Clinical features and management of large cell neuroendocrine lung carcinoma of the lung are poorly described. We report a series of 49 patients with stage IV large cell neuroendocrine lung carcinomas; 47% had brain metastases. In 17 patients with molecular testing, 24% of tumors harbored KRAS mutations. Response to platinum/etoposide in these patients was poorer than historic data for small-cell lung cancer, however prognosis was similar. Background Large cell neuroendocrine carcinoma (LCNEC) accounts for approximately 3% of lung cancers. Pathologic classification and optimal therapies are debated. We report the clinicopathologic features, treatment and survival of a series of patients with stage IV LCNEC. Materials and Methods Cases of pathologically-confirmed stage IV LCNEC evaluated at Memorial Sloan Kettering Cancer Center from 2006 to 2013 were identified. We collected demographic, treatment, and survival data. Available radiology was evaluated by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria. Results Forty-nine patients with stage IV LCNEC were identified. The median age was 64 years, 63% of patients were male, and 88% were smokers. Twenty-three patients (n = 23/49; 47%) had brain metastases, 17 at diagnosis and 6 during the disease course. Seventeen LCNEC patients (35%) had molecular testing, of which 24% had KRAS mutations (n = 4/17). Treatment data for first-line metastatic disease was available on 37 patients: 70% (n = 26) received platinum/etoposide and 30% (n = 11) received other regimens. RECIST was completed on 23 patients with available imaging; objective response rate was 37% (95% confidence interval, 16%–62%) with platinum/etoposide, while those treated with other first-line regimens did not achieve a response. Median overall survival was 10.2 months (95% confidence interval, 8.6–16.4 months) for the entire cohort. Conclusion Patients with stage IV LCNEC have a high incidence of brain metastases. KRAS mutations are common. Patients with stage IV LCNEC do not respond as well to platinum/etoposide compared with historic data for extensive stage small-cell lung cancer; however, the prognosis is similar. Prospective studies are needed to define optimum therapy for stage IV LCNEC.

The spectrum and evolution of proliferation rates in stage IV lung carcinoids is poorly defined. In particular, there are limited data on the prevalence and characteristics of tumors exceeding the standard upper proliferative criteria – as defined largely based on early-stage carcinoids – in metastatic setting.Sixty-six patients with stage IV lung carcinoids were identified, and all evaluable samples (n=132; mean 2 samples per patient) were analyzed for mitotic counts and Ki-67 rate. Clinicopathologic and genomic features associated with elevated proliferation rates (>10 mitoses per 2 mm2 and/or >20% hot-spot Ki-67), and evolution of proliferation rates in serial specimens were analyzed.We found that mitoses and/or Ki-67 exceeded the standard criteria in 35 of 132 (27%) samples, primarily (31/35 cases) from metastatic sites. Although neuroendocrine neoplasms with >10 mitoses per 2 mm2 are currently regarded as de facto neuroendocrine carcinomas, the notion that these cases are part of the spectrum of carcinoids was supported by 1) well-differentiated morphology, 2) conventional proliferation rates in other samples from same patient, 3) genetic characteristics, including the lack of RB1/TP53 alterations in all tested samples (n=19), and 4) median overall survival of 2.7 years, compared to <1 year survival of stage IV neuroendocrine carcinomas in the historic cohorts. In patients with matched primary/metastatic specimens (48 pairs), escalation of mitoses or Ki-67 by ≥10-points was observed in 35% of metastatic samples; clonal relationship in one pair with marked proliferative progression was confirmed by next-generation sequencing. Notably, escalation of proliferation rate was documented in a subset of metastases arising from resected typical carcinoids, emphasizing that the diagnosis of typical carcinoid in primary tumor does not assure low proliferation rate at metastatic sites.In conclusion, stage IV lung carcinoids frequently exceed the standard proliferative criteria established for primary tumors, and commonly exhibit proliferative escalation at metastatic sites. Despite the overlap of proliferation rates, these tumors show fundamental morphologic, genomic and clinical differences from neuroendocrine carcinomas, and should be classified separately from those tumors. Awareness of the increased proliferative spectrum in metastatic carcinoids is critical for their accurate diagnosis. Further studies are warranted to explore the impact of proliferation indices on prognosis and therapeutic responses of patients with metastatic carcinoids.

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Juvenile myelomonocytic leukemia (JMML) is a rare pediatric hematologic malignancy (MDS/MPN disorder) with frequent skin manifestations (36%-48%), mostly as rashes. Very few of these rashes are biopsied, and even fewer are well characterized by immunophenotype. We report 1 such case in a 2-year-old boy with a 1-month history of nonresolving fever, fatigue, and pallor along with a generalized maculopapular skin rash. The child also had mild hepatomegaly. A CBC with differential revealed a hemoglobin value of 8.6 g/L, leukocytosis (WBC count, 55.3 × 10 9 /L), absolute monocytosis (27 × 10 9 /L), immature granulocytes, and a platelet count of 126 × 10 9 /L. The bone marrow aspirate showed a hypercellular marrow with trilineage hematopoiesis, 10% blasts (including promonocytes), increased monocytes (46%), and dysplastic changes in the erythroid and myeloid cell lines. These findings with the absence of a BCR-ABL1 fusion gene and a hemoglobin F level of 3.4% were consistent with the diagnosis of JMML, which was confirmed by subsequent positive GM-CSF hypersensitivity and NRAS mutation studies. A biopsy of the skin rash revealed a dermal infiltrate composed predominantly of mature monocytic cells that were positive for CD68, myeloperoxidase, and lysozyme and negative for CD117, CD1a, and S100. This atypical monocytic infiltrate in the dermis was thus consistent with JMML-associated skin involvement. Skin infiltration by actual leukemic cells, as in our case, can sometimes help in corroborating the diagnosis of JMML, particularly in the early stages when the results of the molecular tests are still pending. Our case thus highlights the potential of positive skin biopsies as a possible diagnostic aid in JMML cases with skin manifestations. One diagnostic pitfall, however, is its resemblance to the skin lesions of Langerhans cell histiocytosis, which can manifest similarly. Negative staining for CD1a and S100 in JMML should help in distinguishing between the 2 entities. Category:Hematopathology