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Diagnosing sarcomas: the role of experience
MINI-SYMPOSIUM: SOFT TISSUE PATHOLOGY
Diagnosing sarcomas: the role of experience
immunophenotype within each tumour type, as well as the observer’s possible unfamiliarity with the sensitivities and specificities of rarely used antibodies. According to figures from the Royal College of Pathologists, in 2010 there were almost 1100 diagnostic pathologists in practice in the United Kingdom; if the cases were evenly distributed, each practitioner might on average see fewer than two soft tissue sarcomas per year. With increasing subspecialization, individuals are likely to be less skilled outside their areas of practice and to have even less exposure to rare soft tissue tumours. It can be therefore extremely challenging for an inexperienced pathologist who occasionally encounters a sarcoma or sarcoma-like lesion to assess malignancy, subtype and grade, which are essential data required by the clinical management team before they can decide the best treatment for each individual patient with a soft tissue tumour. This might include critical decisions on type and extent of surgery, and on use of primary, adjuvant or neoadjuvant irradiation and chemotherapy. Due to their relative rarity, widely varying clinical features, pathological complexity and the need for a multidisciplinary management plan, these tumours are most appropriately diagnosed and managed by rapid referral to a specialist sarcoma centre where clinicians, nursing staff, physical therapists and others have a specific interest and expertise in this area.2 Guidelines have been issued in several countries for reporting sarcomas. These help to ensure that all relevant information is provided to the clinical team and that data are collected in a standardized manner. However, it is not always easy for a pathologist who sees these cases infrequently to interpret the relevant histological features correctly.
Cyril Fisher
Abstract Soft tissue sarcomas are rare but have numerous subtypes, and both benign and malignant soft tissue tumours can show considerable morphological variation. With increasing subspecialization, histopathologists become less skilled outside their areas of practice, and it can be difficult for an inexperienced pathologist to assess malignancy, subtype and grade of a sarcoma as required for management. In different clinicopathological settings, there is a consistent discrepancy rate between referring and expert diagnoses of approximately 25% for diagnosis and grading, with about a 5% malignant-benign change. Soft tissue tumour specimens should therefore be reported by specialist pathologists, within a multidisciplinary team. Furthermore, outcomes are better in specialized centres with dedicated multidisciplinary teams bringing together expertise in imaging, histopathology, surgery and oncology. This should include access to cytogenetic and molecular genetic diagnostic services. Ideally, patients with soft tissue masses suspected to be malignant should be referred to a specialist unit before biopsy.
Keywords audit; diagnosis; histopathology; pathology review; sarcoma; soft tissue tumours
Diagnosis of malignancy A major step in biopsy interpretation for the diagnostic pathologist is the assessment of malignancy, in which there are numerous pitfalls. A common example is identifying nodular fasciitis, a reactive condition, because of its rapid growth, cellularity and mitotic activity, as a spindle cell sarcoma such as leiomyosarcoma or myxofibrosarcoma. Nodular fasciitis (Figure 1) lacks pleomorphism
Introduction Soft tissue sarcomas are rare, accounting for about 1% of malignant neoplasms with an incidence of about 30 per million of population. In the United Kingdom, this represents about 1800 new cases per year. There are more than 200 types of benign and malignant soft tissue tumour, many with several morphological variations and mostly rare, and the literature in this field of pathology continues to expand disproportionately. For example, almost 20% (39/198) of the original papers published in the American Journal of Surgical Pathology in 2010 concerned soft tissue neoplasia. Diagnoses are generally made in accordance with the World Health Organization’s Consensus Classification for soft tissue tumours (2002).1 This, however, does not include tumors of peripheral nerves or of the skin, and in addition, there are a number of reactive or inflammatory conditions that can mimic sarcomas both clinically and histologically. Many pathologists use standard textbooks for a more comprehensive account, but it is usually necessary to have some idea of the likely diagnosis or broad differential diagnosis before being able to access the information provided in this way. Furthermore, many cases need additional techniques for diagnosis, of which the most commonly used is immunohistochemistry. This raises additional difficulties because of the natural variations in
Figure 1 Nodular fasciitis. The cellularity and mitotic activity can lead to a mistaken diagnosis of malignancy. However, there are characteristic stromal microcysts with erythrocyte and lymphocyte extravasation, and pleomorphism and necrosis are absent.
Cyril Fisher MD DSc FRCPath is Professor at the Department of Histopathology, The Royal Marsden NHS Foundation Trust, London, UK. Conflicts of interest: none declared.
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MINI-SYMPOSIUM: SOFT TISSUE PATHOLOGY
but the pathologist often sees ‘mild nuclear atypia’ especially at high magnification and, being anxious not to ‘miss’ a sarcoma overcalls the diagnosis. In addition, positivity for smooth muscle actin in nodular fasciitis can erroneously be assumed to indicate smooth muscle (rather than myofibroblastic) differentiation, even in the absence of other smooth muscle markers such as desmin and h-caldesmon. The pathologist, especially if unaware of the clinical context, is thus falsely reassured that the diagnosis of leiomyosarcoma is the correct one. Conversely, in a smooth muscle tumour with prominent nuclear atypia a diagnosis of symplastic leiomyoma can be made if sparse mitotic activity or minute foci of incipient necrosis are overlooked; in this event, the diagnosis would change significantly, from a benign lesion to leiomyosarcoma grade 2. A more common difficulty is the assessment of atypical features in differentiated adipose tissue neoplasms. In large lipomas, microscopic foci of fat necrosis (Figure 2) can easily be misinterpreted as showing lipoblasts (which are neither necessary nor sufficient for a diagnosis of atypical lipomatous tumour), and multinucleated macrophages as representing atypical cells. The diagnosis of atypical lipomatous tumour (Figure 3) can be facilitated by demonstration of MDM2 and CDK4 amplification by FISH or immunohistochemistry but these investigations are usually available only in specialized centres.
Figure 3 Atypical lipomatous tumour. This shows variably-sized adipocytes and foci of fibrosis with fibrillary collagen, containing scattered enlarged hyperchromatic nuclei. Lipoblasts are not necessary for this diagnosis.
