
seven cases). The large nuclei were round to oval with
moderate pleomorphism. The nuclear membrane irregularities, including nuclear grooves, were present
at least focally in all cases, intranuclear pseudoinclusions were present in three of seven cases, and raisinoid nuclei were present in four of seven cases. The
nucleoli were present in many cells in five of seven
cases; however, they were small and rarely prominent.
The Fuhrman nuclear grade was 2–3 in all cases. Also
noted in two of seven cases was a subpopulation of
larger cells with large, irregular, hyperchromatic nuclei and occasional nucleoli. The background was
clean (or bloody) with no necrosis and no inflammation in any case.
FNABs from RO (Figures 4, 5, and 6) also were
cellular with a similar architectural arrangement of
small clusters and single cells (Table 1). The cells were
large with a low N:C ratio but, in contrast to ChRCC,
their cytoplasm was homogenous and granular in all
cases. The nuclear features also were markedly different with only mild pleomorphism, absent or minimal
nuclear membrane irregularities with no grooves, and
no raisinoid nuclei. Very small nucleoli were observed
in four of six cases. The Fuhrman nuclear index was
1-2 in all cases, with a grade of 2 granted mainly on the
basis of the nucleolar presence. Only in one case were
larger, more hyperchromatic nuclei observed occasionally among otherwise classic-appearing oncocytic
cells. A subpopulation of similar cells with a higher
N:C ratio and the same granular cytoplasm and low
grade nuclei were observed in FNABs from two cases.
The cytologic features differentiating ChRCC from RO
are summarized in Table 2.
DISCUSSION
ChRCC first was described by Thoenes et al. in 1985.10
It is believed that ChRCC shows differentiation toward
the intercalated cells of collecting ducts with numerous cytoplasmic vesicles containing carbonic anhydrases.11 It comprises between 2–5% of RCCs.1,12 Considered a clinicopathologic entity, it has distinct
morphologic, histochemical, ultrastructural, and genetic2,3,10,11,13-15 features that are different from other
types of RCC and RO. The characteristic cytomorphologic features noted in our series included large cells
with variegated cytoplasm in all cases ranging from
dense to granular to flocculent to vacuolated with
perinuclear clearing in some cells. The characteristic
nuclear features included moderate pleomorphism
with irregular nuclear outlines, grooves, pseudoinclusions, and raisinoid nuclei. The nucleoli were relatively rare and smaller than expected compared with
the overall appearance and pleomorphism of the nuclei. The cytologic features corresponded well with the
histopathologic picture, including cytoplasmic and
nuclear characteristics, particularly the admixture of
pale and highly eosinophilic cells with many microvacuolated cells and nuclear hyperchromasia with an
irregular nuclear membrane. These cytoplasmic features are similar to those in what to our knowledge are
the relatively few cases described in the literature7-9
and correspond particularly well with the cases described most recently by Granter and Renshaw.9
It has been noted both in the histopathologic material and in the previous cytologic descriptions of
ChRCC that the most difficult differential diagnosis for
ChRCC most likely is that of an RO.7,9 Renshaw et al.
reported that they were able to identify all four ROs
and two ChRCC successfully in a retrospective review
of 38 renal cell lesions.16 However, on the initial review, only one ChRCC was identified correctly by all
authors and two of the ROs were misinterpreted as
ChRCC. In our review of six cases of RO the most
characteristic features included uniform granular cytoplasm, mild nuclear pleomorphism, round nuclei
with smooth nuclear contour, frequent but not prominent nucleoli, and a subpopulation of smaller cells
with a higher N:C ratio but the same cytoplasmic
features. These match earlier reports.17-20 The differentiating features between the two entities include
both cytoplasmic and nuclear characteristics. The
most typical feature is the variegated appearance of
Cytology of Chromophobe Carcinoma and Oncocytoma/Wiatrowska and Zakowski
165
FIGURES 4 AND 5. Renal oncocytoma showing small clusters and single
cells. Note the uniformity of the cytoplasm (Figure 4: H & E, 3100) (Figure 5:
DiffQuikT, 3200).
cytoplasm in ChRCC and its monomorphism in RO,
with very rare cytoplasmic vacuolation. Also the nuclear features are very different with typical pleomorphism, a very irregular nuclear membrane, and
grooves of raisinoid nuclei with small nucleoli observed in RO. This observation contrasts somewhat
with the report by Akhtar and Ali7 that found the
nuclear morphology of RO and ChRCC to be essentially similar, with no nucleoli observed in RO. We
observed nucleoli, albeit small, in many cells in RO.
Because ChRCC is considered to have a prognosis
intermediate between other types of RCC and RO3-5
the treatment usually is simple nephrectomy, although recently partial nephrectomy has been noted
to be considered more often.21 RO is a benign entity
and can be left untreated, although many physicians
prefer to treat it surgically rather than leave the tumor
in, fearing sampling error and the true diagnosis of
RCC with oncocytic features. Nevertheless, in some
patients (e.g., those with high surgical risk or known
metastatic disease) nonsurgical treatment may be a
viable and preferred option (one of the patients in the
166
CANCER (CANCER CYTOPATHOLOGY) June 25, 1999 / Volume 87 / Number 3
FIGURE 6.
