Journal of Surgical Oncology 2015;111:513–519
Contemporary Diagnostics: Sarcoma Pathology Update JOHN S.J. BROOKS, MD1,2 1
AND
SOLOMON LEE, DO2
Perlman School of Medicine, University of Pennsylvania, Chair of Pathology, Pennsylvania Hospital of the University of Pennsylvania Health System, Philadelphia, Pennsylvania 2 Pennsylvania Hospital of the University of Pennsylvania Health System, Philadelphia, Pennsylvania
Sarcoma diagnosis continues to evolve as new information is discovered. Certain tumors have been downgraded (dermal leiomyosarcoma) and an atypical category designed for others. Recently entities include myxoinflammatory fibroblastic sarcoma, myoepithelioma, and pseudomyogenic hemangioendothelioma. The terms malignant fibrous histiocytoma and hemangiopericytoma are outdated. New immunostains (STAT6, SOX10, ERG) add diagnostic specificity, and new risk assessment models are described for sarcomas where grading and staging has failed to provide adequate prognosis.
J. Surg. Oncol. 2015;111:513–519. ß 2015 Wiley Periodicals, Inc.
KEY WORDS: immunohistochemistry; risk assessment; new entities; sarcoma; new markers
INTRODUCTION Since the field of Soft Tissue Pathology is quite extensive, with nearly 100 different sarcoma types and subtypes, not to mention the myriad of benign mesenchymal tumors, we will concentrate here on specific clinically important areas which have changed within the last decade: 1) a new “atypical” category for some cell types; 2) recently described entities; 3) an update on selected common and uncommon sarcomas; 4) the emergence of new immunohistochemical markers, and 5) the use of risk assessment models for selected sarcomas.
NEW CATEGORY OF ATYPICAL TUMORS In the past, many mesenchymal phenotypes contained lesions which were designated as either benign or malignant; only a handful were considered to be in an “indeterminate” category. Currently, there are three phenotypic entities considered to be in an “atypical” category, filling in the gap between recognizably benign and fully malignant neoplasms. First, regarding smooth muscle neoplasms, it is now generally accepted that the term “cutaneous leiomyosarcoma” was an overstatement. These tumors have not metastasized when confined to the dermis, and therefore have been downgraded to atypical intradermal smooth muscle neoplasms (AISMN) [1]. These rare tumors present as nodules predominantly on the lower extremity or trunk in middle aged adults. Histologically, they are classic smooth muscle tumors with nuclear atypia, increased mitotic rate, and rarely show necrosis or focal subcutaneous invasion [1,2]. Recurrence may be predicted by a positive margin or substantial involvement of the subcutis [3]. There is no evidence that any of these tumors have metastatic potential when confined to the dermis. In contrast, leiomyosarcoma in deeper tissues (discussed later) show very different outcomes. Second, there is now an entity called “atypical vascular lesion” (AVL) which shares some features of angiosarcoma but is not malignant. Occurring in the post-radiation setting, often in the skin of the breast, AVLs present at a median of only 3 years post treatment as small discolored papules that are often multifocal [4]. Histologic overlap with well differentiated angiosarcoma is well known, but features that distinguish AVL include lack of endothelial double layering, lack of tufting, rare to no mitotic figures, and lack of significant cytologic atypia [5,6]. Of the two types, lymphatic or blood vascular, the latter has a higher rate of progression to angiosarcoma. A small
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study analyzing MYC amplification by FISH and immunostains showed positive amplification in secondary angiosarcoma, and no amplification in AVL [7]. Close clinical follow-up is warranted for patients with AVL. Finally, in the nerve sheath category, it is fair to designate specific lesions as “atypical neurofibroma” when there is widely scattered nuclear atypia in the absence of mitotic activity and necrosis. The term “neurofibroma with atypical features” is also used [8]. Only a few clinicopathologic series are reported, but they uniformly show benign behavior for neurofibromas with cytologic atypia as the sole worrisome feature [9,10]. Complete surgical excision appears sufficient for atypical neurofibromas. Any increased cellularity or more diffuse nuclear atypia would be concerning for a low grade malignant peripheral nerve sheath tumor (MPNST).
