Proliferating macrophages in human tumours show characteristics of monocytes responding to myelopoietic growth factors.

Macrophages play essential roles in maintaining tissue homeostasis and immune defence. However, their extensive infiltration into tumours has been linked to adverse outcomes in multiple human cancers. Within the tumour microenvironment (TME), tumour-associated macrophages (TAMs) promote tumour growth and metastasis, making them prime targets for cancer immunotherapy. Recent single-cell analysis suggest that proliferating TAMs accumulate in human cancers, yet their origins and differentiation pathways remain uncertain. Here, we show that a subpopulation of CD163+ TAMs proliferates in situ within the TME of melanoma, lung cancer, and breast cancer. Consistent with their potential role in suppressing anti-tumour activities of T cells, CD163+ TAMs express a range of potent immunosuppressive molecules, including PD-L1, PD-L2, IL-10, and TGF-ß. Other phenotypic markers strongly suggested that these cells originate from CD14+ CCR2+ monocytes, a cell population believed to have minimal capacity for proliferation. However, we demonstrate in vitro that certain myelopoietic cytokines commonly available within the TME induce robust proliferation of human monocytes, especially the combination of interleukin 3 (IL-3) and Macrophage Colony-Stimulating Factor 1 (M-CSF). Monocytic cells cultured with these cytokines efficiently modulate T cell proliferation, and their molecular phenotype recapitulates that of CD163+ TAMs. IL-3-driven proliferation of monocytic cells can be completely blocked by IL-4, associated with the induction of CDKN1A, alongside the upregulation of transcription factors linked to dendritic cell function, such as BATF3 and IRF4. Taken together, our work suggests several novel therapeutic routes to reducing immunosuppressive TAMs in human tumours, from blocking chemokine-mediated recruitment of monocytes to blocking their proliferation.

Appropriate use criteria for ancillary diagnostic testing in dermatopathology: New recommendations for 11 tests and 220 clinical scenarios from the American Society of Dermatopathology Appropriate Use Criteria Committee.

BACKGROUND: Appropriate use criteria (AUC) provide patient-centered physician guidance in test selection. An initial set of AUC was reported by the American Society of Dermatopathology (ASDP) in 2018. AUC reflect evidence collected at single timepoints and may be affected by evolving evidence and experience. The objective of this study was to update and expand AUC for selected tests. METHODS: RAND/UCLA (RAND Corporation [Santa Monica, CA]/University of California Los Angeles) methodology used includes the following: (a) literature review; (b) review of previously rated tests and previously employed clinical scenarios; (c) selection of previously rated tests for new ratings; (d) development of new clinical scenarios; (e) selection of additional tests; (f) three rating rounds with feedback and group discussion after rounds 1 and 2. RESULTS: For 220 clinical scenarios comprising lymphoproliferative (light chain clonality), melanocytic (comparative genomic hybridization, fluorescence in situ hybridization, reverse transcription polymerase chain reaction, telomerase reverse transcriptase promoter), vascular disorders (MYC), and inflammatory dermatoses (periodic acid-Schiff, Gömöri methenamine silver), consensus by panel raters was reached in 172 of 220 (78%) scenarios, with 103 of 148 (70%) rated "usually appropriate" or "rarely appropriate" and 45 of 148 (30%), "appropriateness uncertain." LIMITATIONS: The study design only measures appropriateness. Cost, availability, test comparison, and additional clinical considerations are not measured. The possibility that the findings of this study may be influenced by the inherent biases of the dermatopathologists involved in the study cannot be excluded. CONCLUSIONS: AUC are reported for selected diagnostic tests in clinical scenarios that occur in dermatopathology practice. Adhering to AUC may reduce inappropriate test utilization and improve healthcare delivery.

Utility of teledermatopathology for intraoperative margin assessment of melanoma in situ, lentigo maligna type: A 6 year community practice experience.

BACKGROUND: Achieving negative margins for melanoma in situ, lentigo maligna type can be challenging, particularly on cosmetically sensitive areas. OBJECTIVE: To assess the utility of intraoperative frozen section margin assessment using a teledermatopathology system in the treatment of head and neck lentigo maligna. METHODS AND MATERIALS: Over a 6 year period, 96 patients with lentigo maligna had surgical excisions. The margins were assessed intraoperatively with frozen sections prepared in the manner used in Mohs surgery. The surgeon guided the frozen section slides around the margin while a dermatopathologist assessed the margin remotely. RESULTS: In 2/96 (2.1%) cases, the safety margin was positive (frozen sections were false negative). In 1 further case (1%) there was a recurrence of the melanoma 13 months following the excision. CONCLUSION: The described method is effective in treating melanoma in situ, lentigo maligna type with clearance rates similar to previous studies for Mohs surgery.

