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The CDKN2A gene remains understudied in melanoma compared to BRAF alterations. Inactivation of this tumor suppressor gene through homozygous deletions in the 9p21 chromosomal region leads to cellular proliferation and disrupts pro-apoptotic pathways. Genetic changes in CDKN2A are linked to multiple primary melanomas (MPM), with patients diagnosed with melanoma facing an elevated risk of developing additional primaries. We present the rare case of a 72-year-old Caucasian woman with nine metastasizing melanomas across diverse anatomical sites, posing a diagnostic challenge. Initial diagnosis in 2022 revealed ulcerated superficial spreading melanomas, progressing to intradermal and papillary dermal populations with neurotropism and angiotropism by early 2023. Lymph node metastases were identified, classifying the condition as pT3b N3b. Subsequent assessments in April 2023 revealed clinically suspicious melanocytic lesions diagnosed as intradermal and traumatized junctional nevi. In late 2023, cutaneous pigmented lesions and subcutaneous metastases were confirmed as nodular nevoid low-CSD multiple melanomas. Fluorescence in situ hybridization testing revealed homozygous CDKN2A deletion, necessitating close multidisciplinary collaboration for an optimized care plan for effective monitoring and intervention in this intricate clinical scenario. In summary, this case report highlights the diagnostic challenges of MPM in a single patient. Stressing the importance of immuno-histochemistry and CDKN2A genetic testing, our findings underscore the crucial role of these tools in accurately distinguishing malignant melanocytic proliferations from nevi and characterizing MPM cases. [ABSTRACT FROM AUTHOR]

Background and Objectives: In the realm of the rising incidence of cutaneous and mucous melanoma, CDKN2A mutations characterize familial and multiple primary melanoma cases. The involvement of tumor-infiltrating lymphocytes (TILs) is interconnected with survival rates, but may extend even further. The aim of this study is to verify the accuracy of the classical "naked eye" count of CD8-positive T cells comprised within the tumoral population and peritumoral infiltrate versus that obtained via a special software run by the aid of artificial intelligence (AI), used to determine the percentage of CD8-positive TILs. Materials and Methods: The present retrospective cross-sectional study conducted over a period of 5 years (2018–2022) focused on patients diagnosed with mucous and/or cutaneous melanoma, with a positive family history for melanoma, or personal antecedents of primary malignant melanocytic lesions. The 23 selected cases were diagnosed histopathologically, tested for CDKN2A mutations through fluorescent hybridization in situ, and CD8 immunohistochemistry was performed. The included slides were evaluated both manually (naked-eye examination) and automatically (via QuPath platform) for quantifying the CD8-positive TILs. Results: The number of CD8-positive TILs in melanoma samples has been more accurately identified through the use of an AI-mediated software as compared to the human-eye evaluation performed by experimental pathologists. A higher percentage of CD8-positive intratumoral lymphocytes versus stromal lymphocytes was positively associated with more numerous metastatic sites. Conclusions: The CD8 lymphocytic phenotype harbors major significance in the context of familial and multiple primary melanoma and may comprise a cost-effective investigation meant to help in the establishment of melanoma prognosis and response to immunotherapy. [ABSTRACT FROM AUTHOR]

The CDKN2A gene remains understudied in melanoma compared to BRAF alterations. Inactivation of this tumor suppressor gene through homozygous deletions in the 9p21 chromosomal region leads to cellular proliferation and disrupts pro-apoptotic pathways. Genetic changes in CDKN2A are linked to multiple primary melanomas (MPM), with patients diagnosed with melanoma facing an elevated risk of developing additional primaries. We present the rare case of a 72-year-old Caucasian woman with nine metastasizing melanomas across diverse anatomical sites, posing a diagnostic challenge. Initial diagnosis in 2022 revealed ulcerated superficial spreading melanomas, progressing to intradermal and papillary dermal populations with neurotropism and angiotropism by early 2023. Lymph node metastases were identified, classifying the condition as pT3b N3b. Subsequent assessments in April 2023 revealed clinically suspicious melanocytic lesions diagnosed as intradermal and traumatized junctional nevi. In late 2023, cutaneous pigmented lesions and subcutaneous metastases were confirmed as nodular nevoid low-CSD multiple melanomas. Fluorescence in situ hybridization testing revealed homozygous CDKN2A deletion, necessitating close multidisciplinary collaboration for an optimized care plan for effective monitoring and intervention in this intricate clinical scenario. In summary, this case report highlights the diagnostic challenges of MPM in a single patient. Stressing the importance of immuno-histochemistry and CDKN2A genetic testing, our findings underscore the crucial role of these tools in accurately distinguishing malignant melanocytic proliferations from nevi and characterizing MPM cases.