RECENTLY DESCRIBED ENTITIES Myxoinflammatory Fibroblastic Sarcoma (MIFS) An uncommon low grade sarcoma of distal extremities, this tumor has a combination of three morphologic features: marked inflammation visible at low power, myxoid regions with basophilic mucin-filled cells, and sclerotic areas with scattered arcuate vessels and Reed Sternberg-like “virocytes” with large nucleoli [11,12]. While first reported as inflammatory myxohyaline tumor and acral myxoinflammatory fibroblastic sarcoma, the above MIFS designation was given to it in 2002 by the WHO [13]. Clinically this tumor often presents as a slow growing, painless, and ill defined tumor that is often thought to be a ganglion cyst or tenosynovitis owing to its location. Recent molecular studies have shown a recurrent translocation involving genes TGFBR3 and MGEA5 on chromosomes 1p22 and 10q24 respectively, resulting
*Correspondence to: John S. J. Brooks, MD, Professor of Pathology & Laboratory Medicine, Perlman School of Medicine, University of Pennsylvania; Chair of Pathology, Pennsylvania Hospital of the University of Pennsylvania Health System, Philadelphia, Pennsylvania. E-mail: john. [email protected] Received 19 August 2014; Accepted 10 November 2014 DOI 10.1002/jso.23853 Published online 17 February 2015 in Wiley Online Library (wileyonlinelibrary.com).
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in a unique fusion gene [14,15]. In a note of interest, the same translocation has been identified in hemosiderotic fibrolipomatous tumor, a tumor of distal extremities that frequently recurs like MIFS, and is thought to be a different morphologic manifestation of the same underlying genetic abnormality [15,16]. A complete surgical excision is often curative for MIFS, but local recurrences including multiple recurrences and histologically proven distant metastasis have been reported [11,17].
perivascular growth pattern, and develops in the subcutaneous tissues of the lower and upper extremities, and scattered other sites [26]. Histologically it is composed of oval to round cells with a multilayered concentric growth around thin walled vessels that may be elongated. Immunohistochemistry shows strong expression of smooth muscle actin and h-caldesmon consistent with myoid differentiation. Myopericytomas are almost always benign but malignant counterparts have been reported [27,28]; tumors which contain infiltrative growth, marked atypia, and increased proliferative activity.
Pseudomyogenic Hemangioendothelioma (PHE) This is an entity originally described by Billings et al. [18] as “epithelioid sarcoma-like hemangioendothelioma”, and reported as a series by Fletcher et al. [19] who coined the term. It is so named because tumor cell cytoplasm is elongated and eosinophilic resembling myogenic cells or rhabdomyoblasts. Architecturally, the tumor is often composed of multiple nodules of spindled and epithelioid cells, is often multifocal, and frequently involves multiple tissue planes simultaneously including skin, muscle, and rarely bone. PHE most frequently involves the distal extremities of younger patients. The clinical overlap with epithelioid sarcoma including its epithelioid histology, expression of keratin (AE1/3) by immunohistochemistry, and mimickery of satellite metastasis all may contribute to its misdiagnosis. To avoid this pitfall, careful evaluation is necessary including particular attention to the spindle cell histology, intact INI1 expression, expression of vascular markers (CD31, ERG), and lack of epithelial membrane antigen and CD34 expression by PHE [19,20]. Despite the high grade-like multifocal behavior, PHE appears to be a relatively indolent neoplasm with only a few patients showing lymph node or distant metastasis [19,21].
Myoepithelioma Myoepithelioma or mixed tumor of soft tissue was coined by Kilpatrick and Fletcher [22], and has since replaced the older term parachordoma. It has a peak incidence between 20–40 years of age, and arises preferentially in the deep tissue of limb girdles [23]. Morphologically, the tumor shows varied amounts of mesenchymal and cellular components, with the ovoid or spindled cells forming cords or solid nests in a background of collagenous or chondromyxoid stroma. Cells with vacuolated cytoplasm similar to the physaliferous cells present in chordomas may be present in some tumors. Most myoepitheliomas show only mild cytologic atypia, with very low mitotic activity. Moderate to high grade cytologic atypia with nuclear pleomorphism can occur, and frankly malignant components such as malignant cartilage or bone may also be seen. When epithelial-like nests are absent, the tumor resembles extraskeletal myxoid chondrosarcoma (EMC); indeed when one encounters a possible EMC, one must also consider myoepithelioma, which characteristically expresses keratins, S100, and at least one myoepithelial marker such as calponin, p63, or muscle actins [23,24]. Most myoepitheliomas are clinically and histologically benign. In the largest series of myoepitheliomas, none of the histologically low grade tumors metastasized, and a minority showed local recurrence [23]. A relatively higher proportion of myoepitheliomas in children are aggressive [25]. Of the histologically high grade tumors, a significant number (32%) showed metastasis on mean follow up of 50 months [23] these are designated myoepithelial carcinomas.
