Characterizing Outcomes in Visceral Cutaneous T-Cell Lymphoma: A Single Center Retrospective Study.

INTRODUCTION: Visceral involvement of cutaneous T-cell lymphoma (vCTCL) is a rare but poorly studied complication of CTCL. We aimed to assess clinical characteristics, treatment, and outcomes, associated with vCTCL at our institution. METHODS: We conducted a retrospective review of patients with vCTCL among patients with a confirmed histopathologic diagnosis of CTCL seen at the Winship Cancer Institute in Emory University. vCTCL was defined as a highest TNMB stage of 4B with extracutaneous metastatic disease (M1) pathologically confirmed or strongly clinically suspected based on imaging, symptoms, and the clinical judgment of the treating physician. Patients were selected from our CTCL database containing 656 patients from 1990 to 2022. Clinical characteristics were characterized. Clinical outcomes were measured as overall survival (OS) and progression-free survival (PFS) using Kaplan-Meier curve and univariable Cox regression analysis. RESULTS: Twenty-six of 656 patients with vCTCL were identified. 42.3% of patients were black. Twenty-two patients were diagnosed with MF/SS and 4 had other CTCL subtypes including pcALCL, Gamma-Delta, and Cytotoxic T-Cell Lymphoma. The median PFS and OS were 7.3 months (3.8, 11) and 12.1 months (9.9, 18.2), respectively. Median time to metastasis from initial diagnosis was 12.1 months. The most common M1 sites were liver (19.2%) and lung (42.3%). M1 sites outside of liver or lung were associated with inferior OS (HR 8.9, 95%CI: 2.7-29.5, P-value <.001) and PFS (HR 4.3, 95%CI: 1.44-12.7, P-value = .009). No treatments or baseline factors were associated with improved survival. CONCLUSION: Our retrospective study confirms therapy resistance and dismal outcomes among patients with vCTCL.

Staging lymph nodes and blood at diagnosis in mycosis fungoides identifies patients at increased risk of progression to advanced stage: A retrospective cohort study.

BACKGROUND: Risk factors for progression to advanced-stage mycosis fungoides (MF) are poorly defined. METHODS: The authors performed a single-center, retrospective cohort study among patients with MF at an academic medical center from 1990 to 2020 to identify clinical variables associated with progression to advanced-stage MF (stage IIB-IVB), and 388 patients who had a clinicopathologic diagnosis of early stage (IA-IIA) MF were identified from their cutaneous lymphoma database. Baseline clinical characteristics, laboratory values, imaging, and blood flow cytometry or T-cell receptor gene rearrangement (TCR) data were collected. Logistic regression was used to assess risk factors associated with progression. RESULTS: Overall, 93 of 388 patients (24.0%) progressed to advanced stage. Patients who progressed had an increased risk of death (hazard ratio, 4.50; 95% CI, 2.89-7.00; p < .001). Progression was associated with a higher overall stage at diagnosis, tumor stage, lymph node stage, low-level blood involvement, as measured with TCR data and/or flow cytometry, and elevated lactate dehydrogenase (LDH). Limitations included missing data for LDH, imaging, peripheral blood TCR data, or flow cytometry assessed at diagnosis. CONCLUSIONS: Staging and baseline laboratory assessments with imaging, peripheral blood flow cytometry, TCR data, and LDH in patients who have newly diagnosed MF may identify those who are at risk for progression to advanced stage.

Mechlorethamine Hydrochloride Gel in the Treatment of Mycosis Fungoides-Type Cutaneous T-Cell Lymphoma (MF-CTCL): A Focus on Patient Selection and Special Considerations.

Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma (CTCL) and often has an indolent course, particularly for patients presenting with early-stage (patch/plaque) disease. Early-stage MF is primarily managed with skin-directed therapies. Topical mechlorethamine hydrochloride (nitrogen mustard [NM]) gel has increased tolerability compared to prior NM formulations, though contact dermatitis remains a common side effect. The addition of topical steroids can improve tolerability while maintaining the efficacy of NM gel. Real-world experience supports that NM gel also has a role in combination therapy and as adjunctive therapy in advanced-stage disease. Here we review factors that may influence patient selection for use of NM gel, including MF variants, special patient populations, cost effectiveness, and impact on quality of life for patients with MF.

