Expression of PD-1 and PD-L1 in Extramammary Paget Disease: Implications for Immune-Targeted Therapy.

Extramammary Paget disease (EMPD) is a locally aggressive cutaneous malignancy that usually arises in anogenital or axillary skin. Immune checkpoint inhibitors targeting programmed cell death receptor (PD-1) and/or its ligand (PD-L1) are approved for the treatment of several types of cancer, and response to these generally correlates with increased PD-L1 expression by tumor cells. The expression of PD-L1 and composition and density of the tumor-associated immune infiltrate in EMPD have been little studied. To determine whether EMPD might be amenable to immune checkpoint blockade, we analyzed the expression of PD-1 and PD-L1 and the composition and density of the tumor-associated immune infiltrate in EMPD and evaluated associations between biomarker expression and clinicopathologic parameters. Twenty-one EMPD tumors were evaluated for tumor cell PD-L1 expression and for relative expression and distribution of CD3, CD8, PD-1, and PD-L1 in the tumor-associated immune infiltrate by using a combination of visual and image analysis (Aperio ImageScope). In addition, PD-L1 expression was assessed in 10 cases of mammary Paget disease (MPD). In EMPD cases, PD-L1 was expressed by tumor cells (3/21; 14%) and the tumor-associated immune infiltrate (15/21; 71%), and PD-1 was expressed by the tumor-associated immune infiltrate in all cases analyzed (18/18). However, PD-L1 expression by EMPD tumor cells did not correlate with the density of CD3-, CD8-, or PD-1-positive cells in the tumor-associated immune infiltrate or other clinicopathologic parameters. Furthermore, the density of CD3, CD8, PD-1, and PD-L1 in the tumor-associated immune infiltrate did not correlate with any clinicopathologic parameters evaluated with the exception that CD3 positive values were significantly higher in patients who were still alive (median, 1310 cells/mm2; range, 543-2115;) than in those who died (median, 611 cells/mm2; range, 481-908; p = 0.049). In all MPD cases, PD-L1 was absent in tumor cells but present in the tumor-associated immune infiltrate, and PD-L1 expression in lymphocytes was lower in patients with HER2/neu-positive than in those with HER2/neu-negative disease (p = 0.07). Our findings raise the possibility of therapeutic targeting of the PD-1/PD-L1 axis in EMPD.

Regressed melanocytic nevi secondary to pembrolizumab therapy: an emerging melanocytic dermatologic effect from immune checkpoint antibody blockade.

BACKGROUND: Immune checkpoint antibody blockade is an emerging therapeutic option for treating certain cancers including melanoma. This therapy is associated with dermatologic and systemic toxicities, some of which are more severe than others and may require withholding therapy. CASE REPORTS: We report two patients with melanocytic nevi that regressed with pembrolizumab therapy. The first patient had stage IV BRAF K601E/L584F mutant melanoma that developed a regressed melanocytic nevus while being treated with pembrolizumab. The second patient had stage III BRAF V600R mutant melanoma that was treated with pembrolizumab and dabrafenib, and also developed a regressed melanocytic nevus. Both patients had good response to therapy and stable disease at 8 and 12 months of treatment, respectively. RESULTS: Regressed melanocytic nevi were observed in both patients treated with pembrolizumab for advance-stage melanoma. Immunohistochemical analysis of a regressed melanocytic nevus was associated with an inflammatory infiltrate rich in CD8+ T cells and CD163+, CD11c+ histiocytes. CONCLUSION: Regressed melanocytic nevi are an emerging dermatologic effect from pembrolizumab therapy.

Effects of the Use of a Mallet during Bone Marrow Biopsy Collection on Specimen Quality: A Quality Improvement Project.

