Molecular targets and targeted therapies in pheochromocytoma

Pheochromocytoma and paraganglioma are tumors of chromaffin cells occurring within the adrenal medulla or the sympathetic nervous system, respectively. About 15% of these tumors are malignant, especially in patients with mutations in the subunit B of the succinate dehydrogenase, who have a 40% probability of developing distant metastases. For these malignancies surgery is currently the treatment of choice, but, especially for advanced forms, treatment is unsatisfactory and prognosis is very poor. Thus, novel treatment options for these patients are urgently in need. Recent advances in our understanding of the molecular pathology of pheochromocytoma and paraganglioma have led to the identification of key oncogenic events. Several molecular pathways have been suggested to play a role in these tumors, including the RTKs/Ras/MAPK, PI3K/Akt/mTOR, HIF, HSP90 and mithocondrial proteins involved in energy-producing pathways. This increased knowledge can be matched by the increased number of novel compounds, including tyrosine kinase inhibitors and other novel targeted therapies already in clinical trial for other cancers, targeting signaling pathways important for tumor proliferation, survival and metastatic dissemination. The overarching objective of this research project was to identify mechanism-based, molecularly targeted therapeutic approaches to modulate cancer cell growth and metastatic growth in pheochromocytoma, promoting the translational development of more effective therapeutic options for these tumors. The lack of sensitive animal models of pheochromocytoma has hindered the study of this tumor and in vivo evaluation of antitumor agents.To this end, two in vivo models for the evaluation of efficacy of several molecular targeted therapies were developed: an experimental metastasis model to 3 monitor tumor spreading and a subcutaneous model to monitor tumor growth and spontaneous metastasis. These models offer a platform for sensitive, non-invasive and real-time monitoring of pheochromocytoma primary growth and metastatic burden to follow the course of tumor progression and for testing relevant antitumor treatments in metastatic pheochromocytoma. I then use in vitro experiments and the in vivo models above described to test the efficacy of selective ATP-competitive inhibitors targeting both mTORC1 and mTORC2 complexes, pointing out an important role for the mTOR signaling pathway in the development of pheochromocytoma. Moreover, I investigated also the 90 kDa heat shock protein (Hsp90) as a potential therapeutic target for advanced pheochromocytoma, using both first and second generation Hsp90 inhibitors. As an alternative approach to identify potential drugs that can more rapidly be implemented into clinical trials in patients with metastatic pheochromocytoma or paraganglioma, I used a drug repurposing/repositioning approach. With this strategy, several molecules with potential bioactivity in pheochromocytoma cells were identified, including an example of a combination with synergistic effect

Histopathologic Features of Maculopapular Drug Eruption

Background: Cutaneous adverse drug reaction (CADR) is common in both inpatient and outpatient clinical settings and has been associated with a large variety of medications. Drug reactions represent a significant burden to the healthcare system due to increased hospital stay durations and associated costs. Moreover, some of these reactions may be life-threatening. The most common clinical manifestation of a CADR is a maculopapular drug eruption (MDE). Due to its many clinical mimics and associations with a variety of histopathologic patterns, maculopapular drug eruption is difficult to definitively diagnose from both a clinical and histopathological perspective. Summary: We reviewed the clinical and histopathologic features of 327 cases of MDE from several studies in the literature and summarized characteristic histopathologic findings and their frequencies of occurrence. We found that the most common and suggestive histopathologic features of MDE were epidermal spongiosis, lymphocytic infiltrate, and occasional necrotic keratinocytes; interface change at the DEJ; superficial perivascular and interstitial lymphocytic infiltrate with or without eosinophils and neutrophils in the mid-to-deep dermis and mild papillary dermal edema; and dilation of superficial vessels. The presence of multiple histopathologic patterns within the same tissue specimen is also suggestive of MDE. This review and analysis suggest that a biopsy may improve the diagnostic accuracy by both establishing common and uncommon features associated with MDE and reviewing features that help to exclude other causes of maculopapular eruption. Key Message: Histopathologic criteria for the diagnosis of MDE, while not entirely specific, may aid in establishing a differential that includes a drug eruption. Thus, a biopsy can be a helpful diagnostic tool when MDE is suspected by demonstrating findings suggestive of MDE or by ruling out clinical mimics. However, biopsy results cannot be used in isolation as clinical-pathologic correlation is paramount in MDE

Hereditary Papillary Renal Carcinoma Type I

Abstract Germline missense mutations in the tyrosine kinase domain of the hepatocyte growth factor/scatter factor (HGF/SF) receptor, c-Met, are thought to be responsible for hereditary papillary renal carcinoma (HPRC) type 1, a form of human kidney cancer. In addition to extensive linkage analysis of HPRC families localizing the HPRC type 1 gene within chromosome 7, the demonstration that individual c-Met mutations reconstituted in cultured cells display enhanced and dysregulated kinase activity, and confer cell transformation and tumorigenicity in mice, solidifies this conclusion. Our prior knowledge of HGF/SF biology and c-Met signaling enabled rapid progress in unraveling the molecular pathogenesis of HPRC type 1, and in laying the framework for the development of novel therapeutics for the treatment of this cancer. At the same time, the study of HPRC type 1 has refined our appreciation of the oncogenic potential of c-Met signaling, and challenges our current understanding of HGF/SF and c-Met function in health and disease

