- Email: [email protected]
Characterization of Glomus Tumors of the Kidney
Case Report
Characterization of Glomus Tumors of the Kidney Roger Li,1 Firas G. Petros,1 Charles J. Davis, Jr,2 John F. Ward1 Clinical Practice Points Renal glomus tumors are traditionally thought to be
Potential clincopathologic features increasing the risk
benign mesenchymal tumors of the kidney. We report the first case of recurrent renal glomus tumor after surgical resection, and demonstrate the importance of long-term clinical follow-up.
of metastasis include large size, mild and diffuse nuclear atypia, presence of necrosis, scattered mitoses, and lymphovascular invasion. These risk factors need to be validated in future cases.
Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2017 Elsevier Inc. All rights reserved. Keywords: Glomangioma, Glomus tumor, Kidney neoplasm, Malignant glomus tumor, Vascular tumors
Introduction Glomus tumors are rare mesenchymal neoplasms arising from the neuromyoarterial glomus, a cutaneous structure that functions in temperature regulation via arteriovenous shunting of blood.1 They typically occur as painful nodules in the areas rich in glomus bodies, such as the subungual regions of digits and deep dermis of the palm, wrist, forearm, and foot. Congenital familial multiple glomus tumor leads to multifocal tumors and demonstrates an autosomal dominant inheritance pattern with variable expressivity and incomplete penetrance.2 Mutations in the glomulin gene, located in 1p22.1, have been implicated.3 In addition, somatic mutations involving fragile sites on chromosome 1p were found to complete the Knudson 2-hit model, leading to formation of the glomus tumors.4 Visceral organs are devoid of glomus bodies, and thus rarely give rise to glomus tumors.5 A recent comprehensive review of the literature yielded 19 cases of primary renal glomus tumor, all but 1 of which were localized to the kidney without evidence of malignant progression.5 We report a series of 3 cases of renal glomus tumors accessioned at the Armed Forces Institute of Pathology over a 15-year period. Of these, 1 exhibited pathologic features concerning for local invasion, whereas another suffered distant metastases 7 years after primary resection.
1 Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX 2 Armed Forces Institute of Pathology, Washington, DC
Submitted: Aug 25, 2017; Accepted: Sep 1, 2017 Address for correspondence: John F. Ward, MD, Department of Urology, Unit 1373, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 E-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2017.09.002
Case Reports Case 1
A 31-year-old Caucasian woman presented with total gross hematuria of 1 week duration and 2 days of right-flank pain. She denied weight loss, but did report experiencing “hot flashes” for 6 months. A physical examination demonstrated a smooth, non-tender abdominal mass extending approximately 8 cm below the right costal margin. Computed tomography imaging revealed a 16-cm heterogeneous mass with an area of central necrosis (Figure 1A). There was no evidence of extension into the perirenal space or of renal vein thrombosis. Multiple enlarged lymph nodes were present along the inferior vena cava and inter-aortocaval region. Evaluations by bone scan and chest radiograph were unrevealing for metastasis. A right radical nephrectomy with extended lymphadenectomy was performed in an uncomplicated manner through an extended right subcostal incision. Grossly, the tumor was well-circumscribed and without extrarenal extension. It occupied 80% of the kidney, involving both the cortex and the medulla. The cut surface was variegated (yellow to grayish-white, hemorrhagic, necrotic, and firm) with aberrant small vessels and concentric growth-forming nodules and sheets (Figure 1B). Necrosis was seen in 10% of the tumor specimen. Microscopically, the cells were round and uniform, with centrally placed round nuclei within an amphophilic or eosinophilic cytoplasm. Capillary-size vessels were circumscribed by collars of the small cells (Figure 1C). In other areas, the glomus cells formed a reticular morphology (Figure 1D). Nuclear atypia was rare, and mitotic rate was 10 of 50 high-powered fields (HPFs). Lymphovascular invasion was present. Smooth-muscle actin was expressed by most of the tumor cells (Figure 1E). There was abundant expression of Type IV collagen, and the cells were positive for vimentin and negative for keratin A1/A3. Immunohistochemical stains were also negative for CK7, CK20, CEA, chromogranin, Hale’s colloidal iron, EMA, RCC, and CD10.