CONTEXT: Avoiding procedure-related morphologic distortion such as fragmentation and crush artifact is critical in bone marrow diagnosis. Use of a hammer or mallet, although infrequent, is a known technique of advancing the biopsy needle during specimen collection. OBJECTIVES: We performed a double-blinded, retrospective review of bone marrow biopsies collected by the Interventional Radiology department at our institution in order to assess specimen quality by using this technique. DESIGN: We reviewed 93 bone marrow biopsy specimens collected at our hospitals, between January 2015 and June 2015. Routine bone marrow core biopsy slides were reviewed. The presence of crush artifact, specimen fragmentation, and aspiration artifact, as well as the presence of osteopenia and an overall grade of specimen adequacy, was recorded for each specimen. RESULTS: A sterile mallet was used during the bone marrow biopsy procedure in 29 cases. Use of a mallet was significantly associated with the presence of suboptimal or inadequate specimen quality of bone marrow core biopsy (p<0.005) and was independently associated with severe specimen fragmentation (2+) (p<0.0001). There was no statistically significant association between length of the core and use of a mallet. CONCLUSIONS: Use of a mallet during bone marrow core biopsy collection is significantly associated with morphologic distortion in the form of severe specimen fragmentation and negatively affects specimen adequacy. There is no difference in length of core biopsy as previously thought by using a mallet to advance the needle during the procedure. We recommend that the use of this technique should be avoided during specimen collection.

Summary of expression of SPARC protein in cutaneous vascular neoplasms and mimickers.

BACKGROUND: Serum protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein, which regulates cell proliferation and facilitates intracellular transport of albumin bound particles including chemotherapeutic agents such as Nab-paclitaxel/ABI-007. Therefore the presence of SPARC may achieve higher intra-tumoral drug concentration with lower dosage and thus reduce systemic side-effects. Several trials of ABI-007, in melanoma, show promising clinical activity. DESIGN: Fifty-four cases of dermal based neoplasms were retrieved including 24 angiosarcomas (AS), 10 hemangiomas, 9 nodular melanomas, 4 Kaposi sarcomas (KS), 3 leiomyosarcomas (LMS), 3 atypical fibroxanthomas (AFX) and 1 spindle cell squamous cell carcinoma (SSCC). SPARC immunohistochemistry (IHC) was performed with a mouse monoclonal antibody. RESULTS: SPARC expression was detected in a majority of AS (17/24), melanomas (8/9), AFX (3/3), LMS (3/3) and KS (4/4) with some expression in hemangiomas (3/10), while being negative in SSCC (0/1); and was significantly associated with tumor group (p = 0.017). Although a significant difference in overall survival was observed between SPARC expression groups (positive vs. negative) for all patients, there was no significant difference noted among angiosarcoma patients. CONCLUSION: We have confirmed the presence of SPARC expression in melanoma, KS, LMS and AS and also detected it for the first time in AFX. Since paclitaxel has shown some effectiveness in AS, melanoma and KS, ABI-007 could also be beneficial in these patients.

Polypoid amelanotic melanoma: a diagnostic challenge.

Melanoma is a highly aggressive cutaneous malignancy with considerable risk for metastasis. These malignant tumors are typically pigmented given that they arise from melanocytes capable of producing melanin. Amelanotic melanomas are a rare variant and there is often a delay in diagnosis owing to lack of pigmentation. Although there are various presentations of amelanotic melanoma, a solitary polypoid nodule is unusual and warrants further reporting. Herein, we present a patient with a 3-year history of a tender firm, skin-to-pink colored polypoid nodule. Excisional biopsy and work up showed an aggressive amelanotic melanoma with depth of 20mm and nodal metastasis consistent with stage IIIC disease. This case highlights the necessity of recognition and prompt management of this rare subtype of melanoma.

Tumefactive foreign body giant cell reaction following high-pressure paint injection injury: A case report and review of literature.

High-pressure paint injection injury is an uncommon but well-described injury. The histologic features of long-term paint injection injury with retained material are less recognized. A 46-year-old male presented clinically as "recurrent giant cell tumor of tendon sheath." The right index finger demonstrated fusiform enlargement by a pigmented mass with diffuse infiltration into the soft tissue of the hand. Histologically the tumor showed multiple giant cells in a fibrotic stroma extending into the dermis. There were multiple types of foreign material including diffuse brown black pigment, weakly optically polarizing foreign material and white inclusions with a "train track" appearance. The cells were positive for CD68 and negative for S100 antigen. Further investigation revealed that the patient had a history of high-pressure paint injection injury to his digit 6 years prior. Foreign material injected under high pressure into tissues may result in a pseudo-neoplastic foreign body granulomatous reaction that can mimic giant cell tumor of tendon sheath. Our case demonstrates that this reaction can be florid and can have slow growth over years. A high index of suspicion, a good clinical history and careful examination can distinguish these 2 entities.

A 34-Year-Old Pregnant Woman With Cough, Chest Pain, and a Left Upper Lobe Mass.