Histological subtyping can also present difficulties in tumours composed of spindle cells, epithelioid cells, or small round cells, and in pleomorphic neoplasms. In the abdomen, fibromatosis (Figure 4) can be misdiagnosed as gastrointestinal stromal tumour, especially when there is weak cytoplasmic immunoreactivity for CD117 in the former. Conversely, cytoplasmic immunoreactivity for beta-catenin, which is commonly seen in a variety of myofibroblastic tumours, can be erroneously interpreted as nuclear positivity leading to an incorrect diagnosis of fibromatosis. Low-grade dedifferentiated liposarcoma can also be mistaken for fibromatosis, a problem compounded by the abovementioned difficulty of assessing whether beta-catenin positivity
is truly nuclear. It is not always realized that most myxofibrosarcomas and pleomorphic sarcomas in the abdomen or retroperitoneum are currently considered to represent dedifferentiated liposarcoma (Figures 5 and 6), even in the absence of a well-differentiated component.3 Identification of histological subtypes of liposarcoma and of rhabdomyosarcoma are additional areas of frequent discrepancy. Moderately or poorly differentiated examples of leiomyosarcoma are often reported as undifferentiated pleomorphic sarcoma, and vice versa. This is often once again compounded by misinterpretation as smooth muscle differentiation of focal SMA positivity which is commonly seen in a subplasmalemmal distribution in pleomorphic sarcomas (malignant fibrous histiocytomas) with focal myofibroblastic differentiation. There might also be lack of awareness that even examples of pleomorphic sarcoma that focally display desmin and SMA should not be diagnosed as
Figure 2 Microscopic foci of fat necrosis mimicking lipoblastic differentiation. Nuclear atypia is absent, and immunohistochemistry for MDM2 and CDK4 is negative.
Figure 4 Fibromatosis. This lesion is characterized by parallel fascicles of bland myofibroblasts, evenly dispersed in a collagenous stroma, with scattered mast cells.
Diagnosis of tumour subtype
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Grading Grading of soft tissue sarcomas is an important prognostic factor and a component of some staging systems. Several methods of grading have been proposed, but the most widely used is the three-step system of the French Cancer Centres (FNCLCC)7 that is recommended by the World Health Organization1 and is included in published recommendations for reporting soft tissue tumours in the United States of America8 and the United Kingdom.9 The system is based on three parameters e differentiation, amount of necrosis and mitotic index e each of which is assigned a score between 1 and 3 (0e2 for necrosis). The summation of the scores indicates the grade: a total of 2 or 3 ¼ grade 1, a total of 4e5 ¼ grade 2, and a total of 6e8 ¼ grade 3. Some tumour types are automatically assigned to a fixed grade, and others are of varying grade. Among the latter, differentiation is the parameter that appears to be responsible for the most discrepancy between pathologists. Sarcomas with a differentiation score of 1 are those that closely resemble normal adult tissue to such a degree as to be confused with benign lesions. A differentiation score of 2 is assigned to sarcomas for which the histologic typing is certain, and a score of 3 is attributed to biphasic and monophasic synovial sarcomas, Ewing’s sarcomas, primitive peripheral neuroectodermal tumors (PNETs), sarcomas of doubtful tumour type, and undifferentiated sarcomas. Tumours that show variable differentiation usually do so in a continuous fashion rather than in distinct steps, and sometimes there is marked intralesional variation. Therefore, an individual who does not regularly encounter a range of appearances might find difficulty in assigning the correct differentiation score to any single case. An example of this is grading of smooth muscle tumours (Figures 7e9). Well-differentiated leiomyosarcoma is assigned a differentiation score of 1, ‘conventional’ leiomyosarcoma is scored as 2, and poorly differentiated leiomyosarcoma is scored as 3. In the study of Thway et al,10 all of the major grading errors and 25% of the minor grading errors involved leiomyosarcoma, which was variously under- and over-graded. Since degrees of pleomorphism are not clearly defined, it is sometimes difficult even for the expert to apply the definitions for each differentiation score to gradeable sarcomas such as this. There is also subjective variation in mitosis counting and in evaluation of necrosis. For the latter, a particular difficulty lies in distinguishing hyalinization or infarction from true coagulative necrosis, especially in smooth muscle tumours.11 Also, in the French Cancer Centres grading system, a score of 1 is given when the necrotic area is less than 50%, and a score of 2 when it is more than 50% of the tumour’s cut surface, which is a necessarily subjective assessment (it is not recommended that necrosis be scored in core biopsies).
Figure 5 Dedifferentiated liposarcoma. This area resembles low-grade myxofibrosarcoma. It is more cellular than fibromatosis but shows only mild nuclear pleomorphism.
pleomorphic leiomyosarcoma in the absence of fascicular areas with smooth muscle cytomorphology. The diagnostician also needs to remember the occurrence in soft tissue locations of non-mesenchymal malignant tumours e carcinoma, melanoma, germ cell tumour and even lymphoma e that can mimic spindle, epithelioid, small round cell or pleomorphic sarcomas. They represent about 5%4e6 of cases in review studies. These are usually missed rather than overdiagnosed (the latter cases are less likely to be referred to a sarcoma centre). For example, pleomorphic metastatic carcinoma and undifferentiated sarcoma can have very similar microscopic appearances, but error can be avoided by the knowledge that that most pleomorphic tumors in viscera are carcinomas, by demonstration of significant cytokeratin positivity, and by identification of a likely primary tumour in another site.
Discrepancy rates Published comparisons of cases referred to specialist centres or expert panel reviews have shown that there is a fairly consistent rate of discrepancy between original and expert diagnoses of soft tissue tumours, varying between 20% and 40% (Table 1). This affects diagnosis of malignancy, histological subtype of sarcoma, and grade. Cases referred as malignant but found to be benign on review account for about 5% of patients.10,12 The number of false negative diagnoses (i.e. sarcomas misdiagnosed as benign
Figure 6 Dedifferentiated liposarcoma. Nuclei are immunoreactive for CDK4 (Immunoperoxidase).
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MINI-SYMPOSIUM: SOFT TISSUE PATHOLOGY
Figure 7 Leiomyosarcoma, differentiation score 1. This tumour closely resembles normal smooth muscle.