Epithelioid Variant of Inflammatory Myofibroblastic Tumor (EIMT) Inflammatory myofibroblastic tumor (IMT) is a tumor of intermediate malignancy that usually presents in the lungs or abdominal soft tissues of children and young adults, with occasional multicentricity, variable location and recurrence rates, and rare metastasis [29–31]. Histologically, the vast majority of IMTs show myofibroblastic spindled cells in a background of a myxoid to collagenous stroma, admixed with inflammatory infiltrate of plasma cells and lymphocytes [31]. About 50% of IMTs have an associated translocation involving the ALK gene on chromosome 2p23 [32]. Recently, several reports describe unusual IMTs with round cell or epithelioid morphology (EIMT) and they differ from the usual IMT in displaying an aggressive clinical course [33,34]. In contrast to the conventional IMT, EIMTs show a nuclear membrane staining pattern for ALK on immunohistochemistry, as well as abundant myxoid stroma and prominent neutrophil infiltration on histology. EIMTs also seem to show a male predominance with a high recurrence rate and mortality rate [31]. Overall, EIMTs are an aggressive subset of IMTs that exhibit a specific genetic alteration (RANBP2-ALK fusion) [31,35] and are morphologically as well as clinically distinct.
Unusual Ewing-Like Tumors Aside from classic Ewing Sarcoma characterized by the well established EWSR1 partnered translocations, newly classified are the atypical Ewing-like tumors with unusual translocations and variation in morphology. An apparent majority of these new tumors have CIC/DUX4 fusion [36,37], and a smaller subset shows BCOR/CCNB3 fusion translocations [38]. The CIC/DUX4 set of tumors show higher degree of heterogeneity in nuclear shape and size compared to the round monotonous nuclear shape of classic Ewing sarcoma. Majority of the cases are diffusely positive for CD99 [37]. The BCOR/CCNB3 set of tumors arise preferentially in bone and shares many clinical and pathologic features with Ewing sarcoma, but does not appear to share the oncogenetic biology [38]. In addition, an immunohistochemical stain developed for CCNB3 overexpression appears to be highly specific for this tumor [38,39]. Both these entities appear to have a more aggressive clinical course than classic Ewing sarcoma, with preliminary data showing CIC/DUX4 tumors to be more resistant to standard chemotherapy treatments [40]. As these entities are recent discoveries, more of these cases will need to be gathered to establish clinical course and best regimen of treatment. Diagnosis may be suspected when a possible Ewing sarcoma is negative for the EWSR1 fusion by FISH.
UPDATE ON SELECTED COMMON AND UNCOMMON SARCOMAS
Myopericytoma
Undifferentiated pleomorphic sarcoma (UPS)
The term hemangiopericytoma is now obsolete, with most tumors subsumed into the entity of solitary fibrous tumor (see below). The myopericytoma is in a sense the one true pericytoma, as pericytes are indeed myoid cells. This tumor is a benign myoid tumor with a defining
The term “malignant fibrous histiocytoma” (MFH) is now completely obsolete as it did not describe a true mesenchymal cell type. Thus, pleomorphic sarcomas that lack any specific line of differentiation are now diagnosed as undifferentiated pleomorphic
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Sarcoma Pathology Update sarcoma (UPS). These tumors are often grossly white to pale yellow, often with hemorrhage and necrosis, and arise in deep anatomic locations. The most common histologic pattern includes a combination of a storiform architecture of spindled cells and a variably fibrotic background with randomly distributed highly pleomorphic cells with large bizarre nuclei. Due to the relatively frequent association of UPS with other well differentiated sarcomas, it has been proposed that UPS is a final common pathway of transformation from tumor progression [41]. Clinically, UPS local recurrence rates range from 19– 31%, with a metastatic rate of 31–35%, and a 5 year survival rate of 65– 70%. Prognostic factors include depth, tumor size, grade, histologic type, necrosis and local recurrence [42]. Whenever a potential UPS is encountered, the possibility of dedifferentiated liposarcoma and/or other pleomorphic sarcomas should be considered; thus, UPS should always be a diagnosis of exclusion.