Background and Objectives: In the realm of the rising incidence of cutaneous and mucous melanoma, CDKN2A mutations characterize familial and multiple primary melanoma cases. The involvement of tumor-infiltrating lymphocytes (TILs) is interconnected with survival rates, but may extend even further. The aim of this study is to verify the accuracy of the classical “naked eye” count of CD8-positive T cells comprised within the tumoral population and peritumoral infiltrate versus that obtained via a special software run by the aid of artificial intelligence (AI), used to determine the percentage of CD8-positive TILs. Materials and Methods: The present retrospective cross-sectional study conducted over a period of 5 years (2018–2022) focused on patients diagnosed with mucous and/or cutaneous melanoma, with a positive family history for melanoma, or personal antecedents of primary malignant melanocytic lesions. The 23 selected cases were diagnosed histopathologically, tested for CDKN2A mutations through fluorescent hybridization in situ, and CD8 immunohistochemistry was performed. The included slides were evaluated both manually (naked-eye examination) and automatically (via QuPath platform) for quantifying the CD8-positive TILs. Results: The number of CD8-positive TILs in melanoma samples has been more accurately identified through the use of an AI-mediated software as compared to the human-eye evaluation performed by experimental pathologists. A higher percentage of CD8-positive intratumoral lymphocytes versus stromal lymphocytes was positively associated with more numerous metastatic sites. Conclusions: The CD8 lymphocytic phenotype harbors major significance in the context of familial and multiple primary melanoma and may comprise a cost-effective investigation meant to help in the establishment of melanoma prognosis and response to immunotherapy.

Germline aberrations in the CDKN2A gene are observed in 20%–40% of families susceptible to melanoma. Positive CDKN2A status is associated with early age of onset of melanoma, multiple primary melanomas, and pancreatic cancer. We report here a melanoma patient with a germline mutation c.68G>A p.(Gly23Asp) in CDKN2A who had a history of multiple cutaneous melanomas and a family history consistent with familial atypical multiple mole melanoma (FAMMM) syndrome. He developed oligometastatic disease with BRAF-positive melanoma metastases in soft tissue and gallbladder and was treated with surgical resection followed by combination therapy of PD-1 and CTLA-4 immune checkpoint inhibitor, which resulted in good remission. Molecular analysis of all primary melanomas and both metastatic sites revealed the same BRAF c.1799T>A p.(Val600Glu) V600E mutations.

We report a case of a 60-year-old male with metachronous primary malignancies, pancreatic cancer and malignant melanoma which recurred simultaneously. Both cancers were challenging to diagnose and throughout the case at different times, the presence of two active malignancies obscured the clinical picture. A bleeding gastric lesion found in the stomach 6 months after a distal pancreatectomy for pancreatic adenocarcinoma revealed metastatic melanoma, presumed secondary from a melanoma excised from the patient’s back 2 years previously. During surgery intended to resect the gastric lesion, peritoneal nodularity was identified, with histology confirming metastatic pancreas cancer. This case highlights two main points of interest. Firstly it emphasises the role for consideration of a genetic predisposition in young patients with more than one primary malignancy. The man in this case was not informed of his family history as he was adopted. If he had knowledge of previous family history, he may have been able to provide information to expedite arrival at the diagnosis of a CDKN2A mutation (melanoma-pancreatic carcinoma syndrome). In addition, this case also raises the issue of the challenges we face when treating synchronous primary malignancies. The two malignancies here behaved equally aggressively and posed obstacles for treatment as there is no mutual method of carcinogenesis that could be targeted with treatment; therefore, treatment modalities had to be chosen to treat each malignancy separately. To date, studies evaluating the role for targeted therapy in the setting of CDKN2A mutations have not conclusively provided meaningful benefits to patients.

Recently, the term mixed neuroendocrine non-neuroendocrine neoplasms (MiNEN) has been proposed as an umbrella definition covering different possible combinations of mixed neuroendocrine-exocrine neoplasms. Among these, the adenoma plus neuroendocrine tumor (NET) combination is among the rarest and not formally recognized by the 2019 WHO Classification. In this setting, the debate between either collision tumors or true mixed neoplasms is still unsolved. In this report, a pancreatic intraductal papillary mucinous neoplasm (IPMN) plus a NET is described, and the molecular investigations showed the presence in both populations of the same KRAS, GNAS, and CDKN2A mutations and the amplification of the CCND1 gene. These data prove clonality and support a common origin of both components, therefore confirming the true mixed nature. For this reason, mixed neuroendocrine-exocrine neoplasms, in which the exocrine component is represented by a glandular precursor lesion (adenoma/IPMN) only, should be included into the MiNEN family. [ABSTRACT FROM AUTHOR]