Figure 9 Leiomyosarcoma, differentiation score 3. There is more marked pleomorphism, but a fascicular architecture is still discernible.
tumours) is underestimated in such evaluations since cases reported as benign are not referred to sarcoma units, and might come to light only when they recur or metastasise. The figures are similar in several different countries, for review panels or single centres, and for the type of originating centre e academic centre or general hospital. The discrepancy rate is also surprisingly similar for all types of surgical specimen.10 It might be supposed that a higher error rate would be associated with core biopsies because of the smaller amount of diagnostic material, but in some studies there are similar or higher discrepancy rates for much larger samples from open biopsies and excision specimens. The use of specialized diagnostic techniques, including immunohistochemistry (widely used) and the advent of molecular genetic techniques (useful for refining sarcomas diagnoses13 but mostly available only in specialist centres and therefore applied selectively by the reference pathologist) so far appears not to have impacted the discrepancy rate.
Reasons for discrepancy As noted above, discrepancies are due not only to unfamiliarity with soft tissue tumour pathology and its immunohistochemistry, but also to the intrinsic difficulty of diagnosis in this group of neoplasms. Indeed, as in other areas of tumour pathology such as borderline breast lesions14 or Gleason grading of prostatic carcinoma,15 experts do not always agree among themselves.16 When the reproducibility of the FNCLCC grading system was tested by 15 experienced pathologists on 25 cases, the crude proportion in agreement was 75% for tumour grade, 73% for mitotic index, 74% for differentiation, and 81% for tumour necrosis.17 This is comparable with the discrepancy rates for diagnosis and grading in other published studies. Interobserver variation in soft tissue tumour review panels is also found, especially in diagnosis of leiomyosarcoma and pleomorphic sarcoma NOS (undifferentiated pleomorphic sarcoma or malignant fibrous histiocytoma).4,18 Since most relevant antibodies are available to most pathologists, lack of resources for immunohistochemistry does not appear to be a major contributory factor. It is notable, however, that the most discrepancies occur between tumours that do not have diagnostic genetic aberrations and therefore rely on the observers’ skills rather than resolution by molecular diagnosis.
Guidelines in the UK The Guidance on Cancer Services issued by the National Institute for Health and Clinical Excellence (NICE) includes guidelines for management of soft tissue sarcoma.19 It is recommended that all soft tissue sarcomas should be either first reported or reviewed by a specialist soft tissue sarcoma pathologist. This is defined as a pathologist who regularly reports soft tissue tumours as a significant component of their workload. A specialist pathologist should participate in external quality assessment (EQA), normally through the soft tissue part of the UK National Orthopaedic Pathology EQA scheme, and be a member of a properly constituted sarcoma multidisciplinary team (MDT). All patients with soft tissue tumours assessed in a diagnostic clinic should have their pathology reported by either a specialist soft tissue
Figure 8 Leiomyosarcoma, differentiation score 2. There is moderate nuclear pleomorphism.
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Published studies of discrepancies in diagnosis and grading of soft tissue sarcomas Authors
Country
Group, centre or region
Type of study
Number of cases
Discrepancy in diagnosis %
Discrepancy in grade %
Other
1984
Tetu et al.18
Canada
Expert panel review of referred cases
260
35
e
Intrapanel consensus 84%
1986
Presant et al.4
USA
Panel review for clinical trial entry
216
28
24
1986
Coindre et al.17
France
39
25
Alvegaard et al.5 Shiraki et al.22
Scandinavia USA
Group of 15 pathologists vs expert panel to assess grading system Panel review for clinical trial entry Panel review for clinical trial entry
25
1989 1989
240 488
25 26
40 e
1991 1999
UK Scandinavia
Review at specialist referral centre Panel review for clinical trial entry
376 1000
24 20
e 25
2004 2009
Harris et al.12 Meis-Kindlblom et al.6 Randall et al.23 Thway et al.10
Canadian Tumour Reference Centre Southeastern Cooperative Sarcoma Group French Federation of Cancer Centres Sarcoma Group Scandinavian Sarcoma Group Eastern Cooperative Oncology Group Christie Hospital, Manchester Scandinavian Sarcoma Group
Review at specialist referral centre Review at specialist referral centre
104 349
37 22
25 23
2010
Lurkin et al.24
France, Italy
Panel review of regional cases
366
25
19
Table 1
USA UK
University of Utah Royal Marsden Hospital, London Rhone-Alpes Region
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Year
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MINI-SYMPOSIUM: SOFT TISSUE PATHOLOGY
pathologist or a pathologist nominated by the sarcoma MDT as part of the local diagnostic referral pathway and who has formal links to a specialist soft tissue pathologist. The UK National Orthopaedic Pathology EQA scheme provides two circulations a year each comprising 10 cases of soft tissue tumours and 10 cases of bone pathology. Representative slides with the clinical information, diagnostic imaging where appropriate, and pathological data such as immunohistochemical findings are sent to participants, who submit their suggested diagnoses on a standard proforma. The opinions are anonymized and participants are identified by a code number known only to the scheme’s administrator. Suitable cases are selected without knowledge of the original diagnosis by a co-ordinator (one of the participants) from a ‘bank’ of those provided from time to time by scheme members. The submitted opinions are discussed at a participants’ meeting and each is scored against the consensus diagnosis. Thirty-three individuals, from all parts of the United Kingdom, participate in the soft tissue component of the scheme. EQA aims to demonstrate a common level of performance (in relation to the consensus diagnosis) for routine cases, rather than the ability to diagnose unusual/difficult cases. Satisfactory performance in interpretative EQA is required by individuals for the annual appraisal which all consultants in the UK must undergo, and which will form part of periodic revalidation and relicensing by the General Medical Council. It is also required for peer review (a form of external assessment against predefined standards) of sarcoma services, since the pathologist is a core member of the multidisciplinary clinical management team (MDT). As part of the very high level of regulation of histopathologists in the UK, EQA schemes themselves can be subject to external review and accreditation. Poor performers in EQA are defined as those whose scores repeatedly fall below an agreed level, although there is no certainty about how such individuals should be dealt with.
assessment. A similar referral policy has been the practice in the Scandinavian Sarcoma Group for some years.