Leiomyosarcoma (LMS) This is the spindle cell sarcoma with a most specific growth pattern of alternating bundles and fascicles, and also expresses very specific cell markers (SMA and desmin). Histologically, cytologic atypia, mitotic activity, tumor size, and presence of necrosis are all important determinates in the diagnosis of leiomyosarcoma, but the tumor group as a whole can best be conceptualized based on anatomic site. Location is important in the diagnosis, as criteria differ somewhat depending on the site, and more importantly in the prognosis. Amongst the soft tissue leiomyosarcomas, retroperitoneum is the most common site. Retroperitoneal tumors show female predominance, are typically large (>10 cm), and commonly involve other structures by direct extension [43,44]. Retroperitoneal LMS are aggressive and cause mortality by sequelae of local extension or distant metastases with generally poor outcomes [43,45]. In stark contrast, dermal leiomyosarcomas, or AISMN as previously discussed, do very well with complete excision being almost always curative. Leiomyosarcomas of deep soft tissues are rare and develop in the subcutis or muscle, predominantly in the extremities. These tumors had been reported to be slightly less aggressive than the retroperitoneal counterpart [46,47], although a larger recent study suggests a somewhat worse prognosis than previously suggested [48]. Leiomyosarcomas of large vessels are very rare, and generally carries a poor prognosis due to its location, as well as aggressive tumor behavior. As a general rule, leiomyosarcomas are among the most aggressive sarcomas with the highest death rates. Smooth muscle tumors without necrosis and little to no nuclear atypia may be diagnosed as “leiomyoma of uncertain malignant potential (UMP)” when the mitotic rate is 3 mitosis per 50 high power fields) or tumor size >3.0 cm. No other features showed statistical significance in their study. The high risk group had lower disease specific survival, with patients showing five year mortality of 59%. In contrast, all low risk patients were alive for the duration of the study [98]. Thus, careful and through search for mitotic activity is warranted in smaller, localized tumors.
Solitary Fibrous Tumor (SFT) Predicting the clinical behavior of any single solitary fibrous tumor (SFT) has been a difficult task, and predictions based on histologic features that traditionally define malignancy have had mixed results [99]. While most tumors with bland oval nuclei and rare mitoses behave in a benign fashion, it has been difficult to define the point at which potential for recurrence and metastasis develops. Thus, a large study looked at multiple histologic and clinical parameters with multivariate analysis and has defined a risk stratification scheme for SFTs [100]. The three parameters of patient age (< or >55), size (15 cm), and mitotic index (4/10 hpf) were predictive of both metastasis and disease specific mortality. A scoring system was developed using each of these parameters to accumulate points, with a three tiered risk stratification system divided into low, moderate and high risk groups. No patients from the low risk group developed metastasis or died from disease in the study. The 5 year disease specific survival rates for moderate and high risk groups were 93 and 60%, while 10 years rates were 93 and 0% respectively. The 5 year metastasis-free rates for moderate and high risk groups were 77 and 15%, while 10 years rates were 64 and 0% respectively [100]. In practice, one may continue to use the term malignant SFT for tumor with mitoses >4/10 hpf and/or necrosis; or diagnose a SFT with moderate to high risk and provide the appropriate reference to guide clinical therapy.
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Sarcoma Pathology Update 63. Huang HY, Lal P, Qin J, et al.: Low-grade myxofibrosarcoma: A clinicopathologic analysis of 49 cases treated at a single institution with simultaneous assessment of the efficacy of 3-tier and 4-tier grading systems. Hum Pathol 2004;35:612–621. 64. Evans HL: Low-grade fibromyxoid sarcoma. A report of two metastasizing neoplasms having a deceptively benign appearance. Am J Clin Pathol 1987;88:615–619. 65. Reid R, de Silva MV, Paterson L, et al.: Low-grade fibromyxoid sarcoma and hyalinizing spindle cell tumor with giant rosettes share a common t(7;16)(q34;p11) translocation. Am J Surg Pathol 2003;27:1229–1236. 66. Kim L, Yoon YH, Choi SJ, et al.: Hyalinizing spindle cell tumor with giant rosettes arising in the lung: Report of a case with FUSCREB3L2 fusion transcripts. Pathol Int 2007;57:153–157. 