A rare case of a cystic renal mass with heterotopic ossification and a mini literature review

Abstract

INTRODUCTION:

It is a challenge to make accurate pre-surgical diagnosis for renal tumors. This study is to report the findings, management, and outcome of one rare case of ossification in a cystic renal mass. We present and discuss the pathological characteristics, radiologic features, and treatment alternatives of the patient.

PATIENTS AND METHODS:

A 38 years old female patient had intermittent epigastric pain and microscopic hematuria for two months. Computerized tomography (CT) scan and Magnetic Resonance imaging (MRI) showed a mass with rough edge and dense calcification in the upper pole of the right kidney and normal left kidney. Pre-operative diagnosis is cystic nephroma or cystic renal mass (Bosniak III type, Bosniak renal cyst classification). GFR was within normal limits for age and no other significant laboratory aberrations were noted. Patient underwent a right retroperitoneal laparoscopic partial nephrectomy (margin status was negative). A mini literature review was performed to highlight the principals of diagnosis and treatment of cystic renal mass with heterotopic ossification.

RESULTS:

The entire renal mass was successfully removed from upper pole of the right kidney by laparoscopic nephron sparing surgery. The size of renal mass is 38×35×30 mm³ with thick and hard capsular wall. The cystic cavity contains yellow lipid-like substances without stone. Histological examination revealed renal cyst in which the cyst wall reveals fibrosis and no obvious lining epithelium. The additional unique feature includes the presence of dense calcification and ossification in the renal mass. Localization tissue of yellow bone marrow was detected. No complications occurred in 9 months after surgery during follow-up.

CONCLUSIONS:

Cystic renal mass with heterotopic ossification is a rare case of non-malignant renal tumor. Whether surgery is needed depends to whether patients have symptoms. For symptom renal tumors, laparoscopic nephron sparing surgical procedure is recommended. Furthermore, complete surgical resection of the lesion is needed when the mass is suspected to be malignant. An accurate histologic diagnosis is key in its diagnosis.

Keywords

Renal neoplasm renal cyst calcification metaplasia heterotopic ossification

1 Introduction

Renal masses can be malignant, benign, or inflammatory, or they can be classified based on radiographic appearance (simple cystic, complex cystic, fatty tumors, and others) [1]. Benign renal neoplasms constitute a rather large and heterogeneous group of masses including simple and complex cysts, cortical and metanephric adenomas, angiomyolipoma (AML), oncocytoma, cystic nephroma, mixed epithelial stromal tumor (MEST) and leiomyoma, among others. Renal cysts are common lesions whose malignant potential is stratified by the Bosniak classification [2]. Particularly, cyst septations and calcifications are cornerstones of differentiating the various tiers of cysts.

Cystic nephroma is a rare, non-genetic, benign, cystic lesion. When considering the radiological findings of a cystic renal lesion in which there are areas of calcification, the likelihood of malignant potential is higher, particularly, for renal cell carcinoma or multilocular cystic renal neoplasm of low malignant potential. Though, calcifications are associated with malignant neoplastic masses they can also be found in benign lesions [3]. The presence of calcification may influence the decision to surgically explore or follow up a lesion. To date, few reports have reported on cystic renal mass with ossification. Herein, we present a case of calcification in cystic renal mass with heterotopic ossification, as well as focused review of the literature regarding calcified renal mass with ossification management.

2 Case report

A 38 years old female presented to our institution for intermittent epigastric pain and was found to have a palpable right renal mass. The patient had a history of left ureteral calculi, left renal calculus, hepatic cyst, uterine fibroid and adnexal cysts. She denied a history of diabetes mellitus, hypertension and tuberculosis. On admission, clinical examination revealed no swelling, tenderness and percussive pain in the right lumbar region.

