Renal Cell Carcinoma With Hemangioblastoma-Like Features and Leiomyomatous Stroma: A Rare Case Report and A Potential Pathological Diagnostic Pitfall

Introduction

Hemangioblastoma is an indolent mesenchymal stromal cell tumor that occurs most frequently in the central nervous system, primarily in the cerebellum. Most tumors are sporadic, whereas 20% to 30% occur in patients with Von Hippel-Lindau disease. ¹ Extraneuraxial hemangioblastoma, hemangioblastoma occurring outside the central nervous system, includes tumors originating from paraneuraxial structures, soft tissue, bone, kidney, stomach, and other visceral organs. ² Renal cell carcinoma (RCC) with hemangioblastoma-like features, first reported in 2014 by Montironi et al, has RCC-like and hemangioblastoma-like features. ³ This type of tumor is extremely rare, with only 10 reports in the English literature and two in the Chinese literature.^4-9 The 2022 World Health Organization (WHO) Classification of Tumors of the Urinary System and Male Genital Organs did not introduce it as a new, morphologically defined RCC entity. ¹⁰

Most tumor components have hemangioblastoma-like features, but typical RCC features are invariably found in the tumor. Interstitial-rich capillary networks are common in both components, and the hemangioblastoma-like tumor cells have mild nuclear heterogeneity with eosinophilic or vacuole-rich cytoplasm. ⁹ The two regional immunophenotypes of RCC with hemangioblastoma-like features are not identical because tumor cells in the RCC region are positive for PAX8, RCC, keratin AE1/AE3, EMA, vimentin, and CD10 (MME), and the tumor cells in the hemangioblastoma-like region are positive for inhibin-alpha, vimentin, and PAX8 and are weakly positive or negative for MME. The tumor cells are negative for keratin 7, HMB45, Melan-A, TFE3, TFEB, alpha-SMA, desmin, and H-caldesmon. ⁶ Renal cell carcinoma with (angio) leiomyomatous stroma is listed as a provisional entity in the 2016 WHO classification of renal epithelial tumors. ¹¹ Renal cell carcinoma with hemangioblastoma-like features and leiomyomatous stroma is more rare, with only four examples in the English literature.^7,9 As the RCC component of this type of tumor may be masked by a hemangioblastoma-like component and the latter may not be immunohistochemically distinguishable from hemangioblastoma of renal origin, it can be a diagnostic pitfall, particularly in needle aspiration biopsy samples. Accordingly, it is important to recognize the presence of this particular type of RCC morphology to avoid misdiagnosis. ⁵ Herein, we report a 59-year-old man diagnosed with RCC with hemangioblastoma-like features and leiomyomatous stroma, and perform a literature review to emphasize the requirement for increased awareness of the clinicopathological and molecular features of this particular type of RCC.

Patient Presentation

A 59-year-old man presented to our hospital with right-sided lumbar pain and hematuria persisting for seven months without an obvious trigger. The patient did not report urinary frequency, urgency, dysuria, or painful urination. He had a history of hypertension and tibial fracture, but no history of urological tumors. He had been taking regular blood-pressure-lowering medication for a long time and had good blood pressure control. Urological computed tomography revealed a right renal pelvic lesion, measuring approximately 29 mm × 24 mm, with localized involvement of the upper middle calyx of the right kidney and the upper part of the right ureter (Figure 1). These findings suggested renal pelvic carcinoma, and right nephrectomy and upper right ureterectomy were performed.

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Figure 1.

Radiological findings. (A) Sagittal and (B) axial computed tomography show a right renal pelvic mass, approximately 29 mm× 24 mm in size, with the lesion involving the upper and middle calyces of the right kidney and the upper segment of the right ureter (white arrow).