Clinical Genitourinary Cancer Month 2017
-1
Glomus Tumors of the Kidney Figure 1 Imaging and Histologic Features of a 33-year-old Caucasian Woman With Renal Glomus Tumor (Case 1). A, Venous Phase Post-contrast Computed Tomography Image Showing Mass Arising Within the Interpolar Region of the Right Kidney; B, Grossly, a 13-cm Variegated, Hemorrhagic Tumor Was Seen Involving the Majority of the Kidney; C, Collars of Glomus Cells Surrounding Capillary-sized Vessels; D, Glomus Cells Circumscribe Small Vessels and Form Expanses With a Reticular Morphology; E, Essentially All Glomus Cells Show Strong Immunoreactivity With Smooth Muscle Actin
2
-
After 7 years of uneventful follow-up, the patient was found to have multiple left renal masses. She underwent open partial nephrectomy, yielding 3 distinct tumors, which were 7.4 cm, 5.2 cm, and 7.0 cm in size. Pathologic evaluation of all tumors was consistent with glomus tumors of the kidney. Macroscopic invasion of the peritumoral capsule was present in all 3 tumors, and resection margins were negative of tumor. After another relapse-free interval of 2 years, recurrent masses were again found in the left kidney remnant, spleen, right gluteal muscle, and brain. She went on to resection of her gluteal muscle and magnetic resonance imaging-guided resection of the brain lesion, both confirmed histologically to be metastatic glomus tumor. Thereafter, progressive metastatic disease was found in the lungs, liver, small bowel, and skin. She received 1 cycle of salvage cyclophosphamide, vincristine, and dacarbazine, with minimal effect. Of
Clinical Genitourinary Cancer Month 2017
note, her cutaneous lesions actively expressed IGF-2, causing nonislet cell tumor hypoglycemia requiring treatment with dexamethasone and intravenous glucagon. After multiple hospitalizations and palliative procedures, the patient succumbed to her disease more than 13 years after original diagnosis.
Case 2 An otherwise healthy 33-year-old Caucasian woman was found to have a left-kidney tumor during evaluation of a heart murmur. Nephrectomy revealed a large lobulated and hemorrhagic tumor measuring 9.5 cm by 6.0 cm. The cut surface had a nodular appearance, and the renal vein was filled with a tumor thrombus. The inferior vena cava also contained tumor, and the tricuspid valve had vegetation positive for tumor cells.
Roger Li et al Figure 2 A Network of Capillary-sized Vessels Surrounded by Small, Uniform Glomus Cells (Case 2)
Figure 3 Histologic Features of a 55-year-old Caucasian Male With Renal Glomangiomyoma (Case 3). A, A Nodule of Glomus Cells (Lower Field) Is Circumscribed by Elongated Cells Resembling Mature Smooth-muscle Cells; B, H-Caldesmon Highlights the Smooth-muscle Differentiation; C, Pericellular Type IV Collagen Expression
Microscopically, the tumor consisted of numerous capillary-size vascular channels, and between them were sheets of small cells with vesicular nuclei and little cytoplasm (Figure 2). Widely scattered clones of cells had increased eosinophilic cytoplasm and some nuclear variation. The cells were negative for cytokeratin AE1/AE3 and ICAM 5.2 and were negative for chromogranin synaptophysim, desmin, and CD99 stains. Vimentin was focally positive, and muscle-specific actin was strongly and diffusely reactive. The tumor focally invaded into the renal capsule. The patient was diagnosed with glomus tumor of uncertain malignant potential. We identified this tumor as possibly having some malignant potential, realizing that malignant glomus tumors are rare. We are aware that cardiac metastasis could represent passive transfer from the renal vein as we have seen with renal angiomyolipomas.
