Other New entities in soft tissue tumors.
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1 Other New entities in soft tissue tumors. Angelo Paolo Dei Tos MD Departments of Pathology and Oncology General Hospital of Treviso, Italy Introduction During the past decade classification schemes have evolved continuously. The reappraisal of previously described entities have greatly contributed to major conceptual shifts. Pleomorphic malignant fibrous histiocytoma and hemangiopericytoma still represent the best examples, as their decline have allowed proper recognition of specific sarcoma subtypes such as pleomorphic rhabdomyosarcoma, myxofibrosarcoma, giant cell tumor of soft tissues or solitary fibrous tumor. By contrast, many lesions currently reported as new, with time has become part of spectrum of lesions. Examples are so called lipomatous hemangiopericytoma or giant cell angiofibroma (now both part of the morphologic continuum of solitary fibrous tumor) or hyalinizing spindle cell tumor with giant rosettes that has merged with low-grade fibromyxoid sarcoma to form a single tumor entity. Nonetheless, distinctive new lesions continue to be reported. This brief review will focus on a small group of recently reported mesenchymal lesions. Trendy entities like PEComa and myoepithelial lesions of soft tissue and bone are covered by distinct contributions. Myopericytoma Perivascular neoplasms comprise traditionally glomus tumor and so called hemangiopericytoma (HPC). Whereas glomus tumor represents a welldefined entity, the existence of HPC as a separate entity has been questioned. A number of neoplasms of different lines of differentiation are in fact characterized by a HPC-like vascular growth pattern, and the concept that most HPC represents examples of solitary fibrous tumors has eventually
2 reached a broad consensus. However, there exist lesions composed of cells expressing contractile proteins and organized in a perivascular growth pattern, that fulfills criteria set by Stout in his original description of hemangiopericytoma (1). These distinctive lesions have been collectively labeled as myopericytoma (2,3). Myopericytoma tends to occur in the superficial soft tissue of adults (peak incidence is in the fifth decade). Most frequently it arises in the lower limbs, followed by the upper limbs, trunk and head and neck. Microscopically, myopericytoma is composed of a spindle cell, myoid proliferation, organized in a distinctive perivascular pattern of growth, however a broad morphologic spectrum is observed. Immunohistochemically, most cases express smooth muscle actin and h-caldesmon. Desmin immunopositivity is rarely encountered. The clinical behavior is benign in most cases, however prominent cytologic atypia (which is rarely observed) correlates with potential of local recurrence and also metastatic spread (4). Epithelioid angiomatous nodule Cutaneous epithelioid vascular proliferations comprise a morphologic spectrum ranging from benign, reactive to frankly malignant conditions. A group of morphologically distinct cutaneous epithelioid vascular lesions that does not fit in any of the known entities was reported by Brenn in 2004 and labeled as epithelioid angiomatous nodule (EAN) (5). EAN usually arises in the trunk, extremities and, more rarely, on the face of adult patients with no gender predominance. Clinically, EAN presents as single (or multiple) erythematous to bluish nodules (or papules), of small size and short duration. Microscopically, EAN is composed of a circumscribed, unilobular, mostly solid proliferation of large polygonal epithelioid endothelial cells with vesicular nuclei and conspicuous nucleoli. Nuclear atypia is never observed. EAN is generally associated with a lymphoplasmacytic inflammatory infiltrate most prominent at the periphery of the lesion. Varying numbers of eosinophils are found scattered throughout the lesion. Immunohistochemically, neoplastic cells express common endothelial differentiation markers. Epithelioid angiomatous nodule is a benign, cutaneous vascular lesion, the relevance of
3 which resides in the fact it is not infrequently confused with epithelioid angiosarcoma. Reticular microcystic schwannoma Reticular microcystic schwannoma (RMS) is a rare variant of schwannoma with a distinctive predilection for viscera, especially the gastrointestinal tract (6), and mostly occurring in elderly patients (peak incidence is in the 6 th decade). A female predominance is observed. They are usually small, asymptomatic lesions most often measuring less than 3 cm in size. RMS usually occurs in the stomach, small bowel, and proximal large intestine. Microscopically it exhibits a striking microcystic and reticular lesional growth pattern with anastomosing and intersecting strands of spindle cells. Neoplastic cells tend to distribute around islands of myxoid or collagenous/hyalinized stroma. Mitotic activity is generally low and both atypia and necrosis are absent. RMS differs from usual schwannomas of the gastrointestinal tract also by lacking the characteristic peripheral cuff of lymphocytes. Immunohistochemically, strong