The current trend of practicing medicine necessitates incorporation of latest evidence in diagnosis and management of tumors, depending upon priorities and needs of a community, hospital or an institution.
Demography and need for specialized care

Among the various diagnostic challenges that a clinician and a pathologist face, retroperitoneal soft tissue sarcomas (RPS) are important. Their prognosis is dismal as they are generally detected at a later stage and recurrences are fairly common. About 10% of soft tissue sarcomas (STS) arise in the retroperitoneal tissues. At Tata Memorial Hospital, 7.7 % of soft tissue tumors have been seen in the retroperitoneun during a 10-years study. According to the hospital cancer registry, they form less than 1% of total annual cancer load. Overall incidence of STS’s has been increasing. Recent advances in multidisciplinary care at a hospital like ours form an asset in improved evaluation and care of patients with RPS. It is best to have these tumors evaluated by a specialized soft tissue tumor team. These cases need to be referred at the earliest in view of their late stage of presentation. Elsewhere treated, there are fears of inappropriate tests, positive margins after surgical resection and reduced likelihood of radiotherapy. With an improvement in the surgical expertise of handling abdominal cancers, RPS’s have become important as surgical management offers survival benefit and decreases morbidity.

Clinico-radiological evaluation
Even though these tumors are relatively rare, a pathologist is in a position to offer a final diagnosis for a “soft tissue” mass that is enigmatic to a clinician and a radiologist. However, an accurate pretreatment clinico-radiological evaluation is imperative in all these cases. A radiologist, with the help of computed tomography (CT) can offer the size, extent and location of this tumor. Newer modalities like positron emission tomography (PET) are useful when functional information from these is integrated with anatomical details from CT scan. Apart from staging, imaging is also vital in defining the tumor relationship to the surrounding structures, deciding upon a treatment plan and long term monitoring in individual cases. Imaging (CT) has also revolutionarized procedures like core biopsy and FNAC in yielding diagnostic material in a relatively less invasive way.

Pathological diagnosis
If imaging suggests a clearly resectable RPS, biopsy can be avoided, considering the fear of transperitoneal spread and track implantation. A biopsy should be considered if a gastrointestinal stromal tumor (GIST) is suspected radiologically, if the tumor is unresectable or if metastasis is suspected. Similarly, a biopsy is necessary in a suspected haemato-lymphoid malignancy. Percutaneous core needle biopsy is safe and effective, yielding subtyping and grading of tumor in about 80% cases. The diagnostic accuracy increases with an experienced pathologist. It is important to recognize diagnostic limitations imposed by small sized biopsies in dealing with situations like a homogenous round cell tumor vs a spindle cell tumor. A spindle cell sarcoma might be heterogenous in terms of its grade and histogenetic differentiation and a small biopsy might not be its true representation. Complete clinico-radiological details along with other relevant findings e.g. tumor marker levels could be immensely helpful in situations of a germ cell tumor diagnosis with a limited core biopsy. There would be more of such real time examples with other pathologists.

Simple diagnostic tools like fine needle aspiration cytology (FNAC) have been utilized for making preliminary soft tissue tumor STT diagnoses. FNAC is useful in cases of recurrences and metastasis. On histopathology, set criteria have been well established for histopathological classification and grading of soft tissue sarcomas. Immunohistochemistry and ancillary techniques like cytogenetics and electron microscopy have been helpful in pin pointing these tumors. In case these studies are anticipated, like, in cases of neuroendocrine tumors, PNET’s etc, fresh core biopsy samples should be taken right away and submitted.

Prognostic variables and advances in treatment
In an elegant study by Lewis et al, on analyzing 500 patients with retroperitoneal soft tissue sarcomas treated and followed at a single institution, it was observed that out of various variables; stage at presentation, high histologic grade, unresectable primary tumor, and positive gross margin were strongly associated with the tumor mortality rate. It is important to note that complete tumor respectability necessitates frozen section diagnosis for margin clearance. Jaques et al, while conducting a retrospective study of the management of primary and recurrent soft-tissue sarcomas of the retroperitoneum, found that tumor grade was a significant predictor of outcome as they saw that high-grade tumors were associated with a 20-month median survival time, compared to 80 months for low-grade tumors (n = 49). Ramdas and Chinoy, while conducting a detailed study of 136 cases of adult retroperitoneal soft tissue tumours during a span of 10 years at Tata Hospital observed a higher incidence of malignant forms of soft tissue tumors in this location. Neurogenic (33.3%), lipogenic (29%) and leiomyomatous tumors (17%) were the most frequently observed histological subtypes. Over all survival was found to be low. Adequacy of surgery and grade of tumor were identified as important prognostic variables.

Staging of a STT mass is equally important. The recently updated UICC-TNM staging for soft tissue sarcomas includes variables like grade, size, deep vs superficial location, lymph node status and metastasis. This has been more in the context of sarcomas arising in the extremities. Not all of these variables apply to a RPS. A more plausible clinicopathological post surgical classification system has been proposed for a RPS with 4 classes in a significantly decreasing percentages of 5-year survival rates i.e. I, low-grade/complete resection/ no metastasis; II, high-grade/complete resection/no metastasis; III, any grade/incomplete resection/no metastasis and IV, any-grade/any resection/distant metastasis.