Clinical Presentation and Outcome Differences Between Black Patients and Patients of Other Races and Ethnicities With Mycosis Fungoides and Sézary Syndrome.

Importance: Mycosis fungoides and Sézary syndrome (MF/SS) has an increased incidence in Black patients, but clinical characteristics, treatments, and outcomes have been poorly characterized. Objective: To assess racial differences in presentation and outcome and identify drivers for racial disparities in MF/SS. Design, Setting, and Participants: A retrospective cohort analysis was conducted of 566 patients with MF/SS diagnosed from 1990 to 2020 and seen at the Winship Cancer Institute of Emory University and Grady Memorial Hospital, both in Atlanta, Georgia. Self-reported race and ethnicity were obtained from patient medical records and analyzed as 2 groups: non-Hispanic Black (Black) and all other races and ethnicities, including Asian, Hispanic, White, and unknown/undeclared (non-Black). Main Outcomes and Measures: Univariate and multivariable models and Kaplan-Meier assessments were analyzed for overall survival and time to next treatment. The primary outcome was to assess differences in overall survival by racial and ethnic group. The hypotheses were formulated prior to data collection. Results: Of the 566 patients with MF/SS identified (mean [SD] age 55 [16.4] years; 270 (47.7%) female), 257 were Black and 309 were non-Black. Black race was associated with increased rates of progression to a higher TNMB stage (39.8% in Black patients vs 29.1% in non-Black patients; P < .001) but not survival. Black patients were younger and had increased female predominance, higher TNMB stage, higher tumor stage, nodal involvement, and higher lactate dehydrogenase level compared with non-Black patients with MF/SS. Hypopigmented MF (HMF) was found in 62 patients, who were mostly Black (n = 59). Hypopigmented MF was significantly associated with survival on univariate and multivariable models, with 10-year survival of 100% in patients with HMF compared with 51.8% in patients without HMF. Black race was only associated with inferior outcomes after excluding patients with HMF who were younger than 60 years (hazard ratio [HR], 1.61; 95% CI, 1.02-2.55; P = .04), but not in patients older than 60 years (HR, 1.20; 95% CI, 0.80-1.81; P = .37). On multivariate analysis, among the cohort without HMF who were younger than 60 years, Black race remained statistically significant when controlling for cancer stage and large-cell transformation (HR, 1.27; 95% CI, 1.08-2.87; P = .43). Conclusions and Relevance: In this cohort study, Black patients with MF/SS showed distinct clinical presentations and patterns of progression with heterogeneous outcomes depending on age at presentation and presence of HMF.

T-Cell Receptor Gene Rearrangement Clonality, Flow Cytometry Status, and Associated Outcomes in Early-Stage Cutaneous T-Cell Lymphoma.

IMPORTANCE: The prognostic significance of clonal T-cell receptor (TCR) rearrangement or low-level blood involvement as assessed by flow cytometry for patients with early-stage cutaneous T-cell lymphoma (CTCL) is not clear. OBJECTIVE: To assess the association of low-level blood involvement by TCR clonality and flow cytometry with outcomes for patients with early-stage CTCL. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort analysis was conducted from September 1, 2019, to February 29, 2020, of 322 patients with early-stage (I-IIA) CTCL seen at the Winship Cancer Institute of Emory University and Grady Memorial Hospital. T-cell receptor gene rearrangement and flow cytometry records from the peripheral blood were documented at initial assessment. EXPOSURES: T-cell receptor clonality and peripheral blood flow cytometry. MAIN OUTCOMES AND MEASURES: Univariate and multivariable models and Kaplan-Meier assessments were analyzed for overall survival (OS) and time to next treatment. The primary outcome was OS from diagnosis and time to next treatment, and the hypotheses were formulated prior to data collection. RESULTS: A total of 322 patients (166 female patients [51.6%]; median age at diagnosis, 53.8 years [range, 8.6-87.4 years]) with early-stage CTCL diagnosed from 1990 to 2018 were identified; of these, 258 had data available for both flow cytometry and TCR. Positive results for both TCR clonality and flow cytometry were associated with inferior OS in early-stage CTCL compared with both having negative results (hazard ratio [HR], 2.86; 95% CI, 1.02-8.06; P = .046). Positive results for only TCR clonality or only flow cytometry were not associated with OS (TCR clonality: HR, 1.31; 95% CI, 0.70-2.47; P = .40; flow cytometry: HR, 1.21; 95% CI, 0.58-2.52; P = .61) or time to next treatment (TCR clonality: HR, 1.05; 95% CI, 0.77-1.43; P = .76; flow cytometry: HR, 0.74; 95% CI, 0.47-1.16; P = .12). However, positive flow cytometry results were associated with reduced OS in the stage IIA subgroup (n = 94; HR, 1.17; 95% CI, 1.18-8.74; P = .02). Covariates associated with reduced survival included advanced age at diagnosis, male sex, and higher disease stage. CONCLUSIONS AND RELEVANCE: This cohort study of patients with early-stage CTCL suggests that low-level blood involvement as indicated by positive results for both TCR gene rearrangement and flow cytometry was associated with inferior OS, whereas positive results for either flow cytometry or TCR clonality was not. More precise measurements of blood involvement in CTCL and larger multi-institutional cohorts are needed to validate the prognostic significance of low-level blood involvement in early-stage CTCL.

