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Low-grade clear cell renal cell carcinoma mimicking hemangioma of the kidney: a series of 4 cases.

Clear cell renal cell carcinoma (CCRCC) is the most common type of sporadic kidney cancer in adults and a frequent entity among those associated with end-stage renal disease. (1-3) It has a typical gross appearance of a well-circumscribed golden-yellow mass because of abundant cytoplasmic lipid in malignant cells. (3,4) Microscopically, in addition to characteristic clear cell morphology determined by cytoplasmic lipid and glycogen accumulation, the tumor demonstrates a rich vascular network of fine sinusoid-like capillaries separating nests of neoplastic cells. (3-5) The rich vascular supply of clear cell renal cell carcinoma determines its typical enhancing radiologic appearance in contrast infusion studies. (6) Mixed enhancing pattern with high and low attenuation areas is a characteristic feature of diagnostic imaging in CCRCC. Areas of necrosis or myxoid/cystic degeneration account for the low attenuation. The vasculature seen in these tumors is characteristic and helps pathologists distinguish clear cell renal cell carcinoma from other types of renal cell carcinoma. (3) In the workup of a metastatic lesion, this fine arborizing vasculature is also a useful clue to attribute kidney as the primary site. (7,8) This rich vascularity and its critical role in tumor progression is also targeted as a developing therapy of clear cell renal cell carcinoma. (9,10) Larger tumors frequently demonstrate areas of low cellularity, stromal edema, and hyalinization. (11) Intratumoral hemorrhage is frequent in renal cell carcinoma and may be attributed to its rich vasculature. In this series, we report 4 cases of clear cell renal cell carcinoma that were paucicellular for carcinoma cells associated with an unusual microvasculature pattern mimicking anastomosing hemangioma.

MATERIALS AND METHODS

Following the identification of an index case, slides from 93 consecutive CCRCCs from the surgical pathology files at the Henry Ford Hospital, Detroit, Michigan (2009-2010) were retrospectively reviewed. Two additional cases met the criteria of anastomosing hemangioma-like pattern in CCRCC. A fourth case was derived from consultation material from 1 of the authors (J.I.E.). Follow-up information was obtained from electronic medical records of the patients or from the primary pathologists and urologists. Immunohistochemical staining for CD31 and histochemical stains with Alcian blue pH 2.5 and Verhoeff-van Gieson elastic stain were performed in 3 study cases. Immunohistochemistry for pancytokeratin (AE1/AE3) was performed in 2 cases. One case was subjected to epithelial membrane antigen and CD10 immunohistochemical stains and histochemical staining for periodic acid-Schiff with and without diastase digestion.

RESULTS

The clinical and selected pathologic features are summarized in the Table. There were 3 men and 1 woman, with ages ranging from 40 to 66 years (mean, 48.8 years). One patient presented with nausea and abdominal pain related to tumor. Another patient presented with ischemic bowel disease with subsequent computed tomography demonstrating an incidental renal tumor. The other patient had an asymptomatic tumor discovered on computed tomography screen for pancreatic cancer. The clinical presentation was unknown in 1 patient. Imaging studies were available in 3 patients, with all showing solid masses heterogeneously enhancing with contrast infusion on computed tomography. Two patients underwent total nephrectomy and the other 2 had kidney-sparing excision of the carcinoma (partial nephrectomy). Resection specimens revealed well-demarcated soft red-brown tumors with thick capsules (Figure 1). One tumor had scattered small yellow areas on cut surface. All tumors were limited to the kidney and stage was determined by size (pT1a-2, pT1b--2) according to the 7th edition of the AJCC TNM staging system. (12)

Microscopically, at low-power magnification the tumors were composed of a compact anastomosing capillary network supported in the edematous and myxoid background (Figure 2, A). The density of the vasculature varied with more compact arrangement of the vessels at the periphery of tumors. The complex vascular network comprised from 50% to 95% of tumor volumes (Table). At the periphery of the tumors, the nonneoplastic blood vessels had a focally infiltrative pattern with entrapment of glomeruli and kidney tubules between the vessels (Figure 2, B). There were prominent and tortuous thick-walled arteries and veins with irregular smooth muscle proliferation. Occasional intratumoral malformed larger arteries and veins were seen. Arteries showed thickened intimal layer with Alcian blue--positive mucinous deposits (Figure 2, C, inset). Elastic fibers of internal elastic lamina were duplicated (Figure 2, C), fragmented, and often discontinuous with irregularly thickened muscular walls, particularly in the arteries at the periphery of the tumor. Foci of heterotopic bone formation were seen in 2 cases.