A 34-year-old white woman who was 30 weeks' pregnant initially presented to her primary care physician with a cough for which she was given antibiotics, but she had persistent symptoms. These were followed by chest pain, as a result of which she was referred to our department. She had a past medical history of hypertension, and currently was in her sixth pregnancy, with no reported complications in the previous pregnancies. Review of systems was otherwise negative. She had a three-pack-year smoking history, but denied smoking during her current pregnancy.

Molecular characteristics and potential therapeutic targets in Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin tumour occurring preferentially in elderly and immunosuppressed individuals. Multiple studies have provided insight into the molecular alterations of MCC, leading to the design of several ongoing clinical trials testing chemotherapy, targeted therapy and immunotherapy in patients with recurrent or metastatic disease. The results of some of these studies are available, whereas others are eagerly awaited and will likely shed light on the understanding of MCC biology and potentially improve the clinical outcomes of patients with this rare disease.

Primary Epithelioid Angiosarcoma of Bone with Robust Cell Cycle Progression and High Expression of SPARC: A Case Report and Review of the Literature.

Epithelioid angiosarcoma of bone is a rare entity. Secreted protein acidic and rich in cysteine (SPARC), or osteonectin, is a secreted glycoprotein that has been implicated in tumorigenesis. We report a case of epithelioid angiosarcoma involving the long bones of the lower extremity showing diffuse and strong expression for SPARC immunohistochemistry in tumor cells. Ki-67 was positive in ~50% of tumor cell nuclei and the accompanying mitotic index was 19 mitotic figures/10 high power fields.Expression of SPARC in tumors has been correlated with sensitivity to nanoparticle albumin-bound paclitaxel (Nab-paclitaxel), particularly in the context of robust cell cycle progression into the mitotic phase. This finding could suggest new therapeutic options for further consideration.

Hailey-Hailey disease exacerbated by multiple pregnancies: case report and review of the literature.

Hailey-Hailey disease is a rare chronic skin disorder that is inherited in an autosomal dominant manner. The disease is characterized by development of vesicles and bullae typically in the intertriginous areas. On histology, there is widespread intraepidermal acantholysis causing the "dilapidated brick-wall" appearance. Mutations in the ATP2C1 gene, encoding for P-type Ca2+ transport ATPase, is the primary cause of the disease. The disease manifests around puberty and runs a chronic course with remissions and exacerbations. Ultraviolet light exposure, sweating, friction, stress, and cutaneous infections are the known precipitants of the disease. We report a case of a woman with recurrent flare-ups of Hailey-Hailey disease with repeated pregnancies and remission of her disease during non-pregnancy periods. To our knowledge, this is the first reported case of Hailey-Hailey disease exacerbated by pregnancy.

Immunohistochemical demonstration of isocitrate dehydrogenase 1 (IDH1) mutation in a small subset of prostatic carcinomas.

Recent advances in genomic sequencing have resulted in the discovery of the somatic mutations of cytoplasmic isocitrate dehydrogenase 1 (IDH1) in human solid tumors such as gliomas. The most common IDH1 mutation affects codon 132 and results in the conversion of amino acid residue arginine (R) to histidine (H). This IDH1 mutation is associated with a genetic and clinical characteristic group of gliomas in terms of grade and prognosis. We investigated whether immunohistochemistry (IHC) using a monoclonal antibody against the IDH1 mutant protein could be used in routine surgical pathology for identification of the mutation in solid human tumors. A total of 549 solid human tumors were examined in tissue microarrays, including prostate, thyroid, renal cell, ovarian, endometrial, breast, colorectal, non-small cell lung carcinoma, melanomas, and gliomas. IHC detected the IDH1 mutation in 72% (13/18) anaplastic astrocytomas and 30% (3/10) astrocytomas; however, it failed to detect the mutation in 258 thyroid, 11 renal cell, 10 ovarian, 18 endometrial, 20 breast, 25 colorectal, 22 non-small cell lung carcinoma, 25 melanomas, and 8 thyroid follicular adenomas. In contrast, expression of the IDH1 mutation was noted in 3 of 118 (2.5%) prostate carcinomas. Western blotting and polymerase chain reaction-based sequencing confirmed the mutation in 2 prostate carcinomas. This study indicates that IHC is a reliable method for the pathologic identification of the IDH1 mutation in solid human cancers such as prostate carcinomas.