Narrow excision margins are appropriate for Merkel cell carcinoma when combined with adjuvant radiation: Analysis of 188 cases of localized disease and proposed management algorithm.

BACKGROUND: Merkel cell carcinoma (MCC) management typically includes surgery with or without adjuvant radiation therapy (aRT). Major challenges include determining surgical margin size and whether aRT is indicated. OBJECTIVE: To assess the association of aRT, surgical margin size, and MCC local recurrence. METHODS: Analysis of 188 MCC cases presenting without clinical nodal involvement. RESULTS: aRT-treated patients tended to have higher-risk tumors (larger diameter, positive microscopic margins, immunosuppression) yet had fewer local recurrences (LRs) than patients treated with surgery only (1% vs 15%; P = .001). For patients who underwent surgery alone, 7 of 35 (20%) treated with narrow margins (defined as ≤1.0 cm) developed LR, whereas 0 of 13 patients treated with surgical margins greater than 1.0 cm developed LR (P = .049). For aRT-treated patients, local control was excellent regardless of surgical margin size; only 1% experienced recurrence in each group (1 of 70 with narrow margins ≤1 cm and 1 of 70 with margins >1 cm; P = .56). LIMITATIONS: This was a retrospective study. CONCLUSIONS: Among patients treated with aRT, local control was superb even if significant risk factors were present and margins were narrow. We propose an algorithm for managing primary MCC that integrates risk factors and optimizes local control while minimizing morbidity.

Skin Directed Therapy in Cutaneous T-Cell Lymphoma.

Skin directed therapies (SDTs) serve important roles in the treatment of early stage cutaneous T-cell lymphoma (CTCL)/mycosis fungoides (MF), as well as managing symptoms and improving quality of life of all stages. There are now numerous options for topical therapies that demonstrate high response rates, particularly in early/limited MF. Phototherapy retains an important role in treating MF, with increasing data supporting efficacy and long-term safety of both UVB and PUVA as well as some newer/targeted methodologies. Radiation therapy, including localized radiation and total skin electron beam therapy, continues to be a cornerstone of therapy for all stages of MF.

Generalized fixed drug eruption mimicking CD8+ cutaneous T-cell lymphoma in HIV.

We present a case of a widespread fixed drug eruption histologically mimicking CD8 positive cutaneous T-cell lymphoma (CTCL). CTCL has several potential histological and clinical mimics, and accurate diagnosis relies on a combination of clinicopathological correlation and molecular studies. We add generalized fixed drug eruption to the list of possible CTCL mimics.

Clinical Benefit from Tyrosine Kinase Inhibitors in Metastatic Merkel Cell Carcinoma: A Case Series of 5 Patients.

