Carlos Aliste

Retinoblastoma Loss Modulates DNA Damage Response Favoring Tumor Progression

Senescence is one of the main barriers against tumor progression. Oncogenic signals in primary cells result in oncogene-induced senescence (OIS), crucial for protection against cancer development. It has been described in premalignant lesions that OIS requires DNA damage response (DDR) activation, safeguard of the integrity of the genome. Here we demonstrate how the cellular mechanisms involved in oncogenic transformation in a model of glioma uncouple OIS and DDR. We use this tumor type as a paradigm of oncogenic transformation. In human gliomas most of the genetic alterations that have been previously identified result in abnormal activation of cell growth signaling pathways and deregulation of cell cycle, features recapitulated in our model by oncogenic Ras expression and retinoblastoma (Rb) inactivation respectively. In this scenario, the absence of pRb confers a proliferative advantage and activates DDR to a greater extent in a DNA lesion-independent fashion than cells that express only HRasV12. Moreover, Rb loss inactivates the stress kinase DDR-associated p38MAPK by specific Wip1-dependent dephosphorylation. Thus, Rb loss acts as a switch mediating the transition between premalignant lesions and cancer through DDR modulation. These findings may have important implications for the understanding the biology of gliomas and anticipate a new target, Wip1 phosphatase, for novel therapeutic strategies.

Vemurafenib-Induced Neutrophilic Panniculitis: A New Case and Review of the Literature.

Vemurafenib has proved to be useful in the treatment of patients with unresectable or metastatic melanoma harboring the BRAF-V600E mutation, with better rates of overall and progression-free survival than previous treatments. Adverse cutaneous effects, such as alopecia, pruritus, photosensitivity reactions, verrucous keratosis, keratoacanthomas, or squamous cell carcinomas, have been described. Thirty cases of vemurafenib-associated panniculitis are available in the literature with variable clinical relevance. Only 9 of them exhibited definitive evidence of neutrophilic panniculitis. They all consist of multiple lesions, usually located in the lower limbs. Histopathologically, they have been described as predominantly neutrophilic, lymphocytic, or mixed, more commonly with lobular location. We report an additional case of neutrophilic panniculitis in a 45-year-old woman treated with vemurafenib for metastatic melanoma, presenting as a single lesion on his right leg. The lesion resolved spontaneously and did not need treatment reduction. The presentation of this condition with a single lesion is particularly challenging. Recognition of this association is important given the increasing use of vemurafenib and the potential implications of treatment withdrawal.

Atypical fibroxanthoma showing diffuse staining for CD31.

To the Editor, We read with interest the article by Luzar and Calonje1 reviewing the immunophenotype of atypical fibroxanthoma (AFX). In their article, they state that true cytoplasmic expression of CD31 by the AFX tumor cells is unusual and typically focal. They observed CD31 expression by AFX in only 4 of the 42 cases and only 1 previously reported case has shown this immunohistochemical feature.2 Recently, we had the opportunity to study an AFX located in the nose of a 71-year-old woman. The tumor was located in the dermis and extended to the subjacent subcutis. The surface epidermis was thinned and eroded, but the tumor showed no continuity with it. The tumor was composed mostly of spindle-shaped cells with a few admixed epithelioid cells (Fig. 1). The tumor cells were atypical and showed marked proliferative activity (with up to 7 mitotic figures/mm2). Immunohistochemical analysis was consistent with the diagnosis of AFX, as cytokeratins AE1/AE3, 34ßE12, CK5/6, S-100 protein, HMB45, smooth muscle actin, desmin and epithelial membrane antigen (EMA) all showed a lack of reactivity. Vimentin labeled most of the cells of interest, while CD99 and CD68 were only focally positive. The antibody panel also included CD31. Interestingly, it showed strong and diffuse labeling of virtually all tumor cells with spindled morphology (Fig. 2), and intratumoral vessels were also labeled. As a consequence of the CD31 expression, other vascular antibodies (CD34, factor VIII and D2-40) were also utilized, but all lacked reactivity. On the basis of the overall immunophenotype, a vascular sarcoma was considered to be excluded and the tumor was interpreted as AFX. Immunohistochemistry plays a major role in the diagnosis of AFX, which remains a diagnosis of exclusion. A precise combination of negative and positive staining results enables the correct diagnosis to be made.3 The antibody CD31 reacts with platelet Fig. 1. Low power view of the tumor close to the epidermis, but not infiltrating and showing no continuity between them. The neoplastic cells were mostly spindle-shape with few epithelioid cells.

Granuloma annulare of the penis: a uncommon location for an usual disease.

The subcutaneous clinical variant of granuloma annulare (GA) is rare and tends to present more frequently in children, in locations unusual for conventional GA. Involvement of the penis is exceptional and has been rarely reported. Most cases are located in the shaft of the penis and tend to persist without spontaneous remission. Diagnosis is done only after biopsy, and surgical resection of the lesions is not unusual. We report a new case of subcutaneous GA of the penis in a 13-year-old boy with lesions persistent for the past year. Surgical excision of one of them allowed the correct diagnosis. No further treatment was done, and the condition has not remitted 1 year later. We stress the importance of clinical recognition of unusual presentations of GA to avoid overtreatment of lesions that do not need an aggressive approach.

Cutaneous acute graft‐versus‐host disease with isomorphic disposition over striae distensae in a 12‐year‐old girl

necrolysis. J Am Acad Dermatol 2008; 56: 181–200. 3 Horowitz SB, Stirling AL. Thalidomide-induced toxic epidermal necrolysis. Pharmacotherapy 1999; 352: 1586–1589. 4 Eo WK, Kim SH, Cheon SH, et al. Toxic epidermal necrolysis following thalidomide and dexamethasone treatment for multiple myeloma: a case report. Ann Hematol 2010; 89: 421–422. 5 Hall VC, El-Azhary RA, Bouwhuis S, et al. Dermatologic side effects of thalidomide in patients with multiple myeloma. J Am Acad Dermatol 2003; 48: 548–552.

Kaposi sarcoma following postmastectomy lymphedema.

Classical Kaposi sarcoma (KS) usually appears on lower extremities accompanied or preceded by local lymphedema. However, the development in areas of chronic lymphedema of the arms following mastectomy, mimicking a Stewart–Treves syndrome, has rarely been described. We report an 81‐year‐old woman who developed multiple, erythematous to purple tumors, located on areas of post mastectomy lymphedema. Histopathological examination evidenced several dermal nodules formed by spindle‐shaped cells that delimitated slit‐like vascular spaces with some red cell extravasation. Immunohistochemically, the human herpesvirus type 8 (HHV‐8) latent nuclear antigen‐1 was detected in the nuclei of most tumoral cells confirming the diagnosis of KS. Lymphedema could promote the development of certain tumors by altering immunocompetence. Although angiosarcoma (AS) is the most frequent neoplasia arising in the setting of chronic lymphedema, other tumors such as benign lymphangiomatous papules (BLAP) or KS can also develop in lymphedematous limbs. It is important to establish the difference between AS and KS because their prognosis and treatment are very different. Identification by immunohistochemistry of HHV‐8 is useful for the distinction between KS and AS or BLAP.