Bone & Soft Tissue Pathology

De novo-type De-differentiated Liposarcoma of Retroperitoneum, High Grade, with Secondary (Intra-renal) Involvement of Kidney

Mahul B. Amin
Cedars-Sinai Medical Center
Los Angeles, CA, 90048


Clinical History :
A 41 year old male presented with a two week history of left flank pain. Abdominal CT scan revealed a solid mass lesion in the left flank measuring 12 x 10 x 8 cm. Radiographically the lesion was interpreted as renal cell carcinoma. A radical nephrectomy was performed which showed a large mass predominantly involving the lower pole of the left kidney and the perinephric soft tissue (Case 4, Fig. 1). Microscopically, the tumor had epithelioid and spindle cell morphology (Case 4, Figs. 2-9). The case was received in consultation with a differential diagnosis of sarcomatoid renal cell carcinoma versus epithelioid angiomyolipoma. Outside immunohistochemical stains showed focal positivity for HMB45 and Melan A and negativity for CK 7, CK20, and CD10. Six months later, the patient had a 6 cm in diameter local recurrence in the left renal fossa.


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Gross Pathology:
The left radical nephrectomy specimen showed a large mass measuring 12 cm in diameter involving the lower pole of the kidney and adjacent perinephric tissue. The bulk of the mass involved perinephric soft tissues. The cut surface was nodular, homogenous, fleshy and yellow-tan in color with central areas of necrosis. The pelvicalyceal system was not involved.

The recurrent 6 cm mass in the left renal fossa had a nodular fleshy cut surface with irregular margins.

Microscopic Features:
The tumor involving the kidney was circumscribed and composed of spindled and epithelioid cells with a prominent vascular pattern. The individual tumor cells varied from being rounded to polygonal shaped with abundant pale eosinophilic cytoplasm, to oval to spindled cells with moderate to scant cytoplasm. Numerous tumor giant cells and cells with marked pleomorphism were interspersed throughout the tumor. Nuclear hyperchromasia, anaplasia and high mitotic activity was evident. Some of the epithelioid cells had a micro-vesiculated appearance.

The recurrence showed an overall similar histology except that there were hypo- and hypercellular areas with meningothelial whorl-like pattern. The whorls were composed of concentric lamellae of spindled cells around small caliber vessels.

The adjacent adipose tissue showed irregular fibrous bands with associated atypical hyperchromatic cells with scattered lipoblasts. There were areas with loose myxoid stroma and patchy hyalinization; lymphoid aggregates and inflammatory cells (lymphocytes and plasma cells) were dispersed in the background. There was an abrupt transition between the atypical lipomatous component and the cellular pleomorphic component.

Immunohistochemistry :
Renal and perinephric mass: AE1/AE3, EMA, CD10, SMA, CD34 and S100- Negative. HMB45 and Melan A were focally positive and vimentin was diffusely positive. These stains were performed at outside institution. Melan A was negative when it was repeated.

Recurrent mass: Melan A, Micropthalmia transcription factor were negative and rare cells were positive for HMB45. CD34 was positive in areas of meningothelial-like whorls. Other pertinent markers were negative.

Fluorescent in Situ Hybridization:
FISH analysis performed on paraffin embedded tissue from the recurrence was positive for MDM2 gene amplification.

Diagnosis
De novo-type De-differentiated Liposarcoma of Retroperitoneum, high grade, with secondary (intra-renal) involvement of kidney

Discussion:
This case presents with a range of differential diagnostic considerations and the appropriate diagnosis has prognostic relevance. The differential diagnoses considered for the primary presentation include sarcomatoid differentiation in renal cell carcinoma, a malignant epithelioid angiomyolipoma (PEComa) and a primary renal sarcoma such as synovial sarcoma, malignant peripheral nerve sheath tumor, malignant solitary fibrous tumor, leiomyosarcoma and unclassified high grade sarcoma. Based on the absence of an obvious renal cell carcinoma component, grossly and microscopically unremarkable pelvicalyceal mucosa (against urothelial carcinoma) and negative immunoreaction for multiple epithelial markers, the diagnosis of sarcomatoid differentiation was ruled out. HMB45 was the only melanogenic marker that was very focally positive (primary and recurrence). Smooth muscle actin and other melanogenic markers were negative arguing against an epithelioid angiomyolipoma (PEComa). The diagnosis of de novo-type de-differentiated liposarcoma of retroperitoneum, high grade, with secondary intra-renal involvement of kidney was made on the presence of an atypical lipomatous tumor / well-differentiated liposarcoma (ALT/WDL) in the recurrence with abrupt transition to high grade sarcoma.