Case 3 A 55-year-old Caucasian man with no symptoms and no significant past medical history was undergoing a routine physical examination when microscopic hematuria was revealed on urinalysis. Intravenous pyelography and renal ultrasonography were performed revealing a small, cystic mass within the left kidney. A nephron-sparing nephrectomy was performed without incident. A well-circumscribed, 1.5-cm diameter mass (cystic flocculent) was removed from the renal cortex of this kidney along with a small rim of normal-appearing tissue. The cut surface of this mass revealed multiple tan-gray nodules of rubbery tissue. Microscopically, the cystic appearance was owing to central cystic degeneration rather than hemorrhage or necrosis. The tumor consisted of multiple nodules composed of uniformly rounded cells with eosinophilic cytoplasm, vesicular nuclei, and small nucleoli. Around the periphery of the smallest of the nodules, the cells became spindled and resembled normal smooth-muscle cells (Figure 3A). The latter were reactive for h-Caldesmon (Figure 3B), and both cell types were positive for smooth-muscle actin. In a few nodules, the desmin reacted with many of the glomus cells, and there was diffused pericellular expression of collagen type 4 (Figure 3C). The patient was diagnosed with glomangiomyoma.
Discussion The 3 cases reported herein span the spectrum of malignant potential seen in renal glomus tumors. To date, the vast majority of the reported cases in literature chronicle benign clinical courses after surgical resection, exemplified by case 3 in the current series. Only 1 case of de novo metastatic renal glomus tumor to the spine and pelvic bone has been previously reported.6 We report the first case of recurrent metastasis after surgical excision of the primary tumor. Additionally, case 2 confirms the capability of glomus tumors for local invasion into the renal vein and inferior vena cava. Taken together, these cases directly oppose the conventional perception of low malignant potential associated with this entity.7,8 As illustrated by the clinical course in case 1, surveillance imaging may be required beyond 7 years after surgical resection. Malignant potential of the neoplasm may be deduced from its size as well as macroscopic and microscopic appearances. Specific to case 1, characteristics portending to malignant progression include > 10-cm diameter, mild and diffuse nuclear atypia, presence of necrosis, scattered mitoses, and lymphovascular invasion. However,
Clinical Genitourinary Cancer Month 2017
-3
Glomus Tumors of the Kidney owing to the paucity of renal glomus tumors, these potential predictors of disease recurrence cannot be corroborated. Instead, inferences need to be made from analyses of glomus tumors arising elsewhere in the body. Histologic examination of 2 well-documented cases of metastatic cutaneous glomangiosarcoma both exhibited frequent mitotic figures.9,10 This was corroborated by a study of 52 glomus tumors, identifying high nuclear grade and mitotic activity 5 of 50 HPFs as a potential indicator of malignant potential.11 Consistent with this, the mitotic rate in case 1 was 10 of 50 HPFs. Contrarily, others have demonstrated successful surgical extirpation of tumors exhibiting pleomorphic nuclei as well as high mitotic activity (7 of 50 HPFs).8 However, the results of this study need to be interpreted with caution owing to the insufficient follow-up of 6 months. As demonstrated in case 1, delayed recurrence may occur more than 5 years from the time of surgery. Other factors predisposing an increased 5-year metastatic risk included deep location (P ¼ .004), size more than 2 cm (P ¼ .005), and atypical mitotic figures (P ¼ .004). The implication of these risk factors with regard to the malignant potential of renal glomus tumor is uncertain. However, the classification scheme of atypical glomus tumors proposed by Folpe et al cannot be