Hemangioma-Like Clear Cell Renal Cell Carcinoma Exhibiting Aggressive Behavior and High Stage: A Case Report

Introduction

Clear cell renal cell carcinoma (CCRCC) is the most common renal tumor, accounting for 65% to 70% of all RCCs and approximately 2% of all malignancies.^1,2 Cytological and architectural features such as clear cell morphology, alveolar, nested or tubular growth pattern usually makes distinguishing CCRCC from its mimics straightforward. However, in certain situations, establishing the correct diagnosis can be challenging. Extensive degenerative changes in CCRCC, which can closely mimic a vascular neoplasm, especially a hemangioma, create a diagnostic dilemma. Although CCRCCs characteristically contain a rich vascular network composed of thin-walled blood vessels that surround nests of tumor cells, a purely cystic architecture lacking expansive growth or cells with voluminous clear cytoplasm is extremely rare among CCRCCs. ³

To the best of our knowledge, there are only 14 RCCs exhibiting a predominant hemangioma-like architecture in the literature.^4–11 Although the most recent study by Kojima et al included a total of 9 tumors, only one of them predominantly consisted of a hemangioma-like component. ¹¹ Based on clear cell morphology, these tumors can be broadly divided into 2 groups-clear cell hemangioma-like RCCs and non-clear cell hemangioma-like RCCs. According to the available clinical data, all these tumors behaved non-aggressively (survival data are not available for one tumor) (Table 1).

OPEN IN VIEWER

Table 1.

Summary of Clinical, Morphological and Molecular Features in Hemangioma-Like Renal Cell Carcinomas Reported to Date.

Publication	Age/Sex	Subtype	WHO/ISUP Grade	Hemangioma-Like Component	Genetics (Methods)	Follow-Up*
Kryvenko et al Patient no. 1	40/F	CCRCC	1-2	Anastomosing sinusoid-like small vessels	-	16 (NED)
Patient no. 2	66/M	CCRCC	1-2	Anastomosing sinusoid-like small vessels	-	30 (NED)
Patient no. 3	47/M	CCRCC	1-2	Anastomosing sinusoid-like small vessels	-	32 (NED)
Patient no. 4	42/M	CCRCC	1-2	Anastomosing sinusoid-like small vessels	-	24 (NED)
Montironi et al Patient no. 1	49/M	CCRCC	1	Hemangioblastoma-like	-	36 (NED)
Patient no. 2	32/F	CCRCC	1	Hemangioblastoma-like	-	36 (NED)
Sancheti et al	69/M	CCRCC	-	Hemangioblastoma-like	-	-
Taneja et al	62/F	Unclassified RCC	3	Small capillary-like epithelial spaces	Disomy 7 and 17 (FISH)	12 (NED)
Kim et al Patient no. 1	75/F	CCPRCT	2-3	Hemangioblastoma-like	-	6 (NED)
Patient no. 2	59/M	CCRCC	1	Delicate microvascular proliferation	-	20 (NED)
Huang et al Patient no. 1	33/F	CCRCC	-	Hemangioblastoma-like	No TFE3, TFEB and VHL mutations (FISH)	34
Patient no. 2	66/F	CCRCC	-	Hemangioblastoma-like	No TFE3, TFEB and VHL mutations (FISH)	40
Kong et al	38/F	CCRCC	1-2	Hemangioblastoma-like	TSC2 and SETD2 variations (WES)	18
Kojima et al	65/M	RCC	2	Hemangioblastoma-like	No VHL, ELOC and MTOR mutations (NGS, PCR)	11 (NED)
Present patient	73/M	CCRCC	1-2	Cavernous hemangioma-like epithelial spaces	TET2 and VHL mutations (NGS)	Died within 6 months after diagnosis

Abbrevations: CCRCC, clear cell renal cell carcinoma; CCPRCT, clear cell papillary renal tumor; F, female; FISH, fluorescence in situ hybridization; ISUP, International Society of Urologic Pathology; M, male; NED, no evidence of disease; NGS, next generation sequencing; WES, whole exome sequencing; WHO, World Health Organization.

