Vickie Y. Jo

WHO classification of soft tissue tumours: an update based on the 2013 (4th) edition

Summary The fourth edition of the World Health Organization (WHO) Classification of Tumours of Soft Tissue and Bone was published in February 2013, and serves to provide an updated classification scheme and reproducible diagnostic criteria for pathologists. Given the relative rarity of soft tissue tumours and the rapid rate of immunohistochemical and genetic/molecular developments (not infrequently facilitating recognition of new tumour entities), this updated text edited by a consensus group is important for both practising pathologists and oncologists. The 2013 WHO classification includes several changes in soft tissue tumour classification, including several new entities (e.g., pseudomyogenic haemangioendothelioma, haemosiderotic fibrolipomatous tumour, and acral fibromyxoma), three newly included sections for gastrointestinal stromal tumours, nerve sheath tumours, and undifferentiated/unclassified soft tissue tumours, respectively, various ‘reclassified’ tumours, and a plethora of new genetic and molecular data for established tumour types that facilitate better definition and are useful as diagnostic tools. This article briefly outlines these updates based on the 2013 WHO classification of soft tissue tumours.

Papillary squamous cell carcinoma of the head and neck: frequent association with human papillomavirus infection and invasive carcinoma.

Papillary squamous cell carcinoma (SCC) is an uncommon variant of SCC in the upper aerodigestive tract. It is most frequently located in the larynx, oropharynx, and sinonasal tract, and is more common in older men. Because of its complex exophytic papillary architecture, histologic assessment of underlying invasion can be challenging. Risk factors and pathogenesis are unclear. We reviewed 31 papillary SCCs of the upper aerodigestive tract seen at our institution over a 17-year period with respect to p16 immunoreactivity and human papillomavirus (HPV) status. Twelve papillary SCCs were associated with invasive SCC in their disease course. In our study, more than two-thirds of papillary SCCs in the upper aerodigestive tract were immunoreactive with antibody to p16 and 68% of those lesions had identifiable high-risk HPV by in situ hybridization. As with other HPV-associated SCCs of the upper aerodigestive tract, the majority of HPV-associated papillary SCCs are oropharyngeal (base of tongue and palatine tonsils), although both sinonasal and laryngeal tumors were also associated with infection (67% and 33% of cases, respectively). Given the better prognosis of HPV-associated SCCs of the upper aerodigestive tract, it may be prudent to report the p16 and HPV status of these tumors when they are encountered.

Epithelioid malignant peripheral nerve sheath tumor: clinicopathologic analysis of 63 cases.

Epithelioid malignant peripheral nerve sheath tumor (EMPNST) is rare and differs from conventional malignant peripheral nerve sheath tumor by showing diffuse S-100 protein positivity, infrequent association with NF1, and occasional origin in a schwannoma. Loss of INI1 expression is seen in a subset of tumors. The purpose of this study was to further define clinicopathologic features and outcome data in a large series of EMPNST. Sixty-three cases were identified in consultation files. The patient group consisted of 33 men and 30 women; the median age was 44 years (range, 6 to 80 y). One patient was reported to have NF1. One patient had 3 seemingly separate primary EMPNSTs during his 12-year clinical course. The median tumor size was 3.0 cm (range, 0.4 to 20 cm), and tumors were located most frequently on the lower extremity (30/63; 48%) and trunk (16/63; 25%). Most tumors were superficial (5 dermal, 38 subcutaneous); 15 were subfascial, and 5 were visceral. Microscopically, tumors comprised a relatively uniform but clearly atypical population of epithelioid cells. The majority of tumors demonstrated a multilobular growth pattern, with lobules and nests surrounded by myxoid and/or fibrous stroma. Tumor cells were round, polygonal, or ovoid and had round vesicular nuclei and abundant amphophilic to palely eosinophilic cytoplasm. Focal spindled morphology was seen in one third of cases. Most tumors (55/63; 87%) showed marked cytologic atypia with irregular vesicular nuclei and prominent nucleoli. Mitotic rate ranged from 1 to 46/10 HPF (median, 5/10 HPF); atypical mitotic figures were seen in 7 cases. Necrosis was present in 17 tumors. Twelve tumors were associated with a nerve. Nine tumors arose in a schwannoma (6 conventional type, 3 epithelioid) and 1 in a neurofibroma (in the NF1 patient). All tumors expressed S-100 protein, and the majority showed strong and diffuse staining (87%; 55/63). There was no expression of the melanocytic markers Mart-1/Melan-A (0/58), HMB-45 (0/57), and MiTF (0/9). Other immunohistochemical results included variable staining for GFAP (24/40; 60%) and EMA (4/29; 14%), whereas keratin was consistently negative (0/33). INI1 expression was lost in 67% of tumors examined (35/52). Most tumors were treated by surgical resection; 13 also received chemotherapy and/or radiation. Follow-up data were available for 31 cases and ranged in duration from 3 months to 20 years (median, 36 mo). Twenty-two patients have no evidence of disease at the time of follow-up. Nine patients developed local recurrence, 3 of whom were reported to be disease-free at the time of latest follow-up (44 mo, 19 y, and 20 y). Five patients developed distant metastases, and 4 patients died of disease (including 2 with unresectable recurrent tumors). Recurrence, metastasis, and disease-related death were observed independent of anatomic site or depth. In summary, EMPNST is a morphologically distinct variant that most commonly affects adults on the lower extremity or trunk, although a wide age range and site distribution are seen. Most tumors arise in superficial soft tissue, are diffusely S-100 positive, and two thirds show INI1 loss. On the basis of available follow-up information there is a comparatively low risk for recurrence and metastasis, irrespective of tumor depth.