directly applied to renal glomus tumor, as size > 2 cm and deep location alone qualifies the tumor as a malignant glomus tumor.11 In contrast, many renal glomus tumors larger than 2 cm and located deeper than the muscularis fascia by definition followed benign clinical courses.12 As illustrated in case 2, infiltrative pattern of growth has been previously described in renal glomus tumor.6,13 Whether the locally infiltrative pattern of growth leads to distant metastasis is unknown. Despite many attempts, no follow-up clinical information for case 2 in the current series could be solicited. As such, the clinical course after surgical excision of locally advanced renal glomus tumor remains undetermined. Renal glomus tumors appear as nonspecific, heterogeneous, enhancing lesions on cross-sectional imaging, making preoperative diagnosis difficult. To date, no data exist on needle aspiration or biopsy. Instead, the diagnosis of glomus tumor is made by histologic examination and immunohistochemical analysis postoperatively. In general, glomus tumors exhibit glomus cells, vasculature, and smooth muscle cells, and can be subcategorized as solid glomus tumor, glomangioma, or glomangiomyoma depending on the specific composition.1 Microscopically, branching vascular channels are lined by endothelial cells, interspersed by uniformly round to ovoid glomus cells forming nests, sheets, and trabeculae. Tumor cells have eosinophilic or amphiphilic cytoplasm with well-defined borders and single, centralized, uniform, small “punched out” nucleus. Two distinct histologic patterns have been linked to benign tumor phenotype: symplastic tumors with pleomorphic nuclei without other high-grade features (increased cellularity or increased mitotic activity) and glomangiomatosis with infiltrative growth of vessels invested by glomus cells.11 Although easily distinguished from epithelial tumors of the kidney (ie, renal cell carcinoma), differentiation from other mesenchymal renal tumors may be difficult and often requires immunohistochemical staining. Angiomyolipoma of the kidney, the
4
-
Clinical Genitourinary Cancer Month 2017
most common mesenchymal renal tumor, can be diagnosed using HMB-45 or A103 (Melan-A/Mart-1) staining that highlights the perivascular epithelioid cells.14 Other differential diagnostic considerations include hemangioma or a venous malformation, smooth-muscle neoplasm (epithelioid leiomyoma), carcinoid tumor, paraganglioma, hemangiopericytomas, and juxtaglomerular tumors. Accurate diagnosis is made on immunohistochemical staining in which glomus tumors stain positive for actin and negative for all neuroendocrine markers. Tumors of a neuroendocrine origin show positivity for neuron-specific enolase and chromogranin. Histologically, glomus tumors display a more prominent intercellular basal lamina outlining individual or small groups of cells. These differential mimickers also complicate accurate assessment of the incidence of noncutaneous glomus tumors.
Conclusions Renal glomus tumors are a rare entity traditionally thought to follow a benign clinical course. In light of the current case series, we demonstrate the malignant potential of rare forms of renal glomus tumors. Potential clincopathologic features increasing the risk of metastasis include large size, mild and diffuse nuclear atypia, presence of necrosis, scattered mitoses, and lymphovascular invasion. These predictive features need to be validated in future case reports of this rare tumor.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Gombos Z, Zhang PJ. Glomus tumor. Arch Pathol Lab Med 2008; 132:1448-52. 2. Calduch L, Monteagudo C, Martinez-Ruiz E, et al. Familial generalized multiple glomangiomyoma: report of a new family, with immunohistochemical and ultrastructural studies and review of the literature. Pediatr Dermatol 2002; 19:402-8. 