Desmoplastic Melanoma Research Articles

1355P - Tumour mutational burden and response to PD-1 inhibitors: An analysis of 89 cases of metastatic melanoma

BackgroundThe era of immunotherapy changed considerably prognosis of melanoma. Nonetheless, only around 40% can get benefit from this treatment, with no biomarkers identified for the therapeutic choice. On the basis of emerging clinical evidence, increased Tumor Mutational Burden (TMB) may be associated with higher sensitivity to immunotherapeutic agents. MethodsThe aim of this study was to analyze in advanced melanoma the relationship between the mutation load and: i) the histologic characteristics, ii) locations according to sun exposure and iii) response to PD-1 inhibitors, in advanced melanoma patients, in a retrospective multicentric analysis by sequencing using FoundationOne®. TMB was characterized as the number of somatic protein-coding base substitution or alterations mutations per megabase (Mb). DNA was extracted from paraffin embedded sections of primary tumor or metastasis. TMB was considered low between 1 and 5 muts/Mb, intermediate between 6 and 19, high if>20 muts/Mb. ResultsIn five centers in France, we included between October 2017 and March 2019 101 patients, aged from 16-year to 92-year-old, with metastatic melanomas. Results were available for 89 cases (12% DNA extraction failure). Acral (n=6, 20%), mucosal (n=5, 17%) and uveal melanoma (n=4, 13%) had a lower TMB compared to sun-exposed melanomas. No melanoma of non-sun-exposed areas had high burden (n=0); intermediate TMB was found in 21% (n=8) and low TMB in 63% of cases (n=19). Conversely, melanoma on chronic exposed areas (face and neck) had high TMB (5/7 cases; 71%). Complete and partial remission after 3 months of anti-PD-1 were more often observed in TMB high patients (n=4;20%) whereas in low and intermediate mutational patients, progression was found in respectively 62% (n=24) and 53% (n=16). ConclusionsTMB is affected by a variety of causes, including ultraviolet light in melanoma and smoking in lung cancer. Desmoplastic melanomas have been reported to have a high prevalence of somatic mutations whereas mucosal and acral have a 5-to 10-fold lower. Our study highlights the importance of TMB with higher response to PD-1 blockade. While it has to be confirmed, sun exposed areas or UV-signature may in be a valuable criterion in helping clinical decision-making. Editorial acknowledgementFoundation One Medicine and Roche Laboratories. Legal entity responsible for the studyFrench hospitals. FundingHas not received any funding. DisclosureC. Allayous: Travel / Accommodation / Expenses: BMS; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Amgen. All other authors have declared no conflicts of interest.

Endoscopic transpterygoid approach for resection of trigeminal neurotropic melanoma: Case report and technical note

BackgroundThe endoscopic transpterygoid approach to Meckel's cave is an established technique for resection of trigeminal schwannomas. Modern endoscopes provide excellent intraoperative visualization of anatomic structures and relevant pathology while the minimally-invasive nature of the procedure allows for rapid postoperative recovery. Neurotropic melanoma is a rare clinical entity that often involves the head and neck and can lead to cranial neuropathies when nerve invasion occurs. Pathological diagnosis of this lesion can be challenging due to its rarity and lack of classic melanoma markers such as Melan-A and HMB-45. Case descriptionIn this article, the authors describe the endoscopic transpterygoid approach to a neurotropic melanoma involving the maxillary and infraorbital nerves. To our knowledge, this is the first use of this surgical approach for resection of neurotropic melanoma. ConclusionsEndoscopic approaches to the trigeminal nerve allow for safe and effective resection of these lesions. However, a strong understanding of the microsurgical anatomy is necessary prior to such an undertaking.

Clinical and pathological features of pure and mixed desmoplastic melanomas

Clinical and pathological features of pure and mixed desmoplastic melanomas

Comparing survival outcomes in early stage desmoplastic melanoma with or without adjuvant radiation.