Cutaneous syncytial myoepithelioma: clinicopathologic characterization in a series of 38 cases.

Cutaneous myoepithelial tumors demonstrate heterogenous morphologic and immunophenotypic features. We previously described, in brief, 7 cases of cutaneous myoepithelioma showing solid syncytial growth of ovoid, spindled, or histiocytoid cells. We now present the clinicopathologic features in a series of 38 cases of this distinctive syncytial variant, which were diagnosed between 1997 and 2012 (mostly seen in consultation). There were 27 men and 11 women, with a median age of 39 years (range, 2 mo to 74 y). Primary anatomic sites were the upper extremity (11, including 2 on the hand), upper limb girdle (3), lower extremity (14; 3 on the foot), back (6), face (2), chest (1), and buttock (1); the typical presentation was as either a polypoid or papular lesion. Tumors were well circumscribed and centered in the dermis and ranged in size from 0.3 to 2.7 cm (median 0.8 cm). Microscopically all tumors showed a solid sheet-like growth of uniformly sized ovoid to spindled or histiocytoid cells with palely eosinophilic syncytial cytoplasm. Nuclei were vesicular with fine chromatin and small or inconspicuous nucleoli and exhibited minimal to no atypia. Mitoses ranged from 0 to 4 per 10 HPF; 28 tumors showed no mitoses. Necrosis and lymphovascular invasion were consistently absent. Adipocytic metaplasia, appearing as superficial fat entrapped within the tumor, was seen in 12 cases. Chondro-osseous differentiation was seen in 1 tumor. All tumors examined were diffusely positive for EMA, and the majority showed diffuse staining for S-100 protein (5 showing focal staining). Keratin staining was focal in 1 of 33 tumors and seen in rare cells in 3 other cases. There was also positivity for GFAP (14/33), SMA (9/13), and p63 (6/11). Most lesions were treated by local excision. The majority of tumors tested (14/17; 82%) were positive by fluorescence in situ hybridization for EWSR1 gene rearrangement; testing for potential fusion partners (PBX1, ZNF444, POU5F1, DUX4, ATF1, CREB1, NR4A3, DDIT3, and NFATc2) was negative in all EWSR1-rearranged tumors. No FUS gene rearrangement was detected in 2 tumors lacking EWSR1 rearrangement. Follow-up information is available for 21 patients (mean follow-up 15 mo). One patient with a positive deep margin developed a local recurrence 51 months after initial biopsy. All other patients with available follow-up information, including 11 who had positive deep margins, are alive with no evidence of disease and no reported metastases. In summary, cutaneous syncytial myoepithelioma is a morphologically distinct variant that more frequently affects men, occurs over a wide age range, and usually presents on the extremities. Tumors are positive for S-100 protein and EMA, and, unlike most myoepithelial neoplasms, keratin staining is infrequent. EWSR1 gene rearrangement is present in nearly all tumors tested and likely involves a novel fusion partner. Prior reports describe some risk of recurrence and metastasis for cutaneous myoepithelial tumors; however, the syncytial variant appears to behave in a benign manner and only rarely recurs locally.