67. Folpe AL, Lane KL, Paull G, Weiss SW, et al.: Low-grade fibromyxoid sarcoma and hyalinizing spindle cell tumor with giant rosettes: A clinicopathologic study of 73 cases supporting their identity and assessing the impact of high-grade areas. Am J Surg Pathol 2000;24:1353–1360. 68. Evans HL: Low-grade fibromyxoid sarcoma: A clinicopathologic study of 33 cases with long-term follow-up. Am J Surg Pathol 2011;35:1450–1462. 69. Doyle LA, Moller E, Dal Cin P, et al.: MUC4 is a highly sensitive and specific marker for low-grade fibromyxoid sarcoma. Am J Surg Pathol 2011;35:733–741. 70. Guillou L, Benhattar J, Gengler C, et al.: Translocation-positive low-grade fibromyxoid sarcoma: Clinicopathologic and molecular analysis of a series expanding the morphologic spectrum and suggesting potential relationship to sclerosing epithelioid fibrosarcoma: A study from the French Sarcoma Group. Am J Surg Pathol 2007;31:1387–1402. 71. Rekhi B, Deshmukh M, Jambhekar NA, et al.: Low-grade fibromyxoid sarcoma: A clinicopathologic study of 18 cases, including histopathologic relationship with sclerosing epithelioid fibrosarcoma in a subset of cases. Ann Diagn Pathol 2011;15: 303–311. 72. Rekhi B, Folpe AL, Deshmukh M, Jambhekar NA, et al.: Sclerosing epithelioid fibrosarcoma - a report of two cases with cytogenetic analysis of FUS gene rearrangement by FISH technique. Pathol Oncol Res 2011;17:145–148. 73. Wang WL, Evans HL, Meis JM, et al.: FUS rearrangements are rare in ‘pure’ sclerosing epithelioid fibrosarcoma. Mod Pathol 2012;25:846–853. 74. Goldblum JR, Folpe AL, Weiss SW, et al.: Solitary Fibrous Tumor (hemangiopericytoma) “Enzinger and Weiss’s Soft Tissue Tumors”. Philadelphia, PA: Elsevier Saunders 2014;1002. 75. Albores-Saavedra J, Schwartz AM, Henson DE, et al.: Cutaneous angiosarcoma. Analysis of 434 cases from the Surveillance, Epidemiology, and End Results Program, 1973–2007. Ann Diagn Pathol 2011;15:93–97. 76. Deyrup AT, Miettinen M, North PE, et al.: Pediatric cutaneous angiosarcomas: A clinicopathologic study of 10 cases. Am J Surg Pathol 2011;35:70–75. 77. Tatsas AD, Keedy VL, Florell SR, et al.. Foamy cell angiosarcoma: A rare and deceptively bland variant of cutaneous angiosarcoma. J Cutan Pathol 2010;37:901–906. 78. Pawlik TM, Paulino AF, McGinn CJ, et al.: Cutaneous angiosarcoma of the scalp: A multidisciplinary approach. Cancer 2003;98:1716–1726. 79. Fury MG, Antonescu CR, Van Zee KJ, et al.: A 14-year retrospective review of angiosarcoma: Clinical characteristics, prognostic factors, and treatment outcomes with surgery and chemotherapy. Cancer J 2005;11:241–247. 80. Robinson DR, Wu YM, Kalyana-Sundaram S, et al.: Identification of recurrent NAB2-STAT6 gene fusions in solitary fibrous tumor by integrative sequencing. Nat Genet 2013; 45:180–185.
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Contemporary Diagnostics: Sarcoma Pathology Update JOHN S.J. BROOKS, MD1,2 1
AND
SOLOMON LEE, DO2
Perlman School of Medicine, University of Pennsylvania, Chair of Pathology, Pennsylvania Hospital of the University of Pennsylvania Health System, Philadelphia, Pennsylvania 2 Pennsylvania Hospital of the University of Pennsylvania Health System, Philadelphia, Pennsylvania
Sarcoma diagnosis continues to evolve as new information is discovered. Certain tumors have been downgraded (dermal leiomyosarcoma) and an atypical category designed for others. Recently entities include myxoinflammatory fibroblastic sarcoma, myoepithelioma, and pseudomyogenic hemangioendothelioma. The terms malignant fibrous histiocytoma and hemangiopericytoma are outdated. New immunostains (STAT6, SOX10, ERG) add diagnostic specificity, and new risk assessment models are described for sarcomas where grading and staging has failed to provide adequate prognosis.
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KEY WORDS: immunohistochemistry; risk assessment; new entities; sarcoma; new markers
INTRODUCTION Since the field of Soft Tissue Pathology is quite extensive, with nearly 100 different sarcoma types and subtypes, not to mention the myriad of benign mesenchymal tumors, we will concentrate here on specific clinically important areas which have changed within the last decade: 1) a new “atypical” category for some cell types; 2) recently described entities; 3) an update on selected common and uncommon sarcomas; 4) the emergence of new immunohistochemical markers, and 5) the use of risk assessment models for selected sarcomas.