Two months prior, a color doppler ultrasound of urinary system was obtained for regular follow up of urinary calculi, demonstrating a 33×28×23 mm³ mixed echogenic right upper pole renal mass. An acoustic shadow was also evident. Color Doppler demonstrated no blood flow within the mass (Fig. 1). Computed Tomography scan of the abdomen with contrast demonstrated a 30×25×22 mm³ mass in the upper pole of the right kidney measuring 15–28 Hounsfield units. The mass demonstrated eggshell calcification around the periphery, consistent with a Bosniak III renal cyst. There was no enhancement in the arterial phase, venous phase and excretion phase (Fig. 2). The CT diagnosis of mass was renal cyst or angiomyolipoma(AML).In order to further clarify diagnosis, MRI of kidney showed renal cystic mass (30×23×21 mm³) without obvious enhancement (Fig. 3). Hb at the time was 108 g/L (Normal: 115–150 g/L), urine was unremarkable with the exception of WBC of 27/ul (Normal: < 20 WBC/ul), and urine culture was negative. All other serum chemistry parameters were within normal limits.

Fig. 1

Color Doppler ultrasonography demonstrated good flow to renal parenchyma and no flow to the mass (33 × 28 × 23 mm³) (arrows).

Fig. 2

CT abdomen and pelvis demonstrated a mass (30×25×22 mm³) (arrows) in the right kidney.

Fig. 3

MRI of the abdomen demonstrated renal cystic lesions (30×23×21 mm³) (arrow) (Bosniak III type) in the right kidney. (A: T2 weighted, B: T1 weighted).

3 Treatment

It is difficult to determine whether it is malignancy or not. The patient is very worried about the tumor and required surgery to remove the right renal mass. After informed consent, we performed a retroperitoneal laparoscopic partial nephrectomy. During the operation, we noted that the mass did not invade the collecting system. Grossly, the specimen was hard and markedly enlarged measuring 4.0 cm in greatest dimension, with patchy calcifications on the surface and rough edges. The mass so extensively calcified that it hard to be sectioned with a surgical knife. The interior of the mass had cystic and solid components with thick walls. The cysts contained a yellow lipid-like substance without stones (Fig. 4). Histologic examination of the cyst wall revealed fibrotic changes without an epithelial lining. The wall of the cyst also revealed areas with calcification, ossification (Fig. 5) and inflammatory cell infiltration with atrophic tubules. H&E staining revealed yellow bone marrow tissue with fat cells was found in the cyst wall. No malignant cells were found in the entire renal mass sample through renal histological sections. The patient recovered well and had an uneventful post-operative recovery. The symptoms of epigastric pain disappeared 2 weeks after operation. At 6 months follow up, no flank and lumbar pain had happened. At 9 months post operatively, CT scan demonstrated normal post-operative changes in the area of resection and no residual mass. The patient is still being followed.

Fig. 4

Gross examination of right renal mass. (A) Grossly, the specimen was hard with patchy calcification on the surface with rough edges. (B) The mass had solid and cystic components, the latter of which was filled with a milky, yellow substance.

Fig. 5

Dense ossification in the renal mass with A) bone trabecula, osteocytes in lacuna, lamellar bone matrix at this higher power and B) osteons with bone lacunae and lamellae of bone with lacunae housing the shrunken remains of osteocytes. (H&E stain, x200 [left], x500 [right]).

4 Discussion

Most renal tumors are malignant; one in four renal masses are benign. It is a challenge to make accurate pre-surgical diagnosis for renal tumors. Simple renal cysts are usually asymptomatic and require no treatment. With increased use of CT and ultrasound, many renal cysts are detected incidentally, and the patients are asymptomatic. Calcification is a well-recognized feature of renal neoplasms and the detection of these calcifications are important in the diagnosis and management of these masses [2]. The differentiation of benign cystic lesions of the kidney from those that require surgical management are generally outlined by AUA guidelines however certain properties make this distinction difficult [4].