At this United States and Canadian Academy of Pathology meeting, we present our unique experience of a series of similar cases that we have collected from our consultation files and collaborating institutions. [1] Ten cases presenting as a primary renal mass underwent nephrectomy in which the presenting pathology was a renal/perinephric high grade spindled neoplasm. In all cases the pathologic workup revealed the presence of ALT/WDL. The submitting differential diagnoses in consultation cases included sarcomatoid differentiation in renal cell carcinoma, epithelioid angiomyolipoma and primary sarcoma such as synovial sarcoma and malignant solitary fibrous tumor. In our series of 10 cases, the patient's age ranged from 41 to 81 years with a male to female ratio of 9:1; flank pain was the predominant presenting symptom (70%). One patient presented with renal mass and p ulmonary metastasis. In seven cases, the imaging findings were consistent with a renal cell carcinoma, and in 3 cases, there was a predominant perinephric component with uncertain renal involvement. All cases were hence treated for a preoperative clinical diagnosis of renal cell carcinoma by radical nephrectomy.

The histology of the de-differentiated liposarcoma component in the series showed a intermediate to high grade malignant spindled to epithelioid neoplasm with distinctive meningothelial whorl-like growth in three cases, storiform/pleomorphic malignant fibrohistiocytic histiocytoma (MFH) pattern in three cases, myxoid MFH in one case, fibrosarcoma in one case and high grade pleomorphic sarcoma, not otherwise specified in two cases. One case with meningothelial whorl-like areas had intratumoral metaplastic ossification with fibrous dysplasia-like areas. Gross and / or microscopic involvement of the renal parenchyma was seen in three of seven cases in which renal cell carcinoma was suspected on imaging, the other cases abutted the renal capsule but did not involve it. The histology of well-differentiated component was often subtle and not suspected in all the five cases in the series that were received as consultation cases. Both the adipocytic lipoma-like and sclerosing-type histology were seen with patchy and variable inflammation.

The approach to malignant spindle cell tumor in the kidney requires attention to several important aspects at the gross and microscopic level with appropriate use of ancillary techniques in some cases. Sarcomatoid differentiation in renal cell carcinoma or urothelial carcinoma should be the primary consideration and examination of multiple sections as well as close attention to gross features is necessary to identify a renal cell carcinoma or malignant urothelial component. Epithelioid angiomyolipoma (PEComa) of kidney may morphologically resemble a renal cell carcinoma or rarely may have a prominent sarcomatous component. The epithelioid morphology with eosinophilic cells, arranged singly or in sheets, is the predominant histologic pattern. We have recently finished evaluation a large series of 49 cases of epithelioid angiomyolipoma involving the kidney and our experience is as follows. The age ranged from 14-69 years with male: female ratio of 1:1.2. 30% of cases are associated with tuberous sclerosis; and 47.7% were associated with multiple macro- or microscopic angiomyolipomas of the usual triphasic type. [2] Co-expression of melanogenic (HMB45, Melan A, tyrosinase and microphthalmic transcription factor) and smooth muscle-associated markers (SMA, HHF35 and desmin), along with negativity for cytokeratin markers is confirmatory.

The most important feature for the appropriate recognition of de novo de-differentiated liposarcoma of retroperitoneum secondarily involving the kidney is attention to perinephric fat to recognize ALT/WDL component. The ALT/WDL component may be subtle. Careful examination of multiple sections is usually adequate to find diagnostic areas of liposarcoma. We have recently noted that perinephric fat adjacent to and or away from a renal mass may show atypical changes that may closely mimic an ALT/WDL. [3] These pseudoliposarcomatous changes include variably sized fibrous bands with atypical hyperchromatic nuclei, variation in adipocytic size, lochkern nuclei, myxoid areas and lymphocytic aggregates. [3] In difficult cases where typical lipoblasts are lacking, the diagnosis may be confirmed by FISH studies for MDM2 gene amplification. [4] In our recent experience of 10 de novo de-differentiated liposarcomas involving the kidney/perinephric region, MDM2 gene amplification was seen in two third of the cases. MDM2 gene amplification was not seen in pseudoliposarcomatous cases studied.

