Abstract
OBJECTIVE To study the diagnosis and treatment of chromophobe cell renal carcinoma (CCRC).
METHODS Three cases of CCRC were studied by analyzing the results of an operation, by light microscopy, immunohistochemistry, Hale’s colloidal iron staining and electronmicroscopy (EMC).
RESULTS Doppler ultrasonic and CT features were not specific. Histopathology: Grossly the tumor tissue was homogeneous, light brown in color with central necrotic foci; Light microscopy: Macrocyte, fine reticular cytoplasm with clear cell border; Hale’s colloidal iron staining: positive; positive EMA, CK19, vimentin, Ckpan, and negative S-100; EMC: numerous intracyto-plasmlc membranous small cysts. All patients were followed up for 14.1–31 months (19.7 months on average), one patient had lung metastasis 11 months after resection of a GIII tumor, two alive patients had no local recurrences and metastases.
CONCLUSIONS CCRC is histo–pathologically, immunohistochemically and electron microscopically distinct from other renal cancers. Surgical tumor removal is the best way for treatment. It is probably a type of cancer with low malignant potential and favorable prognosis.
keywords
Chromophobe cell renal carcinoma(CCRC) was first described by Thoenes et al [1] in 1985. Because the gross specimen is morphologically and microscopically similar to other types of renal carcinoma, it is often misdiagnosed. Up to now, 100 plus cases have been reported abroad, and only one group of 7 cases have been reported in China [3]. Three cases of CCRC patients were treated in this hospital from 1992 to 1999, and analyzed by light microscopy, immunohistochemistry, Hale’s collodial iron staining and EMC. With the review of literature the diagnosis and treatment of CCRC were studied as follows.
MATERIALS AND METHODS
Materials
Three male patients were studied between the ages of 62 and 67(average 64 years). One patient was found at a physical check-up, one had left-flank discomfort for one week, and the third had right-flank pain and weight loss for 10 months. All of them had no hematuria nor abdominal mass. One had Hb 9.5g/l, ESR IIImm/lh. IVU in two patients showed distortion and oppression of the renal calices and pelvis; ultrasonography and CT scan indicated space-occupying lesions in the kidney with diameters of 3.3 cm, 5.0 cm and 6.5 cm, respectively. Capsule invasion was found in one, and enhanced area was observed at the center of the mass after intensive CT scan.
Methods
Besides light microscopy with HE staining, all 3 cases were examined by Hale’s collodial iron staining, and immunohistochemical testing EMA, CK19, vimentin, Ckpan and S-100. Two of them were studied by electron microscopy.
RESULTS
Treatment and Follow-up
Radical nephrectomy was performed in two patients, simple nephrectomy was performed in one. All patients were followed-up for 14.1–31 months (mean 19.7 months). In examinations by chest x-ray, ultrasonography and CT scan, one patient showed a 4cm x 3.5cm solid space–occupying lesion over the hilum pulmonis, which was considered to be a lung metastasis. The patient died 3 months later. The other 2 patients were followed up for 14.1 months and 31 months respectively, with no local recurrences or metastasis and are still surviving.
Gross specimens
The CCRCs of all 3 patients were unilateral and solitary located in the renal parenchyma (2 cases at the lower pole, 1 case in the middle part). The average diameter of the tumors was 5.03cm. In one case, the tumor invaded the capsule, though not breaking it. The tumor tissue was grossly homogeneous, the cut surface was light brown in color, and the border was light yellow. One case had a central necrotic focus of 1.5cm. The retroportal lymph node showed no metastases. There was no tumor cell embolus in the renal vein, and the pelvis mucosa was not invaded.