Metaplasia is defined as a transformation of one differentiated tissue type to another, an example of which is the ossification of cartilage to form bone. Ossification is the calcification of soft tissue into a bone-l ike substance [5]. Heterotopic ossification occurs when bone tissue forms outside the skeleton. This phenomenon has been observed in the liver, breast, skin, colorectal and kidneys. It is a recognized but rare phenomenon in renal tumors [5, 6]. Ossification of benign renal tumors, in particular, is rare [7]. The pathogenesis of heterotopic ossification in renal tumors is thought to be due to metaplasia of stromal pluripotent cells into osteoblasts by factors secreted by cancer cells [8 –10]. To our knowledge, few reports on renal cysts with heterotopic ossification have been published.

Though ossification of renal cysts has rarely been reported, several case reports regarding ossification within solid renal masses such as chromophobe and clear cell RCC, teratoma, renal cystic tumoral calcinosis (TC) with ossification and cystic nephroma have been reported (Table 1) [11 –15].

Table 1
Differential diagnosis and treatment among five types of renal mass with calcifications/ossification

Renal cyst with ossification Primary renal teratoma Renal cystic TC Cystic nephroma Chromophobe renal cell carcinoma

Epidemiology - Rare benign disease - Rare renal disease - Rare benign disease - Predominantly postmenopausal females - A distinct subtype of RCC

- Predominantly infant males

Morbidity - Very low incidence - Predominantly inchildren0.7/100,000children/year - Very low incidence - About 200 cases reported –4% to 6% of all RCCs

Etiology - Infection - A congenital origin - Congenital origin - Local inflammation - Some genes mutations - Mutations in the DICER1 gene in pediatric - Multiple chromosomal losses, TP53 mutations

- A part of the spectrum of MEST in adults - Upregulated expression of the c-KIT oncogene

Radiographic features - Eggshell calcification around the mass - Heterogeneous masses - Cystic areas, calcifications, necrosis - Bony components like teeth, phalanges. - CT: circular calcified wall around cystic lesion - KUB: the high-density shadow - Solitary, centrally located - Curvilinear calcifications and septal enhancement - Well-defined homogeneous mass - Hypo-vascular soft tissue enhancement.

Clinical symptoms - Asymptomatic - Abdominal mass, - Intermittent lumbar pain - Flank or abdominal pain - Haematuria - Flank or abdominal pain - Micro-scopichematuria

- Intermittent lumbar pain - Abdominal pain or discomfort

- Pyelonephritis

- Constipation

Treatments - < 2cm: follow up - > 2cm: RN/NSS - RN - NSS - RN Clinical T1 stage: NSS > T1 stage: RN.

Pathology - Calcification &ossification - Yellow bone marrow - Infiltration of inflammatory cells - Atrophic renaltubular - Mature teratomas: skin.bronchial structures, cartilage, neuroglial tissue and teeth. - Immature teratomas: neuroepithelial components - Ossification - Calcium deposition -Infiltration of inflammatory cells - Bone red marrow formation - Fibrous pseudocapsule - Lined by flattened, cuboidal, or hobnail epithelium - Occasionally ossification - Broad trabeculae of polygonal cells - Cytoplasm, prominent cell borders - Multinucleation. - Occasionally ossification

