Phyu P. Aung

NY-ESO-1 expression in synovial sarcoma and other mesenchymal tumors: significance for NY-ESO-1-based targeted therapy and differential diagnosis

A promising targeted therapy against NY-ESO-1 (CTAG 1B) using genetically modified T-cells in synovial sarcomas was recently demonstrated in a clinical trial at the NCI. To investigate the role of NY-ESO-1 immunohistochemistry in patient selection and gain better insight into the incidence of NY-ESO-1 expression in synovial sarcomas and other mesenchymal tumors, we evaluated NY-ESO-1 expression by immunohistochemistry in 417 tumors. This collection of samples included: 50 SS18/SSX1/2 fusion positive synovial sarcomas, 155 gastrointestinal stromal tumors (GIST), 135 other spindle cell sarcomas as well as 77 other sarcomas (chondrosarcoma, osteosarcoma, dedifferentiated liposarcoma, alveolar soft part sarcoma, rhabdomyosarcoma, angiosarcoma, malignant mesothelioma, and Ewings sarcoma). We report that 76% of synovial sarcomas expressed NY-ESO-1 in a strong and diffuse pattern (2−3+, >50–70% of tumor cells). In contrast, only rare cases of other spindle cell mesenchymal tumor expressed NY-ESO-1 (GIST (2/155), malignant peripheral nerve sheath tumors (1/34), and dermatofibrosarcoma protuberans (2/20)). Individual cases of other sarcomas (angiosarcoma, malignant mesothelioma, chondrosarcoma, osteosarcoma, dedifferentiated liposarcoma, alveolar soft part sarcoma, and Ewings sarcoma) were positive for NY-ESO-1. However, no positive cases were identified amongst our cohort of leiomyosarcomas (0/24), hemangiopericytoma/solitary fibrous tumors (0/40), and cellular schwannomas (0/17). In summary, we find that NY-ESO-1 is strongly and diffusely expressed in a majority of synovial sarcomas, but only rarely in other mesenchymal lesions. Beyond its role in patient selection for targeted therapy, immunohistochemistry for NY-ESO-1 may be diagnostically useful for the distinction of synovial sarcoma from other spindle cell neoplasms.

Gastrointestinal histopathology in chronic granulomatous disease: a study of 87 patients.

Gastrointestinal (GI) involvement in chronic granulomatous disease (CGD), a rare genetic immunodeficiency, mimics other inflammatory bowel diseases. We report GI pathology from 87 CGD patients seen at the NIH Clinical Center, with vague to severe clinical symptoms, in whom biopsies (313) had been evaluated (esophagus [23], stomach [71], small bowel [52] including duodenum [39], ileum [12], and jejunum [1], and colon [167]). Additionally reviewed was GI tissue from 15 autopsies. In our patient cohort, the mean age was 22 years (age range, 3 to 44 y; 2:1 male to female ratio). There were pathologic changes in 83/87 (95%) patients; with colon being the most commonly involved site and esophagus the least. There were microgranulomas in 53/87 (61%), pigmented macrophages in 64/87 (74%), tissue eosinophilia in 31/87 (36%), and chronic and/or acute inflammation in 57/87 (66%) patients. A subset of patients had villous shortening in the duodenum (8/39) and ileum (5/12). We identify microgranulomas in 76/167 (46%) colon, 12/52 (23%) small bowel, and 4/71 (6%) gastric biopsies; pigmented macrophages in 109/167 (65%) colon and 7/52 (13%) small bowel biopsies and 14/15 autopsies; chronic and/or acute inflammation in 97/167 (58%) colon, 13/52 (25%) small bowel, 42/71 (59%) gastric, and 5/23 (22%) esophageal biopsies; tissue eosinophilia in 43/167 (26%) colon, 7/52 (13%) small bowel, and 2/71 (3%) gastric biopsies. Only 4/87 (5%) patients had normal histology. No infectious etiology was identified in the majority of inflammatory lesions. We found that mild to severe GI pathology was common in CGD. In addition, microgranulomas, pigmented macrophages, and eosinophilia are not associated with acute (neutrophilic) inflammation.