3. Brouillard P, Olsen BR, Vikkula M. High-resolution physical and transcript map of the locus for venous malformations with glomus cells (VMGLOM) on chromosome 1p21-p22. Genomics 2000; 67:96-101. 4. Amyere M, Aerts V, Brouillard P, et al. Somatic uniparental isodisomy explains multifocality of glomuvenous malformations. Am J Hum Genet 2013; 92:188-96. 5. Almaghrabi A, Almaghrabi N, Al-Maghrabi H. Glomangioma of the kidney: a rare case of glomus tumor and review of the literature. Case Rep Pathol 2017; 2017: 7423642. 6. Lamba G, Rafiyath SM, Kaur H, et al. Malignant glomus tumor of kidney: the first reported case and review of literature. Hum Pathol 2011; 42:1200-3. 7. Sasaki K, Bastacky SI, Hrebinko RL, Parwani AV, Zynger DL. Glomus tumor of the kidney: case report and literature review. Int J Surg Pathol 2011; 19:393-7. 8. Chen YA, Li HN, Wang RC, Hung SW, Chiu KY. Malignant glomus tumor of the kidney: a case report and review of the literature. Clin Genitourin Cancer 2017; 15:e151-3. 9. Brathwaite CD, Poppiti RJ Jr. Malignant glomus tumor. A case report of widespread metastases in a patient with multiple glomus body hamartomas. Am J Surg Pathol 1996; 20:233-8. 10. Watanabe K, Hoshi N, Tsu-Ura Y, Suzuki T. A case of glomangiosarcoma. Fukushima J Med Sci 1995; 41:71-7. 11. Folpe AL, Fanburg-Smith JC, Miettinen M, Weiss SW. Atypical and malignant glomus tumors: analysis of 52 cases, with a proposal for the reclassification of glomus tumors. Am J Surg Pathol 2001; 25:1-12. 12. Onishi T, Kato M, Hoshina A. Glomus tumor of the hypoplastic kidney. Int J Urol 2010; 17:677-8. 13. Gill J, Van Vliet C. Infiltrating glomus tumor of uncertain malignant potential arising in the kidney. Hum Pathol 2010; 41:145-9. 14. Ashfaq R, Weinberg AG, Albores-Saavedra J. Renal angiomyolipomas and HMB45 reactivity. Cancer 1993; 71:3091-7.
Characterization of Glomus Tumors of the Kidney Roger Li,1 Firas G. Petros,1 Charles J. Davis, Jr,2 John F. Ward1 Clinical Practice Points Renal glomus tumors are traditionally thought to be
Potential clincopathologic features increasing the risk
benign mesenchymal tumors of the kidney. We report the first case of recurrent renal glomus tumor after surgical resection, and demonstrate the importance of long-term clinical follow-up.
of metastasis include large size, mild and diffuse nuclear atypia, presence of necrosis, scattered mitoses, and lymphovascular invasion. These risk factors need to be validated in future cases.
Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2017 Elsevier Inc. All rights reserved. Keywords: Glomangioma, Glomus tumor, Kidney neoplasm, Malignant glomus tumor, Vascular tumors
Introduction Glomus tumors are rare mesenchymal neoplasms arising from the neuromyoarterial glomus, a cutaneous structure that functions in temperature regulation via arteriovenous shunting of blood.1 They typically occur as painful nodules in the areas rich in glomus bodies, such as the subungual regions of digits and deep dermis of the palm, wrist, forearm, and foot. Congenital familial multiple glomus tumor leads to multifocal tumors and demonstrates an autosomal dominant inheritance pattern with variable expressivity and incomplete penetrance.2 Mutations in the glomulin gene, located in 1p22.1, have been implicated.3 In addition, somatic mutations involving fragile sites on chromosome 1p were found to complete the Knudson 2-hit model, leading to formation of the glomus tumors.4 Visceral organs are devoid of glomus bodies, and thus rarely give rise to glomus tumors.5 A recent comprehensive review of the literature yielded 19 cases of primary renal glomus tumor, all but 1 of which were localized to the kidney without evidence of malignant progression.5 We report a series of 3 cases of renal glomus tumors accessioned at the Armed Forces Institute of Pathology over a 15-year period. Of these, 1 exhibited pathologic features concerning for local invasion, whereas another suffered distant metastases 7 years after primary resection.
