Sunitinib is a receptor tyrosine kinase inhibitor (TKI) that is front-line therapy for metastatic renal cell carcinoma (mRCC). Its antitumor activity is related to its ability to block tumor cell and ...tumor vasculature cell signaling via several TKI receptors (i.e. vascular endothelial growth factor receptors VEGFRs, platelet-derived growth factors (PDGFs), and stem cell factors). Sunitinib also targets myeloid derived suppressor cells (MDSCs) significantly reducing their accumulation in the peripheral blood and reversing T cell (IFNγ) suppression in both mRCC patients and in murine tumor models. This reduction in immune suppression provides a rationale for combining sunitinib with immunotherapy for the treatment of certain tumor types. Despite these encouraging findings, however, we have observed that sunitinib has variable impact at reducing MDSCs and restoring T cell function within the tumor microenvironment. Given the immunosuppressive and proangiogenic activities of MDSC, it seems plausible that their persistence may contribute to the resistance that develops in sunitinib-treated patients. While sunitinib reduced tumor infiltrating MDSCs in Renca and CT26-bearing mice, coinciding with strong to modest decreases in tumor size respectively, it was ineffective at reducing MDSCs (<35% reduction in Gr1+CD11b+) or tumor burden in 4T1-bearing mice. Persistence of intratumor MDSCs was paralleled by depressed intratumor T cell IFNγ response and increased GM-CSF expression. Additionally, in vitro and in vivo experiments showed that GM-CSF prolongs survival of MDSCs, thus protecting them from the effects of sunitinib via a pSTAT5-dependent pathway. Although preliminary, there is evidence of intratumor MDSC resistance in some mRCC patients following sunitinib treatment. Intratumor MDSC persistence and T cell IFNγ response post nephrectomy in patients receiving sunitinib in a neoadjuvant setting are being compared to RCC patients undergoing nephrectomy without prior sunitinib treatment. Tumors from untreated patients showed suppressed T cell IFNγ response along with substantial expression of MDSCs (5% of total digested cells). Thus far, tumors from 5/8 neoadjuvant patients showed persistence of intratumor MDSCs and low T cell IFNγ production post sunitinib treatment, findings that parallel results from untreated tumors. In the remaining 3 neoadjuvant patients, intratumor MDSCs were detected at low levels which coincided with a T cell IFNγ response similar to that observed with normal donor peripheral T cells. GM-CSF's role in promoting MDSC survival in patient tumors is supported by the observation that GM-CSF is produced in short-term RCC cultures at levels capable of protecting MDSCs from sunitinib-induced cell death. Additionally, persistence of MDSC also may be associated with increased expression of proangiogenic proteins, such as MMP9, MMP8, and IL-8 produced by tumor stromal cells or infiltrating MDSCs. Indeed our findings suggest that the most dominate MDSC subset in RCC patients is the neutrophilic population that produces proangiogenic proteins. We propose that the development of sunitinib resistance is partly mediated by the survival of MDSCs intratumorally, thereby providing sustained immune suppression and angiogenesis.
Gene rearrangements involving the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase gene have been identified in various neoplasms, including inflammatory myofibroblastic tumor and ...epithelioid fibrous histiocytoma. We present an ALK-rearranged cutaneous soft tissue tumor with unique morphologic and immunophenotypic features that are not shared by other entities with ALK rearrangements. The six cases involved two females and four males, aged 18–84 (mean 51) years old. Three tumors were on the back and three on the lower extremities (thigh, knee, shin); ranging from 0.5 to 5.6 (mean 2.1) cm. Four were confined to the dermis; two involved the subcutis. All six cases were characterized by the presence of spindled to ovoid cells arranged in concentric whorls and cords against a myxoid to myxohyaline stroma and relatively cellular aggregates of plump ovoid to epithelioid cells. Four cases showed distinct hyalinized blood vessels. Both cases that involved the subcutis showed peripheral lipofibromatosis-like areas. Tumor-infiltrating lymphocytes were absent to moderate. Severe cytologic atypia or conspicuous mitotic activity was not identified. Immunohistochemically, all tumors diffusely expressed ALK (D5F3) and CD34. All but one tumor was diffusely positive for S100 protein. All tumors were negative for EMA, AE1/AE3, SMA, and SOX10. Next-generation sequencing revealed ALK fusions with FLNA (3 cases), MYH10 (2 cases), and HMBOX1 (1 case) as the partner genes. In all six cases, the breakpoints involved exon 20 of ALK, which preserves the receptor tyrosine kinase domains of ALK in the fusion product. Of the four cases with limited follow-up information (2–18 months), none recurred. In conclusion, we report an ALK-rearranged cutaneous soft tissue tumor characterized by the presence of myxoid spindle cell whorls and cords, and co-expression of ALK, CD34, and frequently S100 protein, we term “superficial ALK-rearranged myxoid spindle cell neoplasm”.