The influence of DNA repair on neurological degeneration, cachexia, skin cancer and internal neoplasms: autopsy report of four xeroderma pigmentosum patients (XP-A, XP-C and XP-D)

BackgroundTo investigate the association of DNA nucleotide excision repair (NER) defects with neurological degeneration, cachexia and cancer, we performed autopsies on 4 adult xeroderma pigmentosum (XP) patients with different clinical features and defects in NER complementation groups XP-A, XP-C or XP-D.ResultsThe XP-A (XP12BE) and XP-D (XP18BE) patients exhibited progressive neurological deterioration with sensorineural hearing loss. The clinical spectrum encompassed severe cachexia in the XP-A (XP12BE) patient, numerous skin cancers in the XP-A and two XP-C (XP24BE and XP1BE) patients and only few skin cancers in the XP-D patient. Two XP-C patients developed internal neoplasms including glioblastoma in XP24BE and uterine adenocarcinoma in XP1BE. At autopsy, the brains of the 44 yr XP-A and the 45 yr XP-D patients were profoundly atrophic and characterized microscopically by diffuse neuronal loss, myelin pallor and gliosis. Unlike the XP-A patient, the XP-D patient had a thickened calvarium, and the brain showed vacuolization of the neuropil in the cerebrum, cerebellum and brainstem, and patchy Purkinje cell loss. Axonal neuropathy and chronic denervation atrophy of the skeletal muscles were observed in the XP-A patient, but not in the XP-D patient.ConclusionsThese clinical manifestations and autopsy findings indicate advanced involvement of the central and peripheral nervous system. Despite similar defects in DNA repair, different clinicopathological phenotypes are seen in the four cases, and therefore distinct patterns of neurodegeneration characterize XP-D, XP-A and XP-C patients.

KBA62 and PNL2: 2 new melanoma markers-immunohistochemical analysis of 1563 tumors including metastatic, desmoplastic, and mucosal melanomas and their mimics.

Identification of metastatic melanoma can be difficult because of its considerable morphologic variation and mimicry of a wide variety of other tumors. The more melanoma-specific melanoma markers, MelanA/MART-1, HMB45, and tyrosinase, used in addition to S100 protein, all have limitations in sensitivity and specificity. In this study, we evaluated 2 new melanoma markers, monoclonal antibodies KBA62 and PNL2 to yet unidentified antigens, using a large panel of metastatic melanomas (n=214), desmoplastic melanomas (n=34), gastrointestinal mucosal melanomas (n=54), benign nevi (n=27), clear cell sarcomas (n=16), and nonmelanocytic tumors (n=1218). Immunoreactivity for KBA62 and PNL2 was found in all pigmented nevi and in 86% and 90% of metastatic melanomas, respectively. Mucosal melanomas showed a similar rate of PNL2 immunoreactivity but somewhat less frequent KBA62 positivity (72%). In addition, KBA62 was found to be a sensitive diagnostic marker for desmoplastic melanoma (28 of 34; 82%), whereas PNL2 was only rarely positive (2 of 34; 6%). KBA62-positive normal tissues included pericytes, vascular and parenchymal smooth muscles, and basal cells of complex epithelia, including myoepithelia, whereas PNL2 labeled only melanocytes and neutrophils. Among nonmelanocytic tumors, those that were KBA62 positive were nodular fasciitis, leiomyoma and leiomyosarcoma, gastrointestinal stromal tumors, benign and malignant nerve sheath tumors, synovial sarcoma, and subsets of various carcinomas, especially those with squamous cell/stratified epithelial differentiation. PNL2 positivity in nonmelanocytic tumors was more restricted but occurred consistently in angiomyolipoma and other perivascular epitheloid cell tumor and in chronic myeloid leukemia tissue infiltrates. KBA62 may assist in the identification of desmoplastic melanomas, but its widespread occurrence in nonmelanomas limits utility. PNL2 is highly specific for melanomas but lacks reactivity with desmoplastic melanomas. It is also an excellent supplementary marker for perivascular epitheloid cell tumor at various sites.

Primary neuroendocrine tumors of the kidney: Morphological and molecular alterations of an uncommon malignancy