Macroscopically, a polypoid mass measuring 45 mm × 30 mm × 15 mm was observed in the renal pelvis with a grayish-reddish solid surface. There was a pedunculated mass in the renal pelvis, the pedicle of which was connected to the upper pole of the kidney, and there was a gray-yellow mass in the renal parenchyma, measuring 25 mm × 20 mm × 20 mm, with medium gray-yellow solidity on the cut surface, poorly delineated from the surrounding tissues, and not easily peeled off from the surrounding foci of the renal fat capsule. Histopathologically, two regions of tumor were observed at low magnification (Figure 2A). One of these two regions was hemangioblastoma-like, with polygonal epithelioid tumor cells, mildly eosinophilic cytoplasm arranged in sheets, mildly cellular with visible nucleoli, no obvious mitotic figures, and abundant branching blood vessels in the interstitium (Figure 2B). Furthermore, there was renal vein invasion by the tumor cells (Figure 2C). The other two regions were RCC-like with nested or vesicular tumor cells, clear cytoplasm, visible nucleoli, and a tumor interstitium rich in a network of thin-walled capillaries (Figure 2D). In the RCC-like areas the stroma was fibromuscular (Figure 2E). In some regions, the tumor cells transitioned from hemangioblastoma-like regions to RCC-like regions, where the border between the two was indistinct and intermingled (Figure 2F). In hemangioblastoma-like areas, the tumor cells were negative for keratin AE1/AE3 and diffusely positive for S100 and inhibin alpha. In contrast, RCC-like areas had the opposite pattern (Figure 3A-C). In addition, all the tumor cells were diffusely positive for vimentin and PAX8 (Figure 3D and E). The RCC-like areas were diffusely positive for CA9 and the hemangioblastoma-like areas were mostly positive for CA9 (Figure 3F). Moreover, all the tumor cells were negative for CD117 (KIT), TFE3, P504S, ALK, GATA3, HMB-45, and MelanA.

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Figure 2.

Histopathological findings. (A) Low magnification demonstrates the presence of two distinct areas within the tumor (magnification, 100×). (B) The upper left region is hemangioblastoma-like, with tumor cells that are cytoplasmic, mildly eosinophilic, polygonal, and mild, with abundant interstitial branching vessels (magnification, 400×). (C) The hemangioblastoma-like tumor cells are invading the renal vein (magnification, 10×). (D and E) The lower right region is renal cell carcinoma-like, with tumor cells having clear cytoplasm and a nested or vesicular arrangement, accompanied by a rich network of interstitial capillaries and focal fibromyxoma-like mesenchyme (magnification, 200×). (F) There is a mutual transition and integration of the two regions (magnification, 200×).

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Figure 3.

Immunohistochemical findings. In the hemangioblastoma-like area (upper left), tumor cells are keratin AE1/AE3-negative (A) and diffusely positive for S100 (B) and inhibin-alpha (C), while the renal cell carcinoma-like area (lower right) has the opposite pattern (magnification, 100×). There is diffuse positivity for vimentin (D) and PAX8 (E) in all tumor cells (magnification, 100×). (F) CA9 is diffusely positive in the lower right portion and predominantly positive in the upper left portion (magnification, 100×).

Finally, the diagnosis of RCC with hemangioblastoma-like features and leiomyomatous stroma was confirmed based on the radiological, histopathological, and immunohistochemical findings. The patient recovered well and was discharged without any postoperative treatment. The patient was followed up for 12 months postoperatively, and there were no signs of tumor recurrence or metastasis.

Discussion

Hemangioblastoma is uncommonly reported in sites other than the neuraxis, and studies have focused on the potential diagnostic pitfalls of misdiagnosing renal hemangioblastoma as clear cell RCC because of the histopathological similarities. ¹² PAX8, an organ-associated cell lineage development factor, may assist in the differentiation of these two tumors. It is expressed in normal renal, thyroid, and developing Müllerian duct epithelium, and is expressed in renal cell tumors, thyroid epithelial tumors, and tumors in the epithelium of the Müllerian ducts; however, it is not expressed in, angiomyolipoma, or juxtaglomerular cell tumor. ¹³ Nevertheless, it is important to note that approximately 50% of renal hemangioblastomas are focally positive for PAX8. ¹⁴ The relationship between these extremely rare renal tumors and renal hemangioblastoma has not been clarified. Initially, it was postulated be a morphological subtype of RCC; however, as data on RCC with hemangioblastoma-like features accumulated, this hypothesis has become less convincing. ¹⁴