We recently described novel dermal tumors with melanocytic differentiation and morphologic and biological similarities to cutaneous clear cell sarcoma, including CRTC1::TRIM11 cutaneous tumor, and ...clear cell tumors with melanocytic differentiation and either ACTIN::MITF or MITF::CREM. Here, we describe a series of 3 patients presenting with tumors reminiscent of CRTC1::TRIM11 cutaneous tumor, found to demonstrate a novel MED15::ATF1 fusion. All 3 patients were children (5-16 years old). Primary excision of case 1 showed a circumscribed wedge-shaped silhouette with peripheral intercalation into collagen fibers and scattered lymphoid aggregates. All 3 tumors abutted the epidermis; one showed a junctional component. Tumors were highly cellular and comprised of monomorphic, oval-to-round epithelioid cells arranged in vague nests and short fascicles in variably fibrotic stroma. Mitotic rate was high (hotspot 6-12/mm2), without atypical mitoses. Necrosis was focally present in case 3. All cases showed strong, diffuse nuclear staining for SOX10 and MITF (2/2) but showed variable expression for S100 protein (1/3) and other melanocytic markers—Melan-A (focal in 2/3), HMB45 (focal in 1/3), and Pan-Melanoma (patchy in 1/1). Whole-exome RNA sequencing demonstrated a MED15::ATF1 fusion without any other notable alterations. Cases 1 and 2 were completely excised without recurrence (12 months). Case 3 developed a grossly apparent regional lymph node spread shortly after primary biopsy. The patient was treated with wide excision, radiation, cervical lymph node dissection (4/46 with >75% lymph node replacement), and neoadjuvant and adjuvant nivolumab (alive without disease at cycle 11). This series is presented to aid in future diagnosis of this novel dermal tumor with melanocytic differentiation and emphasize the potential for aggressive biologic behavior, which should be considered in patient management planning.
Background
Screening borderline Spitz tumors with p16 immunohistochemistry (IHC) has known utility. The applicability to other melanocytic neoplasms is not well defined.
Methods
Cases (N = 104) of ...blue, cellular blue, epithelioid blue, congenital pattern, deep penetrating, desmoplastic, desmoplastic Spitz, acral, “epithelioid” nevi, nevoid melanoma, melanoma with a precursor nevus, and non‐nevoid melanoma with Breslow thickness > 0.5 mm were stained for p16.
Results
Lesions showed either a single uniform pattern of expression (single/homogeneous pattern: positive, checkerboard, rare, or lost) or multiple regionally distributed patterns (multiple/heterogeneous pattern). Most cases (78%, n = 81) showed single pattern expression. Within single pattern cases, total loss was restricted to melanoma (7/81/9%). Multiple patterns were more common in melanoma (12/23, 52%). Within multiple pattern (22%, n = 23) lesions, those with a total loss component (7/23; 30%) were malignant. Total p16 loss (diffuse or regional) was not seen in a subset of nevoid melanomas (1/8; 12.5%), melanomas arising in nevi (2/6; 33%), and non‐nevoid melanomas (6/9; 66%). Total p16 loss (single pattern or part of multiple patterns) captured 61% (14/23) of melanomas and no nevi.
Conclusion
p16 IHC may be useful in dermal‐based melanocytic lesions. Total p16 loss is seen only in melanoma. Multiple pattern expression should prompt careful evaluation.
Cutaneous melanocytic tumor with CRTC1::TRIM11 fusion (CMTCT) is a recently described dermally based neoplasm with melanocytic differentiation. It can easily be confused with clear cell sarcoma and ...metastatic melanoma. Our understanding of this lesion, including its potential for aggressive disease, has been limited by the small number of previously reported cases (13) and the limited clinical follow-up data. Here, we report a series of 41 CMTCT confirmed by molecular studies. We find that the lesion shows highly uniform and reproducible morphologic, immunohistochemical, and genetic features across a wide variety of anatomic locations and age groups. Among 22 cases with follow-up, 1 local recurrence and 1 nodal metastasis were identified. Our data support the classification of CMTCT as a unique nosologic entity and emphasize the importance of distinguishing this entity from its histologic mimics, especially clear cell sarcoma and metastatic melanoma, to guide therapy and establish accurate prognostic expectations.
Cutaneous myxoma (CM) is an uncommon benign neoplasm of skin, which may be sporadic or arise in association with syndromes such as Carney complex. There has been only one large case series describing ...CM. We report 54 additional cases of CM; patients had a mean age of 55 years (range = 7–91), with a female-to-male ratio of 1.3. Most occurred on the trunk (n = 19), with the back being the most common site. The remainder presented on the lower extremity (n = 18), head and neck (n = 10), and arm (n = 7). Histopathologically, they were relatively circumscribed, nodular, and centered in the dermis. All had abundant myxoid stroma, a thin, arborizing vascular network, and spindled to stellate cells with no to mild atypia without mitotic activity. Follicular induction, stromal neutrophils, and intranuclear inclusions were present in 35%, 25%, and 61% of cases, respectively. Collagen trapping, splitting of collagen fibers, and encircling of hair follicles or eccrine glands were encountered in a subset. Thirty-nine cases were treated with shave excision, whereas 12 cases underwent wide local excision. Follow-up data were available for 28 of 54 cases (mean = 50 months). Only one case recurred at 36 months. This study suggests CM has a lower risk of local recurrence than previously reported.