Primary neuroendocrine (NE) tumors of the kidney (PNRTs) are rare and frequently mistaken for other renal and urothelial cancers. We evaluated morphological and molecular findings of 11 PNRTs classified according to the World Health Organization classification of lung NE tumors. Patients included 5 men and 6 women with a median age of 50 years. These tumors occurred in the left (5/11), right (3/11), and horseshoe (1/11) kidney. The histologic patterns were predominantly solid, trabecular, and pseudoglandular. Lymphovascular invasion and calcification were found in 3 and 1 cases, respectively. There were 2 atypical and 9 typical carcinoids. At the time of surgery, 2 patients with atypical carcinoids had hepatic metastasis, and 1 of the typical carcinoid patients had lymph node metastasis. All cases showed <1% proliferative rate, except 2 cases with hepatic metastasis, which showed 3% to 5% with MIB1/Ki-67 immunostaining. Immunostainings were frequently positive for synaptophysin, chromogranin, CD56, CD99, and neuron-specific enolase. Follow-up data (average 4 years) were available for 6 patients. Two patients with distant metastasis were alive with disease, and four patients with no metastasis were alive without disease. We evaluated the association of PNRT and loss of heterozygosity (LOH) on chromosome 3p21 and found LOH in 2 of 3 cases. However, the comparative genomic hybridization study (2/2) did not demonstrate significant chromosomal imbalances. We conclude that PNRTs are positive for NE markers and may have LOH on chromosome 3p21. PNRTs should be classified as NE tumors in other sites, and proliferative rate can be an indicator of aggressive behavior/metastasis.

Expression of New York esophageal squamous cell carcinoma-1 in primary and metastatic melanoma

New York esophageal squamous cell carcinoma-1 (NY-ESO-1), a cancer testis antigen, is an ideal target for adoptive cell transfer immunotherapy. Evidence from several clinical trials in melanoma and other malignancies shows the potential value of targeting the NY-ESO-1 antigen in immune-based therapy of metastatic tumors. However, the incidence of NY-ESO-1 expression in metastatic melanoma is unknown, and thus, it is unclear how many patients might benefit from this therapy. In this study, we analyzed NY-ESO-1 expression in 222 melanoma specimens, including 16 primary and 206 metastatic tumors. Our results support previous findings showing higher expression of NY-ESO-1 in metastatic (58/206; 28.2%) versus primary (0/16) tumors. In addition, our results show that the epithelioid subtype of melanoma has the highest incidence of NY-ESO-1 expression. These findings provide evidence of the value of this specific adoptive cell transfer therapy for the treatment of metastatic melanoma.

Immunophenotypic shift of CD4 and CD8 antigen expression in primary cutaneous T-cell lymphomas: a clinicopathologic study of three cases.

Primary cutaneous T‐cell lymphomas (CTCL) comprise a heterogeneous group of neoplasms with diverse clinical behavior. Mycosis fungoides (MF) is the most common type of CTCL. Immunophenotypical shift during progression of the disease is a rare event and its significance is unknown. We present three primary CTCL cases that showed an immunophenotypical shift and poor prognosis. Conventional hematoxylin/eosin and immunohistochemical‐stained sections were examined in all the cases. Molecular analysis for rearrangement of the T‐cell receptor (TCR) gene was performed in two cases. One case was classified as MF, while the other two lacked epidermotropism, and were considered primary cutaneous peripheral T‐cell lymphoma (PTCL), NOS. Two cases were CD3+/CD4+ and one case was CD3+/CD8+ at diagnosis. The first two patients suffered many relapses and eventually, new CTCL lesions with a CD3+/CD8+ phenotype were observed. Both cases revealed identical clonal TCR rearrangements on the initial and late lesions, supporting the interpretation of a single clonal proliferation with different phenotypes. The third case progressed with skin recurrences and pulmonary lesions with a predominant CD3+/CD4+/CD8− phenotype. All cases manifested poor prognosis and two patients died of lymphoma. Immunophenotypical shift between CD4 and CD8 in CTCL seems to be a rare phenomenon that may be associated with disease progression.

Microvessel density, lymphovascular density, and lymphovascular invasion in primary cutaneous melanoma - Correlation with histopathologic prognosticators and BRAF status

The relationship between microvessel density (MVD), lymphovascular density (LVD), and lymphovascular invasion (LVI) in primary cutaneous melanoma (PCM) remains unclear. Given this, a total of 102 PCMs were assessed for MVD (vascular endothelial growth factor receptor 2 and Endocan), LVD (D2-40), and LVI (immunostaining with D2-40/S-100 and hematoxylin and eosin); tumoral S-100A13, vascular endothelial growth factor receptor 2, and Endocan; and BRAF status. LVD was associated with MVD (P = .01). MVD was higher in PCMs with depth greater than or equal to 2 mm and ulceration (P = .04, .05), whereas LVD was higher in PCMs with depth greater than or equal to 2 mm and mitoses (P = .03, .02). After adjusting for MVD and LVD, only ulceration was associated with LVI (P < .02). A BRAF mutation was seen in 30.4% cases, and when present, both LVD and host response (P = .0008 and .04, respectively) were significantly associated with MVD. Immunostaining with S-100A13 was noted in 99% of cases and a significant association noted only with ulceration (P = .05). Immunostaining increased LVI positivity (46.5% versus 4.9% by hematoxylin and eosin, P < .0001). MVD and LVD are not associated with LVI, appear to be closely related with each other, and are associated with select markers of poor prognosticative value. The association between a host response and LVD and MVD in PCMs with a BRAF mutation suggests that they exhibit potential for strategizing immunotherapies.

