David L. Stockman

Malignant gastrointestinal neuroectodermal tumor: clinicopathologic, immunohistochemical, ultrastructural, and molecular analysis of 16 cases with a reappraisal of clear cell sarcoma-like tumors of the gastrointestinal tract.

The clinical, histologic, immunophenotypic, ultrastructural, and molecular features of a distinctive gastrointestinal tumor are described. Sixteen patients, 8 women and 8 men aged 17 to 77 years (mean age, 42 y; 63% less than 40 y) presented with abdominal pain, intestinal obstruction, and an abdominal mass. Mean tumor size was 5.2 cm (range, 2.4 to 15.0 cm). The tumors arose in the small bowel (10), stomach (4), and colon (2) and were histologically characterized by a sheet-like or nested population of epithelioid or oval-to-spindle cells with small nucleoli and scattered mitoses. Five cases showed focal clearing of the cytoplasm. Scattered osteoclast-type multinucleated giant cells were present in 8 cases. The tumor cells were positive for S-100 protein, SOX10, and vimentin in 100% of cases, for CD56 in 70%, for synaptophysin in 56%, for NB84 in 50%, for NSE in 45%, and for neurofilament protein in 14% of cases. All cases tested were negative for specific melanocytic, gastrointestinal stromal tumors, epithelial, and myoid markers. Ultrastructural examination of 5 cases showed features of primitive neuroectodermal cells with clear secretory vesicles, dense-core granules, occasional gap junctions, and no evidence of melanogenesis. EWSR1 gene rearrangement was assessed by fluorescence in situ hybridization in 14 cases. Twelve cases (86%) showed split EWSR1 signal consistent with a chromosomal translocation involving EWSR1. One case showed extra intact signals, indicating that the nuclei possessed either extra copies of the EWSR1 gene or chromosome 22 polysomy. Only 1 case showed no involvement of the EWSR1 gene. Six cases demonstrated rearrangement of the partner fusion gene ATF1 (46%), and 3 showed rearrangement of CREB1 (23%); 2 cases lacked rearrangement of either partner gene. Clinical follow-up was available in 12 patients and ranged from 1.5 to 106 months. Six patients died of their tumors (mean survival, 32 mo; 83% less than 24 mo). At last follow-up, 4 patients were alive with regional, lymph node, and liver metastases, and 2 patients were alive with no evidence of disease. The tumor described here is an aggressive form of neuroectodermal tumor that should be separated from other primitive epithelioid and spindle cell tumors of the gastrointestinal tract. The distinctive ultrastructural features and absence of melanocytic differentiation serve to separate them from soft tissue clear cell sarcomas involving the gastrointestinal tract. The designation “malignant gastrointestinal neuroectodermal tumor” is proposed for this tumor type.

Value of p63 and podoplanin (D2-40) immunoreactivity in the distinction between primary cutaneous tumors and adenocarcinomas metastatic to the skin: a clinicopathologic and immunohistochemical study of 79 cases