* Months.

In this study, we report the first CCRCC with a purely hemangioma-like growth pattern and an aggressive clinical course characterized by venous invasion.

Materials and Methods

The submitted tissues were processed and stained with hematoxylin and eosin according to standard procedures as described previously. ¹²

Immunohistochemistry

Immunohistochemical assays were performed on an automated immunostainer Benchmark Ultra (Ventana Medical System, Inc., Tucson, AZ, USA) using an ultraView Universal DAB Detection Kit (Ventana) or ultraView Universal Alkaline Phosphatase Red Detection Kit (Ventana). An antigen retrieval technique was part of the immunostaining process. Detailed information about the antibodies employed is provided in Table 2.

OPEN IN VIEWER

Table 2.

Summary of Antibodies Used for Immunohistochemistry.

Antibody	Clone	Dilution	Manufacturer	Catalog number
AMACR	SP116	Predilute	Ventana	790-6011
Carbonic anhydrase 9	EP161	Predilute	Ventana	760-6080
CD10	SP67	Predilute	Ventana	790-4506
CD31	JC70	Predilute	Ventana	760-4378
CD34	QBEnd/10	Predilute	Ventana	760-2620
Estrogen receptor	SP1	Predilute	Ventana	790-4324
ERG	EPR3864	Predilute	Ventana	790-4576
Fumarate hydratase	J-13	1:3000	Santa Cruz	Sc-100743
GATA3	L50-823	Predilute	Ventana	760-4897
High-molecular-weight keratin	34ßE12	Predilute	Ventana	790-4373
HMB45	HMB45	Predilute	Ventana	790-4366
Inhibin alpha	MRQ-63	Predilute	Ventana	760-6081
Keratin AE1/AE3	AE1/AE3/PCK26	Predilute	Ventana	760-2595
Keratin 7	SP52	Predilute	Ventana	790-4462
Keratin 20	SP33	Predilute	Ventana	790-4431
Melan-A	A103	Predilute	Ventana	790-2990
PAX8	MRQ-50	Predilute	Ventana	760-4618
Progesterone receptor	1E2	Predilute	Ventana	790-2223
SMA	1A4	Predilute	Ventana	760-2833
S100	4C4.9	Predilute	Ventana	790-2914
TFE3	MRQ-37	Predilute	Ventana	760-4622
Thyroglobulin	2H11 + 6E1	Predilute	Ventana	760-2671
TTF1	SP141	Predilute	Ventana	790-4756

Abbreviations: SMA, smooth muscle actin; TFE3, transcription factor binding to IGHM enhancer 3; TTF1, thyroid transcriptional factor 1.

Case Report

Pathological Features

A nephrectomy specimen of the left kidney with a total size of 200 × 105 × 80 mm was delivered to the department of pathology. Sectioning of the renal hilus revealed the renal vein containing an intraluminal tumoral thrombus that extended 10 mm beyond the resection margin; confirmed through histological examination (Figure 1A, B). The wall of the ureter was of normal thickness, and the mucosa had a smooth appearance. The renal artery was only slightly affected by atherosclerosis, without significant narrowing or thrombosis. Careful macroscopic examination of the soft tissues of the hilum did not reveal lymph nodes or the extension of the tumor into the adjacent fat. Subsequently, the kidney was longitudinally divided into anterior and posterior halves, revealing a 68 × 55 × 55 mm tumor originating from the renal parenchyma (not from the pelvis). The cut surface showed relatively well-demarcated masses of moderately firm consistency with haemorrhage and dark purple coloration, surrounded by a fibrous pseudocapsule. No extension through the renal capsule into the surrounding adipose tissue or involvement of the renal pelvis was observed. The pathological stage of the tumor was pT3a pNx according to the 8th edition of the AJCC TNM staging system.

OPEN IN VIEWER

Figure 1.

Morphological and immunohistochemical features of hemangioma-like clear cell renal cell carcinoma.