NEW CATEGORY OF ATYPICAL TUMORS In the past, many mesenchymal phenotypes contained lesions which were designated as either benign or malignant; only a handful were considered to be in an “indeterminate” category. Currently, there are three phenotypic entities considered to be in an “atypical” category, filling in the gap between recognizably benign and fully malignant neoplasms. First, regarding smooth muscle neoplasms, it is now generally accepted that the term “cutaneous leiomyosarcoma” was an overstatement. These tumors have not metastasized when confined to the dermis, and therefore have been downgraded to atypical intradermal smooth muscle neoplasms (AISMN) [1]. These rare tumors present as nodules predominantly on the lower extremity or trunk in middle aged adults. Histologically, they are classic smooth muscle tumors with nuclear atypia, increased mitotic rate, and rarely show necrosis or focal subcutaneous invasion [1,2]. Recurrence may be predicted by a positive margin or substantial involvement of the subcutis [3]. There is no evidence that any of these tumors have metastatic potential when confined to the dermis. In contrast, leiomyosarcoma in deeper tissues (discussed later) show very different outcomes. Second, there is now an entity called “atypical vascular lesion” (AVL) which shares some features of angiosarcoma but is not malignant. Occurring in the post-radiation setting, often in the skin of the breast, AVLs present at a median of only 3 years post treatment as small discolored papules that are often multifocal [4]. Histologic overlap with well differentiated angiosarcoma is well known, but features that distinguish AVL include lack of endothelial double layering, lack of tufting, rare to no mitotic figures, and lack of significant cytologic atypia [5,6]. Of the two types, lymphatic or blood vascular, the latter has a higher rate of progression to angiosarcoma. A small
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study analyzing MYC amplification by FISH and immunostains showed positive amplification in secondary angiosarcoma, and no amplification in AVL [7]. Close clinical follow-up is warranted for patients with AVL. Finally, in the nerve sheath category, it is fair to designate specific lesions as “atypical neurofibroma” when there is widely scattered nuclear atypia in the absence of mitotic activity and necrosis. The term “neurofibroma with atypical features” is also used [8]. Only a few clinicopathologic series are reported, but they uniformly show benign behavior for neurofibromas with cytologic atypia as the sole worrisome feature [9,10]. Complete surgical excision appears sufficient for atypical neurofibromas. Any increased cellularity or more diffuse nuclear atypia would be concerning for a low grade malignant peripheral nerve sheath tumor (MPNST).
RECENTLY DESCRIBED ENTITIES Myxoinflammatory Fibroblastic Sarcoma (MIFS) An uncommon low grade sarcoma of distal extremities, this tumor has a combination of three morphologic features: marked inflammation visible at low power, myxoid regions with basophilic mucin-filled cells, and sclerotic areas with scattered arcuate vessels and Reed Sternberg-like “virocytes” with large nucleoli [11,12]. While first reported as inflammatory myxohyaline tumor and acral myxoinflammatory fibroblastic sarcoma, the above MIFS designation was given to it in 2002 by the WHO [13]. Clinically this tumor often presents as a slow growing, painless, and ill defined tumor that is often thought to be a ganglion cyst or tenosynovitis owing to its location. Recent molecular studies have shown a recurrent translocation involving genes TGFBR3 and MGEA5 on chromosomes 1p22 and 10q24 respectively, resulting
*Correspondence to: John S. J. Brooks, MD, Professor of Pathology & Laboratory Medicine, Perlman School of Medicine, University of Pennsylvania; Chair of Pathology, Pennsylvania Hospital of the University of Pennsylvania Health System, Philadelphia, Pennsylvania. E-mail: john. [email protected] Received 19 August 2014; Accepted 10 November 2014 DOI 10.1002/jso.23853 Published online 17 February 2015 in Wiley Online Library (wileyonlinelibrary.com).
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in a unique fusion gene [14,15]. In a note of interest, the same translocation has been identified in hemosiderotic fibrolipomatous tumor, a tumor of distal extremities that frequently recurs like MIFS, and is thought to be a different morphologic manifestation of the same underlying genetic abnormality [15,16]. A complete surgical excision is often curative for MIFS, but local recurrences including multiple recurrences and histologically proven distant metastasis have been reported [11,17].
perivascular growth pattern, and develops in the subcutaneous tissues of the lower and upper extremities, and scattered other sites [26]. Histologically it is composed of oval to round cells with a multilayered concentric growth around thin walled vessels that may be elongated. Immunohistochemistry shows strong expression of smooth muscle actin and h-caldesmon consistent with myoid differentiation. Myopericytomas are almost always benign but malignant counterparts have been reported [27,28]; tumors which contain infiltrative growth, marked atypia, and increased proliferative activity.
Pseudomyogenic Hemangioendothelioma (PHE) This is an entity originally described by Billings et al. [18] as “epithelioid sarcoma-like hemangioendothelioma”, and reported as a series by Fletcher et al. [19] who coined the term. It is so named because tumor cell cytoplasm is elongated and eosinophilic resembling myogenic cells or rhabdomyoblasts. Architecturally, the tumor is often composed of multiple nodules of spindled and epithelioid cells, is often multifocal, and frequently involves multiple tissue planes simultaneously including skin, muscle, and rarely bone. PHE most frequently involves the distal extremities of younger patients. The clinical overlap with epithelioid sarcoma including its epithelioid histology, expression of keratin (AE1/3) by immunohistochemistry, and mimickery of satellite metastasis all may contribute to its misdiagnosis. To avoid this pitfall, careful evaluation is necessary including particular attention to the spindle cell histology, intact INI1 expression, expression of vascular markers (CD31, ERG), and lack of epithelial membrane antigen and CD34 expression by PHE [19,20]. Despite the high grade-like multifocal behavior, PHE appears to be a relatively indolent neoplasm with only a few patients showing lymph node or distant metastasis [19,21].