TERT and TERT promoter in melanocytic neoplasms: Current concepts in pathogenesis, diagnosis, and prognosis.

BACKGROUND AND OBJECTIVE: Located on chromosome locus 5p15.33, telomerase reverse transcriptase (TERT or hTERT) encodes the catalytic subunit of telomerase which permits lengthening and preservation of telomeres following mitosis. Mutations in TERT promoter (TERT-p) upregulate expression of TERT, allowing survival of malignant cells and tumor progression in wide variety of malignancies including melanoma. The objective of this review is to examine the roles of TERT and TERT-p in the pathogenesis, diagnosis, and prognostication of cutaneous melanoma. METHODS: All studies of TERT or TERT-p in cutaneous melanocytic neoplasms with the following inclusion criteria were reviewed: publication date between 2010 and 2019, English language, and series of ≥3 cases were reviewed for evidence supporting the role of TERT in pathogenesis, diagnosis, and prognosis. Studies with <3 cases or focused primarily on mucosal or uveal melanocytic tumors were excluded. RESULTS AND CONCLUSION: TERT-p mutations are frequent in chronic and non-chronic sun damage melanoma and correlate with adverse prognosis, inform pathogenesis, and may provide diagnostic support. While TERT-p mutations are uncommon in acral melanoma, TERT copy number gains and gene amplification predict reduced survival. Among atypical spitzoid neoplasms, TERT-p mutations identify biologically aggressive tumors and support the diagnosis of spitzoid melanoma. TERT-p methylation may have prognostic value in pediatric conventional melanoma and drive tumorigenesis in melanoma arising within congenital nevi. Finally, TERT-p mutations may aid in the differentiation of recurrent nevi from recurrent melanoma.

Muir-Torre syndrome appropriate use criteria: Effect of patient age on appropriate use scores.

BACKGROUND: Muir-Torre syndrome (MTS) is a rare inherited syndrome, with an increased risk of sebaceous and visceral malignancy. Prior reports suggest screening for mismatch repair (MMR) deficiency may be warranted in patients <50 years and when sebaceous neoplasms are located on a non-head and neck location. Previously, appropriate use criteria (AUC) were developed for clinical scenarios in patients >60 years concerning the use of MMR protein immunohistochemistry (MMRP-IHC). This analysis explores the appropriateness of testing in patients ≤60 years. METHODS: Panel raters from the AUC Task Force rated the use of MMRP-IHC testing for MTS for previously rated scenarios with the only difference being age. RESULTS: Results verify the previously developed AUC for the use of MMRP-IHC in neoplasms associated with MTS in patients >60 years. Results also show that in patients ≤60 years with a single sebaceous tumor on a non-head and neck site, MMRP-IHC testing should be considered. Testing can also be considered with a 2-antibody panel on periocular sebaceous carcinoma in younger patients. CONCLUSIONS: Our findings align with known evidence supporting the need to incorporate clinical parameters in identifying patients at risk for MTS, with age being a factor when considering MMRP-IHC testing.

Appropriate use criteria in dermatopathology: Initial recommendations from the American Society of Dermatopathology.

BACKGROUND: Appropriate use criteria (AUC) provide physicians guidance in test selection, and can affect health care delivery, reimbursement policy, and physician decision-making. OBJECTIVES: The American Society of Dermatopathology, with input from the American Academy of Dermatology and the College of American Pathologists, sought to develop AUC in dermatopathology. METHODS: The RAND/UCLA appropriateness methodology, which combines evidence-based medicine, clinical experience, and expert judgment, was used to develop AUC in dermatopathology. RESULTS: With the number of ratings predetermined at 3, AUC were developed for 211 clinical scenarios involving 12 ancillary studies. Consensus was reached for 188 (89%) clinical scenarios, with 93 (44%) considered "usually appropriate" and 52 (25%) "rarely appropriate" and 43 (20%) having "uncertain appropriateness." LIMITATIONS: The methodology requires a focus on appropriateness without comparison between tests and irrespective of cost. CONCLUSIONS: The ultimate decision to order specific tests rests with the physician and is one where the expected benefit exceeds the negative consequences. This publication outlines the recommendations of appropriateness-the AUC for 12 tests used in dermatopathology. Importantly, these recommendations may change considering new evidence. Results deemed "uncertain appropriateness" and where consensus was not reached may benefit from further research.

Evidence behind the use of molecular tests in melanocytic lesions and practice patterns of these tests by dermatopathologists.