Microscopically, at low magnification, a renal tumor entirely composed of variably sized cysts with diffuse intracystic hemorrhage, imparting a hemangioma-like appearance was detected at first glance (Figure 1C-F). The irregular blood filled spaces were lined by a single layer of flattened or low cuboidal cells with mild nuclear pleomorphism, inconspicuous small nucleoli (grade 2 according to the World Health Organization (WHO)/International Society of Urologic Pathology (ISUP) classification), and predominantly eosinophilic cytoplasm with a minimal number of cells having inconspicuous clear cytoplasm. The stroma was sparse and consisted of delicate fibrovascular septa containing small vessels and aggregates of small lymphocytes (Figure 1G). Haemosiderin deposits and increased fibrosis were focally present. Despite careful histopathological examination of more than 15 tumor tissue paraffin blocks, features such as increased mitotic activity, atypical mitoses, sarcomatoid/rhabdoid differentiation, necrosis, solid growth or typical clear cell morphology were not observed (areas of tumor that appeared macroscopically suspicious for solid growth were completely submitted).

Imunohistochemical staining showed diffuse positivity for keratin AE1/AE3 (Figure 1H) and carbonic anhydrase 9 (CA9; box-like) (Figure 1I) and focal positivity for PAX8, CD10 (MME) and alpha-methylacyl-CoA racemase (AMACR). Conversely, staining with antibodies against CD31, CD34, ERG (Figure 1J) (these antibodies labeled only stromal vessels), keratins 7 and 20, GATA3, estrogen and progesterone receptors, high molecular weight keratins, smooth muscle actin (SMA), thyroglobulin (TG), thyroid transcriptional factor 1 (TTF1),transcription factor binding to IGHM enhancer 3 (TFE3), melan-A (MLANA), HMB45 (PMEL), 2-succino-cysteine (2SC), S100 and inhibin alpha (INHA) was completely negative. Immunohistochemical expression of fumarate hydratase (FH) was retained.

Next generation sequencing analysis revealed a clinically significant c.3481dup, p.(Arg1161LysfsTer13) and c.2050del, p.(Gln684Asnfs4) mutations of the tet methylcytosine dioxygenase 2 (TET2) gene and c.296, p.(Pro99GlnfsTer60) mutation of the von Hippel-Lindau (VHL) gene. No clinically significant amplification or fusion transcript of any of the examined genes was identified.

After careful consideration of all the above pathological features, a final diagnosis of CCRCC was rendered.

Discussion

CCRCC is the most frequent renal tumor exhibiting various architectural patterns, with solid, alveolar, and tubular being the most common. Cystic structures and intratumoral hemorrhage are also frequently recognized, but a predominant or pure hemangioma-like growth among CCRCC is exceedingly rare.^4–11

The present CCRCC exhibited several peculiar features including a purely hemangioma-like growth with no other detectable architectural patterns. The entire tumor consisted of numerous, variably sized cystic spaces and branching ectatic channels filled with blood and separated by sparse intervening fibrous stroma. The overall architecture was highly suggestive of cavernous hemangioma. However, on closer inspection, the lining cells exhibited rather epithelial than endothelial morphology, predominantly appearing as low cuboidal with mildly irregular round, oval or elongated nuclei, focally visible small nucleoli, and a narrow rim of pale eosinophilic cytoplasm with indistinct cell borders. The epithelial nature of the lining cells was unequivocally confirmed immunohistochemically by the positivity of keratin AE1/AE3 and the negativity of several vascular markers, definitively ruling out vascular neoplasia. Consistent with CCRCC, our tumor was further positive for CA9 (diffusely), PAX8 and AMACR (both focally) and completely negative for high molecular weight keratins and keratin 7 (among others).