Light microscopy and Hale’s collodial iron staining
Under light microscopy, the tumor cells were large or medium large with rich cytoplasm laid out in sheet form. Occasionally, a tubuloalveolar structure was observed, with focal necrosis. Tumor cells of this group had a distinct border, similar to plant cells. Tumor cells were classified into 3 types. Type I: the diameter was a little smaller than the other 2 types; cytoplasm was eosinophilic and granular; circular nucleolus in the center; Type II: a little larger than type I; very similar to type I, except for a transparent area around the nucleolus; binucleate cells could be observed. Type III: larger than type II; with richer reticular and transparent cytoplasm; transparent area around the nucleolus could be observed. Some cells of type–III were quite large, presenting transparent and reticular expansion of the cytoplasm (balloon cells)(Fig. 1, 2). Migration and transition could be seen in these cells. Tumor cells were often a mixture of 3 types of cells, and the majority were of type II. Fuhrman (1982) grade: 2 cases of grade II, 1 case of grade III. With Hale’s collodial iron staining, the tumor cell cytoplasm was a diffuse blue.
CCRC, composed of type I and II cells, with clear membrane, part of CCRC cells are of tubuloalveolar structure. HE×400.
CCRC, balloon cells. HE×400.
Immunohistochemistry and EMC
Immunohistochemistry: the tumor cell EMA test showed focal or diffuse positive, collecting–tubule cell positive, staining was in the cytoplasm; Positive CK19, Ckpan, and negative S-100. Positive vimentin in collecting tubule and tumor cells could be seen (Fig. 3-5).
CRC, tumor cells positive for Hale’s collodial iron staining, ×400.
CCRC, EMA distribution in tumor cells, ×400.
CCRC, vimentin positive in tumor cells, ×300.
EMC: cell conjunctions were in desmosome form. Many small cysts with a single membrane and diameter of 100–350nm were in tumor cells, and rarely other organelles were observed (Fig. 6). The quantity and distribution of small cysts were significantly different in various types of tumor cells. Type I: none or very few small cysts could be seen in the cytoplasm, with mitochondria, RER, lysosome, and some glycogen. Type II: numerous to many small cysts could be seen in the cytoplasm, mostly in the perikaryon around the nucleus. Type III: rich in cytoplasm, small cysts were replaced by cytoplasm. Pathological diagnosis: CCRC.
CCRC, EMC: Numerous intracytoplasmic membranous small cysts. EMC×12,000.
DISCUSSION
Clinical features
The incidence of CCRC is 2.4%–4.5%[1,2,4,5]. The age of onset is about 60. CCRC can also occur in children [6]. There is no significant difference between genders. The patients in this group had a median age of 64, and all were males. CCRC is often unilateral and solitary. It has been reported that more than half of the patients have flank pain, a mass and weight loss, some with anemia and elevated ESR [4,5]. The case No. 3 in our study had pain, weight loss, anemia and ESR elevation, suggesting malignancy.
Radiographic features
Ultrasonic and CT scan often show a homogenous solid mass. Sometimes necrosis or cystic degeneration may be observed at the tumor center, and some contain central scars [4]. The foci are observed as low density after a CT scan, so CCRC is difficult to distinguish from other types of renal carcinoma (Fig. 7).
CCRC, CT intensive scan can be seen at right kidney’s lateral border solid tumor, low density, homogenous, and distinct border.
Pathological features and colloidial iron staining
Grossly, the tumors are in a global or nodular shape, with sizes from 2cm to 22cm [4,7]. They are often in the middle part of the renal parenchyma, with a clear border, protruding to the kidney surface or into the renal pelvis. The cut surface is uniformly light brown, and some areas are light yellow. There are central necrotic foci. The appearance is not as brilliant as a clear-cell carcinoma. Microscopically, tumor cells are often arranged in sheets and acini, sometimes in tubes, rarely in papillary form. Tumor cells are large, with rich cytoplasm and a distinct border, similar to plant cells[8]. These two features are different from other renal cancers. Tumor cells in this group are classified into 3 types: type I (eosinophilic), type II and type III, close to what Akhtar et al reported [9]. This is different from previous classification of 2 types: classic type and eosinophilic type [2]. TNM stage is T2N0M0. Hale’s collodial iron staining: positive; the appearance of cytoplasm is diffuse granules in blue staining (ultrastructure suggests small cysts and mitochondria). It can be distinguished from other subtypes of renal carcinoma, which are Hale’s collodial iron staining negative, and oncocyte eosinophilic staining negative, or cell–top staining positive [6].