Recurrent Nevus Phenomenon Developing within a Keloid

The recurrent nevus phenomenon represents the persistence of a nevus within a scar from a prior biopsy site, with the acquisition of clinical and histologic features frequently overlapping with those of melanoma, posing relevant diagnostic challenges. Similar features are recognized in nevi that have undergone recent or chronic trauma and in sclerosing nevi. Any type of nevus may be subject to this phenomenon. Keloids are exuberant scars with an exaggerated accumulation of dense dermal collagen. Here we report a case of a 42-year-old woman with the incidental finding of an atypical melanocytic proliferation developing within a keloidal scar. The patient presented with a progressively enlarging auricular lesion three years after a piercing procedure. Upon histological examination, attentive scrutiny of the margin revealed an atypical compound melanocytic proliferation, predominantly single-celled at the junction but occasionally nested, with cytologic atypia and architectural disorder. This atypical proliferation was found emerging above a keloid. We interpreted the lesion as an atypical melanocytic lesion with features resembling the recurrent nevus phenomenon. This case raises awareness in recognizing these melanocytic lesions as benign, thereby avoiding overdiagnosis and unnecessary treatment

A Case of Tumor of Follicular Infundibulum Involving the Vulva

Tumor of the follicular infundibulum or infundibuloma is a relatively rare benign adnexal tumor usually solitary and located in the head, neck, and trunk. Here we present a 70-year-old woman with a tender vulvar lesion. Histopathologic exam shows a well-circumscribed lesion with a subepidermal horizontally oriented, plate-like proliferation of pale appearing squamous epithelial cells with numerous points of connections with the overlying epidermis and peripheral palisading. Overall these histopathologic features are consistent with the diagnosis of tumor of follicular infundibulum involving genital skin

Delayed-onset cutaneous eruption associated with lenalidomide in setting of multiple myeloma

Lenalidomide (LEN) is increasingly being used for the treatment of multiple myeloma (MM). Adverse cutaneous reactions to LEN are common and present almost exclusively within one month of initiating therapy. We report a case of delayed-onset LEN-associated eruption presenting over three years after starting treatment. Histopathologic findings are also described, which are infrequently reported for LEN-associated eruptions. Our case serves as a reminder that proper recognition and management of LEN-associated eruption is important in the treatment of MM. Dermatologists should be aware of the potential for delayed presentations of adverse cutaneous reactions to LEN, even years after initiation

Correlation of MET and PD-L1 Expression in Malignant Melanoma

The proto-oncogene MET, the hepatocyte growth factor (HGF) receptor, is a transmembrane receptor tyrosine kinase (RTK) with a prominent role in tumor metastasis and resistance to anti-cancer therapies. Melanoma demonstrates relatively frequent MET aberrations, including MET gene amplification. Concurrently, programmed death-ligand 1 (PD-L1), with its ability to evade anti-tumor immune responses, has emerged as a prominent therapeutic target in melanoma and other malignancies and its expression is used as a predictive biomarker of response to immunotherapy. We performed immunohistochemistry analysis of MET and PD-L1 in 18 human melanoma cell lines derived from both primary and metastatic lesions, and in a human melanoma tissue microarray containing one hundreds melanocytic lesions, including primary cutaneous melanomas, primary mucosal melanomas, metastatic melanomas and benign melanocytic nevi as controls. After color deconvolution, each core was segmented to isolate staining and calculate the percentage of positive cells. Overall, MET expression was higher in tumors with increased PD-L1 expression. Moreover, a robust correlation between MET and PD-L1 expression was found in samples from metastatic melanoma and not in primary cutaneous or mucosal melanoma. These data suggest that relative expression levels of these proteins in combination is a marker of advanced disease and testing for expression of these markers should be considered in patients with melanoma

Ichthyosiform Pityriasis Rubra Pilaris-Like Eruption Secondary to Ponatinib Therapy: Case Report and Literature Review

Tyrosine kinase inhibitors have revolutionized the chemotherapy arena as targeted therapies for a multitude of malignancies. They are more selective than conventional chemotherapy, and often elicit fewer systemic adverse events, however toxicities still exist. Cutaneous toxicities are common and their management presents a novel challenge to physicians and patients. Ponatinib is a third-generation tyrosine kinase inhibitor increasingly reported to cause cutaneous eruption. A 50-year-old woman with a history of chronic myelogenous leukemia presented with a 4-month history of worsening atrophic and ichthyosiform pink plaques involving the axillae, thighs and abdomen; red patches were also observed on the cheeks and forehead. She was started on the third-generation, ponatinib, 5 months earlier because of disease refractory to previous therapies including interferon, imatinib, dasatinib and bosutinib. A skin biopsy revealed perifollicular fibrosis, alternating orthokeratosis and parakeratosis, and a sparse perivascular lymphocytic infiltrate consistent with a pityriasis rubra pilaris-like reaction. Topical tretinoin 0.025% cream was initiated, resulting in resolution within 3 weeks without discontinuation of ponatinib. A review of previous reports identified significant similarities among the ponatinib-induced drug reactions. Here, we highlight not only that cutaneous eruptions occur on ponatinib therapy, but that the dermatologic manifestations are characteristic and unique, and benefit from retinoid therapy, without requiring interruption of vital chemotherapy

Multiple desmoplastic Spitz nevi with BRAF fusions in a patient with ring chromosome 7 syndrome

Patients with non-supernumerary ring chromosome 7 syndrome have an increased incidence of hemangiomas, café-au-lait spots, and melanocytic nevi. The mechanism for the increased incidence of these benign neoplasms is unknown. We present the case of a 22-year-old man with ring chromosome 7 and multiple melanocytic nevi. Two nevi, one on the right ear and the other on the right knee, were biopsied and diagnosed as desmoplastic Spitz nevi. Upon targeted next-generation DNA sequencing, both harbored BRAF fusions. Copy number alterations and fluorescence in situ hybridization (FISH) for BRAF suggested that the fusions arose on the ring chromosome 7. Hence, one reason for increased numbers of nevi in patients with non-supernumerary ring chromosome 7 syndrome may be increased likelihood of BRAF fusions, due to the instability of the ring chromosome