Through a comprehensive literature review, we identified 13 reported examples of RCC with hemangioblastoma-like features, including the present tumor, summarized in Table 1. All tumors were in adults aged between 32 years and 87 years (mean age, 61 years), with an almost equal man-to-women ratio (6:5), and the left and right kidneys were affected in almost equal proportions (6:7). Tumors were generally small in diameter, 1.3 to 8.5 mm (mean diameter 39 mm). All reports of patients that were treated surgically, whether partial or radical nephrectomy was performed, tended to have a favorable prognosis without postoperative treatment. The histopathological features and molecular findings are summarized in Table 2. The RCC components of these tumors varied and included clear cell RCC, clear cell papillary renal cell tumor, and RCC with (angio) leiomyomatous stroma. However, in most tumors, the RCC component was clear cell RCC (Table 2). In clear cell RCC-like areas, tumors grow in sheet, solid, vesicular, tubular, or papillary forms. The tumors have clear cells to eosinophilic cells. ¹⁴ In most patients, the RCC components were low nuclear grade with early clinical staging. The proportion of the hemangioblastoma-like component varied, and in a few lesions, it was significantly dominant. In the hemangioblastoma-like areas there was vascular proliferation, with stroma-like hyaline cells tightly mixed with thin-walled blood vessels, and there were no tumor cells. Some tumor cells had hyaline globules or vacuoles, while a few scattered tumor cells had pleomorphic or bizarrely shaped nuclei. ¹⁴ It is particularly noteworthy that when the hemangioblastoma-like component is clearly predominant, it may be misdiagnosed as hemangioblastoma, morphologically and immunohistochemically. Although this can be a diagnostic pitfall, particularly for needle aspiration biopsy samples, awareness of the possibility of the presence of this type of RCC is important. Transition zones are typically found between these two components.^4-9 In addition, there was rarely intratumor necrosis and lymphovascular invasion. Leiomyomatous stroma was present in approximately 50% of the specimens. Limited data suggest that specific molecular alterations, including the TSC2, SETD2, and MTOR genes, are often associated with concomitant leiomyomatous stroma. It had been hypothesized in the literature that RCC with hemangioblastoma-like features and RCC with (angio) leiomyomatous stroma might be in a common tumor spectrum. However, current evidence lacks sufficient samples and comprehensive analyses to confirm this hypothesis. ¹⁴ Tumor cells in RCC-like regions were positive for PAX8, CA9, MME, EMA, keratin AE1/AE3, RCC markers, and keratin 7, and negative for P504S, inhibin-alpha, and S100. In contrast, tumor cells in hemangioblastoma-like regions were positive for inhibin-alpha and S100, and negative for keratin 7. For the other antibody stains, tumor cells in hemangioblastoma-like regions had immunological characteristics similar to those in clear-cell RCC-like regions.^4-9

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Table 1.

Cases of Reported Cases of Renal Cell Carcinoma With Hemangioblastoma-Like Features (Including the Current Case).

Reference	Case no.	Age (years)	Gender	Side	Size (cm)	Operation mode	Survival (follow-up)
Montironi et al 3	1-2	49, 32	F, M	Right	5.5, 3.2	Partial nephrectomy, Radical nephrectomy	NED (36 months)
Sancheti et al 4	3	69	M	Left	6.5	Radical nephrectomy	NA
Kim et al 5	4	75	F	Left	4.0	Partial nephrectomy	NED (6 months)
Huang et al 6	5-6	NA	NA	Right, Left	4.5, 8.5	Radical nephrectomy	NA
Kong et al 7	7	38	F	Right	2.0	Partial nephrectomy	NED (18 months)
Lei et al 8	8	49	F	Right	2.0	Partial nephrectomy	NED (12 months)
Kojima et al 9	9-12	65, 70, 78, 87	M, M, M, F	Right, Left, Left, Left	1.3, 1.8, 1.5, 3.0	NA	NED (19 months), NED (11 months), NED (10 months), NED (3 months)
Current case	13	59	M	Right	7.0	Total nephrectomy	NED (14 months)

Abbreviations: F, female; M, male; NA, not applicable (not done); NED, no evidence of disease.

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Table 2.

Pathological Characteristics and Molecular Findings of Reported Cases of Renal Cell Carcinoma With Hemangioblastoma-Like Features (Including the Current Case).