•Cutaneous myxoma is a benign myxoid neoplasm of skin•This is the largest clinicopathologic study of cutaneous myxoma till date.•We compared the clinicopathologic features of the cases in our series with the features described in the previous studies and also with a pooled data group of case reports of cutaneous myxoma between 1996-2020.•This study revealed a lower local recurrence rate in cutaneous myxoma compared to previous studies.
A cutaneous melanocytic tumor with morphologic overlap with clear cell sarcoma, but defined by CRTC1‐TRIM11 gene fusion, was recently described in a series of five adult patients. Here, we expand the ...clinicopathologic features of this entity by four additional cases which include pediatric presentation, exophytic growth, and propensity to occur on the head. Patients (2F; 2M) had a median age of 41 years (range 11‐59). Sites of involvement included leg, ear, and face. Tumors were circumscribed, unencapsulated, mostly limited to the dermis, and varied from 5 to 35 mm. One case was exophytic. Lesional cells were arranged in nests and fascicles, and were monomorphic and fusiform with moderate pale to clear cytoplasm, occasional nuclear pseudo‐inclusions, and small to prominent nucleoli. Mitotic rate was variable (rare to 12/10 HPF, median 3/10 HPF). The pediatric case showed increased nuclear pleomorphism, tumor necrosis, and mitotic figures. All cases showed strong, diffuse nuclear staining for SOX10, but were negative or focal for S100 protein, HMB45 and Melan‐A expression. Cases were positive by FISH technique and/or RNA sequencing for a TRIM11 rearrangement/fusion, and negative for EWSR1 rearrangement. This series is presented to aid in further characterization of this novel melanocytic tumor.
Abstract
Objective
The objective of this prospective study is to compare the prevalence and severity of nausea and vomiting in the first trimester between singleton pregnancies conceived from ...stimulated in vitro fertilization (IVF) and frozen embryo transfer cycles (FET).
Methods
All women were recruited at 6 weeks gestation and filled in the modified Pregnancy-Unique Quantification of Emesis and Nausea (PUQE) to document whether they had any experience of nausea and vomiting weekly till 12 weeks gestation. The primary outcome was the prevalence of nausea and vomiting and the secondary outcomes included severity of nausea and vomiting and pregnancy outcomes.
Results
A total of 360 pregnant women were recruited and 171 were in the stimulated IVF group and 189 in the FET group. The overall return rate was 82.2% (81.8% in the stimulated IVF group and 82.5% in the FET group). Nausea and vomiting were worse in the FET group compared with the IVF group. There were significantly more women who felt nauseated or sick in the FET group (p value = 0.032 for week 11 and p value = 0.046 for week 12); significantly more women with a longer duration of nausea in the FET group (p value = 0.044 for week 7 and p value = 0.030 for week 8); significantly more women with more vomiting in a day in the FET group (p value = 0.042) and significantly more women with retching or dry heaves in the FET group (p value = 0.030 for week 8 and p value = 0.028 for week 11).
Conclusion
Nausea and vomiting were significantly more prevalent and severe in the FET group when compared with the stimulated IVF group.
IntroductionLow vitamin D status is prevalent among women with polycystic ovary syndrome (PCOS). The objective of the study is to assess the effect of vitamin D supplementation on (1) the ovulation ...rate to letrozole and (2) other reproductive, endocrine and metabolic outcomes after 1 year of supplementation in women with PCOS.Methods and analysisThis is a multicentre, randomised, double-blind, controlled clinical trial. A total of 220 anovulatory women with PCOS diagnosed by the Rotterdam criteria will be recruited. They will be randomly assigned to either the (1) vitamin D supplementation group or (2) placebo group. Those in the vitamin D group will take oral Vitamin D3 50 000 IU/week for 4 weeks, followed by 50 000 IU once every 2 weeks for 52 weeks. Those who remain anovulatory after 6 months will be treated with a 6-month course of letrozole (2.5 mg to 7.5 mg for 5 days per cycle titrated according to response) for ovulation induction. The primary outcome is the ovulation rate. All statistical analyses will be performed using intention-to-treat and per protocol analyses.Ethics and disseminationEthics approval was sought from the Institutional Review Board of the participating units. All participants will provide written informed consent before joining the study. The results of the study will be submitted to scientific conferences and peer-reviewed journals.Trial registration number NCT04650880.
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