Conclusion The rarity of soft tissue sarcomas and the additional lack of experience in surgical pathologists due to subspecialization can result in major and minor diagnostic discrepancies. Early referral to experienced pathologists who work in multidisciplinary teams in specialist centres and deal with a large number and variety of cases should increase accuracy of pathological diagnosis of soft tissue neoplasms and thereby contribute to improvement in quality of patient care. A reduction in malpractice claims might also be anticipated. A
REFERENCES 1 Fletcher C, Unni K, Mertens F, eds. World Health Organization classification of tumours. Pathology and genetics of tumours of soft tissue and bone. Lyon: IARC Press, 2002. 2 Johnson GD, Smith G, Dramis A, Grimer RJ. Delays in referral of soft tissue sarcomas. Sarcoma 2008; 2008: 378574. 3 Coindre JM, Mariani O, Chibon F, et al. Most malignant fibrous histiocytomas developed in the retroperitoneum are dedifferentiated liposarcomas: a review of 25 cases initially diagnosed as malignant fibrous histiocytoma. Mod Pathol 2003; 16: 256e62. 4 Presant CA, Russell WO, Alexander RW, Fu YS. Soft-tissue and bone sarcoma histopathology peer review: the frequency of disagreement in diagnosis and the need for second pathology opinions. The Southeastern Cancer Study Group experience. J Clin Oncol 1986; 4: 1658e61. 5 Alvegard TA, Berg NO. Histopathology peer review of high-grade soft tissue sarcoma: the Scandinavian Sarcoma Group experience. J Clin Oncol 1989; 7: 1845e51. 6 Meis-Kindblom JM, Bjerkehage B, Bohling T, et al. Morphologic review of 1000 soft tissue sarcomas from the Scandinavian Sarcoma Group (SSG) Register. The peer-review committee experience. Acta Orthop Scand Suppl 1999; 285: 18e26. 7 Coindre JM. Grading of soft tissue sarcomas: review and update. Arch Pathol Lab Med 2006; 130: 1448e53. 8 Rubin BP, Cooper K, Fletcher CD, et al. Protocol for the examination of specimens from patients with tumors of soft tissue. Arch Pathol Lab Med 2010; 134: e31e9. 9 Fisher C. Dataset for cancer histopathology reports on soft tissue sarcomas. Royal College of Pathologists, http://www.rcpath.org/ resources/pdf/g094datasetsofttissue.pdf; 2009. 10 Thway K, Fisher C. Histopathological diagnostic discrepancies in soft tissue tumours referred to a specialist centre. Sarcoma 2009; 2009: 741975. 11 Lim D, Gilks B, Longacre T, Nucci MR, Soslow RA, Oliva E. Interobserver variability in the interpretation of tumor cell necrosis (TCN) in uterine leiomyosarcoma (LMS). Mod Pathol 2011; 24(suppl 1): 256A. 12 Harris M, Hartley AL, Blair V, et al. Sarcomas in north west England: I. Histopathological peer review. Br J Cancer 1991; 64: 315e20. 13 Thway K, Rockcliffe S, Gonzalez D, et al. Utility of sarcoma-specific fusion gene analysis in paraffin-embedded material for routine diagnosis at a specialist centre. J Clin Pathol 2010; 63: 508e12. 14 Rosai J. Borderline epithelial lesions of the breast. Am J Surg Pathol 1991; 15: 209e21.
Guidelines in other countries Guidelines for clinical management of soft tissue tumours include similar provisions for pathology review in Europe and the US. The clinical recommendations for soft tissue sarcomas of The European Society for Medical Oncology (ESMO) acknowledge the need for accurate diagnosis and state that a pathological expert second opinion is recommended in all cases where the original diagnosis was made outside reference centres.20 In the USA, the National Comprehensive Cancer Network guidelines indicate that ‘pathologic assessment of biopsies and resection specimens should be carried out by an experienced sarcoma pathologist’ although the amount of experience is not defined.21 Similar recommendations are in preparation by the Royal College of Pathologists of Australasia (Dr Christine Hemmings, personal communication). The ESMO guidelines also mandate multidisciplinary treatment planning (involving pathologists, radiologists, surgeons, radiation therapists, medical oncologists, and paediatric oncologists if applicable) in reference centres for sarcomas and/or within reference networks sharing multidisciplinary expertise and treating a high number of patients annually. They additionally suggest that all patients with an unexplained deep soft tissue mass, or with a superficial lesion of soft tissues having a diameter of >5 cm, or arising in the paediatric age group, be referred before biopsy, so that the latter can be performed as part of the multidisciplinary
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15 Allsbrook Jr WC, Mangold KA, Johnson MH, et al. Interobserver reproducibility of Gleason grading of prostatic carcinoma: urologic pathologists. Hum Pathol 2001; 32: 74e80. 16 Raab SS, Grzybicki DM. Quality in cancer diagnosis. CA Cancer J Clin 2010; 60: 139e65. 17 Coindre JM, Trojani M, Contesso G, et al. Reproducibility of a histopathologic grading system for adult soft tissue sarcoma. Cancer 1986; 58: 306e9. 18 Tetu BHA, McCaughey WTE, Lagace R. Evaluation des divergences d’opinion sur le diagnostic histopathologique des tumeurs des tissus mous. Ann Pathol 1984; 4: 267e71. 19 Improving outcomes for people with sarcoma. The manual. London: National Institute for Health and Clinical Excellence, 2006. 20 Casali PG, Blay JY. Soft tissue sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010; 21(suppl 5): v198e203. 21 NCCN Practice Guidelines in Oncology. Soft Tissue Sarcoma. v.2, http://www.nccn.org/professionals/physician_gls/f_guidelines.asp; 2010. 22 Shiraki M, Enterline HT, Brooks JJ, et al. Pathologic analysis of advanced adult soft tissue sarcomas, bone sarcomas, and mesotheliomas. The Eastern Cooperative Oncology Group (ECOG) experience. Cancer 1989; 64: 484e90.
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23 Randall RL, Bruckner JD, Papenhausen MD, Thurman T, Conrad 3rd EU. Errors in diagnosis and margin determination of soft-tissue sarcomas initially treated at non-tertiary centers. Orthopedics 2004; 27: 209e12. 24 Lurkin A, Ducimetiere F, Vince DR, et al. Epidemiological evaluation of concordance between initial diagnosis and central pathology review in a comprehensive and prospective series of sarcoma patients in the Rhone-Alpes region. BMC Cancer 2010; 10: 150.
Practice points C
C
C
C
339
Soft tissue tumours are rare but comprise many different histological types. Pathological expertise is required for the microscopic distinction between benign and malignant soft tissue tumours and to correctly assess subtype of sarcoma and grade. Specialist sarcoma pathologists should see sufficient numbers of cases, be part of a multidisciplinary management team, and take part in regular external quality assessment. The best outcomes are obtained in patients with soft tissue tumours who are referred to a specialized multidisciplinary management team, preferably before biopsy.