p63 Immunohistochemical Staining Is Limited in Soft Tissue Tumors

p63 is a p53 homolog that is expressed in various normal epithelial tissues and epithelial malignancies. Its expression in mesenchymal lesions has not been examined in depth; therefore, we studied p63 expression by immunohistochemical analysis in 650 soft tissue tumors. We found that p63 expression is limited in soft tissue tumors. The majority of tumors studied were p63-, including all cases of angiosarcoma, lipomatous neoplasms, dermatofibrosarcoma protuberans, solitary fibrous tumor, schwannoma, neurofibroma, gastrointestinal stromal tumor, and leiomyosarcoma. Nuclear p63 reactivity was found in a subset of soft tissue myoepithelioma and myoepithelial carcinoma of soft tissue, cellular neurothekeoma, soft tissue perineurioma, Ewing sarcoma/peripheral neuroectodermal tumor, diffuse-type giant cell tumor, and giant cell tumor of soft parts. Infrequent, weak, or focal p63-staining patterns were observed in low-grade fibromyxoid sarcoma, malignant peripheral nerve sheath tumor, extraskeletal myxoid chondrosarcoma, myxofibrosarcoma, proximal-type epithelioid sarcoma, synovial sarcoma, embryonal rhabdomyosarcoma, desmoplastic small round cell tumor, atypical fibroxanthoma, and spindle cell melanoma. Absent p63 expression is typical for most soft tissue tumors, including most (but not all) that would be in the differential diagnosis of spindle cell squamous carcinoma.

Low-grade sinonasal adenocarcinomas: the association with and distinction from respiratory epithelial adenomatoid hamartomas and other glandular lesions.

Sinonasal adenocarcinomas (SNACs) are uncommon malignancies that show a variety of growth patterns. These lesions are classified as intestinal or nonintestinal, the latter subclassified as low grade or high grade. We have noted that some low-grade nonintestinal SNACs are associated with respiratory epithelial adenomatoid hamartomas (REAHs), also rare lesions that have recently been shown to be neoplastic. We reviewed 29 nonintestinal low-grade SNACs seen at our institution over a 20-year period, with particular attention to morphology and concomitant REAHs. Nine (31%) low-grade SNACs demonstrated a predominantly exophytic and papillary growth pattern, and 18 (72%) had a more tubular growth pattern. Two (7%) were categorized as “other.” Six low-grade tubular SNACs were associated with REAHs. An immunohistochemical panel was performed on 2 of these cases; neoplastic cells were immunoreactive with antibodies to CK7 and S100 protein and nonreactive with antibodies to CK20, similar to other low-grade SNACs. No basal cells or myoepithelial differentiation was seen with immunohistochemical stains for p63 and 34βE12. This association of low-grade tubular SNACs with REAHs suggests that REAHs may be related to some adenocarcinomas.

Epithelioid rhabdomyosarcoma: clinicopathologic analysis of 16 cases of a morphologically distinct variant of rhabdomyosarcoma.

Rhabdomyosarcoma (RMS), which affects mainly pediatric patients, is currently classified into 3 major categories: embryonal, alveolar, and pleomorphic. We have identified a distinct variant of RMS that is characterized by epithelioid morphology, reminiscent of poorly differentiated carcinoma or melanoma, for which we propose the designation “epithelioid RMS.” We examined the clinicopathologic features of 16 such cases, which were received in consultation between 1991 and 2009. Ten patients were men, and 5 were women (gender was unknown in 1 case), with a median age of 70.5 years (range 14 to 78). Primary anatomic sites were upper extremity (4), lower extremity (2), head and neck (3), trunk (3), hypopharynx (1), and left atrium (1). Two patients presented with nodal metastases (neck and mediastinal) with unknown primary sites. Of the tumors in somatic locations, 10 were intramuscular, and 2 were subcutaneous. Tumor size ranged from 3 to 8.5 cm; the tumors had nodular fleshy cut surfaces, grossly appreciable necrosis, and infiltrative edges. Microscopically, tumors showed sheet-like growth of uniformly sized epithelioid cells with abundant amphophilic-to-eosinophilic cytoplasm, large vesicular nuclei, and frequently prominent nucleoli. Necrosis and infiltration into adjacent structures (such as skeletal muscle or fat) were present in all cases, and mitotic counts were high (median count 23 per 10 high-power fields) with frequent atypical forms. By immunohistochemistry, all tumors showed diffuse desmin expression, and myf-4 immunostaining was diffuse to multifocally positive. S100-protein was absent in all cases. Cytokeratin was negative in 12 cases and very focally positive in 4 cases. Clinical follow-up information was available for 11 cases (median duration 10 mo). Most patients underwent surgical resection with chemotherapy and/or radiation (none with RMS-specific protocols). Two patients had multiple recurrences, and 2 patients developed satellite nodules near the primary lesion. Six patients had regional lymph node metastases, and 6 patients developed distant metastases, most commonly to the lung. So far, 7 patients have died of disease, 5 within 1 year and 2 within 5 years. Epithelioid RMS is a novel morphologically distinct variant of RMS that closely mimics carcinoma or melanoma. It primarily affects older patients, with a male predilection. The clinical course as determined thus far is aggressive.