A literature search revealed only one tumor ⁶ that closely resembled our current one. It involved a 62-year-old woman with an incidentally detected kidney tumor measuring 26 mm in the largest dimension. Its architecture was highly suggestive of a capillary hemangioma, as a network of anastomosing tiny capillary-like spaces was microscopically present. However, the luminal structures were positive for various keratins, CA9, and PAX8, thereby ruling out their vascular origin. We encountered a similar situation with some morphological and immunohistochemical differences. These were the larger size of the vascular spaces, the absence of tubulocystic structures formed by flattened eosinophilic cells, and the complete negativity for high molecular weight keratins and keratin 7 observed in our tumor. In terms of classification, the authors mainly considered CCRCC, but genetic and some immunohistochemical findings did not correspond to this entity. The tumor was positive for high molecular weight keratins and keratin 7, while fluorescence in situ hybridization analysis revealed disomy for chromosomes 7 and 17, with no detectable rearrangement of the TFE3 and TFEB genes (ruling out translocation RCC). As the key event in the molecular biology of CCRCC is the loss of the short arm of chromosome 3, the authors could not accurately classify the tumor and designated it as “unclassified hemangioma-like renal carcinoma.” Following this study, our tumor is only the second report of non-CCRCC exhibiting exclusively a hemangioma-like architecture.

There are only a few CCRCCs with a predominant hemangioma-like architecture in the literature. Kryvenko et al reported a series of 4 tumors with a complex vascular architecture composed of anastomosing capillary-sized vessels in a loose myxoid background, constituting 50% to 95% of the total tumor volume. ⁴ Regarding clinical features, the affected individuals were 3 men and 1 woman, aged 40 to 62 years. Interestingly, 3 of these patients were under 50 years of age, which is not entirely typical for CCRCC, as it mostly develops in patients in their 6th decade or older. Although both our study and that of Kryvenko et al describe CCRCCs with hemangioma-like architecture, there are considerable differences. While our tumor consisted exclusively of medium-sized and large vessel-like spaces lined by epithelium, the tumors in Kryvenko's series were predominantly composed of CD31-positive small vessels, producing a sinusoidal vascular pattern, interspersed with scattered foci of individual tumor cells exhibiting clear cell morphology. Thus, our tumor differs from those described in Kryvenko's series in several aspects. First, we did not find typical architectural or cytological features of CCRCC, and second, the lesional spaces were not vascular but epithelial in nature. Conversely, one of the few similarities between these two studies was the low nuclear grade of the tumor cells (1 to 2 according to the WHO/ISUP classification). An additional small series was reported by Kim et al, who published 2 renal cell carcinomas with clear cell morphology predominantly growing in a hemangioma-like fashion. ⁵ The first tumor affected a 75-year-old woman and corresponded to clear cell papillary renal tumor, with a vascular component consisting of small proliferating capillaries intermixed with microvacuolated stromal cells showing scattered atypia (ie, hemangioblastoma-like features). The second tumor developed in a 59-year-old man, whose histology revealed a homogeneous microvascular proliferation with scattered small groups of clear tumor cells (corresponding to CCRCC) in the background. Consistent with our study, high-grade features such as tumor necrosis, sarcomatoid/rhabdoid differentiation or increased mitotic activity (including atypical forms) were not described in any of these tumors. In fact, the studies by Kim and Kryvenko shared many similarities, as they reported renal cell tumors composed of small proliferating vessels arranged in various patterns, containing a minor component of tumor cells with clear cytoplasm.^4,5 These features thus fundamentally differed from our tumor, as we observed neither the typical clear cell morphology nor true vascular proliferation.

Molecular genetic testing performed in our current tumor identified mutations of the VHL and TET2 genes. Rearrangement of the VHL gene definitively confirmed the diagnosis of CCRCC. Compared to VHL, much less is known about the TET2 gene. It is located on chromosome 4q24 and is most likely a tumor suppressor gene. Its detailed functions are not yet known and it seems to be involved in the development of some hematological disorders including malignancies.^14,15

