PET/CT scan and biopsy-driven approach for safe anti-PD-1 therapy discontinuation in patients with advanced melanoma.

BACKGROUND: Limited data exist on safe discontinuation of antiprogrammed cell death protein 1 (PD-1) therapy in responding patients with advanced melanoma. The use of 18fluorodeoxyglucose (18FDG)-PET/CT scan and tumor biopsy for assessment of active disease may be an effective predictive biomarker to guide such treatment decisions. METHODS: A retrospective study of 122 patients with advanced melanoma treated with anti-PD-1 monotherapy or anti-PD-1/anticytotoxic T-lymphocyte-associated protein 4 combination therapy at Georgetown Lombardi Comprehensive Cancer Center was conducted. Uveal melanoma patients and those receiving concurrent experimental therapy were excluded. Baseline characteristics, treatment outcomes, and survival were analyzed. Patients who decided to come off treatment typically after 12 months using CT scan radiographic complete response (CR), 18FDG-PET/CT scan complete metabolic response (CMR) or tumor biopsy of a non-CR/CMR tumor site negative for active disease (possible pathological CR) were identified and compared with patients who discontinued treatment due to toxicity while their disease was in control. Event-free survival (EFS) was assessed from the last dose of anti-PD-1 therapy to progression requiring subsequent treatment (surgery, radiation, and/or systemic therapy) or referral to hospice/death due to melanoma. RESULTS: 24 (20%) patients discontinued treatment by choice with no active disease and 28 (23%) patients discontinued treatment due to toxicity with disease control after 12-month and 4-month median treatment durations, respectively. Similar baseline characteristics were observed between cohorts except higher prior receipt of ipilimumab (29% vs 7%; p=0.036) and fewer BRAF mutant positive disease (17% vs 41%; p=0.064) in patients off treatment by choice. Three-year EFS rates were 95% and 71%, respectively. No significant associations between EFS and sex, disease stage, lactate dehydrogenase elevation, BRAF status, prior systemic therapy, ECOG performance status, presence of brain metastases, or combination versus monotherapy were observed. Tumor biopsies led to alternative management in 3/10 patients due to active metastatic melanoma or second malignancy. CONCLUSIONS: Anti-PD-1 therapy discontinuation after 12 months when no active disease is observed on CT scan, PET/CT scan or tumor biopsy may have low rates of disease relapse in patients with advanced melanoma. Biopsy of residual disease may frequently lead to a change in management. These findings are undergoing validation in the EA6192 trial.

Pancreatic Panniculitis in an 18-Month-Old with Complete DiGeorge Syndrome.

Pancreatic panniculitis, characterized by tender, erythematous subcutaneous nodules occurring most commonly on the lower extremities, occurs in 2% of cases of pancreatic disease. We present a rare case of pancreatic panniculitis in a child with complete DiGeorge syndrome.

Merkel cell carcinoma (primary neuroendocrine carcinoma of skin) mimicking basal cell carcinoma with review of different histopathologic features.

Merkel cell carcinoma (MCC) is a rare but highly aggressive malignancy, which often has typical histopathologic and immunohistochemical (IHC) features. Sometimes the diagnosis is missed because of atypical histological or aberrant IHC findings. A case of MCC that showed irregular lobules of basaloid cells with keratotic areas on the initial shave biopsy is being reported. IHC showed positive staining for high-molecular weight cytokeratin but negative staining for cytokeratin 20, findings consistent with basal cell carcinoma. Subsequent excision specimen showed histopathologic features more typical of MCC. IHC still was negative for cytokeratin 20 but positive for synaptophysin. Review of the literature shows other examples of MCC with basal cell carcinoma-like features. Various other histopathologic differentiations of MCC include those that demonstrate squamous cell and eccrine carcinoma features and those that show melanocytic, lymphomatous, sarcomatous, muscular, and atypical fibroxanthoma-like features. Different histopathologic patterns and mimics of MCC are reviewed to help prevent dermatopathologists from misdiagnosing this aggressive tumor.

NGFR (p75) expression in cutaneous scars; Further evidence for a potential pitfall in evaluation of reexcision scars of cutaneous neoplasms, in particular desmoplastic melanoma.

Desmoplastic melanoma is a rare variant of malignant melanoma composed of spindle cells in a collagenous matrix. The antibody against NGFR (low affinity nerve growth factor receptor, also known as p75) stains cells of desmoplastic melanoma with high sensitivity; however, the specificity of this marker is not well established. Although there are established histologic criteria for recognition of desmoplastic melanoma, the evaluation of residual disease in cutaneous reexcision scars can be challenging. If residual spindle cells in scar are sufficiently atypical and NGFR positive, their presence could be interpreted as residual desmoplastic melanoma. In this study, we reevaluated the use of antibody against NGFR to detect residual disease in reexcision specimens of melanocytic neoplasms as the previously published works are contradictory. Our data indicate that anti-NGFR antibody stains many cells in the scar, some of which seem to be myofibroblasts, nerve twigs, and Schwann cells. Our findings further suggest that NGFR is not a suitable marker to evaluate reexcision scars for desmoplastic melanoma, especially as a sole marker, as its specificity is low.

Recurrent erythema multiforme triggered by progesterone sensitivity.

Determining the underlying etiology of recurrent erythema multiforme (EM) can be a difficult endeavor. Although infection with herpes simplex virus (HSV) has been implicated in some cases, the precise trigger of a given patient's recurrent EM often remains elusive. We discuss the case of a woman with a recurrent blistering eruption that was clinically and histopathologically consistent with EM. An investigation into the etiology of the patient's EM suggested that HSV was not the causative factor but instead pointed toward a hormonal influence that we interpret as autoimmune progesterone dermatitis (APD). This case is presented to highlight the importance of considering hormonal triggers in women with recurrent EM that consistently flares during the luteal phase of the menstrual cycle, the point at which serum progesterone levels peak. A brief review of the literature regarding the diagnosis, histopathology, etiology and treatment of APD is further provided.