Desmoplastic melanoma (DM) due to its rare and locally aggressive nature, can be difficult to study and to treat effectively. Whether the optimal treatment approach for these tumors should include adjuvant radiation has been unclear in the literature. In this retrospective study of the National Cancer Database, 2390 patients with localized DM were included for analysis. 2082 were treated with wide local excision (WLE) and 308 were treated with wide local excision and adjuvant radiation therapy (WLE + RT). Overall survival (OS) in these groups was compared on crude and adjusted analyses utilizing Cox proportional hazards regression modeling. There was no difference in OS at 1, 3, and 5 years on initial analysis. Subsequent multivariate analysis and propensity score analysis showed a survival benefit in those treated with WLE + RT. Multivariate analysis demonstrated significantly decreased OS in cases of residual tumor following surgical excision. Adjuvant radiation was more likely to be performed for tumors on the head and neck, tumors with higher pathologic American Joint Committee on Cancer stage and T classifications, and tumors with positive surgical margins. This is the first study to demonstrate significantly improved OS in early-stage DM patients treated with WLE + RT compared to WLE alone.

Melanoma In Situ, Treated With Mohs Surgery, Upstaged to a Desmoplastic Melanoma

Melanoma In Situ, Treated With Mohs Surgery, Upstaged to a Desmoplastic Melanoma

Desmoplastic Melanoma: Clinical Characteristics and Survival in the US Population.

ObjectiveDesmoplastic melanoma (DM) is a rare variant of invasive malignancy of the skin pigmented cells. We present a comprehensive study reporting on US demographics, disease characteristics, and survival, to contribute to the current knowledge and raise awareness of this rare disease.Materials and methodsThe demographics of DM patients diagnosed from January 1, 2004, to December 31, 2015, were obtained by querying the National Cancer Database. The characteristics of DM were compared with common malignant melanoma (CMM) using univariate and multivariate regression models. Five-year overall survival (OS) curves were estimated using Kaplan-Meier analyses and the Cox proportional regression model.ResultsOur query found 5,895 patients diagnosed with DM and 292,939 patients with CMM. DM tended to present at an older age, a more advanced stage, and with a Breslow depth greater than 4 mm at diagnosis (P<.05). The Kaplan-Meier survival analysis demonstrated a five-year OS for DM and CMM of 75% and 76%, respectively, without any statistical difference (P=.07). Cox regression analysis demonstrated that age at diagnosis and comorbidities were independent predictors of five-year OS for DM (P<.001).ConclusionsOlder age, advanced stage, and higher Breslow depth were found to be independent positive factors associated with DM.

Amelanotic melanoma.

Cutaneous amelanotic melanoma (AM) is a rare amelanotic or a hypomelanotic subtype of melanoma, comprising only 0.4-27.5% of all melanoma cases. The mean age of the patients is over 50 years, and the male/female ratio varies from 0.5 to 4. Patients with red hair, type I skin, freckles, lack of nevi on the back, a sun-sensitive phenotype, or previous AM history are more likely to develop AMs. As AMs lack pigmentation, their appearances vary and can mimic many benign and malignant conditions, thus presenting a diagnostic challenge. AMs are composed of greater proportions of nodular melanoma, acral lentiginous melanoma, and desmoplastic melanoma than pigmented melanomas. They also present with thicker Breslow thickness, higher mitotic rate, more frequent ulceration, higher tumor stage, and lower survival than pigmented melanomas.

Gamma Knife Radiosurgery and Immunotherapy as Primary Treatment for a Malignant Tumor of the Cranial Base Beginning as Lentigo Maligna: A Case Report