BACKGROUND Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine skin cancer. The estimated 5-year survival of patients with metastatic disease is approximately 14%. Cytotoxic chemotherapy is associated with a modest median progression-free survival (PFS) of only 3 months. In recent studies, immunotherapy with anti-PD-1/anti-PD-L1 antibodies has demonstrated a high response rate in immunocompetent patients (>50% in chemotherapy-naïve patients) and responses are typically durable. However, approximately 50% of immunocompetent patients do not respond to immunotherapy. In addition, immunosuppressed patients have limited therapeutic options. Hence, there is a significant unmet need for effective treatments in these subpopulations. CASE REPORT We describe 5 patients (out of 24 total) with metastatic MCC who were treated with a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI), either pazopanib (n=4) or cabozantinib (n=1), with clinical benefit. One patient had a complete response to pazopanib after 3 months of therapy. Four patients had stabilization of disease that lasted from 5 months to 3.5 years. In an immunosuppressed patient with psoriatic arthritis, stabilization of MCC was also associated with improvement in his arthritis that allowed cessation of immunosuppression. Patients did not develop any unusual toxicities from VEGFR-TKIs. CONCLUSIONS Treatment with VEGFR-TKIs demonstrated clinical benefit in this selected small group of patients with metastatic MCC. Prospective investigation of VEGFR-TKIs is warranted in this population, especially in patients with disease refractory to immunotherapy.

Neutron Radiation Therapy for Treatment of Refractory Merkel Cell Carcinoma.

We describe the first reported use of neutron radiation therapy for successful palliation of treatment refractory Merkel cell carcinoma. The patient was a 78-year-old man with Merkel cell carcinoma involving the scalp and bilateral cervical lymph nodes. The extensive coalescing scalp lesions were locally destructive, painful, and highly detrimental to his overall quality of life, and he had previously progressed through 3 courses of conventional x-ray-based radiation therapy and multiple immunotherapy regimens. We treated him with neutron radiation therapy, and he experienced a complete and durable local response with minimal toxicity. High linear energy transfer particle therapy approaches deserve consideration as a treatment option in cancers that are refractory to standard radiation therapy.

Viral oncoprotein antibodies as a marker for recurrence of Merkel cell carcinoma: A prospective validation study.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive skin cancer with a recurrence rate of >40%. Of the 2000 MCC cases per year in the United States, most are caused by the Merkel cell polyomavirus (MCPyV). Antibodies to MCPyV oncoprotein (T-antigens) have been correlated with MCC tumor burden. The present study assesses the clinical utility of MCPyV-oncoprotein antibody titers for MCC prognostication and surveillance. METHODS: MCPyV-oncoprotein antibody detection was optimized in a clinical laboratory. A cohort of 219 patients with newly diagnosed MCC were followed prospectively (median follow-up, 1.9 years). Among the seropositive patients, antibody titer and disease status were serially tracked. RESULTS: Antibodies to MCPyV oncoproteins were rare among healthy individuals (1%) but were present in most patients with MCC (114 of 219 patients [52%]; P < .01). Seropositivity at diagnosis independently predicted decreased recurrence risk (hazard ratio, 0.58; P = .04) in multivariate analyses adjusted for age, sex, stage, and immunosuppression. After initial treatment, seropositive patients whose disease did not recur had rapidly falling titers that became negative by a median of 8.4 months. Among seropositive patients who underwent serial evaluation (71 patients; 282 time points), an increasing oncoprotein titer had a positive predictive value of 66% for clinically evident recurrence, whereas a decreasing titer had a negative predictive value of 97%. CONCLUSIONS: Determination of oncoprotein antibody titer assists in the clinical management of patients with newly diagnosed MCC by stratifying them into a higher risk seronegative cohort, in which radiologic imaging may play a more prominent role, and into a lower risk seropositive cohort, in which disease status can be tracked in part by oncoprotein antibody titer. Cancer 2017;123:1464-1474. © 2016 American Cancer Society.

Response rates and durability of chemotherapy among 62 patients with metastatic Merkel cell carcinoma.