nuclear and cytoplasmic positivity for S-100 and variably strong glial fibrillary acidic protein staining is generally observed. The histologic appearance of RMS raises a broad differential diagnosis, which includes gastrointestinal stromal tumor, perineurioma, and in more epithelioid examples, even an epithelial malignancy. Awareness of the entity and the use of an immunohistochemical panel of differentiation markers allows proper classification in most cases. RMS is an entirely benign neural neoplasm with no significant recurrent potential. Plexiform angiomyxoid tumor of the stomach Very recently, Takahashi and coworker have reported the occurrence in the gastric antrum of adult patients (peak incidence is in the 4 th decade) of a distinctive mesenchymal lesion characterized by a strikingly plexiform pattern of growth (7) The neoplasm can attain a large size and is composed of a
4 cytologically bland spindle cell proliferation, separated by abundant intercellular myxoid matrix, and associated with a rich capillary size vascular network. Cytologic atypia is generally absent and mitotic count very low. Immunohistochemically, tumor cells express alpha-smooth muscle actin and muscle actin, whereas are consistently negative for KIT, DOG1, CD34, and S- 100 protein. All cases analyzed so far have not shown mutations in the KIT or PDGFRA gene. As preliminary ultrastructural data seemed to point to myofibroblastic differentiation the authors proposed to label the lesion as plexiform angiomyxoid tumor of the stomach (PAMT). PAMT appears to be a benign entity, however, the frequently observed ulceration of the gastric mucosa may lead to potentially fatal gastrointestinal bleeding. A larger confirmatory series has been recently reported suggesting to modify the original label into plexiform fibromyxoma (8). Whatever the name, PAMT should be separated from GIST, nerve sheath tumors, and other fibromyxoid neoplasms Epithelioid myxofibrosarcoma Myxofibrosarcoma (MFS) is one of the most common soft tissue sarcomas of elderly patients and is exhibits a predilection for the superficial soft tissues of the limbs. Classic forms are represented by a multinodular, most often superficial proliferation composed of variably atypical neoplastic cells, mucinladen pseudolipoblasts, set in richly vascularized myxoid stroma. Recently, Nascimento and collaborators reported on a variant of myxofibrosarcoma that, while keeping most of the clinicopathologic features of the classic variant, is characterized by a striking epithelioid morphology, being therefore termed epithelioid myxofibrosarcoma (EMFS) (9). EMFS is typically characterized by a multinodular, infiltrating growth pattern with alternation of hypercellular and hypocellular myxoid areas. The presence of characteristic, prominent curvilinear vessels is almost often seen. Neoplastic cells tend to arrange singly and in small clusters, or sheets, wherein they show epithelioid morphology with round nuclei, vesicular chromatin, prominent nucleoli, and moderate amounts of eosinophilic cytoplasm. The epithelioid areas tend to be
5 multifocal with admixed areas of conventional MFS. Immunostains are most often negative for common differentiation markers. Differential diagnosis tends to be broad and include carcinoma, melanoma, and myoepithelial malignancies. EMFS tends to occur in the limbs of elderly patients (peak incidence is in the 6 th decade). EMFS in most cases is a high-grade sarcoma. A 70% local recurrence rate, associated with a 50% metastatic rate make EMFS a clinically more aggressive than conventional type myxofibrosarcoma. Pseudomyogenic hemangioendothelioma. Pseudomyogenic hemangioendothelioma (PMEHE) accounts as the most recently reported mesenchymal lesions (10). PMEHE represents a low-grade putative vascular malignancy most often occurring in the soft tissues of young adults. A male predominance is observed. Two third of the cases arise in the limbs followed by the trunk and the head and neck region. Multifocality has been reported in more than 60% of cases and half of cases were superficially located. Microscopically most tumor cells exhibit a spindled morphology, and are arranged in fascicles and sheets. A striking cytoplasmic eosinophilia reminiscent of rhabdomyoblastic differentiation is observed, along with vesicular nuclei harboring variably prominent nucleoli. Immunohistochemically, all tumors were positive for cytokeratin AE1/AE3 and FLI1, whereas approximately half of the cases variably expressed CD31. INI1 nuclear expression is preserved in all tumors tested so far. Clinically half of the patients experienced local recurrence within one year from diagnosis. Metastastic spread seems to be fairly rare as only one patient developed lymph node metastasis, and a second one developed widespread tumor dissemination. PMEHE may be closely related to the lesion previously reported under the name epithelioid sarcoma-like hemangioendothelioma (11). The recognition of this entity is crucial, in particular if the discrepancy between morphology and clinical behavior is considered.