Myoepithelioma Myoepithelioma or mixed tumor of soft tissue was coined by Kilpatrick and Fletcher [22], and has since replaced the older term parachordoma. It has a peak incidence between 20–40 years of age, and arises preferentially in the deep tissue of limb girdles [23]. Morphologically, the tumor shows varied amounts of mesenchymal and cellular components, with the ovoid or spindled cells forming cords or solid nests in a background of collagenous or chondromyxoid stroma. Cells with vacuolated cytoplasm similar to the physaliferous cells present in chordomas may be present in some tumors. Most myoepitheliomas show only mild cytologic atypia, with very low mitotic activity. Moderate to high grade cytologic atypia with nuclear pleomorphism can occur, and frankly malignant components such as malignant cartilage or bone may also be seen. When epithelial-like nests are absent, the tumor resembles extraskeletal myxoid chondrosarcoma (EMC); indeed when one encounters a possible EMC, one must also consider myoepithelioma, which characteristically expresses keratins, S100, and at least one myoepithelial marker such as calponin, p63, or muscle actins [23,24]. Most myoepitheliomas are clinically and histologically benign. In the largest series of myoepitheliomas, none of the histologically low grade tumors metastasized, and a minority showed local recurrence [23]. A relatively higher proportion of myoepitheliomas in children are aggressive [25]. Of the histologically high grade tumors, a significant number (32%) showed metastasis on mean follow up of 50 months [23] these are designated myoepithelial carcinomas.
Epithelioid Variant of Inflammatory Myofibroblastic Tumor (EIMT) Inflammatory myofibroblastic tumor (IMT) is a tumor of intermediate malignancy that usually presents in the lungs or abdominal soft tissues of children and young adults, with occasional multicentricity, variable location and recurrence rates, and rare metastasis [29–31]. Histologically, the vast majority of IMTs show myofibroblastic spindled cells in a background of a myxoid to collagenous stroma, admixed with inflammatory infiltrate of plasma cells and lymphocytes [31]. About 50% of IMTs have an associated translocation involving the ALK gene on chromosome 2p23 [32]. Recently, several reports describe unusual IMTs with round cell or epithelioid morphology (EIMT) and they differ from the usual IMT in displaying an aggressive clinical course [33,34]. In contrast to the conventional IMT, EIMTs show a nuclear membrane staining pattern for ALK on immunohistochemistry, as well as abundant myxoid stroma and prominent neutrophil infiltration on histology. EIMTs also seem to show a male predominance with a high recurrence rate and mortality rate [31]. Overall, EIMTs are an aggressive subset of IMTs that exhibit a specific genetic alteration (RANBP2-ALK fusion) [31,35] and are morphologically as well as clinically distinct.
Unusual Ewing-Like Tumors Aside from classic Ewing Sarcoma characterized by the well established EWSR1 partnered translocations, newly classified are the atypical Ewing-like tumors with unusual translocations and variation in morphology. An apparent majority of these new tumors have CIC/DUX4 fusion [36,37], and a smaller subset shows BCOR/CCNB3 fusion translocations [38]. The CIC/DUX4 set of tumors show higher degree of heterogeneity in nuclear shape and size compared to the round monotonous nuclear shape of classic Ewing sarcoma. Majority of the cases are diffusely positive for CD99 [37]. The BCOR/CCNB3 set of tumors arise preferentially in bone and shares many clinical and pathologic features with Ewing sarcoma, but does not appear to share the oncogenetic biology [38]. In addition, an immunohistochemical stain developed for CCNB3 overexpression appears to be highly specific for this tumor [38,39]. Both these entities appear to have a more aggressive clinical course than classic Ewing sarcoma, with preliminary data showing CIC/DUX4 tumors to be more resistant to standard chemotherapy treatments [40]. As these entities are recent discoveries, more of these cases will need to be gathered to establish clinical course and best regimen of treatment. Diagnosis may be suspected when a possible Ewing sarcoma is negative for the EWSR1 fusion by FISH.