Apart from hemangioma, the main differential diagnostic considerations of the current tumor were multilocular cystic renal neoplasm of low malignant potential (MCNLMP) and MCNLMP-like TFE3-rearranged RCC. Consistent with MCNLMP, we found exclusively cystic spaces lined by a single layer of flattened epithelial cells, with no detectable cell clusters or expansive growth. On the other hand, we did not observe cells with voluminous clear cytoplasm surrounded by prominent cell membranes, which are pathognomonic for MCNLMP. ³ We considered different cytological features together with intraluminal hemorrhages to be the result of extensive regressive changes diffusely affecting the tumor. Hypothetically, the peculiar morphology of our tumor could correspond to the incipient stage of spontaneous regression of the tumor tissue; a phenomenon that has been recently reported in one case study. ¹⁶ Once MCNLMP is considered, it is crucial to differentiate it from cystic CCRCC, as MCNLMP behaves in a benign fashion, whereas CCRCC is a malignant neoplasm. Unfortunately, this is not reliably feasible using ancillary studies due to the overlapping immunohistochemical and molecular genetic features between the two tumors. In such differential diagnostic consideration, it is necessary to rely primarily on microscopic findings. Lack of high-grade features such as necrosis, increased mitotic activity, atypical mitosis, vascular invasion, sarcomatoid/rhabdoid differentiation or extrarenal spread into renal sinus or perinephric fat help to reliable distinguish MCNLMP from CCRCC. ³ MCNLMP-like TFE3-rearranged RCC that has been recently described in one case study, ¹⁷ was ruled out using molecular genetic testing.

Of the 14 hemangioma-like RCCs reported to date, 8 showed a hemangioblastoma-like morphology.^4–11 As a result of this fact, we very carefully examined our tumor in more than 15 tissue blocks, but we did not identify areas clearly mimicking hemangioblastoma. Recently, the concept of “hemangioblastoma-like” RCC has evolved. Based on the recently published series by Kojima et al, ¹¹ it seems important to distinguish between RCC with hemangioblastoma-like features and CCRCC resembling hemangioblastoma. All RCC with hemangioblastoma-like features were clinically indolent, lacked adverse prognostic parameters, were positive for S100, inhibin alpha, CA9, keratin 7, and high molecular weight keratins, and showed both CCRCC-like areas (consisting of tubular epithelial structures) and hemangioblastoma-like areas (consisting of short spindle cells and vessels that predominated over the tumor cells). In contrast, hemangioblastoma-like areas of CCRCCs resembling hemangioblastoma were composed of sparse spindle cells and vessels interspersed with tumor cells exhibiting clear cell morphology. None of the RCC with hemangioblastoma-like features showed mutations of the VHL gene, while 2 tumors harbored MTOR mutations. In our tumor, RCC with hemangioblastoma-like features was excluded on the basis of distinct morphological, immunohistochemical, and molecular genetic features (again, our tumor lacked overt hemangioblastoma-like morphology, was S100, inhibin alpha, keratin 7 and high molecular weight keratins negative, and displayed VHL mutation).

In addition to the peculiar features mentioned above, our tumor was unique in one more aspect. Despite the bland-appearing epithelial cell morphology, we detected direct spread of the tumor into the segmental branch of the renal vein (corresponding to stage pT3a). This finding was very surprising, as we did not observe any other worrisome feature that would indicate aggressive behavior. Based on the detected venous invasion, we definitively ruled out MCNLMP and finally classified the tumor as CCRCC with a pure hemangioma-like growth pattern. In this way, the current tumor differs from all previously published hemangioma-like RCCs, which, according to the available data, behaved non-aggressively and showed low-grade morphology.^4–10 The clinical aggressiveness of our tumor is further underlined by the very likely metastatic spread to the skeleton and deterioration of the general condition leading to the death of the patient less than 6 months after diagnosis.

Conclusion

In this report, we describe an unusual CCRCC forming exclusively blood filled hemangioma-like spaces lined by cytologically bland epithelial cells lacking clear cell morphology. To date, all reported clear-cell and non-clear cell RCCs mimicking hemangioma have been low-grade and non-aggressive. Our tumor is thus first of its kind that, despite a deceptively bland histology, invaded the renal vein and behaved aggressively.

Despite the peculiar architecture, the immunophenotype and molecular genetics of our tumor corresponded to CCRCC, indicating that the unusual growth pattern standing between hemangioma and MCNLMP is likely the result of extensive regressive changes and does not represent a distinct (novel) entity.

Finally, our study highlights that RCC should be included in the differential diagnostic consideration of renal vascular neoplasms and expands the spectrum of entities that can mimic hemangioma.