Low power and insert of
renal oncocytoma demonstrating round,
regular nuclei without grooves and homogenous granular cytoplasm (DiffQuikT, 3100).
current study had biopsy proven metastatic melanoma at the time of the diagnosis of RO; the patient
did not undergo surgery and died 2 years later of
melanoma).
Other important differential diagnostic considerations for ChRCC are clear and granular cell types
of RCC. The features of RCC include large clusters of
cells with abundant, clear to finely vacuolated,
wispy, or granular cytoplasm; many stripped nuclei
due to cytoplasmic fragility; centrally located round
to slightly irregular nuclei with pale chromatin; and
prominent nucleoli. Hyaline globules and phagocytized red blood cells may be observed in the cytoplasm of RCC. Renshaw et al.16 pointed out that in
general the cells of clear cell RCC form larger groups
and have more uniform nuclear size and round
shape than cells of ChRCC. In comparing ChRCC
and the granular cell variant of RCC, Akhtar and Ali7
noted indistinct cellular borders with irregular outlines and large nuclei with open chromatin and
single, well developed nucleoli in the latter entity.
With regard to other, less common differential diagnoses of ChRCC, the ones that arose from our
initial diagnosis included adrenal cortical carcinoma and transitional cell carcinoma (TCC). The
differential diagnosis between adrenal cortical carcinoma and RCC, particularly of the granular or
clear cell variants, often is difficult or virtually impossible by morphology alone.22 FNAB of adrenal
cortical carcinoma can vary in appearance from
bland, lipid-laden cells to anaplastic malignant cells
with dense acidophilic cytoplasm. Occasional giant
bizarre as well as spindle cells can be observed. The
nuclei also vary from small and round to large and
anaplastic with irregularities of the nuclear membrane, abnormal chromatin, and prominent nucleoli. Occasionally oncocytic cells can be present.23
However, unlike ChRCC, perinuclear clearing with
raisinoid nuclei (koilocyte-like) is not a feature of
adrenal cortical carcinoma. In addition, an increase in the nuclear grade of this entity is accompanied by the presence of prominent nucleoli. With
regard to the differential diagnosis between ChRCC
and TCC, low grade TCC usually has papillary
groups of nearly normal transitional cells with minimal nuclear atypia whereas high grade lesions show
relatively dense cytoplasm with only scattered vacuoles with no flocculent or microvacuolated qualities.
The nuclei are high grade with coarse chromatin
and prominent nucleoli with no koilocyte-like appearance.24
Conclusions
ChRCC has distinct cytologic features that allow for
the correct diagnosis on FNAB. ChRCC can be differentiated from RO when attention is paid to cytoplasmic and particularly nuclear features. Although not
usually a critical consideration, the distinction of
ChRCC from RO may be important in certain clinical
settings.
Cytology of Chromophobe Carcinoma and Oncocytoma/Wiatrowska and Zakowski
TABLE 2
Differentiating Cytologic Features between Chromophobe Renal Cell
Carcinoma and Renal Oncocytoma
ChRCC
RO
7/7
7/7
7/7
5/6
6/6
6/6
7/7
7/7
0/7
6/7
6/7
7/7
3/7
6/7
—
Mod 6/7
7/7
—
7/7
Mild 7/7
7/7
3/7
4/7
Mod 5/7
Mild/Mod 7/7
7/7
—
5/7
2–3
1/7
2/7
0/7
6/6
0/6
6/6
6/6
6/6
2/6
0/6
0/6
6/6
Mild 4/6
6/6
5/6
6/6
Mild 2/6
0/6
1/6
0/6
Mild 5/6
Mild 6/6
—
Rare 3/6
4/6
1–2
0/6
0/6
0/6
6.
7.
High/moderate cellularity
Small clusters/single cells
Large, round oval cells
Cytoplasm
Abundant
Variegated
Uniform
Granular
Flocculent
Vacuolated
Perinuclear clearing
Thick/prominent cytoplasmic membrane
Well defined cytoplasmic membrane
Cellular pleomorphism
Low N:C ratio
Binucleation
Round/oval, mod/large nuclei
Irregular nuclear membrane
Nuclear grooves
Intranuclear inclusions
Raisinoid nuclei
Nuclear pleomorphism
Hyperchromasia
Chromocenters
Clumpy chromatin
Nucleoli
Fuhrman nuclear grade
Mitosis
Cells with large hyperchromatic irreg nuclei
Necrosis
ChRCC: chromophobe renal cell carcinoma; RO: renal oncocytoma; mod: moderate; N:C: nuclear:
cytoplasmic; irreg: irregular.
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