Ó 2011 Elsevier Ltd. All rights reserved.
Diagnosing sarcomas: the role of experience
immunophenotype within each tumour type, as well as the observer’s possible unfamiliarity with the sensitivities and specificities of rarely used antibodies. According to figures from the Royal College of Pathologists, in 2010 there were almost 1100 diagnostic pathologists in practice in the United Kingdom; if the cases were evenly distributed, each practitioner might on average see fewer than two soft tissue sarcomas per year. With increasing subspecialization, individuals are likely to be less skilled outside their areas of practice and to have even less exposure to rare soft tissue tumours. It can be therefore extremely challenging for an inexperienced pathologist who occasionally encounters a sarcoma or sarcoma-like lesion to assess malignancy, subtype and grade, which are essential data required by the clinical management team before they can decide the best treatment for each individual patient with a soft tissue tumour. This might include critical decisions on type and extent of surgery, and on use of primary, adjuvant or neoadjuvant irradiation and chemotherapy. Due to their relative rarity, widely varying clinical features, pathological complexity and the need for a multidisciplinary management plan, these tumours are most appropriately diagnosed and managed by rapid referral to a specialist sarcoma centre where clinicians, nursing staff, physical therapists and others have a specific interest and expertise in this area.2 Guidelines have been issued in several countries for reporting sarcomas. These help to ensure that all relevant information is provided to the clinical team and that data are collected in a standardized manner. However, it is not always easy for a pathologist who sees these cases infrequently to interpret the relevant histological features correctly.
Cyril Fisher
Abstract Soft tissue sarcomas are rare but have numerous subtypes, and both benign and malignant soft tissue tumours can show considerable morphological variation. With increasing subspecialization, histopathologists become less skilled outside their areas of practice, and it can be difficult for an inexperienced pathologist to assess malignancy, subtype and grade of a sarcoma as required for management. In different clinicopathological settings, there is a consistent discrepancy rate between referring and expert diagnoses of approximately 25% for diagnosis and grading, with about a 5% malignant-benign change. Soft tissue tumour specimens should therefore be reported by specialist pathologists, within a multidisciplinary team. Furthermore, outcomes are better in specialized centres with dedicated multidisciplinary teams bringing together expertise in imaging, histopathology, surgery and oncology. This should include access to cytogenetic and molecular genetic diagnostic services. Ideally, patients with soft tissue masses suspected to be malignant should be referred to a specialist unit before biopsy.
Keywords audit; diagnosis; histopathology; pathology review; sarcoma; soft tissue tumours
Diagnosis of malignancy A major step in biopsy interpretation for the diagnostic pathologist is the assessment of malignancy, in which there are numerous pitfalls. A common example is identifying nodular fasciitis, a reactive condition, because of its rapid growth, cellularity and mitotic activity, as a spindle cell sarcoma such as leiomyosarcoma or myxofibrosarcoma. Nodular fasciitis (Figure 1) lacks pleomorphism
Introduction Soft tissue sarcomas are rare, accounting for about 1% of malignant neoplasms with an incidence of about 30 per million of population. In the United Kingdom, this represents about 1800 new cases per year. There are more than 200 types of benign and malignant soft tissue tumour, many with several morphological variations and mostly rare, and the literature in this field of pathology continues to expand disproportionately. For example, almost 20% (39/198) of the original papers published in the American Journal of Surgical Pathology in 2010 concerned soft tissue neoplasia. Diagnoses are generally made in accordance with the World Health Organization’s Consensus Classification for soft tissue tumours (2002).1 This, however, does not include tumors of peripheral nerves or of the skin, and in addition, there are a number of reactive or inflammatory conditions that can mimic sarcomas both clinically and histologically. Many pathologists use standard textbooks for a more comprehensive account, but it is usually necessary to have some idea of the likely diagnosis or broad differential diagnosis before being able to access the information provided in this way. Furthermore, many cases need additional techniques for diagnosis, of which the most commonly used is immunohistochemistry. This raises additional difficulties because of the natural variations in
Figure 1 Nodular fasciitis. The cellularity and mitotic activity can lead to a mistaken diagnosis of malignancy. However, there are characteristic stromal microcysts with erythrocyte and lymphocyte extravasation, and pleomorphism and necrosis are absent.
Cyril Fisher MD DSc FRCPath is Professor at the Department of Histopathology, The Royal Marsden NHS Foundation Trust, London, UK. Conflicts of interest: none declared.
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but the pathologist often sees ‘mild nuclear atypia’ especially at high magnification and, being anxious not to ‘miss’ a sarcoma overcalls the diagnosis. In addition, positivity for smooth muscle actin in nodular fasciitis can erroneously be assumed to indicate smooth muscle (rather than myofibroblastic) differentiation, even in the absence of other smooth muscle markers such as desmin and h-caldesmon. The pathologist, especially if unaware of the clinical context, is thus falsely reassured that the diagnosis of leiomyosarcoma is the correct one. Conversely, in a smooth muscle tumour with prominent nuclear atypia a diagnosis of symplastic leiomyoma can be made if sparse mitotic activity or minute foci of incipient necrosis are overlooked; in this event, the diagnosis would change significantly, from a benign lesion to leiomyosarcoma grade 2. A more common difficulty is the assessment of atypical features in differentiated adipose tissue neoplasms. In large lipomas, microscopic foci of fat necrosis (Figure 2) can easily be misinterpreted as showing lipoblasts (which are neither necessary nor sufficient for a diagnosis of atypical lipomatous tumour), and multinucleated macrophages as representing atypical cells. The diagnosis of atypical lipomatous tumour (Figure 3) can be facilitated by demonstration of MDM2 and CDK4 amplification by FISH or immunohistochemistry but these investigations are usually available only in specialized centres.
Figure 3 Atypical lipomatous tumour. This shows variably-sized adipocytes and foci of fibrosis with fibrillary collagen, containing scattered enlarged hyperchromatic nuclei. Lipoblasts are not necessary for this diagnosis.