In the context of distinct meningothelial whorl-like areas and renal neoplasia, two tumors are worthy of mention. Extranodal follicular dendritic cell tumor, which to my knowledge has not involved the kidney. It is characterized by proliferation of spindle to ovoid cell that form fascicles, storiform patterns and whorls, the latter remniscent of meningioma. There may be rare multinucleated tumor giant cells. The diagnosis is confirmed by CD21, CD23 and CD35 immunomarkers. [5] Metanephric stromal tumor (MST) is a unique pediatric tumor that occurs in the age range of <1 to 11 years with nearly equal sex ratio. The cytomorphology of MST is typically bland and contrasts with the usually overt sarcomatous nature of de-differentiated liposarcoma. The tumors are variably cellular in which spindle cells surround entrapped renal tubules or blood vessels forming "onion skin" rings or collarettes. Striking angiodysplasia and juxtaglomerular hyperplasia is noted. [6]

If the morphologic presentation of a mass in the kidney is that of a monophasic sarcoma, the differential diagnoses also includes: synovial sarcoma, malignant peripheral nerve sheath tumor, malignant solitary fibrous tumor and leiomyosarcoma; the latter most frequently arises in the renal vein /or its branches. A judicious panel of immunohistochemical markers including: AE1/ AE3, SMA, desmin, S100, CD34, CD99, and Bcl2 should help in appropriate characterization. [7, 8, 9, 10]

An approach and the differential diagnostic considerations of malignant spindle cell neoplasms involving the kidney based on the above discussion is summarized in the table below.

Differential Diagnoses of Malignant Spindle Cell Neoplasms Involving Kidney

Spindle cell component with distinct epithelial differentiation :
  • Renal cell carcinoma with sarcomatoid change

  • Urothelial carcinoma with sarcomatoid change

  • Synovial sarcoma, biphasic
Spindle cell component with epithelioid cell type :
  • Epithelioid angiomyolipoma (PEComa)

  • Sarcomatoid carcinoma, not otherwise specified

  • Sarcoma including malignant peripheral nerve sheath tumor, leiomyosarcoma, pleomorphic sarcoma, not otherwise specified
Spindle cell component with pure ALT/WDL :
  • De-differentiated liposarcoma
Monophasic malignant spindle cell component :
  • Synovial sarcoma

  • Solitary fibrous tumor

  • Malignant peripheral nerve sheath tumor

A precise histopathologic classification from the differential diagnostic considerations listed above is critical for appropriate therapeutic stratification and prognosis. The treatment protocols for sarcomatoid differentiation in renal cell carcinoma, malignant epithelioid angiomyolipoma (PEComa) and sarcomas involving the kidney are often institutional dependant but usually vary between the three categories. The prognosis of sarcomatoid differentiation in renal cell carcinoma and urothelial carcinoma is very poor with median survival of 19 months and 30 months respectively. Long time survival is distinctively rare. [11, 12] Epithelioid angiomyolipoma of the kidney (PEComa} is considered to be a potentially malignant tumor. In our experience of 49 cases, recurrence was noted in 20%, metastasis in 42.5% (27.5% of cases had metastasis at the time of presentation) and disease-related mortality in 32.4%. [2, 13, 14] The prognosis of sarcomas involving the kidney is dependent on several parameters including histologic type, high tumor grade, presence of metastasis at presentation, incomplete surgical resection and positive surgical margins. [15] Synovial sarcoma in my experience is the most common among sarcoma histologic subtypes involving the kidney. Several recent reports indicate that these patient's have a particularly poor survival (6 – 8 months). [8]

In our recent experience with 10 de novo de-differentiated liposarcomas involving kidney, the outcome was available in 7 cases (mean 10 months, median 6 months); half of the cases recurred and one had pulmonary metastasis at the presentation indicating high recurrence potential in the short to intermediate range follow up. In an analysis of 155 cases of de-differentiated liposarcomas from various sites with median follow up of 3 years, local recurrence was seen in 41%, metastasis in 17%, and disease-related mortality in 28%. [16]

In summary, in my experience, sarcomatoid renal cell carcinoma is the most common malignant spindle cell neoplasm involving the kidney. Epithelioid angiomyolipoma (PEComa) only rarely presents as a predominantly spindle cell tumor. A range of sarcomas of different histologies and grade may also involve the kidney usually as a primary neoplasm, and the approach is similar to that employed for soft tissue counterparts once the other two categories are excluded. This particular case exemplifies yet a unique and perhaps not so esoteric diagnostic challenge posed by the most common retroperitoneal sarcoma, ALT/WDL which may be subtle or overlooked due to the more striking de-differentiated component.