Two cutaneous malignant melanomas at the same anatomic site: a case report with molecular evaluation.

Patients who have had malignant melanoma are at an increased risk of developing a second primary melanoma compared with the general population risk of developing a first melanoma. Many of these second primary melanomas occur at a similar anatomic site as the first lesion. Determining whether a second lesion is indeed a separate primary vs. a metastasis or locoregional recurrence can be very difficult histologically. We report the case of a patient who developed a second melanoma, 2 years after the initial diagnosis, within 3 cm of the site of the original lesion. Because of distinct histomorphologic features, the second lesion was favored to be a separate primary. However, because of the nearly identical anatomic location, molecular testing for loss of heterozygosity and BRAF mutation was performed to help further make this distinction. The first lesion was found to have loss of heterozygosity and a BRAF mutation that were not present in the second lesion. While these tests cannot elucidate the true molecular origin of these lesions, they provide a useful clinical tool to assess whether a second lesion should be treated as a recurrence or as a separate lesion with unique biologic potential.

Effects of high-dose IFNalpha2b on regional lymph node metastases of human melanoma: modulation of STAT5, FOXP3, and IL-17.

PURPOSE: Signal transducer and activator of transcription 5 (STAT5) and STAT3 oppose one another in regulation of the reciprocal development of CD4+CD25+FOXP3+ regulatory T cells (Treg) and T helper 17 (Th17). A reduction in STAT3 is associated with up-regulation of Treg, and STAT5 activation promotes Treg differentiation or function while constraining Th17 generation. The effects of IFNalpha on STAT signaling in relation to tumor tissue Treg and Th17 have not been documented in humans beyond the observations that IFNalpha2b down-regulates STAT3. EXPERIMENTAL DESIGN: Following diagnostic biopsy and before definitive surgery, 20 doses of high-dose IFNalpha2b (HDI) were administered to patients with stage IIIB melanoma who gave written informed consent. Lymph node biopsies, in which both total STAT3 and phosphorylated STAT3 were down-regulated by HDI, were probed with STAT5, FOXP3, CD4, and interleukin 17 (IL-17) with immunohistochemistry and/or immunofluorescence techniques. RESULTS: The percentage of FOXP3+ lymphocytes determined by immunohistochemistry was up-regulated from 3.06 +/- 0.65% to 9.86 +/- 1.27% (n = 13, P = 0.0002), and this observation was confirmed by immunofluorescence evaluation of CD4+FOXP3+ Tregs. HDI induced STAT5 up-regulation (five cases observed) in melanoma cells and lymphocytes but did not induce the generation of IL-17-expressing lymphocytes. Increased STAT5 expression was associated with increased FOXP3 expression among lymphocytes, and STAT5 was constitutively activated among both melanoma cells and lymphocytes. CONCLUSION: IFNalpha2b up-regulates STAT5 and down-regulates STAT3, in conjunction with up-regulation of Treg and inhibition of IL-17-expressing lymphocytes in melanoma tissues. These findings suggest that the effects of IFNalpha may be potentiated through interference with the response of Tregs and/or STAT5.

Mitoses in conventional melanocytic nevi.

Given that nevi may grow in size, mitotic figures may be expected in melanocytic nevi. We reviewed the literature for studies addressing this issue. We sought to determine the number of mitotic figures we might discover upon review of a group of randomly collected, conventional nevi. We reviewed 157 nevi from patients and found seven nevi exhibiting mitotic figures, comprising 4% of our sample. We noted the location of the mitoses within the nevi, the presence of any congenital features, as well as other features such as signs of inflammation or irritation. Through this study we have shown that occasional mitoses occur within unremarkable, conventional nevi.

Skeletal muscle regeneration: report of a case presenting as a cutaneous nodule following blunt trauma to the lip.

Skeletal muscle (SM) regeneration is a pleomorphic yet benign reaction pattern that follows injury to SM and has been reported to simulate histologically various malignancies such as squamous cell carcinoma and rhabdomyosarcoma. A 61-year-old man presented with a 4-month history of an enlarging nodule on the upper lip following blunt trauma. An initial punch biopsy was non-diagnostic. A deeper biopsy revealed a multilobular proliferation of atypical and pleomorphic cells with vesicular nuclei, prominent nucleoli, and large amphophilic cytoplasm. Immunoperoxidase studies showed these cells to be positive for muscle-specific actin and desmin and negative for S-100 protein and smooth muscle actin. Based on these findings, a diagnosis of skeletal muscle regeneration (SMR) was made. To our knowledge, this is the first report of SMR presenting clinically as a rapidly growing cutaneous nodule on the lip following blunt trauma.

Cutaneous oncocytoma - a report of three cases and review of the literature.

The oncocyte is a cell characterized by capacious, eosinophilic, finely granular cytoplasm, and lesions composed primarily of oncocytes are termed oncocytomas. Whereas oncocytic metaplasia has been reported in various cutaneous neoplasms, oncocytomas typically occur in the kidneys, thyroid and salivary glands and are uncommon in the dermatopathology literature. We present three cases of cutaneous oncocytoma so that dermatopathologists are cognizant of this uncommon entity. Although some believe that oncocytomas are locally aggressive lesions, our cases indicate that their clinical course is perhaps as banal as their histology.