Histological subtyping can also present difficulties in tumours composed of spindle cells, epithelioid cells, or small round cells, and in pleomorphic neoplasms. In the abdomen, fibromatosis (Figure 4) can be misdiagnosed as gastrointestinal stromal tumour, especially when there is weak cytoplasmic immunoreactivity for CD117 in the former. Conversely, cytoplasmic immunoreactivity for beta-catenin, which is commonly seen in a variety of myofibroblastic tumours, can be erroneously interpreted as nuclear positivity leading to an incorrect diagnosis of fibromatosis. Low-grade dedifferentiated liposarcoma can also be mistaken for fibromatosis, a problem compounded by the abovementioned difficulty of assessing whether beta-catenin positivity
is truly nuclear. It is not always realized that most myxofibrosarcomas and pleomorphic sarcomas in the abdomen or retroperitoneum are currently considered to represent dedifferentiated liposarcoma (Figures 5 and 6), even in the absence of a well-differentiated component.3 Identification of histological subtypes of liposarcoma and of rhabdomyosarcoma are additional areas of frequent discrepancy. Moderately or poorly differentiated examples of leiomyosarcoma are often reported as undifferentiated pleomorphic sarcoma, and vice versa. This is often once again compounded by misinterpretation as smooth muscle differentiation of focal SMA positivity which is commonly seen in a subplasmalemmal distribution in pleomorphic sarcomas (malignant fibrous histiocytomas) with focal myofibroblastic differentiation. There might also be lack of awareness that even examples of pleomorphic sarcoma that focally display desmin and SMA should not be diagnosed as
Figure 2 Microscopic foci of fat necrosis mimicking lipoblastic differentiation. Nuclear atypia is absent, and immunohistochemistry for MDM2 and CDK4 is negative.
Figure 4 Fibromatosis. This lesion is characterized by parallel fascicles of bland myofibroblasts, evenly dispersed in a collagenous stroma, with scattered mast cells.
Diagnosis of tumour subtype
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Grading Grading of soft tissue sarcomas is an important prognostic factor and a component of some staging systems. Several methods of grading have been proposed, but the most widely used is the three-step system of the French Cancer Centres (FNCLCC)7 that is recommended by the World Health Organization1 and is included in published recommendations for reporting soft tissue tumours in the United States of America8 and the United Kingdom.9 The system is based on three parameters e differentiation, amount of necrosis and mitotic index e each of which is assigned a score between 1 and 3 (0e2 for necrosis). The summation of the scores indicates the grade: a total of 2 or 3 ¼ grade 1, a total of 4e5 ¼ grade 2, and a total of 6e8 ¼ grade 3. Some tumour types are automatically assigned to a fixed grade, and others are of varying grade. Among the latter, differentiation is the parameter that appears to be responsible for the most discrepancy between pathologists. Sarcomas with a differentiation score of 1 are those that closely resemble normal adult tissue to such a degree as to be confused with benign lesions. A differentiation score of 2 is assigned to sarcomas for which the histologic typing is certain, and a score of 3 is attributed to biphasic and monophasic synovial sarcomas, Ewing’s sarcomas, primitive peripheral neuroectodermal tumors (PNETs), sarcomas of doubtful tumour type, and undifferentiated sarcomas. Tumours that show variable differentiation usually do so in a continuous fashion rather than in distinct steps, and sometimes there is marked intralesional variation. Therefore, an individual who does not regularly encounter a range of appearances might find difficulty in assigning the correct differentiation score to any single case. An example of this is grading of smooth muscle tumours (Figures 7e9). Well-differentiated leiomyosarcoma is assigned a differentiation score of 1, ‘conventional’ leiomyosarcoma is scored as 2, and poorly differentiated leiomyosarcoma is scored as 3. In the study of Thway et al,10 all of the major grading errors and 25% of the minor grading errors involved leiomyosarcoma, which was variously under- and over-graded. Since degrees of pleomorphism are not clearly defined, it is sometimes difficult even for the expert to apply the definitions for each differentiation score to gradeable sarcomas such as this. There is also subjective variation in mitosis counting and in evaluation of necrosis. For the latter, a particular difficulty lies in distinguishing hyalinization or infarction from true coagulative necrosis, especially in smooth muscle tumours.11 Also, in the French Cancer Centres grading system, a score of 1 is given when the necrotic area is less than 50%, and a score of 2 when it is more than 50% of the tumour’s cut surface, which is a necessarily subjective assessment (it is not recommended that necrosis be scored in core biopsies).
Figure 5 Dedifferentiated liposarcoma. This area resembles low-grade myxofibrosarcoma. It is more cellular than fibromatosis but shows only mild nuclear pleomorphism.
pleomorphic leiomyosarcoma in the absence of fascicular areas with smooth muscle cytomorphology. The diagnostician also needs to remember the occurrence in soft tissue locations of non-mesenchymal malignant tumours e carcinoma, melanoma, germ cell tumour and even lymphoma e that can mimic spindle, epithelioid, small round cell or pleomorphic sarcomas. They represent about 5%4e6 of cases in review studies. These are usually missed rather than overdiagnosed (the latter cases are less likely to be referred to a sarcoma centre). For example, pleomorphic metastatic carcinoma and undifferentiated sarcoma can have very similar microscopic appearances, but error can be avoided by the knowledge that that most pleomorphic tumors in viscera are carcinomas, by demonstration of significant cytokeratin positivity, and by identification of a likely primary tumour in another site.
Discrepancy rates Published comparisons of cases referred to specialist centres or expert panel reviews have shown that there is a fairly consistent rate of discrepancy between original and expert diagnoses of soft tissue tumours, varying between 20% and 40% (Table 1). This affects diagnosis of malignancy, histological subtype of sarcoma, and grade. Cases referred as malignant but found to be benign on review account for about 5% of patients.10,12 The number of false negative diagnoses (i.e. sarcomas misdiagnosed as benign
Figure 6 Dedifferentiated liposarcoma. Nuclei are immunoreactive for CDK4 (Immunoperoxidase).
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Figure 7 Leiomyosarcoma, differentiation score 1. This tumour closely resembles normal smooth muscle.
Figure 9 Leiomyosarcoma, differentiation score 3. There is more marked pleomorphism, but a fascicular architecture is still discernible.
tumours) is underestimated in such evaluations since cases reported as benign are not referred to sarcoma units, and might come to light only when they recur or metastasise. The figures are similar in several different countries, for review panels or single centres, and for the type of originating centre e academic centre or general hospital. The discrepancy rate is also surprisingly similar for all types of surgical specimen.10 It might be supposed that a higher error rate would be associated with core biopsies because of the smaller amount of diagnostic material, but in some studies there are similar or higher discrepancy rates for much larger samples from open biopsies and excision specimens. The use of specialized diagnostic techniques, including immunohistochemistry (widely used) and the advent of molecular genetic techniques (useful for refining sarcomas diagnoses13 but mostly available only in specialist centres and therefore applied selectively by the reference pathologist) so far appears not to have impacted the discrepancy rate.