Primary Cutaneous T-Cell Lymphomas Showing Gamma-Delta (γδ) Phenotype and Predominantly Epidermotropic Pattern are Clinicopathologically Distinct From Classic Primary Cutaneous γδ T-Cell Lymphomas.

Primary cutaneous gamma-delta (&ggr;&dgr;) T-cell lymphoma is a rare disease that typically involves the dermis and subcutis. Cases of primary cutaneous T-cell lymphomas showing &ggr;&dgr; phenotype and predominantly epidermotropic pattern (E&ggr;&dgr;TCL) are not well defined. In this series, cases of primary cutaneous T-cell lymphomas showing &ggr;&dgr; phenotype were reviewed and classified as predominantly epidermotropic (E&ggr;&dgr;TCL) when >75% of lymphoma cells resided in the epidermis or predominantly dermal and/or subcutaneous (DS&ggr;&dgr;TCL). Clinical, pathologic, and immunophenotypic features were compared in 27 biopsies from 13 patients of E&ggr;&dgr;TCL and 13 biopsies from 7 patients of DS&ggr;&dgr;TCL. The lymphoma cells were diffusely positive for CD3 and T-cell receptor (TCR)&ggr;, mostly positive for granzyme B and TIA-1, variably positive for CD8, CD7, and CD30, and negative for CD4 and TCR&bgr;. Two patients with E&ggr;&dgr;TCL had dissemination to lymph nodes and 1 to the lung; 1 patient with DS&ggr;&dgr;TCL had gastrointestinal involvement. The median survival of patients with E&ggr;&dgr;TCL was not reached, and with a median follow-up of 19.2 months, 3/13 died. In contrast, the median survival of patients with DS&ggr;&dgr;TCL was 10 months, and after a median follow-up of 15.6 months, 5/5 died (P<0.01). E&ggr;&dgr;TCL is a rare presentation of cutaneous T-cell lymphoma that can be distinguished from DS&ggr;&dgr;TCL based on the extent of epidermotropism and has a better prognosis and longer median survival than DS&ggr;&dgr;TCL. However, although E&ggr;&dgr;TCL resembles mycosis fungoides clinically and histologically, a subset of E&ggr;&dgr;TCL is more likely to behave more aggressively than typical mycosis fungoides.

Prognostic implication of lymphovascular invasion detected by double immunostaining for D2-40 and MITF1 in primary cutaneous melanoma

Background:Lymphovascular invasion (LVI) is associated with adverse outcomes in primary cutaneous melanoma (PCM). Detection of LVI by hematoxylin and eosin staining alone is 0%–6%, but targeting lymphovascular structures increases the detection rate. Objective:To examine the prognostic significance of LVI detected by immunostaining for D2-40 and microphthalmia-associated transcription factor 1 (MITF1) in PCM. Methods:The authors retrospectively analyzed 120 PCM samples. We compared the LVI detection rates of immunostaining for D2-40 only (22%), double staining for D2-40 and MITF1 (38%), and hematoxylin and eosin, and examined the association of LVI with clinicopathologic variables and clinical outcomes. Results:Immunolabeling with both methods significantly increased the LVI detection rate. Double staining for D2-40 and MITF1 as well as D2-40–detected LVI was significantly associated with increased Breslow thickness, number of mitoses, and sentinel lymph node (SLN) metastasis. D2-40–detected LVI was also associated with ulceration. Although the difference was not significant, double staining for D2-40 and MITF1 allowed for easier detection of LVI than D2-40 alone. Limitations:This study was conducted in a tertiary referral institution; therefore, a referral bias cannot be excluded. Conclusions:Immunolabeling increased detection of LVI in PCM. Because LVI is a positive predictive marker for SLN metastasis, the authors propose using anti-D2-40 and anti-MITF1 in the evaluation of LVI in patients with PCM with a certain risk of SLN metastasis.