1 Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX 2 Armed Forces Institute of Pathology, Washington, DC
Submitted: Aug 25, 2017; Accepted: Sep 1, 2017 Address for correspondence: John F. Ward, MD, Department of Urology, Unit 1373, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 E-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2017.09.002
Case Reports Case 1
A 31-year-old Caucasian woman presented with total gross hematuria of 1 week duration and 2 days of right-flank pain. She denied weight loss, but did report experiencing “hot flashes” for 6 months. A physical examination demonstrated a smooth, non-tender abdominal mass extending approximately 8 cm below the right costal margin. Computed tomography imaging revealed a 16-cm heterogeneous mass with an area of central necrosis (Figure 1A). There was no evidence of extension into the perirenal space or of renal vein thrombosis. Multiple enlarged lymph nodes were present along the inferior vena cava and inter-aortocaval region. Evaluations by bone scan and chest radiograph were unrevealing for metastasis. A right radical nephrectomy with extended lymphadenectomy was performed in an uncomplicated manner through an extended right subcostal incision. Grossly, the tumor was well-circumscribed and without extrarenal extension. It occupied 80% of the kidney, involving both the cortex and the medulla. The cut surface was variegated (yellow to grayish-white, hemorrhagic, necrotic, and firm) with aberrant small vessels and concentric growth-forming nodules and sheets (Figure 1B). Necrosis was seen in 10% of the tumor specimen. Microscopically, the cells were round and uniform, with centrally placed round nuclei within an amphophilic or eosinophilic cytoplasm. Capillary-size vessels were circumscribed by collars of the small cells (Figure 1C). In other areas, the glomus cells formed a reticular morphology (Figure 1D). Nuclear atypia was rare, and mitotic rate was 10 of 50 high-powered fields (HPFs). Lymphovascular invasion was present. Smooth-muscle actin was expressed by most of the tumor cells (Figure 1E). There was abundant expression of Type IV collagen, and the cells were positive for vimentin and negative for keratin A1/A3. Immunohistochemical stains were also negative for CK7, CK20, CEA, chromogranin, Hale’s colloidal iron, EMA, RCC, and CD10.
Clinical Genitourinary Cancer Month 2017
-1
Glomus Tumors of the Kidney Figure 1 Imaging and Histologic Features of a 33-year-old Caucasian Woman With Renal Glomus Tumor (Case 1). A, Venous Phase Post-contrast Computed Tomography Image Showing Mass Arising Within the Interpolar Region of the Right Kidney; B, Grossly, a 13-cm Variegated, Hemorrhagic Tumor Was Seen Involving the Majority of the Kidney; C, Collars of Glomus Cells Surrounding Capillary-sized Vessels; D, Glomus Cells Circumscribe Small Vessels and Form Expanses With a Reticular Morphology; E, Essentially All Glomus Cells Show Strong Immunoreactivity With Smooth Muscle Actin
2
-
After 7 years of uneventful follow-up, the patient was found to have multiple left renal masses. She underwent open partial nephrectomy, yielding 3 distinct tumors, which were 7.4 cm, 5.2 cm, and 7.0 cm in size. Pathologic evaluation of all tumors was consistent with glomus tumors of the kidney. Macroscopic invasion of the peritumoral capsule was present in all 3 tumors, and resection margins were negative of tumor. After another relapse-free interval of 2 years, recurrent masses were again found in the left kidney remnant, spleen, right gluteal muscle, and brain. She went on to resection of her gluteal muscle and magnetic resonance imaging-guided resection of the brain lesion, both confirmed histologically to be metastatic glomus tumor. Thereafter, progressive metastatic disease was found in the lungs, liver, small bowel, and skin. She received 1 cycle of salvage cyclophosphamide, vincristine, and dacarbazine, with minimal effect. Of
Clinical Genitourinary Cancer Month 2017
note, her cutaneous lesions actively expressed IGF-2, causing nonislet cell tumor hypoglycemia requiring treatment with dexamethasone and intravenous glucagon. After multiple hospitalizations and palliative procedures, the patient succumbed to her disease more than 13 years after original diagnosis.
Case 2 An otherwise healthy 33-year-old Caucasian woman was found to have a left-kidney tumor during evaluation of a heart murmur. Nephrectomy revealed a large lobulated and hemorrhagic tumor measuring 9.5 cm by 6.0 cm. The cut surface had a nodular appearance, and the renal vein was filled with a tumor thrombus. The inferior vena cava also contained tumor, and the tricuspid valve had vegetation positive for tumor cells.