The distinction of metastatic carcinomas to the skin from poorly differentiated primary cutaneous carcinomas and sometimes primary benign adnexal tumors can pose a significant diagnostic challenge. The purpose of this study was to evaluate the role of p63 and podoplanin (D2‐40) immunoreactivity for separating primary skin tumors vs. cutaneous metastases of carcinomas from internal organs. Thirty seven primary tumors and 42 cutaneous metastatic adenocarcinomas were evaluated. The 37 primary cutaneous tumors included 14 cases of benign adnexal tumors, 9 malignant skin adnexal neoplasms, and 14 primary squamous and basal cell carcinomas. The 42 metastatic adenocarcinomas all corresponded to metastases from patients with a well‐documented history of a primary tumor at another location. We found variable positivity with podoplanin in all primary cutaneous neoplasms including spiradenoma (6/6), hidradenoma (2/4), cylindroma (3/3), desmoplastic trichilemmoma (1/1), poorly differentiated squamous cell carcinoma (4/4), sebaceous carcinoma (1/1), basal cell carcinoma (4/10), trichilemmal carcinoma (2/2), eccrine carcinoma (3/3), microcystic adnexal carcinoma (1/1), adnexal carcinoma NOS (1/1), and porocarcinoma (1/1). In contrast, all metastatic carcinomas were negative (0/42) for podoplanin. In regards to p63, all cases of primary cutaneous tumors were positive for p63 (37/37); in contrast, all cutaneous metastatic carcinomas were negative (0/42). Sensitivity, specificity, and positive and negative predictive values of podoplanin and p63 immunoreactivity to separate primary skin neoplasms from metastatic carcinomas were 78.4, 100.0, 100.0 and 84.0% for podoplanin, respectively, and 100.0, 100.0, 100.0 and 100.0% for p63, respectively. The differences in p63 and podoplanin immunohistochemical expression between primary skin tumors and metastatic carcinomas to the skin were statistically significant (p < 0, 0001). The results of our study suggest that the combined expression of p63 and podoplanin are a useful adjunct for the diagnosis of skin tumors in the clinical setting of a questionable metastasis and may be relatively specific for distinguishing primary skin tumors from metastatic carcinomas to the skin.

ERG and FLI1 protein expression in epithelioid sarcoma

Epithelioid sarcoma is a rare, aggressive keratin-positive sarcoma that co-expresses CD34 in 50% of cases and may mimic an angiosarcoma. Recently, we have observed one case of epithelioid sarcoma that labeled for ERG, an ETS family regulatory transcription factor, which is considered to be a reliable marker for vascular differentiation. We investigated the prevalence of nuclear expression of ERG and FLI1, a homologous transcription factor, in these tumors. A formalin-fixed paraffin-embedded tissue microarray of 37 epithelioid sarcomas was examined. Immunohistochemistry was performed using anti-ERG monoclonal antibody to the N-terminus, anti-ERG monoclonal antibody to the C-terminus and anti-FLI1 monoclonal antibody. Comparison was made with CD34, CD31, and D2-40 labeling. The extent of immunoreactivity was graded according to the percentage of positive tumor cell nuclei (0: no staining; 1+: <5%; 2+: 5–25%; 3+: 26–50%; 4+: 51–75%; and 5+: 76–100%), and the intensity of staining was graded as weak, moderate, or strong. Nuclear staining for the N-terminus of ERG was seen in 19 out of 28 cases: 10 with diffuse(4 to 5+) strong/moderate labeling; 1 with 2+ moderate labeling and 8 with weak labeling (1 to 4+, 2 each). Focal staining for the C-terminus of ERG was seen in only 1 out of 29 cases (2+ moderate). FLI1 labeling was seen in nearly all (28 out of 30) cases: 16 with diffuse (5+) predominantly moderate labeling, and 8 cases with diffuse(5+) weak labeling. The remainder had variable moderate (1 to 3+) or weak (1 to 4+) FLI1 staining. CD34 was positive in 22 out of 30 cases and D2-40 was found to be positive in 22 out of 31 cases. All cases were negative for CD31 (0 out of 30). Epithelioid sarcoma can label with antibodies to the N-terminus of ERG, FLI1, and D2-40, which may cause diagnostic confusion for a vascular tumor. A panel of other antibodies including SMARCB1 and CD31 should be used in evaluating these tumors. ERG antibody selection is also critical, as those directed against the C-terminus are less likely to label epithelioid sarcoma.

The histomorphologic spectrum of primary cutaneous diffuse large B-cell lymphoma: a study of 79 cases.