Metastatic spread of facial melanoma to cranial nerves causing neuropathy was described as early as 1989. 1 Jain S. Allen P.W. Desmoplastic malignant melanoma and its variants. A study of 45 cases. Am J Surg Pathol. 1989; 13: 358-373 Crossref PubMed Scopus (203) Google Scholar The trigeminal nerve is involved in several reported cases. 1 Jain S. Allen P.W. Desmoplastic malignant melanoma and its variants. A study of 45 cases. Am J Surg Pathol. 1989; 13: 358-373 Crossref PubMed Scopus (203) Google Scholar , 2 Kano H. Niranjan A. Novotny Jr., J. Bhatnagar J. Flickinger J.C. Lunsford L.D. Radiosurgery for desmoplastic melanoma of the head and neck using the Leksell Gamma Knife Perfexion technology: A case report. Stereotact Funct Neurosurg. 2009; 87: 61-65 Crossref PubMed Scopus (3) Google Scholar , 3 Majoie C.B. Hulsmans F.J. Castelijns J.A. Walter A. Bras J. Peeters F.L. Perineural tumor extension of facial malignant melanoma: CT and MRI. J Comput Assist Tomogr. 1993; 17: 973-975 Crossref PubMed Scopus (17) Google Scholar , 4 Peterson H.E. Larson E.W. Fairbanks R.K. et al. Gamma knife radiosurgery treatment for metastatic melanoma of the trigeminal nerve and brainstem: A case report and a review of the literature. Case Rep Neurol Med. 2013; 2013: 256962 PubMed Google Scholar , 5 Tritschler P. Rezazadeh Azar A. De Coene B. Maraite N. Michotte A. Trigeminal melanoma metastasis. Clin Neuroradiol. 2014; 24: 51-54 Crossref PubMed Scopus (5) Google Scholar , 6 Walters H. Lewis E. Wolper R. Yachnis A.T. Green J. Lewis S. Neurotropic melanoma of the trigeminal nerve: A case of atypical facial pain. J Oral Maxillofac Surg. 2008; 66: 547-550 Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar Presenting signs and symptoms may include hypoesthesia, paresthesia, and facial pain. Common magnetic resonance imaging (MRI) findings include abnormal nerve enlargement, masseter denervation atrophy, and enhancement within Meckel's cave. 7 Majoie C.B. Hulsmans F.J. Verbeeten Jr., B. et al. Trigeminal neuralgia: Comparison of two MR imaging techniques in the demonstration of neurovascular contact. Radiology. 1997; 204: 455-460 Crossref PubMed Scopus (79) Google Scholar , 8 Majoie C.B. Hulsmans F.J. Verbeeten Jr., B. et al. Perineural tumor extension along the trigeminal nerve: Magnetic resonance imaging findings. Eur J Radiol. 1997; 24: 191-205 Abstract Full Text PDF PubMed Scopus (40) Google Scholar It is difficult to diagnose metastatic disease without histologic confirmation, but metastases should be highly considered in a patient presenting with a cranial neuropathy, history of a facial lesion, and remarkable image findings.

Desmoplastic melanoma: Demographic and clinicopathological features and disease-specific prognostic factors.

Desmoplastic melanoma (DM) is a rare morphological subtype of melanoma that remains uncharacterized. The aim of the present study was to investigate the incidence of DM, its general demographics, clinicopathological features and disease-specific prognostic factors. DM cases were sampled from the Surveillance, Epidemiology and End Results (SEER) program from between 1973 and 2017. A total of 3,657 cases (median age, 68 years) were identified. The results indicated that DM primarily occurred in Caucasian subjects, with a male-to-female ratio of 2:1. Statistically significant overall survival (OS) and disease-specific survival (DSS) rate differences were identified according to sex, age, treatment, T stage, N stage and SEER historic tumor stage (P<0.05). In multivariate Cox regression analysis, age >68 years, male sex, American Joint Committee on Cancer (AJCC) stage II and III, and SEER historic tumor stage of the regional tumor were all factors associated with poorer OS and DSS rates. The findings also revealed that surgical treatment was associated with favorable DSS and OS rates. In conclusion, DM occurred primarily in Caucasian subjects of 60–80 years of age, with predominance in males. Furthermore, age, sex, AJCC stage, SEER historic tumor stage and surgical treatment were identified as independent prognostic factors of DM in terms of DSS and OS.