6 References. 1. Stout AP, Murray MR. Hemangiopericytoma: a vascular tumor featuring Zimmermann s pericytes. Ann Surg 1942;116: Granter SR, Badizadegan K, Fletcher CD. Myofibromatosis in adults, glomangiopericytoma, and myopericytoma: a spectrum of tumors showing perivascular myoid differentiation. Am J Surg Pathol. 1998; 22: Mentzel T, Dei Tos AP, Sapi Z, Kutzner H. Myopericytoma of skin and soft tissues: clinicopathologic and immunohistochemical study of 54 cases. Am J Surg Pathol 2006; 30: Brenn T, Fletcher CD. Cutaneous epithelioid angiomatous nodule: a distinct lesion in the morphologic spectrum of epithelioid vascular tumors. Am J Dermatopathol 2004; 26: McMenamin ME, Fletcher CD. Malignant myopericytoma: expanding the spectrum of tumours with myopericytic differentiation. Histopathology 2002; 41: Liegl B, Bennett MW, Fletcher CD. Microcystic/reticular schwannoma: a distinct variant with predilection for visceral locations. Am J Surg Pathol 2008; 32: Takahashi Y, Shimizu S, Ishida T, Aita K, Toida S, Fukusato T, Mori S. Plexiform angiomyxoid myofibroblastic tumor of the stomach. Am J Surg Pathol 2007; 31:
7 8. Miettinen M, Makhlouf HR, Sobin LH, Lasota J. Plexiform fibromyxoma: a distinctive benign gastric antral neoplasm not to be confused with a myxoid GIST. Am J Surg Pathol 2009; 33: Nascimento AF, Bertoni F, Fletcher CD. Epithelioid variant of myxofibrosarcoma: expanding the clinicomorphologic spectrum of myxofibrosarcoma in a series of 17 cases. Am J Surg Pathol. 2007; 31: Hornick JL, Flecther CDM. Pseudomyogenic hemangioendothelioma: a distinctive often multicentric tumor with indolent behavior. Am J Surg Pathol 2011; in press. 11. Billings SD, Folpe AL, Weiss SW. Epithelioid sarcoma-like hemangioendothelioma. Am J Surg Pathol. 2003; 27:
8 Newly Recognized Soft Tissue Tumors Angelo Paolo Dei Tos M.D. Departments of Pathology & Oncology Treviso, ITALY
9 New Entity Reappraisal of lesions already described previously MFH, HPC Resuscitation of an entity that had been abandoned Pleomorphic RMS, GCT of Soft Tissues New clinicopathologic entities
10 Clinical History 50 year old male with a 2 cm, subcutaenous lump on thigh
11
12
13
14 SMA
15 H-Caldesmon
16 Diagnosis Myopericytoma
17 M > F Myopericytoma Peak incidence in 5th decade (age range: ) Lower limbs > upper limbs > head & neck > trunk Subcutaneous, solitary (rarely multiple), most often painless
18 Myopericytoma Oval spindle shaped myoid cell Perivascular growth pattern Glomus type features = glomangiopericytoma SMA + True hemangiopericytomas (?)