	Renal cyst with ossification	Primary renal teratoma	Renal cystic TC	Cystic nephroma	Chromophobe renal cell carcinoma
Epidemiology	- Rare benign disease	- Rare renal disease	- Rare benign disease	- Predominantly postmenopausal females	- A distinct subtype of RCC
				- Predominantly infant males
Morbidity	- Very low incidence	- Predominantly inchildren0.7/100,000children/year	- Very low incidence	- About 200 cases reported	–4% to 6% of all RCCs
Etiology	- Infection - A congenital origin	- Congenital origin	- Local inflammation - Some genes mutations	- Mutations in the DICER1 gene in pediatric	- Multiple chromosomal losses, TP53 mutations
				- A part of the spectrum of MEST in adults	- Upregulated expression of the c-KIT oncogene
Radiographic features	- Eggshell calcification around the mass	- Heterogeneous masses - Cystic areas, calcifications, necrosis - Bony components like teeth, phalanges.	- CT: circular calcified wall around cystic lesion - KUB: the high-density shadow	- Solitary, centrally located - Curvilinear calcifications and septal enhancement	- Well-defined homogeneous mass - Hypo-vascular soft tissue enhancement.
Clinical symptoms	- Asymptomatic	- Abdominal mass,	- Intermittent lumbar pain	- Flank or abdominal pain - Haematuria	- Flank or abdominal pain - Micro-scopichematuria
			- Intermittent lumbar pain	- Abdominal pain or discomfort
		- Pyelonephritis
		- Constipation
Treatments	- < 2cm: follow up - > 2cm: RN/NSS	- RN	- NSS	- RN	Clinical T1 stage: NSS > T1 stage: RN.
Pathology	- Calcification &ossification - Yellow bone marrow - Infiltration of inflammatory cells - Atrophic renaltubular	- Mature teratomas: skin.bronchial structures, cartilage, neuroglial tissue and teeth. - Immature teratomas: neuroepithelial components	- Ossification - Calcium deposition -Infiltration of inflammatory cells - Bone red marrow formation	- Fibrous pseudocapsule - Lined by flattened, cuboidal, or hobnail epithelium - Occasionally ossification	- Broad trabeculae of polygonal cells - Cytoplasm, prominent cell borders - Multinucleation. - Occasionally ossification

Abbreviations: CN = cystic nephroma,CRCC = chromophobe renal cell carcinoma, RCC = renal cell carcinoma, TC = tumoral calcinosis, MEST = mixed epithelial stromal tumor, CT = computed Tomography,KUB=kidney and upper bladder, NSS = nephron-sparing surgery, RN = radical nephrectomy, CM = centimeter.

Chromophobe RCC, which accounts for 4% to 6% of RCC subtypes, has typical radiological features including a well-defined homogeneous mass with hypovascular soft tissue enhancement [16]. Teratomas are rare neoplasms with tissue derivatives of all three germ layers with renal teratomas being one of the least common locations [17 –19]. These lesions typically present with palpable abdominal mass and pain and mature teratomas often have CT demonstratable bronchial structures with cartilage, neuroglial tissue, and teeth as evidence of organogenesis [13]. Tumoral calcinosis (TC) is a condition where calcium deposition occurs in in soft tissues around the large joints, forming tumor-like nodular calcifications [5]. Radiologically, CT may show a calcified wall surrounding a cystic lesion. Pathology in renal TC demonstrates the presence of fibrous tissues, calcium deposition and infiltrated inflammatory cells in the calcified wall with ossification and red bone marrow formation within the calcified wall [14]. Cystic nephroma (CN) usually present as a unilateral, multicystic renal mass without solid nodules. Radiologically, most cystic nephromas are solitary, centrally located, and commonly demonstrate curvilinear calcifications, herniation into the collecting system, and septal enhancement [20]. Histologically, cystic nephromas are well encapsulated by a thick fibrous pseudocapsule and are composed of cysts lined by flattened, cuboidal, or hobnail epithelium. The stromal component can range from dense paucicellular collagen to markedly cellular fascicles of spindle cells, closely resembling ovarian stroma [21]. In our study, the mass was solid with cystic components with thick wall and hard texture. The cystic cavity contained bone marrow with fat, calcification with evidence of ossification and a few atrophic tubules with no obvious epithelium lining the cyst wall. These findings are inconsistent with the aforementioned diagnoses.

Calcifications can be observed in both benign and malignant cystic lesions and can locate in the wall or within septations [22, 23]. As such, it may be difficult to distinguish these cysts as benign or having malignant potential based on imaging alone as the Bosniak criteria relies heavily on septations and calcifications for classification of cystic renal masses. For Bosniak III renal mass over 50% are malignant [2], and as such surgical resection is recommended. Renal mass biopsy (RMB) may be considered however, the false-negative rate of RMB was thought to be 18%, too high to justify routine use [11]. A positive biopsy merely confirms the need for surgery and a biopsy result that is negative for malignancy does not alter patient treatment because uncertainty will still exist as to whether a sampling error has occurred [15].