Accuracy of partial biopsies in the management of cutaneous melanoma.

The recommended method for histopathological diagnosis of cutaneous melanoma is excisional biopsy, although partial biopsies (shave and punch) are often used. Following a partial biopsy, treatment guidelines recommend a narrow excisional biopsy to plan definitive management. There is limited evidence on the benefits of direct wide local excision (WLE) following diagnostic partial biopsies. Retrospective cohort study of cutaneous melanoma cases, from two tertiary referral centres from January 2013 to December 2015. Demographic and histopathological data, including tumour thickness (T-stage) from initial biopsy and subsequent excisions, were collected. Logistic regression was used to examine histopathological T-staging between biopsy and subsequent excisions (upstaging). 2304 melanomas (2157 patients) were identified; 455 shave, 308 punch, 14 incisional and 1527 excisional biopsies. Out of 1527, 5 (<1%) excisional biopsies were upstaged from original biopsy T-stage to final WLE; compared to 28/455 (6%) for shave, 45/308 (15%) for punch and 2/14 (14%) for incisional biopsies. Histopathology upstaging were increased with punch (OR, 52.1; 95% CI, 20.5-132.4. P<0.001) and shave biopsy (OR, 20.0; 95% CI, 7.7-52.0. P<0.001) compared to excisional biopsy. Upstaging rates of 9.4% for desmoplastic (OR, 6.9; 95% CI, 2.4-19.7. P<0.001) and 21.9% for acral lentiginous (OR, 18.4; 95% CI, 6.9-49.2. P<0.001) melanomas were elevated compared to 1.4% for superficial spreading melanoma. In most cases, partial biopsy (particularly shave biopsy) can provide sufficient information to plan for definitive surgical melanoma management. Punch and incisional biopsies have elevated upstaging rates, a consideration in planning therapy. Partial biopsies of desmoplastic or acral lentiginous melanomas have high rates of upstaging and should have a complete excision prior to definitive treatment.

Diagnostic utility of dual 5-hydroxymethylcytosine/Melan-A immunohistochemistry in differentiating nodal nevus from metastatic melanoma: An effective first-line test for the workup of sentinel lymph node specimen.

Distinguishing benign nodal nevus from metastatic melanoma can be diagnostically challenging, with important clinical consequences. Recently, the loss of epigenetic marker, 5-hydroxymethylcytosine (5-hmC) expression by immunohistochemistry has been found in melanomas and atypical melanocytic neoplasms. About 41 metastatic melanomas and 20 nodal nevi were retrieved. Nuclear 5-hmC (brown) and cytoplasmic Melan-A Red (red) double immunohistochemical staining was performed. Total or partial loss of nuclear expression of 5-hmC was noted in 40/41 metastatic melanomas; these tumor cells were strongly positive for Melan-A Red, except in one case of desmoplastic melanoma. All cases of nodal nevus showed uniformly retained nuclear expression of 5-hmC accompanied by strong Melan-A Red cytoplasmic staining. In two cases containing both nodal nevus and metastatic melanoma, all tumor cells were positive for Melan-A Red, but a nuclear expression of 5-hmC was selectively absent only in the melanoma tumor cells. Dual 5-hmC/Melan-A Red immunohistochemistry is highly specific in distinguishing nodal nevus from metastatic melanoma. Our protocol for brown and red chromogens used in this study provides excellent color contrast and is easy to interpret. Furthermore, this dual staining method allows the preservation of limited tumor tissue, which could be used for potential molecular studies.

Normal Expression of SRY-related HMG-BOX Gene 10 (SOX-10) in Recent and Old Cutaneous Scars is a Potential Mimicker of Desmoplastic Malignant Melanoma.