At high power, 2 patterns of vascular architecture were identified. The tumors demonstrated either dense anastomosing sinusoid-like vasculature (Figure 2, D) with scant chronic inflammatory cells or a central large "feeding" vessel surrounded by capillary-type vessels with swollen endothelium (Figure 2, E). Hobnail appearance of endothelial cells was focally seen in the sinusoidal vasculature (Figure 2, D). No hyaline globules were seen in the endothelial cells on hematoxylin-eosin or periodic acid-Schiff stains. Thrombosis, extravasated red blood cells, and hemosiderin-laden macrophages were also seen. Three cases had a very scant amount of tumor, mostly represented by individual tumor cells or small islands of tumor cells aggregated around the vasculature (Figure 2, F). One case had scattered foci of CCRCC with conventional architecture intermixed with areas of anastomosing hemangioma-like vasculature. Three tumors were Fuhrman nuclear grade 2 and 1 tumor showed grade 1 nuclei. (13) The epithelial nature of these tumor cells and/or nests was confirmed by positive pancytokeratin (AE1/AE3) and epithelial membrane antigen stains (Figure 2, F, inset). The carcinoma cells were also focally positive for CD10 stain. Immunohistochemistry revealed that many cells that were originally interpreted as lymphocytes with artificial halo effect were tumor cells dispersed individually between blood vessels (Figure 2, F).

COMMENT

Clear cell renal cell carcinoma is the most frequent sporadic malignancy in the adult kidney and a frequent entity among those seen in patients with end-stage renal disease. (1-3) One of the distinctive features of clear cell renal cell carcinoma is characteristic microvasculature separating the nests of neoplastic cells. (3-5) Some authors stress the importance of the vascular architecture in clear cell renal cell carcinoma as one of its most important diagnostic features. (4) Despite the kidney being a vasculature-rich organ, primary vascular lesions of the kidney are rare. Brown et al (14) identified only around 200 renal hemangiomas and 25 angiosarcomas in the English language literature. A new variant of unusual tentatively benign vascular neoplasm seen in the genitourinary system, and particularly the kidney, has been recently described under the designation of anastomosing hemangioma by Montgomery and Epstein (15) and Kryvenko et al. (16)

We describe 4 cases of clear cell renal cell carcinoma with extensive loss of epithelial tumor cells accompanied by vascular proliferation closely resembling anastomosing hemangioma. Foci analogous to more traditional hemangioma composed of a larger central feeding vessel surrounded by vaguely lobular vascular proliferation were seen as well. As described in the original publication, anastomosing hemangioma overlaps morphologically with anastomosing and hobnail hemangiomas seen in soft tissue and skin and with well-differentiated angiosarcoma. However, to our knowledge, neither of the above entities has been reported in the genitourinary system. It should be noted that anastomosing hemangioma taxonomy has not yet been uniformly accepted although we consider this lesion to be a unique clinicopathologic entity found in the genitourinary system.

Radiologically, the tumors in our series presented as solitary solid renal masses heterogeneously enhancing in the nephrogenic phase of contrast infusion. Analogous radiologic presentations of anastomosing hemangioma and other benign vascular lesions of the kidney have been reported. (16-18) The unique histology of RCC was seen in younger patients, with 3 individuals being less than 50 years of age. There is no distinct explanation for such age distribution; however, better immune response in younger patients may be in part responsible for degeneration of tumor cells. Grossly, CCRCC mimicking anastomosing hemangioma had a red-brown color (Figure 1), in contrast to the bright yellow color typically seen in clear cell renal cell carcinoma. This unusual gross appearance may be attributed to the loss of tumor cells and rich hypervascular network. A similar gross appearance may be seen in anastomosing hemangioma and other benign vascular tumors of the kidney. (14-16) Microscopically, the architecture and extent of the vasculature were essentially identical to those seen in anastomosing hemangioma. Partial or complete spontaneous regression of CCRCC and its metastases has been rarely reported. (19-21) Intratumoral hemorrhage, calcification, and poorly vascularized loose myxoid stroma with or without hyalinization associated with partial loss of neoplastic tissue are commonly seen in CCRCC. (11) However, an extensive hemangioma-like vascular proliferation is exceptional. The infiltrative vascular pattern at the periphery of the lesions and hobnail appearance of endothelial cells are additional mimickers of low-grade angiosarcoma. However, both of these features have been described in anastomosing hemangioma, (15,16) and other features of angiosarcoma in the vascular areas were not seen. (14)