Reasons for discrepancy As noted above, discrepancies are due not only to unfamiliarity with soft tissue tumour pathology and its immunohistochemistry, but also to the intrinsic difficulty of diagnosis in this group of neoplasms. Indeed, as in other areas of tumour pathology such as borderline breast lesions14 or Gleason grading of prostatic carcinoma,15 experts do not always agree among themselves.16 When the reproducibility of the FNCLCC grading system was tested by 15 experienced pathologists on 25 cases, the crude proportion in agreement was 75% for tumour grade, 73% for mitotic index, 74% for differentiation, and 81% for tumour necrosis.17 This is comparable with the discrepancy rates for diagnosis and grading in other published studies. Interobserver variation in soft tissue tumour review panels is also found, especially in diagnosis of leiomyosarcoma and pleomorphic sarcoma NOS (undifferentiated pleomorphic sarcoma or malignant fibrous histiocytoma).4,18 Since most relevant antibodies are available to most pathologists, lack of resources for immunohistochemistry does not appear to be a major contributory factor. It is notable, however, that the most discrepancies occur between tumours that do not have diagnostic genetic aberrations and therefore rely on the observers’ skills rather than resolution by molecular diagnosis.
Guidelines in the UK The Guidance on Cancer Services issued by the National Institute for Health and Clinical Excellence (NICE) includes guidelines for management of soft tissue sarcoma.19 It is recommended that all soft tissue sarcomas should be either first reported or reviewed by a specialist soft tissue sarcoma pathologist. This is defined as a pathologist who regularly reports soft tissue tumours as a significant component of their workload. A specialist pathologist should participate in external quality assessment (EQA), normally through the soft tissue part of the UK National Orthopaedic Pathology EQA scheme, and be a member of a properly constituted sarcoma multidisciplinary team (MDT). All patients with soft tissue tumours assessed in a diagnostic clinic should have their pathology reported by either a specialist soft tissue
Figure 8 Leiomyosarcoma, differentiation score 2. There is moderate nuclear pleomorphism.
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Published studies of discrepancies in diagnosis and grading of soft tissue sarcomas Authors
Country
Group, centre or region
Type of study
Number of cases
Discrepancy in diagnosis %
Discrepancy in grade %
Other
1984
Tetu et al.18
Canada
Expert panel review of referred cases
260
35
e
Intrapanel consensus 84%
1986
Presant et al.4
USA
Panel review for clinical trial entry
216
28
24
1986
Coindre et al.17
France
39
25
Alvegaard et al.5 Shiraki et al.22
Scandinavia USA
Group of 15 pathologists vs expert panel to assess grading system Panel review for clinical trial entry Panel review for clinical trial entry
25
1989 1989
240 488
25 26
40 e
1991 1999
UK Scandinavia
Review at specialist referral centre Panel review for clinical trial entry
376 1000
24 20
e 25
2004 2009
Harris et al.12 Meis-Kindlblom et al.6 Randall et al.23 Thway et al.10
Canadian Tumour Reference Centre Southeastern Cooperative Sarcoma Group French Federation of Cancer Centres Sarcoma Group Scandinavian Sarcoma Group Eastern Cooperative Oncology Group Christie Hospital, Manchester Scandinavian Sarcoma Group
Review at specialist referral centre Review at specialist referral centre
104 349
37 22
25 23
2010
Lurkin et al.24
France, Italy
Panel review of regional cases
366
25
19
Table 1
USA UK
University of Utah Royal Marsden Hospital, London Rhone-Alpes Region
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Year
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MINI-SYMPOSIUM: SOFT TISSUE PATHOLOGY
pathologist or a pathologist nominated by the sarcoma MDT as part of the local diagnostic referral pathway and who has formal links to a specialist soft tissue pathologist. The UK National Orthopaedic Pathology EQA scheme provides two circulations a year each comprising 10 cases of soft tissue tumours and 10 cases of bone pathology. Representative slides with the clinical information, diagnostic imaging where appropriate, and pathological data such as immunohistochemical findings are sent to participants, who submit their suggested diagnoses on a standard proforma. The opinions are anonymized and participants are identified by a code number known only to the scheme’s administrator. Suitable cases are selected without knowledge of the original diagnosis by a co-ordinator (one of the participants) from a ‘bank’ of those provided from time to time by scheme members. The submitted opinions are discussed at a participants’ meeting and each is scored against the consensus diagnosis. Thirty-three individuals, from all parts of the United Kingdom, participate in the soft tissue component of the scheme. EQA aims to demonstrate a common level of performance (in relation to the consensus diagnosis) for routine cases, rather than the ability to diagnose unusual/difficult cases. Satisfactory performance in interpretative EQA is required by individuals for the annual appraisal which all consultants in the UK must undergo, and which will form part of periodic revalidation and relicensing by the General Medical Council. It is also required for peer review (a form of external assessment against predefined standards) of sarcoma services, since the pathologist is a core member of the multidisciplinary clinical management team (MDT). As part of the very high level of regulation of histopathologists in the UK, EQA schemes themselves can be subject to external review and accreditation. Poor performers in EQA are defined as those whose scores repeatedly fall below an agreed level, although there is no certainty about how such individuals should be dealt with.
assessment. A similar referral policy has been the practice in the Scandinavian Sarcoma Group for some years.