Desmoplastic malignant melanoma (DMM) is an amelanotic spindle cell proliferation that can be mistaken for a cutaneous scar. The distinction can be difficult in reexcisions because DMM is negative for conventional melanoma markers such as HMB-45 and Melan-A, and scars may be positive for S-100 protein and SOX-10. We compare a total of 12 DMM cases with 8 reexcision and 35 old non-reexcision cutaneous scars using SOX-10 immunohistochemical stains. Cell quantification was performed on captured images using ImageJ 1.51t. SOX-10 was expressed in DMM (100%, 12/12), and reexcision (75%, 6/8), atrophic (88%, 22/25), hypertrophic (100%, 8/8), and keloid-type (100%, 2/2) scars. The cellular density of SOX-10 positive cells in DMM (822.9±116.9 cells/mm, mean±SEM) was significantly higher than in any scar subgroup (hypertrophic: 188.4±20.40 cells/mm, atrophic: 83.78±11.13 cells/mm, reexcision: 96.72±30.13 cells/mm, P<0.0001). Hypercellular areas in reexcision scars showed dense positivity as hypocellular areas in DMM (upper limit for scars: 258.42 positive cells/mm vs. lower limit for DMM: 292.42 positive cells/mm). SOX-10 positive cells in scars are predominantly monomorphic and small following the overall directionality of the tissue. In contrast, DMM cells exhibited enlarged atypical nuclei with a haphazard distribution, invasion as single cells or in clusters, and tropism for adnexal structures (58%) and neurovascular bundles (67%). In conclusion, cutaneous scars contain SOX-10 positive cells. The evaluation of residual DMM needs careful attention to morphologic characteristics to avoid over-interpretation of SOX-10 immunostains.

Vasodilator Hydralazine Promotes Nanoparticle Penetration in Advanced Desmoplastic Tumors.

Desmoplastic tumors are normally resistant to nanoparticle-based chemotherapy due to dense stroma and limited particle permeability inside the tumor. Herein, we reported that hydralazine (HDZ)-an antihypertension vasodilator-would dramatically promote nanoparticle penetration in advanced desmoplastic tumors. First, a HDZ-liposome system was developed for tumor-selective delivery of HDZ. After three injections of HDZ-liposomes at a dose of 15 mg/kg, the tumor stroma was remarkably reduced, along with ameliorated tumor hypoxia in murine models of desmoplastic melanoma (BPD6). Furthermore, HDZ-liposome treatment altered the immunosuppressive tumor microenvironment, which provided opportunities for applying this therapeutic system to aid immunotherapy in desmoplastic tumors. Using DiD-loaded liposome as a model nanoparticle, we showed that HDZ-liposome treatment significantly increased nanoparticle accumulation and penetration inside desmoplastic tumors. As a result, one single injection of doxorubicin-liposomes at a dose of 5 mg/kg resulted in strong tumor inhibition effect after HDZ-liposome pretreatment in the advanced desmoplastic melanoma with sizes over 400 mm3. Because HDZ is a widely used antihypertension drug, the findings here should be readily translatable for clinical benefits.

An unusual case of cutaneous desmoplastic melanoma

Desmoplastic malignant melanoma (DMM) is an extremely rare subtype, encompassing up to 1% of all melanoma cases, worldwide. DMM features a prolonged clinical course and a variable clinical picture, which usually delays the exact diagnosis.

A Case of Desmoplastic Melanoma in a Patient with Parkinson's Disease.

A Case of Desmoplastic Melanoma in a Patient with Parkinson's Disease.

Tumor mutational burden and response to programmed cell death protein 1 inhibitors in a case series of patients with metastatic desmoplastic melanoma

Abstract Desmoplastic melanoma (DM) represents an infrequently occurring and distinct histologic pattern of melanomas, often lacking mutations in genes typically altered in conventional melanomas including BRAF , NRAS , and KIT . We aimed at better characterizing the genetic profile of this subgroup of melanomas to match patients with available therapies. Pathology reports were reviewed for 1,240 consecutive melanoma cases sequenced by comprehensive genomic profiling (CGP) using a hybrid-capture based next generation sequencing during the course of clinical care. The mutational profile of the 12 DM identified was compared with the remaining 1,228 melanomas examined. We report a median tumor mutational burden (TMB) of 77 mutations per megabase (mut/Mb) in DM, which was significantly greater than a median of 35 mut/Mb in non-DM. A UV DNA damage signature was detected in 10/12 (83%) DM. For a subset of patients with available clinical course, we report that 100% (5/5) had clinical benefit from treatment with PD-1 inhibitors as monotherapy. TMB and UV signature show significant promise as an approach to identify patients who are likely to benefit from PD-1 targeted immunotherapy.