Primary cutaneous large B-cell lymphomas (PCLBCL) have historically been a matter of debate in the literature. The 2005 World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) classification scheme segregated cutaneous B-cell lymphomas into 3 groups: primary cutaneous marginal zone B-cell lymphoma, primary cutaneous follicle center cell lymphoma, and primary cutaneous diffuse large B-cell lymphoma (PCDLBCL), “leg type” (PCDLBCL-LT). Additionally, the WHO-EORTC classification scheme utilized the term PCLBCL “other” not otherwise specified (NOS) type for rare cases of PCLBCL not belonging to either the “leg type” or the primary cutaneous follicle center cell lymphoma group. In this study, we retrospectively assessed the histomorphologic features of 79 cases of PCDLBCLs, including those of “leg type” and “other” NOS type, to further categorize the histologic spectrum of these unusual cutaneous neoplasms. The histologic diagnosis of PCLBCL usually poses little diagnostic difficulty; however, some cases may adopt unusual or unfamiliar appearances mimicking other lymphoproliferative disorders or other malignant neoplasms. Seventy-nine cases, occurring in 37 men and 42 women, aged 34-94 years, were analyzed. Fifty-three cases were classified as “leg type” and 26 cases were classified as “other” NOS type using the WHO-EORTC classification. Of the 53 cases classified as “leg type,” 33 were women and 20 were men; of the 26 cases of “other” NOS type, 9 were women and 17 were men. In the “leg type” category, 31 cases were located on the lower extremities, 5 cases on the face, 5 cases on the arm, 3 cases on the chest, 2 cases on the shoulder, 2 cases on the back, 1 case on the trunk, 1 case on the buttock, 1 case on the supraclavicular area, 1 case on the head, and 1 case on the flank. Of the “other” NOS type category, 8 cases were located on the face, 5 cases on the shoulder, 3 cases on the head, 2 cases on the abdomen, 2 cases on the chest, 1 case on the trunk, 1 on the vulva, 1 on the axilla, 1 on the back, 1 on the neck, and 1 on the hip. Most cases assessed showed the classic morphologic appearance of PCDLBCL, but cases mimicking Burkitt lymphoma (starry-sky pattern), natural killer-cell (NK) lymphoma, mycosis fungoides (epidermotropism), low-grade B-cell lymphomas, epithelial malignancies, and Merkel cell carcinoma were encountered in this series. The high frequency of these rare histologic patterns can be explained by a bias associated with consultation practice. Careful histologic examination and immunohistochemical stains were used to establish the correct diagnosis. The differential diagnosis of PCDLBCL is broad and difficult to define histologically. Knowledge of these rare histologic variants is necessary to avoid misinterpretation of these cases as nonlymphoid malignancies.

Immunolabeling pattern of podoplanin (d2-40) may distinguish basal cell carcinomas from trichoepitheliomas: a clinicopathologic and immunohistochemical study of 49 cases.

When the morphologic distinction between basal cell carcinomas (BCCs) and tichoepitheliomas is unclear, it poses a rare diagnostic challenge as the commonly defined histologic criterion is insufficient for differentiating these two neoplasms from each other. Their distinction is clinically important because the risk of progressive disease in BCC can be problematic, and trichoepitheliomas misinterpreted as BCC burdens the patient with an inaccurate diagnosis and consequential inappropriate surgery. Podoplanin (D2-40) is a well-known lymphatic endothelial surface marker that has been postulated to be upregulated in the outer root sheath of hair follicles and cutaneous neoplasms, such as adnexal tumors, squamous cell carcinomas, etc. We studied the expression of D2-40 by immunohistochemistry to determine if this marker could reliably differentiate these neoplasms from each other. A total of 49 cutaneous tumors, including 22 cases of trichoepitheliomas and 27 cases of BCC were examined. Of the 27 cases of BCC, 18 cases were located in the head and neck area, 5 on upper extremities, and 4 on the back. Of the 22 cases of trichoepitheliomas, all were from the head and neck area. D2-40 expression was present in 21/22 cases of trichoepitheliomas; 11 cases were diffusely positive (50%), 10 cases were focally positive (45.5%), and 1 case was negative (4.5%). D2-40 expression was present in 6/27 cases of BCC; 2 cases were diffusely positive (7.4%), 4 cases were focally positive (14.8%), and 21 cases were negative (77.8%). In summary, D2-40 expression was only weakly and focally positive in BCC (22.2% of cases) and diffusely and weakly positive in trichoepitheliomas (95.5% of cases). The sensitivity and specificity of D2-40 immunoreactivity to separate trichoepitheliomas from BCCs was 95.5% and 77.8%, respectively. This data suggests that D2-40 expression could be a useful potential marker to distinguish BCCs from trichoepitheliomas, especially when there is a high index of histologic suspicion for either of these two tumors. Our results also suggest that BCC can show differentiation toward the outer root sheath of hair follicles.