EMC features and Immunohistochemistry
Major electron microscopic features: There are numerous membranous circular or ovoid small cysts (100–350nm) in the cytoplasm. Fat droplets and glycogen are rare. This feature is different from other subtypes of renal carcinoma. Small cysts are a structure of material of fine reticular cytoplasm under light microscopy. Small cysts may originate from expansion of the outer membrane of mitochondria [9]. Recently, eosinophilic cells have been classified into 2 subtypes [10]: type A: a medium amount of small cysts in the cytoplasm; medium to a rich quantity of mitochondria containing tubular crests; similar to type II cells. Type B: there are no or few small cysts in the cytoplasm; however, there is a medium to rich quantity of mitochondria containing focal cluster or laminar crests; similar to type I cells. The existence of mitochondria (average diameter 0.5nm) is the structural basis of eosinophilic cytoplasm under microscopy. In this group, immunohistochemical test results of tumor cells are close to reports elsewhere: EMA(+), CK19(+), Ckpan(+), and S-100 (–). Vimentin (+) is the difference between other groups [3,7]. Because EMA (+) and vimentin(+) are in both collecting tubes and tumor cells, and tumor cells contain carbonic anhydrase, so one may suggest that CCRC originates from renal collecting tubules [11]. However, some researchers think that CCRC originates from inserted epithelial cells of distal renal tubules [8].
Genetic features
Cytogenetic study has proven the uniqueness of CCRC genetic features: allelic loss at chromosomes 1p, 2p, 6p, 10p, 13q, 17q, and 21q [12]. The loss of chromosome No. 3 short arm in renal cell carcinoma cells is not expressed in CCRC cells. The chromosome’s mutation leads to an interaction with mitochondrial genes and nuclear genes.
Diagnosis and Treatment
The clinical features of CCRC are not specific compared with other subtypes of renal carcinoma. It is difficult to distinguish CCRC from other renal epithelial carcinoma with radiographic methods. Confirmation needs pathological studies, especially ultrastructure and Hale’s collodial iron staining [9,13–15]. Surgical removal of the tumor is the best way for treatment. Simple or radical nephrectomy is indicated in cases where the tumors are>3cm; for tumors<3cm, partial nephrectomy or tumor enucleation can be done. The reported prognosis of CCRC is better than that of other types of kidney cancer, and it is a type of cancer with a low malignant potential [2–5]. The grade and stage of CCRC are the major factors for prognosis. Crotty et al [4] observed 50 patients, with an average follow-up time of 6 years. Of them 36(72%) were alive at last follow-up except for three who died of cancer relapse or metastases. A total of 11 patients (22%) died of an unrelated illness (average of 7.3 years after treatment). In this study, one patient had lung metastasis 11 months after tumor resection, and died 3 months later, which might be related not only to the cachexia, but also to poor differentiation of tumor cells (GIII) and tumor capsule infiltration. The other two patients who survived had no local recurrence and metastases. As to the long–term survival rate, further observation is needed.
In conclusion, CCRC is a kind of renal epithelial carcinoma different from clear renal carcinoma. CCRC cells have a distinct cell membrane and fine reticular cytoplasm. Hale’s collodial iron staining: positive; EMC: numerous intracytoplasmic membranous small cysts. Surgical removal of the tumor is the best way for treatment. The prognosis is favorable.
- Received January 20, 2004.
- Accepted March 29, 2004.
- Copyright © 2004 by Tianjin Medical University Cancer Institute & Hospital and Springer
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