BACKGROUND: The gold standard for the diagnosis of melanocytic lesions is histologic examination. However, as histologic examination can have its limitations, there are many clinical scenarios in which additional testing may be appropriate in an attempt to render a definitive diagnosis. METHODS: A literature review for three ancillary tests-comparative genomic hybridization (CGH)/single-nucleotide polymorphism (SNP) array, fluorescence in situ hybridization (FISH), and gene expression profiling by quantitative reverse transcription polymerase chain reaction (qRT-PCR)-was compiled and current use patterns were tabulated. Survey of the practice patterns of these tests by dermatopathologists was also accessed in the attendees of the American Society of Dermatopathology Annual Meeting (Chicago, 2016). RESULTS: Here we summarize the use of these molecular tests in melanocytic lesions. We found that 54.4% of the respondents surveyed utilize (or expect consultants to utilize) molecular testing of melanocytic lesions in their practice when appropriate. CONCLUSIONS: CGH/SNP arrays, FISH testing, and qRT-PCR applied to melanocytic lesions have allowed for more accurate classification. Just over half of those surveyed use molecular testing for melanocytic lesion with the majority sending their cases out for completion of the molecular test.

Appropriate use criteria in dermatopathology: Initial recommendations from the American Society of Dermatopathology.

BACKGROUND: Appropriate use criteria (AUC) provide physicians guidance in test selection, and can affect health care delivery, reimbursement policy and physician decision-making. OBJECTIVES: The American Society of Dermatopathology, with input from the American Academy of Dermatology and the College of American Pathologists, sought to develop AUC in dermatopathology. METHODS: The RAND/UCLA appropriateness methodology, which combines evidence-based medicine, clinical experience and expert judgment, was used to develop AUC in dermatopathology. RESULTS: With the number of ratings predetermined at 3, AUC were developed for 211 clinical scenarios involving 12 ancillary studies. Consensus was reached for 188 (89%) clinical scenarios, with 93 (44%) considered "usually appropriate," 52 (25%) "rarely appropriate" and 43 (20%) "uncertain appropriateness." LIMITATIONS: The methodology requires a focus on appropriateness without comparison between tests and irrespective of cost. CONCLUSIONS: The ultimate decision of when to order specific test rests with the physician and is one where the expected benefit exceeds the negative consequences. This publication outlines the recommendations of appropriateness-AUC for 12 tests used in dermatopathology. Importantly, these recommendations may change considering new evidence. Results deemed "uncertain appropriateness" and where consensus was not reached may benefit from further research.

Multiple perineuriomatous melanocytic nevi.

Perineuriomatous differentiation in solitary cutaneous melanocytic nevi has been described. We present an unusual case of a patient with multiple such perineuriomatous nevi. This presentation raises the possibility that a germline mutation may be responsible for the pathogenesis of these unusual lesions.

Erosive Pustular Dermatosis of the Scalp with Urate-Like Crystals.

Follicular urate-like crystals were first described in Necrotizing Infundibular Crystalline Folliculitis (NICF), a rare cutaneous disorder with multiple waxy folliculocentric papules. Similar crystal accumulation may be seen within follicular infundibulae as an incidental finding. We describe a case showing identical crystals occurring within the horn-like crusts of a patient with erosive pustular dermatosis of the scalp (EPDS), a condition which due to its presentation can often be mistaken for nonmelanoma skin cancer. A brief overview of erosive pustular dermatosis of the scalp (EPDS) is presented in this paper.

Spindle Cell Lipomas in Women: A Report of 53 Cases.

Spindle cell lipomas (SCL) are typically tumors of the upper back/neck (shawl region) of men (80% to 90%). In general, there is a frequent tendency to restrict the diagnosis to this specific clinical scenario and a hesitancy to diagnose SCL in women. We hypothesized that SCL in women have a more varied presentation. A total of 395 SCL were diagnosed at our institution over the last 11 years. The diagnosis of SCL in women was confirmed by re-review. Immunohistochemical stains for CD34, desmin, estrogen receptor, and p16 were performed. In a subset, fluorescence in situ hybridization to detect Retinoblastoma1 (RB1) gene deletion was performed. Of 395 SCLs, 331 (86%) occurred in men; 53 (14%) occurred in women (11 cases excluded). Of the 64 SCL in women, 58 had available material. In total, 53 of 58 were confirmed as SCL. Women were younger at diagnosis (median, 51 y; range, 5 to 76 y) compared with men (64 y; range, 23 to 98 y), P<0.0001, t test. SCL in women typically occurred outside the shawl distribution (36/53, 68%) compared with men (95/331, 29%) (P<0.001), including extremities (16/53, 30% vs. 32/331, 10%) and face (11/53, 21% vs. 47/331, 14%). Dermal SCL in women were also relatively common (16/53, 30%). The cases demonstrated varying proportions of bland spindled cells, ropey collagen, myxoid matrix, and adipocytes. By immunohistochemistry, 46/46 were CD34, 48 of 48 were desmin negative, 33 of 42 were estrogen receptor negative, and 29 of 42 had loss of p16 expression. In total, 12 of 14 showed RB1 loss by fluorescence in situ hybridization. SCL in women frequently occurs in unconventional locations and in at a slightly younger patient age.