Cytotoxic chemotherapy is commonly used to treat advanced Merkel cell carcinoma (MCC). However, its efficacy in distant metastatic MCC patients is unclear, in part because most prior reports aggregated these patients with those receiving adjuvant chemotherapy and combined chemoradiation for whom prognosis and outcomes may differ. In this retrospective study, we analyzed detailed records from 62 patients with distant metastatic MCC treated with cytotoxic chemotherapy. Efficacy outcomes including response rate (RR), durability of response (DOR), progression-free survival (PFS), and overall survival (OS) were evaluated. In this cohort, platinum plus etoposide was the most commonly used first-line regimen (69%). RR to first-line chemotherapy was 55% (34/62) with complete responses (CR) in 13% (8/62) and partial responses (PR) in 42% (26/62) while 6% (4/62) had stable disease and 39% (24/62) had progressive disease. Median PFS was 94 days and median OS was 9.5 months from start of chemotherapy. Among responding patients (n = 34), median PFS was 168 days and median DOR was 85 days. Among 30 of the 62 patients who received second-line chemotherapy, RR was 23% (7/30; 1 CR, 6 PR), median PFS was 61 days, and median DOR was 101 days. In summary, first-line chemotherapy is associated with a high RR in metastatic MCC, but responses are typically not durable, and the median PFS is only 3 months. These results suggest rapid emergence of chemoresistance in MCC tumors, and may serve as a useful comparator for immunotherapies currently being explored for metastatic MCC.

Paraneoplastic syndromes (PNS) associated with Merkel cell carcinoma (MCC): A case series of 8 patients highlighting different clinical manifestations.

BACKGROUND: Paraneoplastic syndromes (PNS) are commonly associated with neuroendocrine cancers, such as small cell lung cancer. OBJECTIVES: We examined the association of PNS in Merkel cell carcinoma (MCC), a rare neuroendocrine skin cancer. METHODS: We identified PNS associated with MCC based on chart review of a Seattle-based repository and examined the incidence of MCC-associated hyponatremia in an independent cohort within Kaiser Permanente Northern California. RESULTS: Eight PNS cases were identified from the Seattle repository. Three distinct PNS types were observed: cerebellar degeneration (1 case), Lambert-Eaton myasthenic syndrome (2 cases), and malignancy-associated hyponatremia (5 cases). Moreover, the incidence of severe hyponatremia (serum sodium <125 mmol/L) coincident with MCC was identified among 4.3% (9 of 211) patients with MCC in the Kaiser Permanente Northern California cohort. LIMITATIONS: We did not have access to complete medical records on all patients so it was not possible to determine the prevalence of PNS in MCC. CONCLUSIONS: MCC can be associated with PNS similar to those found in other neuroendocrine cancers. Clinicians should be aware of these presentations as PNS often precede the identification of the underlying malignancy and usually resolve with appropriate treatment of the cancer.

Postoperative radiation therapy is associated with a reduced risk of local recurrence among low risk Merkel cell carcinomas of the head and neck.

PURPOSE: Merkel cell carcinoma (MCC) is a rare and often aggressive skin cancer. Typically, surgery is the primary treatment. Postoperative radiation therapy (PORT) is often recommended to improve local control. It is unclear whether PORT is indicated in patients with favorable Stage IA head and neck (HN) MCC. METHODS AND MATERIALS: We conducted a retrospective analysis of 46 low-risk HN MCC cases treated between 2006 and 2015. Inclusion criteria were defined as a primary tumor size of ≤ 2 cm, negative pathological margins, negative sentinel lymph node biopsy, and no immunosuppression. Local recurrence (LR) was defined as tumor recurrence within 2 cm of the primary surgical bed and estimated with the Kaplan-Meier method. RESULTS: Omission of PORT was offered to all 46 patients, of which 23 patients received PORT and 23 did not. No patient received adjuvant chemotherapy. There were no significant differences in surgical margins, tumor size, depth, lympho-vascular invasion status, or demographics between the two patient groups. Median follow-up for all patients was 3.7 years. Six of the 23 patients who did not receive PORT developed an LR. Compared to the group that received PORT, there was a significantly higher risk of LR in the group treated without PORT (26% vs. 0%, P = .02). Median time to LR was 11 months. All local failures were effectively salvaged. There was no difference in MCC-specific and overall survival between the 2 groups. CONCLUSIONS: For patients with HN MCC, omission of PORT was associated with a significantly higher risk of local recurrence even among those patients with the lowest-risk tumors (i.e., Stage IA without immune suppression). Thus, it is important to weigh the benefits of PORT against the side effect profile on a case-specific basis for each patient.