Nephron-sparing surgery is the treatment of choice for T1 RCC since it preserves kidney function. For complex cystic renal mass with heterotopic ossification, surgical intervention is required for both diagnosis and treatment [2, 12]. Although published reports regard nephrectomy as the classic treatment modality for renal mass [24, 25], we suggest that NSS may be the optimal treatment if the diagnosis of complex cystic mass is made. Differentiating this wide variety of both benign and malignant masses is difficult using cross-sectional imaging and can only be made using pathological examination from the surgical specimen [26, 27]. Given this, surgical excision using minimally invasive partial nephrectomy with appropriate margins is necessary to obtain a definitive diagnosis and eliminating the risk of disease progression. For renal masses whose benign and malignant are not clear, the choice of surgical resection or follow-up is controversial. In this case, we carried prophylactic resection of the tumor to identify the nature of the tumor.

Knowledge of the variable common features for each cystic renal mass can aid in narrowing the differential diagnosis and prompt surgical management [28]. Whether a laparoscopic surgery is needed depends to whether patients have symptoms. The combination of clinical, biochemical, and radiological features may help in lesion characterization, but only histology can provide the definite diagnosis. Therefore, for non-symptoms renal tumors, laparoscopic renal biopsy plus nephrectomy procedures is recommended. The prognostic significance of calcification and ossification in cystic renal mass remains unclear because of few cases reported. As pathologists and urologists become aware of this rare entity, further studies of larger series may further elucidate its clinical and prognostic significance.

5 Conclusion

Herein, we report a rare case of cystic renal mass with heterotopic ossification. X-ray examinations provide the information about the location and size of calcification but cannot give a definitive diagnosis. Pathological evaluation is critical in determining whether tumor is benign or malignant. As was the case herein, renal masses that appear malignant may be ossified renal cysts without malignant potential. Because it is challenging for surgeons to determine pathology purely based on imaging studies, surgical intervention including laparoscopic nephron sparing surgical procedure may be necessary required for both diagnosis and therapy. Long-term follow up may be indicated as the natural history of this disease is not well described in the literature.

Conflict of interest

No author has any financial interest or Conflict of interest to describe.

References

Warren

K.S.

and McFarlane

, The Bosniak classification of renal cystic masses, BJU International 95 (2005), 939–942.

Silverman

S.G.

, Pedrosa

, Ellis Hindman

J.H.

, et al., Bosniak classification of cystic renal masses, Version 2019: An update proposal and needs assessment, Radiology 292 (2019), 475–488.

, Pawel

B.R.

, Hill

D.A.

, et al., Pediatric cystic nephroma is morphologically, immunohistochemically, and genetically distinct from adult cystic nephroma,, The American Journal of Surgical Pathology 41 (2017), 472–481.

Wood

C.G.

3rd , Stromberg

L.J.

3rd , Harmath

C.B.

, et al., CT and MR imaging for evaluation of cystic renal lesions and diseases, Radiographics 35 (2015), 125–141.

Huang

R.S.

, Brown

R.E.

and Buryanek

, Heterotopic ossification in metastatic colorectal carcinoma: case report with morphoproteomic insights into the histogenesis, Annals of Clinical and Laboratory Science 44 (2014), 99–103.

Singh

, Sinha

R.J.

, Sankhwar

S.N.

and Dalela

, Heterotopic bone formation in renal cell carcinoma: a diagnostic challenge, Indian Journal of Cancer 45 (2008), 126–127.

Liu

, Tripp

and Layfield

L.J.

, Heterotopic ossification: review of histologic findings and tissue distribution in a 10-year experience, Pathology, Research and Practice 203 (2007), 633–640.

Ranganathan

, Loder

, Agarwal

, et al., Heterotopic ossification: Basic-science principles and clinical correlates, The Journal of Bone and Joint Surgery American 97 (2015), 1101–1111.

Agarwal

, Sorkin

and Levi

, Heterotopic ossification and hypertrophic scars, Clinics in Plastic Surgery 44 (2017), 749–755.

10.

Israel

G.M.

and Bosniak

M.A.