19 Classic HPC-like Angioleiomioma-likelike Myofibroma-like Cellular Atypical/Malignant Morphology
20 Classic type
21 HPC-like
22 Angioleiomyoma-likelike
23 Myofibroma-like
24 Hypcdllular
25 Cellular MP
26 Malignant/atypical myopericytoma
27 Hemangiopericytoma 1942, Stout and Murray Concept of perivascular (pericytic) neoplasm Pericyte Rouget (1873) Zimmermann (1923) Subsequent integration of lesions with HPC-like vascular pattern
28 HPC Diagnosis of exclusion Closely related (synonymous) with SFT Avoid creation of new monster Myopericytoma = true HPC
29 Hemangiopericytoma Spindle cells Perivascular pattern of growth Contractile properties SMA +/h-caldesmon +
30 Hemangiopericytoma = Myopericytoma
31 Clinical History 52 year old male with a 6 cm, mass located in the right thigh
32
33 Immunohistochemistry Vimentin + Scattered AE1/AE3 + ve cells
34 Diagnosis Epithelioid Myxofibrosarcoma
35
36 Myxoid Sarcomas Myxoid DFSP Myxoid Liposarcoma Myxofibrosarcoma Low Grade fibromyxoid sarcoma Myxoid Chondrosarcoma Myxoid Leyomiosarcoma Embryonal Rhabdomyosarcoma Acral myxoid fibrosarcoma
37 Myxofibrosarcoma Angervall, 1977 Myxoid MFH of Enzinger Spectrum of myxoid lesions High grade = myxoid MFH Histologic grade related to clinical outcome
38 Myxofibrosarcoma Elderly patients Lower limbs >upper limbs > limb girdles 2/3 subcutis, 1/3 deep seated IHC: vimentin, MSA and SMA (focal) Low grade no Mets High grade 30% metastatic rate Lungs > bone > mets Overall 5 years = 60%
39
40
41 Epithelioid Myxofibrosarcoma Elderly patients Limbs 50% metastatic rate Lungs > bone 73% recurrence rate Overall 5 years = 37% More aggressive then ordinary myxofibrosarcoma
42 Clinical History 52 year old male with a 6 cm, mass located in stomach Diagnosed as GIST
43 S-100
44 Diagnosis Microcystic-reticular reticular schwannoma
45
46 Microcystic-reticular reticular schwannoma Peak incidence in the sixth decades (any age) GI tract followed by superficial soft tissue of the extremities Striking microcystic and reticular lesional growth pattern S100 +; GFAP +/-
47
48
49
50 Microcystic-reticular reticular schwannoma Clinical behavior seems benign with no reported recurrences Differential diagnosis mainly with GIST KIT, DOG1 +
51 Clinical History 41 year old female with a 4 cm, ulcerated mass located in the stomach
52
53
54
55
56 SMA DES h-cal KIT
57 Diagnosis Plexiform angiomyxoid myofibroblastic tumor of the stomach
58
59
60 Plexiform angiomyxoid myofibroblastic tumor of the stomach Few cases reported Elderly patients with gastrointestinal hemorrhage due to mucosal ulceration GI tract Striking plexiform growth pattern Cytologically bland spindle cells set in intercellular myxoid matrix Rich capillary sized vascular network Variable expression of myogenic markers
61
62 Plexiform angiomyxoid myofibroblastic tumor of the stomach EM: myofibroblastic differentiation No mutations in the KIT and PDFGRA genes reported Clinical behavior seems to be benign Gastric bleeding potentially represents a life-threatening condition
63 Adults 12 cases Gastric antrum Benign clinicall behavior
64 Clinical History 18 year old male with a 3 cm, subcutaneous lump in the calf Basketball player
65
66
67
68 Cytokeratin AE1/AE3
69 CD31
70 IHC Cytokeratina AE1/AE3 + CD31 + CD34 INI1 + Smooth muscle actin focally +
71 Diagnosis Pseudomyogenic Hemangioendothelioma
72 Pseudomyogenic Hemangioendothelioma 50 cases (Fletcher & Hornick) Male predominance Peak incidence in 3rd decade 54% lower limb, 24% upper limb, 18% trunk, 4% head & neck Local recurrences in 58% LN mets in one case
73 Pseudomyogenic Hemangioendothelioma Plump spindle cells Brightly eosinophilic cytoplasm Immunohistochemical co-expression of epithelial and vascular markers Relationships with epithelioid sarcoma- like hemangioendothelioma
74 Stout AP Cancer Mar-Apr;15:400-9
75 Martin JF et al. Ann Anat Path :484
76 Acknowledgements Pathology Licia Laurino Sabrina Rossi Salvatore Romeo Cytogenetics Lucia Zanatta Laura Valori Eleonora Cappelletto Francesca Pol Molecular Pathology Luisa Toffolatti Marta Campo Dell Orto Giovanna Gallina Elisa Squizzato Irene Carraretto Serena Chinellato
77
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