Squamous cell carcinoma with enteric adenocarcinomatous differentiation.

We report a highly unusual case of a primary cutaneous squamous cell carcinoma (SCC) with intermixed enteric-type adenocarcinomatous dedifferentiation and a small component of undifferentiated mesenchymal differentiation. We believe this is the first time this form of phenotypic plasticity has been described in cutaneous SCC.

Polymorphous sweat gland carcinoma: a report of two cases.

Polymorphous sweat gland carcinoma (PSGC) is a rare adnexal neoplasm with characteristic variegated histopathologic findings and low-grade clinical behavior. First described in 1994, only 11 cases have been reported in the literature. It is named for the multiplicity of architectural patterns that may be present: solid, tubular, trabecular, pseudopapillary and cylindromatous. Owing to the multiple architectural patterns, the differential diagnosis is broad, including metastatic adenocarcinoma and other adnexal neoplasms with ductular differentiation. We present two new cases of PSGC and review the literature on this rare tumor.

Predicting lymph node metastases in cutaneous squamous cell carcinoma: use of a morphological scoring system.

BACKGROUND: Predicting which patients will develop nodal metastasis from cutaneous squamous cell carcinoma (cSCC) remains difficult. This study evaluates a recently described histological risk model validated for mucosal head and neck SCC (HNSCC) when applied to cutaneous tumours. In this model, morphologic variables including worst pattern of invasion, lymphocytic host response and perineural invasion were shown to predict disease recurrence, loco regional recurrence and overall survival in mucosal HNSCC. METHODS: Patients with cSCC and known metastatic spread were identified from the author's database over a 5-year period between July 2007 and July 2012. Histology specimens from the original primary tumour were separately analysed by 2 histopathologists. Scores were compared against T-Stage matched control specimens without metastatic spread. RESULTS: 27 patients with metastatic cSCC were identified. Scores for worst pattern of invasion (WPOI) were significantly higher in individuals with lymph node metastases (p=0.02). CONCLUSIONS: Adverse pattern of invasion, defined as presence of small tumour islands or tumour satellites may be an independent risk factor for developing nodal metastases in cSCC. These tumours are difficult to investigate histopathologically as it is difficult to be confident the correct primary is chosen for study.

Periocular intralymphatic histiocytosis or localized Melkersson-Rosenthal syndrome?

We describe three cases of periocular edema with histopathologic features of intralymphatic histiocytosis without extravascular granulomas. All were elderly males with no other significant medical problems. Previous reports of periocular Melkersson-Rosenthal syndrome are identical clinically, and some reports show illustrations of intralymphatic histiocytosis histopathologically, in addition to other features typical of the syndrome. Given the lack of associated diseases or other features of the Melkersson-Rosenthal triad, some of these cases may be better defined as periocular intralymphatic histiocytosis.

Differentiation between malignant melanoma and Spitz tumour has improved over the past decade due to modern pathological techniques.

A 10-year-old boy was diagnosed with a thick neurotropic melanoma of the lip in 2002. He is alive and well without evidence of disease recurrence 10 years later. We applied modern pathologic techniques to this lesion to highlight recent advances in melanoma diagnostics.

Evaluation of the prognostic significance of follicular extension in actinic keratoses.

OBJECTIVE: To determine the prognostic significance of follicular extension in actinic keratosis. DESIGN: Retrospective, case-controlled study. SETTING: Mount Sinai Dermatopathology Services. PATIENTS/PARTICIPANTS: Out of a randomly selected pool of 1,000 biopsies, 104 cases of actinic keratosis with follicular extension and 104 cases of actinic keratosis without follicular extension were chosen for the study (56.7% male; mean [SD] age, 67.5 [11.8] years; age range, 28-93). MAIN OUTCOME MEASURES: Presence of follicular extension and location of the actinic keratosis. Age and gender of the patient. Number of previously diagnosed squamous cell carcinomas, basal cell carcinomas, and melanomas per patient. RESULTS: Patients with follicular extension of actinic keratosis were 1.8 times more likely to have a previous history of invasive carcinoma than patients without follicular extension. Patients with follicular extension were 11 times more likely to have a previous history of invasive melanoma than patients with actinic keratoses without follicular extension. Patients with follicular extension were more likely to be male, had an older average age, and more often presented with lesions on their leg when compared to patients with actinic keratoses lacking follicular extension. CONCLUSION: Patients presenting with actinic keratoses with follicular extension were more likely to have increased risk factors for skin cancer. These findings have implications for identifying patient factors predictive of progression of actinic keratosis to invasive carcinoma, providing potentially valuable patient screening guidelines.