, Calcification in cystic renal masses: is it important in diagnosis? Radiology 226 (2003), 47–52.

11.

S.L.

, Fishman

I.J.

and Shannon

R.L.

, Chromophobe renal cell carcinoma with extensive calcification and ossification, Annals of Diagnostic Pathology 6 (2002), 244–247.

12.

Zhang

, Zhang

, Wang

, et al., Challenges in the diagnosis of calyceal diverticulum: A report of two cases and review of the literature, Journal of X-ray Science and Technology 27 (2019), 1155–1167.

13.

Idrissi-Serhrouchni

, El-Fatemi

, El madi

, et al., Primary renal teratoma: a rare entity, Diagnostic Pathology 8 (2013), 107.

14.

Xia

, Liu

, Yang

, et al., A case report: renal cystic tumoural calcinosis with ossification and bone marrow formation, BMC urology 20 (2020), 106.

15.

Zhang

, Zhang

, Wang

, et al., Challenges in the diagnosis of severe renal trauma in child: A case report and literature review, Journal of X-ray Science and Technology 28 (2020), 357–367.

16.

AlGhamdi

M.H.

, AlShabyli

N.A.

and Alayed

, Chromophobe Renal Cell Carcinoma Presenting as a Cystic Renal Mass: Case Report and Review of the Literature, The American Journal of Case Reports 20 (2019), 631–634.

17.

Nirmal

T.J.

, Krishnamoorthy

and Korula

, Primary intrarenal teratoma in an adult: A case report and review of literature, Indian Journal of Urology 25 (2009), 404–406.

18.

Jones

N.M.

and Kiely

E.M.

, Retroperitoneal teratomas–potential for surgical misadventure, Journal of Pediatric Surgery 43 (2008), 184–186.

19.

Moll

, Krenauer

, Bierbach

, et al., Mixed hepatoblastoma and teratoma of the liver in a 3-year-old child: a unique combination and clinical challenge, Diagnostic Pathology 4 (2009), 37.

20.

Granja

M.F.

, O’Brien

A.T.

, Trujillo

, et al., Multilocular cystic nephroma: A systematic literature review of the radiologic and clinical findings, American Journal of Roentgenology 205 (2015), 1188–1193.

21.

Kurian

J.J.

, Jehangir

and Korula

, Multiloculated Cystic Renal Tumors of Childhood: Has the Final Word Been Spoken, Journal of Indian Association of Pediatric Surgeons 23 (2018), 22–26.

22.

Saltzman

A.F.

, Carrasco

Jr. , Colvin

A.N.

, et al., Can a modified Bosniak classification system risk stratify pediatric cystic renal masses? The Journal of Urology 200 (2018), 434–439.

23.

Zhong

, Cao

, Guan

, et al., Renal cyst masses (Bosniak category II-III) may be over evaluated by the Bosniak criteria based on MR findings, Medicine 96 (2017), e9361.

24.

Kashan

, Ghanaat

, Hötker

A.M.

, et al., Cystic renal cell carcinoma: A report on outcomes of surgery and active surveillance in patients retrospectively identified on pretreatment imaging, The Journal of Urology 200 (2018), 275–282.

25.

Capitanio

and Montorsi

, Renal cancer, Lancet (London, England) 387 (2016), 894–906.

26.

Dong

, Wang

, Zhang

, et al., Multilocular cystic nephroma treated with laparoscopic nephron-sparing surgery: A case report, Canadian Urological Association Journal 8 (2014), E545–7.

27.

Large

M.C.

, Al-Ahmadie

, Shalhav

A.L.

and Zorn

K.C.

, Mixed epithelial stromal renal tumor with dystrophic ossification: a case report and literature review, The Canadian Journal of Urology 16 (2009), 4690–4693.

28.

Sambataro

, Sambataro

, Zaccara

, et al., Tumoral calcinosis of the spine in the course of systemic sclerosis: report of a new case and review of the literature, Clinical and Experimental Rheumatology 33 (2015), S175–178.