Roger Li et al Figure 2 A Network of Capillary-sized Vessels Surrounded by Small, Uniform Glomus Cells (Case 2)
Figure 3 Histologic Features of a 55-year-old Caucasian Male With Renal Glomangiomyoma (Case 3). A, A Nodule of Glomus Cells (Lower Field) Is Circumscribed by Elongated Cells Resembling Mature Smooth-muscle Cells; B, H-Caldesmon Highlights the Smooth-muscle Differentiation; C, Pericellular Type IV Collagen Expression
Microscopically, the tumor consisted of numerous capillary-size vascular channels, and between them were sheets of small cells with vesicular nuclei and little cytoplasm (Figure 2). Widely scattered clones of cells had increased eosinophilic cytoplasm and some nuclear variation. The cells were negative for cytokeratin AE1/AE3 and ICAM 5.2 and were negative for chromogranin synaptophysim, desmin, and CD99 stains. Vimentin was focally positive, and muscle-specific actin was strongly and diffusely reactive. The tumor focally invaded into the renal capsule. The patient was diagnosed with glomus tumor of uncertain malignant potential. We identified this tumor as possibly having some malignant potential, realizing that malignant glomus tumors are rare. We are aware that cardiac metastasis could represent passive transfer from the renal vein as we have seen with renal angiomyolipomas.
Case 3 A 55-year-old Caucasian man with no symptoms and no significant past medical history was undergoing a routine physical examination when microscopic hematuria was revealed on urinalysis. Intravenous pyelography and renal ultrasonography were performed revealing a small, cystic mass within the left kidney. A nephron-sparing nephrectomy was performed without incident. A well-circumscribed, 1.5-cm diameter mass (cystic flocculent) was removed from the renal cortex of this kidney along with a small rim of normal-appearing tissue. The cut surface of this mass revealed multiple tan-gray nodules of rubbery tissue. Microscopically, the cystic appearance was owing to central cystic degeneration rather than hemorrhage or necrosis. The tumor consisted of multiple nodules composed of uniformly rounded cells with eosinophilic cytoplasm, vesicular nuclei, and small nucleoli. Around the periphery of the smallest of the nodules, the cells became spindled and resembled normal smooth-muscle cells (Figure 3A). The latter were reactive for h-Caldesmon (Figure 3B), and both cell types were positive for smooth-muscle actin. In a few nodules, the desmin reacted with many of the glomus cells, and there was diffused pericellular expression of collagen type 4 (Figure 3C). The patient was diagnosed with glomangiomyoma.
Discussion The 3 cases reported herein span the spectrum of malignant potential seen in renal glomus tumors. To date, the vast majority of the reported cases in literature chronicle benign clinical courses after surgical resection, exemplified by case 3 in the current series. Only 1 case of de novo metastatic renal glomus tumor to the spine and pelvic bone has been previously reported.6 We report the first case of recurrent metastasis after surgical excision of the primary tumor. Additionally, case 2 confirms the capability of glomus tumors for local invasion into the renal vein and inferior vena cava. Taken together, these cases directly oppose the conventional perception of low malignant potential associated with this entity.7,8 As illustrated by the clinical course in case 1, surveillance imaging may be required beyond 7 years after surgical resection. Malignant potential of the neoplasm may be deduced from its size as well as macroscopic and microscopic appearances. Specific to case 1, characteristics portending to malignant progression include > 10-cm diameter, mild and diffuse nuclear atypia, presence of necrosis, scattered mitoses, and lymphovascular invasion. However,
Clinical Genitourinary Cancer Month 2017
-3