Use of clinical next-generation sequencing to identify melanomas harboring SMARCB1 mutations

SMARCB1 (INI1/BAF47/SNF5) encodes a part of a multiprotein complex that regulates gene expression through chromatin remodeling. SMARCB1 expression is lost or downregulated in multiple human tumors, including epithelioid sarcoma, meningioma and rhabdoid tumors of the brain, soft tissue and kidney.

Activity of c-Met/ALK inhibitor crizotinib and multi-kinase VEGF inhibitor pazopanib in metastatic gastrointestinal neuroectodermal tumor harboring EWSR1-CREB1 fusion

Malignant gastrointestinal neuroectodermal tumor (GNET) is an aggressive rare tumor, primarily occurring in young adults with frequent local-regional metastases and recurrence after local control. The tumor is characterized by the presence of EWSR1-ATF1 or EWSR1-CREB1 and immunohistochemical positivity for S-100 protein without melanocytic marker positivity. Due to poor responses to standard sarcoma regimens, GNET has a poor prognosis, and development of effective systemic therapy is desperately needed to treat these patients. Herein, we present a patient with a small bowel GNET who experienced recurrent hepatic and skeletal metastases after a primary resection. Comprehensive genomic profiling (CGP) in the course of clinical care with DNA and RNA sequencing demonstrated the presence of an exon 7 to exon 6 EWSR1-CREB1 fusion in the context of a diploid genome with no other genomic alterations. In a clinical trial, the patient received a combination of 250 mg crizotinib with 600 mg pazopanib quaque die and achieved partial response and durable clinical benefit for over 2.8 years, and with minimal toxicity from therapy. Using a CGP database of over 50,000 samples, we identified 11 additional cases that harbor EWSR1-CREB1 and report clinicopathologic characteristics, as these patients may also benefit from such a regimen.

Contents Vol. 91, 2016

A.B. Benson, Chicago, Ill. A. Chang, Singapore A.L. Cheng, Taipei J.F. Cleary, Madison, Wis. M. Dietel, Berlin P. Dufour, Strasbourg M.S. Ernstoff, Buffalo, N.Y. M.G. Fakih, Duarte, Calif. J.J. Grau, Barcelona H. Gronemeyer, Illkirch D.F. Hayes, Ann Arbor, Mich. C.S. Johnson, Buffalo, N.Y. M.J. Kelley, Durham, N.C. L. Kumar, New Delhi P.J. Loehrer, Indianapolis, Ind. J.R. Marshall, Buffalo, N.Y. S. Monfardini, Milan R. Nagler, Haifa R. Ohno, Nagoya B. Pestalozzi, Zurich H.M. Pinedo, Amsterdam E.A. Repasky, Buffalo, N.Y. A. Semczuk, Lublin E.F. Smit, Amsterdam C.N. Sternberg, Rome R. Stupp, Zurich M.S. Tallman, New York, N.Y. S. Tanaka, Hiroshima M. Tian, Houston, Tex. D.L. Trump, Buffalo, N.Y. T. Wiegel, Ulm W. Yasui, Hiroshima H. Zhang, Hangzhou City Editor-in-Chief