Reference	Case no.	Subtype	WHO/ISUP grade	pT	HB (%)	Necrosis	LVI	LMS	Molecular findings
Montironi et al 3	1-2	CCRCC	1	T1b- 1, T1a- 1	70%- 1, 60%- 1	Absent	Absent	Absent	NA
Sancheti et al 4	3	CCRCC	NA	T3a	>50%	Present	Present	Absent	NA
Kim et al 5	4	CCPRCC	2-3	T1a	NA	Absent	Absent	NA	NA
Huang et al 6	5-6	CCRCC	NA	T1b- 1, T2a- 1	NA	Absent	Absent	NA	FISH; No TFE3 or TFEB gene translocation
Kong et al 7	7	RCCLMS	1-2	T1a	<50%	Absent	Absent	Present	NGS; Presence of TSC2 and SETD2 gene mutations
Lei et al 8	8	CCRCC	1	T1a	>50%	Absent	Absent	NA	NA
Kojima et al 9	9-12	RCC	1-2	T1a	40%- 3, 90%- 1	NA	Absent	Present- 3, Absent-1	NGS; Presence of MTOR gene mutations- 2, No specific variants were detected- 2
Current case	13	RCC	2	T3a	80%	Present	Present	Present	NA

Abbreviations: CCRCC, clear cell renal cell carcinoma; CCPRCC, clear cell papillary renal cell carcinoma; HB, hemangioblastoma-like area in the tumor; ISUP, International Society of Urologic Pathology; LVI, lymphovascular invasion; LMS, leiomyomatous stroma; NA, not applicable (not done); RCC, renal cell carcinoma; RCCLMS, renal cell carcinoma with (angio) leiomyomatous stroma; WHO, World Health Organization.

It is necessary to differentiate this entity from a variety of tumors, including RCC, hemangioblastoma, paraganglioma, MITF gene translocation-associated RCC family of tumors, and perivascular epithelioid cell neoplasm (PEComa). Renal cell carcinoma can present with multiple morphological patterns but, in essence, belong to the same tumor, unlike RCC with hemangioblastoma-like features, which contains two distinct components in its essential manifestations. ¹⁵ The main point of differentiation from hemangioblastoma of the kidney is that there was only one element of hemangioblastoma and no element of RCC. ¹⁶ Paraganglioma tumor cell morphology can be similar to that in hemangioblastoma-like regions, but it expresses neurogenic markers as well as support cells expressing S100. ¹⁷ MITF family translocation-associated RCC family tumors include Xp11.2 translocation/TFE3 gene fusion-associated RCC, TFEB, and TFEC gene translocation RCC. Histopathologically, the tumor cells have diverse morphology, with solid nested, papillary, tubular or sheet-like arrangement, clear, eosinophilic or light stained cytoplasm, psammoma bodies and calcification, and some have intracytoplasmic melanin granules; immunohistochemical detection of TFE3, TFEB, and TFEC could assist in the diagnosis, and the diagnosis could be confirmed by fluorescence in-situ hybridization detection of the TFE3, TFEB, and TFEC genes in uncertain lesions.^6,18 PEComa, predominantly found in the kidney, has four components in varying proportions: adipose, thick-walled malformed or thin-walled blood vessels, spindle-shaped smooth-muscle-like cells, and epithelioid cells. Immunohistochemically, PEComa tumor cells express smooth muscle (alpha-SMA, desmin, and H-caldesmon) and melanin (HMB45, Melan-A, PNL2, and MITF) markers but rarely express TFE3. ¹⁹

Conclusion

In summary, we report a highly unusual yet instructive tumor of RCC with hemangioblastoma-like features that may represent a potential diagnostic pitfall in histopathology. The diagnosis of this type of tumor is largely based on a combination of clinicopathology, immunophenotyping, and molecular testing when necessary. A thorough understanding of these characteristics may assist in averting the risk of misdiagnosis. In addition, when diagnosing renal hemangioblastoma, it is imperative to consider the possibility of the presence of this tumor entity. This may assist histopathologists to more easily recognize this type of tumor. Regardless of the presence of leiomyomatous stroma, RCC with hemangioblastoma-like features without postoperative recurrence or metastasis have been consistently reported. The superior prognosis may be related to the RCC component, which tends to have a lower nuclear grading of cells and earlier staging, but more specimens and long-term observations are required to determine the biological behavior and prognosis. In addition, it remains to be determined whether these tumors are a new tumor entity or a morphological variant of RCC.