Glomus Tumors of the Kidney owing to the paucity of renal glomus tumors, these potential predictors of disease recurrence cannot be corroborated. Instead, inferences need to be made from analyses of glomus tumors arising elsewhere in the body. Histologic examination of 2 well-documented cases of metastatic cutaneous glomangiosarcoma both exhibited frequent mitotic figures.9,10 This was corroborated by a study of 52 glomus tumors, identifying high nuclear grade and mitotic activity 5 of 50 HPFs as a potential indicator of malignant potential.11 Consistent with this, the mitotic rate in case 1 was 10 of 50 HPFs. Contrarily, others have demonstrated successful surgical extirpation of tumors exhibiting pleomorphic nuclei as well as high mitotic activity (7 of 50 HPFs).8 However, the results of this study need to be interpreted with caution owing to the insufficient follow-up of 6 months. As demonstrated in case 1, delayed recurrence may occur more than 5 years from the time of surgery. Other factors predisposing an increased 5-year metastatic risk included deep location (P ¼ .004), size more than 2 cm (P ¼ .005), and atypical mitotic figures (P ¼ .004). The implication of these risk factors with regard to the malignant potential of renal glomus tumor is uncertain. However, the classification scheme of atypical glomus tumors proposed by Folpe et al cannot be directly applied to renal glomus tumor, as size > 2 cm and deep location alone qualifies the tumor as a malignant glomus tumor.11 In contrast, many renal glomus tumors larger than 2 cm and located deeper than the muscularis fascia by definition followed benign clinical courses.12 As illustrated in case 2, infiltrative pattern of growth has been previously described in renal glomus tumor.6,13 Whether the locally infiltrative pattern of growth leads to distant metastasis is unknown. Despite many attempts, no follow-up clinical information for case 2 in the current series could be solicited. As such, the clinical course after surgical excision of locally advanced renal glomus tumor remains undetermined. Renal glomus tumors appear as nonspecific, heterogeneous, enhancing lesions on cross-sectional imaging, making preoperative diagnosis difficult. To date, no data exist on needle aspiration or biopsy. Instead, the diagnosis of glomus tumor is made by histologic examination and immunohistochemical analysis postoperatively. In general, glomus tumors exhibit glomus cells, vasculature, and smooth muscle cells, and can be subcategorized as solid glomus tumor, glomangioma, or glomangiomyoma depending on the specific composition.1 Microscopically, branching vascular channels are lined by endothelial cells, interspersed by uniformly round to ovoid glomus cells forming nests, sheets, and trabeculae. Tumor cells have eosinophilic or amphiphilic cytoplasm with well-defined borders and single, centralized, uniform, small “punched out” nucleus. Two distinct histologic patterns have been linked to benign tumor phenotype: symplastic tumors with pleomorphic nuclei without other high-grade features (increased cellularity or increased mitotic activity) and glomangiomatosis with infiltrative growth of vessels invested by glomus cells.11 Although easily distinguished from epithelial tumors of the kidney (ie, renal cell carcinoma), differentiation from other mesenchymal renal tumors may be difficult and often requires immunohistochemical staining. Angiomyolipoma of the kidney, the
4
-
Clinical Genitourinary Cancer Month 2017
most common mesenchymal renal tumor, can be diagnosed using HMB-45 or A103 (Melan-A/Mart-1) staining that highlights the perivascular epithelioid cells.14 Other differential diagnostic considerations include hemangioma or a venous malformation, smooth-muscle neoplasm (epithelioid leiomyoma), carcinoid tumor, paraganglioma, hemangiopericytomas, and juxtaglomerular tumors. Accurate diagnosis is made on immunohistochemical staining in which glomus tumors stain positive for actin and negative for all neuroendocrine markers. Tumors of a neuroendocrine origin show positivity for neuron-specific enolase and chromogranin. Histologically, glomus tumors display a more prominent intercellular basal lamina outlining individual or small groups of cells. These differential mimickers also complicate accurate assessment of the incidence of noncutaneous glomus tumors.
Conclusions Renal glomus tumors are a rare entity traditionally thought to follow a benign clinical course. In light of the current case series, we demonstrate the malignant potential of rare forms of renal glomus tumors. Potential clincopathologic features increasing the risk of metastasis include large size, mild and diffuse nuclear atypia, presence of necrosis, scattered mitoses, and lymphovascular invasion. These predictive features need to be validated in future case reports of this rare tumor.
Disclosure The authors have stated that they have no conflicts of interest.
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