Clinically Relevant Molecular Subtypes in Leiomyosarcoma

Purpose: Leiomyosarcoma is a malignant neoplasm with smooth muscle differentiation. Little is known about its molecular heterogeneity and no targeted therapy currently exists for leiomyosarcoma. Recognition of different molecular subtypes is necessary to evaluate novel therapeutic options. In a previous study on 51 leiomyosarcomas, we identified three molecular subtypes in leiomyosarcoma. The current study was performed to determine whether the existence of these subtypes could be confirmed in independent cohorts. Experimental Design: Ninety-nine cases of leiomyosarcoma were expression profiled with 3′end RNA-Sequencing (3SEQ). Consensus clustering was conducted to determine the optimal number of subtypes. Results: We identified 3 leiomyosarcoma molecular subtypes and confirmed this finding by analyzing publically available data on 82 leiomyosarcoma from The Cancer Genome Atlas (TCGA). We identified two new formalin-fixed, paraffin-embedded tissue-compatible diagnostic immunohistochemical markers; LMOD1 for subtype I leiomyosarcoma and ARL4C for subtype II leiomyosarcoma. A leiomyosarcoma tissue microarray with known clinical outcome was used to show that subtype I leiomyosarcoma is associated with good outcome in extrauterine leiomyosarcoma while subtype II leiomyosarcoma is associated with poor prognosis in both uterine and extrauterine leiomyosarcoma. The leiomyosarcoma subtypes showed significant differences in expression levels for genes for which novel targeted therapies are being developed, suggesting that leiomyosarcoma subtypes may respond differentially to these targeted therapies. Conclusions: We confirm the existence of 3 molecular subtypes in leiomyosarcoma using two independent datasets and show that the different molecular subtypes are associated with distinct clinical outcomes. The findings offer an opportunity for treating leiomyosarcoma in a subtype-specific targeted approach. Clin Cancer Res; 21(15); 3501–11. ©2015 AACR.

Human papillomavirus-associated squamous cell carcinoma of the upper aerodigestive tract.

The association of human papillomavirus with the development of head and neck squamous cell carcinomas has been better elucidated over the past 20 years. In this review article, we examine the role of the virus in the development of these tumors. We discuss the clinical and pathologic features of human papillomavirus-associated squamous cell carcinomas of the head and neck. Immunohistochemical findings and those of other ancillary techniques are also reviewed. We further review the prognosis and treatment of these tumors. Finally, a detailed discussion is provided regarding the differential diagnosis that must be considered when confronting these squamous neoplasms.

Usefulness of translocation-associated immunohistochemical stains in the fine-needle aspiration diagnosis of salivary gland neoplasms.

Fine‐needle aspiration diagnosis of pleomorphic adenoma (PA) and adenoid cystic carcinoma (ACC) is challenging due to cytologic overlap with one another and with other salivary gland tumors having prominent epithelial and myoepithelial components. Recognition of characteristic chromosomal aberrations in several salivary gland tumors, including PA and ACC, has the potential to resolve diagnostic uncertainty, but molecular diagnostics are not routinely available. To leverage these molecular alterations, the authors examined a panel of commercially available immunostains directed at commonly overexpressed proteins in translocation‐associated PA (PLAG1 and HMGA2) and ACC (MYB) to assess their diagnostic usefulness.