Acknowledgement to the Reviewers

www.karger.com/ocl Banke Agarwal, Saint Louis, Mo., USA Bharat B. Aggarwal, Houston, Tex., USA Jaffer A. Ajani, Houston, Tex., USA Salah-Eddin Al-Batram, Frankfurt a.M., Germany Roberto Angioli, Rome, Italy Jorge Aparicio, Valencia, Spain Carl Atkins, Albany, N.Y., USA Georges Azzi, Miami, Fla., USA Eishi Baba, Fukuoka, Japan Moo Jun Baek, Cheonan, Korea Lodovico Balducci, Tampa, Fla., USA Klaus H. Baumann, Marburg, Germany Wolf O. Bechstein, Frankfurt a.M., Germany Yves Bécouarn, Bordeaux, France Al B. Benson, Chicago, Ill., USA Patrick Boland, Buffalo, N.Y., USA Philip Bonomi, Chicago, Ill., USA Marius G. Bredell, Zumikon, Switzerland Fátima Carneiro, Porto, Portugal Yee Chao, Taipei, Taiwan Yao-Tseng Chen, New York, N.Y., USA Ann-Lii Cheng, Taipei, Taiwan Dennis S. Chi, New York, N.Y., USA James Cleary, Madison, Wis., USA Manola Comar, Trieste, Italy Renzo Corvò, Genoa, Italy Allan Covens, Toronto, Ont., Canada Paola Di Bonito, Rome, Italy Reinhard Dummer, Zurich, Switzerland Michael Duruisseaux, Grenoble, France Janice P. Dutcher, Bronx, N.Y., USA Monika Eichholzer, Zurich, Switzerland Bernhard J. Eigl, Vancouver, B.C., Canada Robert M. Eisele, Homburg, Germany Peter M. Ellis, Hamilton, Ont., Canada Günter Emons, Göttingen, Germany Nobuyuki Enomoto, Yamanashi, Japan Marwan G. Fakih, Duarte, Calif., USA Nicola Fazio, Milan, Italy Steven Feigenberg, Baltimore, Md., USA Clemens Feistritzer, Innsbruck, Austria Alexandra R. Fernandes, Caparica, Portugal Thiago Ferreira, Campinas, Brazil Petra Feyer, Berlin, Germany Ralph S. Freedman, Houston, Tex., USA César O. Freytes, San Antonio, Tex., USA Martin Früh, St. Gallen, Switzerland Masashi Fujii, Tokyo, Japan Val Gebski, Sydney, N.S.W., Australia Tarik Gheit, Lyon, France Alan M. Gillespie, Sheffield, UK Priscila Goncalves, Bethesda, Md., USA Juan-José Grau, Barcelona, Spain Frank Griesinger, Oldenburg, Germany Kathrin M. Gschwendtner, Freiburg, Germany Dominique Guenot, Strasbourg, France Stephan L. Haas, Stockholm, Sweden John D. Hainsworth, Nashville, Tenn., USA Shalaka Hampras, Tampa, Fla., USA Sheng-Po Hao, Taipei, Taiwan John H. Healey, New York, N.Y., USA Stephanie Hehlgans, Frankfurt a.M., Germany Masashi Hirooka, Toon, Ehime, Japan Wouter Hogendoorn, Rotterdam, The Netherlands Shigeo Horie, Tokyo, Japan Nadine Houédé, Nimes, France M.A. Huber, San Antonio, Tex., USA Jutta Hübner, Berlin, Germany Nuhad K. Ibrahim, Houston, Tex., USA Masafumi Ikeda, Chiba, Japan Misa Imai, Tokyo, Japan Takeshi Isobe, Izumo, Japan Namiki Izumi, Tokyo, Japan Long R. Jiao, London, UK Robin L. Jones, Seattle, Wash., USA Hrishi B. Joshi, Cardiff, UK Vassilos Karavassilis, Thessaloniki, Greece Shunsuke Kato, Tokyo, Japan Satoshi Kato, Morioka, Japan Nancy Kemeny, New York, N.Y., USA Hyung Jin Kim, Suwon, Korea Duck-Woo Kim, Seongnam, Korea Lee Su Kim, Ahnyang, Korea Yasushi Kojima, Shinjuku-ku, Japan Shigehiro Kokubu, Kawasaki, Japan Srinadh Komanduri, Chicago, Ill., USA Susan Krown, New York, N.Y., USA Takashi Kumada, Ogaki, Japan Takayasu Kurata, Osaka, Japan