UPDATE ON SELECTED COMMON AND UNCOMMON SARCOMAS
Myopericytoma
Undifferentiated pleomorphic sarcoma (UPS)
The term hemangiopericytoma is now obsolete, with most tumors subsumed into the entity of solitary fibrous tumor (see below). The myopericytoma is in a sense the one true pericytoma, as pericytes are indeed myoid cells. This tumor is a benign myoid tumor with a defining
The term “malignant fibrous histiocytoma” (MFH) is now completely obsolete as it did not describe a true mesenchymal cell type. Thus, pleomorphic sarcomas that lack any specific line of differentiation are now diagnosed as undifferentiated pleomorphic
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Sarcoma Pathology Update sarcoma (UPS). These tumors are often grossly white to pale yellow, often with hemorrhage and necrosis, and arise in deep anatomic locations. The most common histologic pattern includes a combination of a storiform architecture of spindled cells and a variably fibrotic background with randomly distributed highly pleomorphic cells with large bizarre nuclei. Due to the relatively frequent association of UPS with other well differentiated sarcomas, it has been proposed that UPS is a final common pathway of transformation from tumor progression [41]. Clinically, UPS local recurrence rates range from 19– 31%, with a metastatic rate of 31–35%, and a 5 year survival rate of 65– 70%. Prognostic factors include depth, tumor size, grade, histologic type, necrosis and local recurrence [42]. Whenever a potential UPS is encountered, the possibility of dedifferentiated liposarcoma and/or other pleomorphic sarcomas should be considered; thus, UPS should always be a diagnosis of exclusion.
Leiomyosarcoma (LMS) This is the spindle cell sarcoma with a most specific growth pattern of alternating bundles and fascicles, and also expresses very specific cell markers (SMA and desmin). Histologically, cytologic atypia, mitotic activity, tumor size, and presence of necrosis are all important determinates in the diagnosis of leiomyosarcoma, but the tumor group as a whole can best be conceptualized based on anatomic site. Location is important in the diagnosis, as criteria differ somewhat depending on the site, and more importantly in the prognosis. Amongst the soft tissue leiomyosarcomas, retroperitoneum is the most common site. Retroperitoneal tumors show female predominance, are typically large (>10 cm), and commonly involve other structures by direct extension [43,44]. Retroperitoneal LMS are aggressive and cause mortality by sequelae of local extension or distant metastases with generally poor outcomes [43,45]. In stark contrast, dermal leiomyosarcomas, or AISMN as previously discussed, do very well with complete excision being almost always curative. Leiomyosarcomas of deep soft tissues are rare and develop in the subcutis or muscle, predominantly in the extremities. These tumors had been reported to be slightly less aggressive than the retroperitoneal counterpart [46,47], although a larger recent study suggests a somewhat worse prognosis than previously suggested [48]. Leiomyosarcomas of large vessels are very rare, and generally carries a poor prognosis due to its location, as well as aggressive tumor behavior. As a general rule, leiomyosarcomas are among the most aggressive sarcomas with the highest death rates. Smooth muscle tumors without necrosis and little to no nuclear atypia may be diagnosed as “leiomyoma of uncertain malignant potential (UMP)” when the mitotic rate is 3 mitosis per 50 high power fields) or tumor size >3.0 cm. No other features showed statistical significance in their study. The high risk group had lower disease specific survival, with patients showing five year mortality of 59%. In contrast, all low risk patients were alive for the duration of the study [98]. Thus, careful and through search for mitotic activity is warranted in smaller, localized tumors.
Solitary Fibrous Tumor (SFT) Predicting the clinical behavior of any single solitary fibrous tumor (SFT) has been a difficult task, and predictions based on histologic features that traditionally define malignancy have had mixed results [99]. While most tumors with bland oval nuclei and rare mitoses behave in a benign fashion, it has been difficult to define the point at which potential for recurrence and metastasis develops. Thus, a large study looked at multiple histologic and clinical parameters with multivariate analysis and has defined a risk stratification scheme for SFTs [100]. The three parameters of patient age (< or >55), size (15 cm), and mitotic index (4/10 hpf) were predictive of both metastasis and disease specific mortality. A scoring system was developed using each of these parameters to accumulate points, with a three tiered risk stratification system divided into low, moderate and high risk groups. No patients from the low risk group developed metastasis or died from disease in the study. The 5 year disease specific survival rates for moderate and high risk groups were 93 and 60%, while 10 years rates were 93 and 0% respectively. The 5 year metastasis-free rates for moderate and high risk groups were 77 and 15%, while 10 years rates were 64 and 0% respectively [100]. In practice, one may continue to use the term malignant SFT for tumor with mitoses >4/10 hpf and/or necrosis; or diagnose a SFT with moderate to high risk and provide the appropriate reference to guide clinical therapy.
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