Desmoplastic melanoma.

Desmoplastic melanoma (DM) is a rare melanoma variant that has unique biology and pathology compared with conventional melanoma (non-DM). Importantly, DM is classified into pure and mixed histologic subtypes, which have been correlated with outcomes. Management of DM broadly mirrors that of non-DM; however, there are unique considerations for DM that influence treatment approaches. This paper will provide a contemporary overview of this disease and will review the literature regarding the management of DM.

Unusual Clinical Presentations of Malignant Melanoma: A Review of Clinical and Histologic Features with Special Emphasis on Dermatoscopic Findings.

This review presents the main challenges encountered when diagnosing unusual variants of malignant melanoma with the aim of raising awareness to allow application of the most appropriate treatment strategies. Although these melanomas are often rare, their misdiagnosis potentially jeopardizes patients’ health and survival, and has medicolegal implications. The clinical and histologic presentations of melanoma vary greatly, and assessment of uncommon melanomas can be difficult for practitioners because of their scarcity and resemblance to other dermatologic entities. The most problematic melanoma types are desmoplastic melanoma, polypoid melanoma, primary dermal melanoma, verrucous malignant melanoma, pigmented epithelioid melanocytoma, mucosal melanoma, follicular melanoma and melanoma with non-melanocytic differentiation. The two most difficult-to-diagnose subtypes of melanoma are the nevoid and the amelanotic melanomas. Some specific attributes of these variants can be more easily recognized with digital dermatoscopy, facilitating early detection and possibly avoiding invasive procedures. Key cases with the most notable clinical, dermatoscopic, and histopathologic features are presented, highlighting the practical issues of making an accurate diagnosis and choosing the best therapy.

Expression of TLE1 in Malignant Melanoma With Spindle Cell Morphology: A Potential Diagnostic Pitfall

Transducer-like enhancer of split 1 (TLE1) immunohistochemistry is widely used as a biomarker of synovial sarcoma. Spindle cell or desmoplastic melanoma can morphologically mimic synovial sarcoma. The aim of this study was to investigate the expression of TLE1 in melanomas with a spindle cell morphology. A search of the surgical pathology files resulted in 57 cases of melanomas diagnosed with a spindle cell or desmoplastic component. After review, 8 cases had no definitive dermal spindle cell component and 7 cases had insufficient tissue remaining and were excluded from the study. A total of 42 melanomas were examined for TLE1 immunohistochemistry using a mouse monoclonal antibody (Cell Marque, clone 1F5). Strength and percentage of nuclear TLE1 positivity was graded on a scale from 0 to 3+. Staining for TLE1 was considered positive for 2 to 3+ and negative for 0 to 1+. Nuclear TLE1 expression was identified in 24 (57%) of the 42 melanoma cases with spindle cell morphology (2+, n = 14; 3+, n = 10). TLE1 was considered negative in 18 cases (43%), of which most contained weak staining (1+, n = 14 [33%]) and only a small subset did not show any staining (0, n = 4 [10%]). TLE1 frequently highlights melanomas with spindle cell morphology and is a potential diagnostic pitfall. Therefore, when evaluating spindle cell tumors in which the differential may include both a melanoma and synovial sarcoma, TLE1 expression should be interpreted with caution and in conjunction with an immunohistochemical panel.

Utility of p53 Immunohistochemical Stain in Distinction of Desmoplastic Melanoma From a Neurofibroma

Utility of p53 Immunohistochemical Stain in Distinction of Desmoplastic Melanoma From a Neurofibroma