The presence of heterotopic bone formation is an unusual feature of clear cell renal cell carcinoma, (11,22,2) 3 possibly related to degenerative areas of tumor. Although we saw it in 50% of our cases, however, ossification has not been previously reported in anastomosing hemangioma or other vascular neoplasms of the kidney. Carcinoma cells in vascular areas were distributed in a single cell pattern, and, because of their low nuclear grade, they closely mimicked lymphocytes with artificial halo effect. Even with thorough sampling, immunohistochemical stains were needed in 2 cases to establish the exact nature of the neoplasm. In cases where a hemangioma-like vasculature pattern represents only a fraction of a CCRCC, percutaneous imaging-guided renal needle biopsy could be misinterpreted as a primary vascular neoplasm. If the diagnosis of benign vascular neoplasm is considered in an excision specimen, it is very important to extensively sample (entire submission of smaller tumors) the lesion that may identify areas diagnostic of renal cell carcinoma. The interpretation of imaging-guided needle core biopsies of the renal masses with similar morphology may be challenging. One should consider pancytokeratin and CD10 immunostaining in such cases so as not to mislabel Fuhrman grade 1 individual carcinoma cells with clear cytoplasm as lymphocytes with artificial halo effect.

In summary, we report an unusual histologic pattern of low Fuhrman nuclear grade clear cell renal cell carcinoma with rich anastomosing vascularity and paucity of carcinoma cells. The findings were misleading both grossly and microscopically and mimicked anastomosing hemangioma. Caution should be exercised while interpreting imaging-guided needle biopsies of renal masses with rich vasculature. In excision, extensive sampling and immunohistochemical workup of what is deemed to be a vascular neoplasm of the kidney is needed to rule out the presence of individual carcinoma cells or small clusters of carcinoma cells.

References

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(2.) Tickoo SK, dePeralta-Venturina MN, Harik LR, et al. Spectrum of epithelial neoplasms in end-stage renal disease: an experience from 66 tumor-bearing kidneys with emphasis on histologic patterns distinct from those in sporadic adult renal neoplasia. Am I Surg Pathol. 2006; 30(2):141-153.

(3.) Grignon DJ, Che M. Clear cell renal cell carcinoma. Clin Lab Med. 2005; 25(2):305-316.

(4.) Tickoo SK, Vankalakunti M, Reuter VE. Clear cell renal cell carcinoma. In: Amin MB, McKenneyJK, Tickoo SK, Paner GP, Shen SS, Velazquez EF, Cubilla AL, Ro JY, Reuter VE, eds. Diagnostic Pathology: Genitourinary. Altona, Manitoba, Canada: Amirsys; 2010:1.34-1.41.

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(13.) Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am I Surg Pathol. 1982; 6(7):655-663.

(14.) Brown JG, Folpe AL, Rao P, et al. Primary vascular tumors and tumor-like lesions of the kidney: a clinicopathologic analysis of 25 cases. Am I Surg Pathol. 2010; 34(7):942-949.

(15.) Montgomery E, Epstein JI. Anastomosing hemangioma of the genitourinary tract: a lesion mimicking angiosarcoma. Am ISurgPathol. 2009; 33(9):1364-1369.

(16.) Kryvenko ON, Gupta NS, Meier FA, Lee MW, Epstein JI. Anastomosing hemangioma of the genitourinary system: eight cases in the kidney and ovary with immunohistochemical and ultrastructural analysis. Am I Clin Pathol. 2011; 136(3):450-457.

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Oleksandr N. Kryvenko, MD; Leonardo Roquero, MD; Nilesh S. Gupta, MD; Min W. Lee, MD; Jonathan I. Epstein, MD

Accepted for publication April 19, 2012.

From the Department of Pathology, Henry Ford Hospital, Detroit, Michigan (Drs Kryvenko, Roquero, Gupta, and Lee); and the Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland (Dr Epstein). Dr Kryvenko is now located at The Johns Hopkins Hospital, Department of Pathology, Baltimore, Maryland.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Oleksandr N. Kryvenko, MD, The Johns Hopkins Hospital, Weinberg 2242, 401 N. Broadway, Baltimore, MD 21231 (e-mail: okryven2@jhmi.edu).

Clinicopathologic Characteristics of 4 Patients

Case    Age,          Operation          Tumor      Gross
        y/Sex                            Size    Appearance

1       40/F    Nephrectomy, L            4.4    Red-brown
2       66/M    Nephrectomy, R            5.5    Red-brown
3       47/M    Partial nephrectomy, L    2.5    Red-brown
4       42/M    Partial nephrectomy, L    3.5    Red-brown
                                                   to yellow

Case   Age,    Vasculature,   Follow-up
       y/Sex        %

1      40/F         95        NED, 16 mo
2      66/M         95        NED, 30 mo
3      47/M         80        NED, 32 mo
4      42/M         50        NED, 24 mo

Abbreviation: NED, no evidence of disease.


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Author:Kryvenko, Oleksandr N.; Roquero, Leonardo; Gupta, Nilesh S.; Lee, Min W.; Epstein, Jonathan I.
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Report
Date:Feb 1, 2013
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