References :
  1. Balzar B, Gupta R, Rao P, Paner GP, Amin MB, et al. Dedifferentiated liposarcoma presenting as a primary renal mass resulting in a nephrectomy: a report of 10 cases with discussion of differential diagnostic implications. Mod Pathol 2009; 22(suppl 1): 158A.

  2. Nese N, Martignoni G, Fletcher CD, Gupta R, Pan CC, Kim H, Sato K, Bonetti F, Pea M, Amin M, Hes O, Svec A, Amin MB. Renal perivascular epithelioid cell tumors (PEComa), so called Epithelioid angiomyolipoma (EAML): Analysis of 61 cases including 49 pure/predominant epithelioid (P-PEComa) morphology and parameters associated with malignant outcome. Mod Pathol 2009; 22(suppl 1): 186A.

  3. Balzar B, Gupta R, Lazar AJ, Rao P, Amin MB. Pseudoliposarcomatous changes in the perinephric adipose tissue of nephrectomy specimens mimicking well differentiated retroperitoneal liposarcoma: evaluation in 200 nephrectomies. Mod Pathol 2009; 22(suppl 1): 158A.

  4. Sirvent N, Coindre JM, Maire G, et al. Detection of MDM2-CDK4 amplification by fluorescence in situ hybridization in 200 paraffin-embedded tumor samples: utility in diagnosing adipocytic lesions and comparison with immunohistochemistry and real-time PCR. Am J Surg Pathol 2007 Oct; 31(10): 1476-89.

  5. Youens KE, Waugh MS. Extranodal follicular dendritic cell sarcoma. Arch Pathol Lab Med 2008 Oct; 132(10): 1683-7.

  6. Argani P, Beckwith JB. Metanephric stromal tumor: report of 31 cases of a distinctive pediatric renal neoplasm. Am J Surg Pathol 2000 Jul; 24(7): 917-26.

  7. Divetia M, Karpate A, Basak R, Desai SB. Synovial sarcoma of the kidney. Ann Diagn Pathol 2008 Oct; 12(5): 333-9.

  8. Fine SW, McCarthy DM, Chan TY, Epstein JI, Argani P. Malignant solitary fibrous tumor of the kidney: report of a case and comprehensive review of the literature. Arch Pathol Lab Med 2006 Jun; 130(6): 857-61.

  9. Naslund MJ, Dement S, Marshall FF. Malignant renal schwannoma. Urology 1991 Nov; 38(5): 477-9.

  10. Skinnider BF, Folpe AL, Hennigar RA, et al. Distribution of cytokeratins and vimentin in adult renal neoplasms and normal renal tissue: potential utility of a cytokeratin antibody panel in the differential diagnosis of renal tumors. Am J Surg Pathol 2005 Jun; 29(6): 747-54.

  11. de Peralta-Venturina M, Moch H, Amin M, et al. Sarcomatoid differentiation in renal cell carcinoma: a study of 101 cases. Am J Surg Pathol 2001 Mar; 25(3): 275-84.

  12. Perez-Montiel D, Wakely PE, Hes O, Michal M, Suster S. High-grade urothelial carcinoma of the renal pelvis: clinicopathologic study of 108 cases with emphasis on unusual morphologic variants. Mod Pathol 2006 Apr; 19(4): 494-503.

  13. Amin MB. Epithelioid angiomyolipoma. In: Eble JN, Sauter G, Epstein JI (eds). Pathology and Genetics of Tumours of the Urinary System and Male Genital organs., Vol.: Lyon, 2004, p 68.

  14. Eble JN, Amin MB, Young RH. Epithelioid angiomyolipoma of the kidney: a report of five cases with a prominent and diagnostically confusing epithelioid smooth muscle component. Am J Surg Pathol 1997 Oct; 21(10): 1123-30.

  15. Dotan ZA, Tal R, Golijanin D, Synder ME, Antonescu C, Brennan MF, Russo P. Adult genitourinary sarcoma: the 25-year Memorial Solan-Kettering experience. J Urol 2006 Nov; 176(5): 2033-88.

  16. Henricks WH, Chu YC, Goldblum JR, Weiss SW. Dedifferentiated liposarcoma: a clinicopathological analysis of 155 cases with a proposal for an expanded definition of dedifferentiation. Am J Surg Pathol 1997 Mar; 21(3): 271-81.