Conclusion The rarity of soft tissue sarcomas and the additional lack of experience in surgical pathologists due to subspecialization can result in major and minor diagnostic discrepancies. Early referral to experienced pathologists who work in multidisciplinary teams in specialist centres and deal with a large number and variety of cases should increase accuracy of pathological diagnosis of soft tissue neoplasms and thereby contribute to improvement in quality of patient care. A reduction in malpractice claims might also be anticipated. A
REFERENCES 1 Fletcher C, Unni K, Mertens F, eds. World Health Organization classification of tumours. Pathology and genetics of tumours of soft tissue and bone. Lyon: IARC Press, 2002. 2 Johnson GD, Smith G, Dramis A, Grimer RJ. Delays in referral of soft tissue sarcomas. Sarcoma 2008; 2008: 378574. 3 Coindre JM, Mariani O, Chibon F, et al. Most malignant fibrous histiocytomas developed in the retroperitoneum are dedifferentiated liposarcomas: a review of 25 cases initially diagnosed as malignant fibrous histiocytoma. Mod Pathol 2003; 16: 256e62. 4 Presant CA, Russell WO, Alexander RW, Fu YS. Soft-tissue and bone sarcoma histopathology peer review: the frequency of disagreement in diagnosis and the need for second pathology opinions. The Southeastern Cancer Study Group experience. J Clin Oncol 1986; 4: 1658e61. 5 Alvegard TA, Berg NO. Histopathology peer review of high-grade soft tissue sarcoma: the Scandinavian Sarcoma Group experience. J Clin Oncol 1989; 7: 1845e51. 6 Meis-Kindblom JM, Bjerkehage B, Bohling T, et al. Morphologic review of 1000 soft tissue sarcomas from the Scandinavian Sarcoma Group (SSG) Register. The peer-review committee experience. Acta Orthop Scand Suppl 1999; 285: 18e26. 7 Coindre JM. Grading of soft tissue sarcomas: review and update. Arch Pathol Lab Med 2006; 130: 1448e53. 8 Rubin BP, Cooper K, Fletcher CD, et al. Protocol for the examination of specimens from patients with tumors of soft tissue. Arch Pathol Lab Med 2010; 134: e31e9. 9 Fisher C. Dataset for cancer histopathology reports on soft tissue sarcomas. Royal College of Pathologists, http://www.rcpath.org/ resources/pdf/g094datasetsofttissue.pdf; 2009. 10 Thway K, Fisher C. Histopathological diagnostic discrepancies in soft tissue tumours referred to a specialist centre. Sarcoma 2009; 2009: 741975. 11 Lim D, Gilks B, Longacre T, Nucci MR, Soslow RA, Oliva E. Interobserver variability in the interpretation of tumor cell necrosis (TCN) in uterine leiomyosarcoma (LMS). Mod Pathol 2011; 24(suppl 1): 256A. 12 Harris M, Hartley AL, Blair V, et al. Sarcomas in north west England: I. Histopathological peer review. Br J Cancer 1991; 64: 315e20. 13 Thway K, Rockcliffe S, Gonzalez D, et al. Utility of sarcoma-specific fusion gene analysis in paraffin-embedded material for routine diagnosis at a specialist centre. J Clin Pathol 2010; 63: 508e12. 14 Rosai J. Borderline epithelial lesions of the breast. Am J Surg Pathol 1991; 15: 209e21.
Guidelines in other countries Guidelines for clinical management of soft tissue tumours include similar provisions for pathology review in Europe and the US. The clinical recommendations for soft tissue sarcomas of The European Society for Medical Oncology (ESMO) acknowledge the need for accurate diagnosis and state that a pathological expert second opinion is recommended in all cases where the original diagnosis was made outside reference centres.20 In the USA, the National Comprehensive Cancer Network guidelines indicate that ‘pathologic assessment of biopsies and resection specimens should be carried out by an experienced sarcoma pathologist’ although the amount of experience is not defined.21 Similar recommendations are in preparation by the Royal College of Pathologists of Australasia (Dr Christine Hemmings, personal communication). The ESMO guidelines also mandate multidisciplinary treatment planning (involving pathologists, radiologists, surgeons, radiation therapists, medical oncologists, and paediatric oncologists if applicable) in reference centres for sarcomas and/or within reference networks sharing multidisciplinary expertise and treating a high number of patients annually. They additionally suggest that all patients with an unexplained deep soft tissue mass, or with a superficial lesion of soft tissues having a diameter of >5 cm, or arising in the paediatric age group, be referred before biopsy, so that the latter can be performed as part of the multidisciplinary
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15 Allsbrook Jr WC, Mangold KA, Johnson MH, et al. Interobserver reproducibility of Gleason grading of prostatic carcinoma: urologic pathologists. Hum Pathol 2001; 32: 74e80. 16 Raab SS, Grzybicki DM. Quality in cancer diagnosis. CA Cancer J Clin 2010; 60: 139e65. 17 Coindre JM, Trojani M, Contesso G, et al. Reproducibility of a histopathologic grading system for adult soft tissue sarcoma. Cancer 1986; 58: 306e9. 18 Tetu BHA, McCaughey WTE, Lagace R. Evaluation des divergences d’opinion sur le diagnostic histopathologique des tumeurs des tissus mous. Ann Pathol 1984; 4: 267e71. 19 Improving outcomes for people with sarcoma. The manual. London: National Institute for Health and Clinical Excellence, 2006. 20 Casali PG, Blay JY. Soft tissue sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010; 21(suppl 5): v198e203. 21 NCCN Practice Guidelines in Oncology. Soft Tissue Sarcoma. v.2, http://www.nccn.org/professionals/physician_gls/f_guidelines.asp; 2010. 22 Shiraki M, Enterline HT, Brooks JJ, et al. Pathologic analysis of advanced adult soft tissue sarcomas, bone sarcomas, and mesotheliomas. The Eastern Cooperative Oncology Group (ECOG) experience. Cancer 1989; 64: 484e90.
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23 Randall RL, Bruckner JD, Papenhausen MD, Thurman T, Conrad 3rd EU. Errors in diagnosis and margin determination of soft-tissue sarcomas initially treated at non-tertiary centers. Orthopedics 2004; 27: 209e12. 24 Lurkin A, Ducimetiere F, Vince DR, et al. Epidemiological evaluation of concordance between initial diagnosis and central pathology review in a comprehensive and prospective series of sarcoma patients in the Rhone-Alpes region. BMC Cancer 2010; 10: 150.
Practice points C
C
C
C
339
Soft tissue tumours are rare but comprise many different histological types. Pathological expertise is required for the microscopic distinction between benign and malignant soft tissue tumours and to correctly assess subtype of sarcoma and grade. Specialist sarcoma pathologists should see sufficient numbers of cases, be part of a multidisciplinary management team, and take part in regular external quality assessment. The best outcomes are obtained in patients with soft tissue tumours who are referred to a specialized multidisciplinary management team, preferably before biopsy.
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