Although, histologic subtyping of a STS seems to have taken a back seat as a prognostic parameter in its clinical worklist, it becomes imperative in cases of close differential diagnoses, when therapies vary considerably. Diagnosis of a round cell tumor like rhabdomyosarcoma or a primitive neuroectodermal tumor (PNET) necessitates treatment with specific chemotherapeutic regimes, in contrast to spindle cell sarcomas, where surgery is the mainstay. Immunohistochemistry, cytogenetics and ultrastructural analysis significantly add as objective evidence eg. MIC-2 positivity and specific translocations like t (11, 22) in substantiating a diagnosis of a PNET. This subjects the patient to an intense chemotherapeutic regime.
A recent step in cancer treatment is targeted therapy with the latest example of analysis of mutation in KIT gene, known to have a major effect on treatment response and survival of GIST. The drug (Gleevac) finds active use in our hospital in these patients. Activating mutations in the platelet-derived growth factor receptor @ (PDGFRA) gene have also been proposed to be driving GIST’s. Another example is of synovial sarcomas, which are being thought to be expressing epidermal growth factor receptors. The epidermal growth factor receptor inhibitor gefitinib is currently being evaluated in a phase 2 trial of patients with synovial sarcoma conducted by the European Organization for Research and Treatment of Cancer (EORTC). Emerging gene-array and proteomic techniques are further being applied to identify potential treatment targets, which may help to individualize therapy. In this way, the range in therapeutic options is expanding for retroperitoneal soft tissue sarcomas, which otherwise have an inexorable course. This has been possible with the advent of ancillary techniques, which need to be judiciously applied from the diagnostic and prognostic point of view.

To cite an example of a diagnostic algorithm for a RPS, it would be helpful for recognizing whether the retroperitoneal spindle cell sarcoma is a GIST vs a non-GIST. Further, spindle cell sarcomas should be graded into low and high grades along with tumor differentiation. Efforts should be made to recognize specific clinicopathologic entities such as leiomyosarcoma which needs to be graded as low, intermediate or high grade, and synovial sarcomas which tend to have an unfavorable outcome. Soft tissue sarcomas need to be sought out from organ based spindle cell tumors e.g. sarcomatoid variant of renal cell carcinoma. It is quite relevant to correlate radiological findings with pathological features in all these cases.

To summarize, an adequate pathology report on soft tissue sarcomas should include tumor size, histologic typing, grading, status of resections margins. A comment on pathologic staging and results of ancillary techniques (electron microscopy, cytogenetics and molecular genetics) should also be made.

References :

1.  Chiappa A, Zbar AP, Biffi R, Bellomi M, Orecchia R, Marsiglia H et al. Primary and recurrent retroperitoneal sarcoma: factors affecting survival and long-term outcome. Hepatogastroenterol 2004; 51(59): 1304-9.

2. Clasby R, Tilling K, Smith MA, Fletcher CD. Variable management of soft tissue sarcoma: regional audit with implications for specialist care. Br J Surg 1997; 84: 1692-6.

3. Greene FL, Page DL, Fleming ID, et al. eds. AJCC cancer staging manual. 6th ed. New York: Springer-Verlag, 2002.

4. Guillou L, Coindre JM, Bonichon F, et al. Comparative study of the National Cancer Institute and French Federation of Cancer Centers Sarcoma Group grading systems in a population of 410 adult patients with soft tissue sarcoma. J Clin Oncol 1997; 15:350-362.

5. Jaques DP, Coit DG, Hajdu SI, Brennan MF. Management of primary and recurrent soft-tissue sarcoma of the retroperitoneum. Ann Surg. 1990; 212(1): 51-9.

6. Lewis JJ, Leung D, Woodruff JM, Brennan MF. Retroperitoneal soft-tissue sarcoma: analysis of 500 patients treated and followed at a single institution. Ann Surg. 1998; 228(3): 355-65.

7. Nielsen TO, West RB, Linn SC, et al. Molecular characterisation of soft tissue tumors: a gene expression study. Lancet 2002; 359:1301-1307.

8. Pirayesh A, Chee Y, Helliwell TR, Hershman MJ, Leinster SJ, Fordham MV, Poston GJ. The management of retroperitoneal soft tissue sarcoma: a single institution experience with a review of the literature. Eur J Surg Oncol. 2001; 27(5): 491-7.

9. Ramdas A, Chinoy RF. Adult retroperitoneal soft tissue tumors-A cinicopathological study (Dissertation). P.1-37.

10. Rekhi B, Bhatnagar D, Bhatnagar A, Saxena S. Cytomorphological study of soft tissue neoplasms-Role of fluorescent immunocytochemistry in diagnosis. Cytopathol 2005; 16 (5): 219-226.

11. Spillane AJ. Retroperitoneal sarcoma: time for a change in attitude? ANZ J Surg 2001; 71(5): 303-8

12. Van Dalen T, Hennipman A, Van Coevorden F, et al. Evaluation of a clinically applicable post-surgical classification system for primary retroperitoneal soft-tissue sarcoma. Ann Surg Oncol 2004; 11:483-490.