We report a case of a 60-year-old male with metachronous primary malignancies, pancreatic cancer and malignant melanoma which recurred simultaneously. Both cancers were challenging to diagnose and throughout the case at different times, the presence of two active malignancies obscured the clinical picture. A bleeding gastric lesion found in the stomach 6 months after a distal pancreatectomy for pancreatic adenocarcinoma revealed metastatic melanoma, presumed secondary from a melanoma excised from the patient's back 2 years previously. During surgery intended to resect the gastric lesion, peritoneal nodularity was identified, with histology confirming metastatic pancreas cancer. This case highlights two main points of interest. Firstly it emphasises the role for consideration of a genetic predisposition in young patients with more than one primary malignancy. The man in this case was not informed of his family history as he was adopted. If he had knowledge of previous family history, he may have been able to provide information to expedite arrival at the diagnosis of a CDKN2A mutation (melanoma-pancreatic carcinoma syndrome). In addition, this case also raises the issue of the challenges we face when treating synchronous primary malignancies. The two malignancies here behaved equally aggressively and posed obstacles for treatment as there is no mutual method of carcinogenesis that could be targeted with treatment; therefore, treatment modalities had to be chosen to treat each malignancy separately. To date, studies evaluating the role for targeted therapy in the setting of CDKN2A mutations have not conclusively provided meaningful benefits to patients. [ABSTRACT FROM AUTHOR]

In 3-5 % of all cases of pancreatic ductal adenocarcinoma (PDAC), hereditary factors influence etiology. While surveillance of high-risk individuals may improve the prognosis, this study describes two very different outcomes in patients with screen-detected lesions. In 2000, a surveillance program of carriers of a CDKN2A/p16- Leiden-mutation consisting of annual MRI was initiated. Patients with a suspected pancreatic lesion undergo CT-scan and Endoscopic Ultrasound, and surgery is offered when a lesion is confirmed. In 2015, two patients with a screen-detected solid lesion were identified. In both patients, lesions were visible on MRI and CT scan, while the EUS was unremarkable. Surgical resection of the head of the pancreas resulted in nearly fatal complications in the first patient. This patient was shown to have a benign lesion. In contrast, timely identification of an early cancer in the second patient was accompanied by an uneventful postoperative course. These cases underline the risks inherent to a PDAC prevention program. All patients should be fully informed about the possible outcomes before joining a surveillance program. [ABSTRACT FROM AUTHOR]

Thee authors describe a case of a man who was simultaneously diagnosed with nodular melanoma, two superficial and two in situ melanomas. Development of multiple primary melanomas is a rare but well recognized disease, with an estimated incidence ranging from 1.75% to 8.5% in melanoma patients. The diagnosis of primary melanoma increases the risk of additional primary melanomas. A total skin examination has therefore to be performed during follow up of melanoma patients for early detection of further malignant melanomas. [ABSTRACT FROM AUTHOR]

Oncologists who are aware of the progress in hereditary cancer syndrome diagnosis, and, in particular, of how this effort may be effectively facilitated through a comprehensive family history in concert with molecular genetic studies, are in the envious position of designing highly targeted screening and management programs for the membership of these cancer-prone families. The Lynch syndrome is discussed as a clinical model wherein the presence of mismatch repair mutations provides a high level of diagnostic certainty for the initiation of targeted cancer screening and management. The familial atypical multiple mole melanoma—pancreatic cancer (FAMMM—PC) syndrome, on the other hand, provides another model with cancer-control potential. Given its phenotypic features of multiple atypical nevi, high total body mole count and cutaneous malignant melanoma, coupled with the integral association of PC in a subset of FAMMM kindreds with the CDKN2A germline mutation, this may result in a perhaps lower level of diagnostic certainty when compared with the Lynch syndrome. This knowledge may impact upon progress in the earlier diagnosis of melanoma and provide an impetus for creative diagnostic methods in PC, a disease that, at this time, demonstrates a mortality rate virtually identical to its incidence rate. [ABSTRACT FROM AUTHOR]

Metastatic renal cell carcinoma (mRCC) is the important factor for patient mortality, meanwhile gene mutation constantly changes cancer prognosis in tumor process. Exploring the driver mutation in mRCC process become more and more important. We obtained the 15 paired primary and metastatic mRCC samples and analyzed specific mutation genes in the metastatic foci (SMGs) by next generation sequencing. Moreover, we explored the Correlated networks, Pathway and Gene Ontology (GO) enrichment results, prediction analysis of AS sites and prognosis of survival. We identify EPCAM, TMEM127, EZH2, EXT1, CDKN2A, PRF1, AIP, CDK4, PRKARIA as SMGs and find that CDKN2A mutation sites affect the prognosis of mRCC by altering splicing elements. Based on the differential analysis for SMGs in KIRC, we found that EPCAM, PRF1 and EZH2 were differential expression in both primary tumors with metastasis compared to primary tumors without metastasis or metastatic tissues. By the AS prediction analysis, we suggest that CDKN2A mutation sites play an important role for RCC metastasis by affecting the p16/p14 expression. The SMGs could provide new molecular cues associated with tumor metastasis and have potential clinical implications for cancer prognosis and treatment. Definitive conclusions await further validation and follow up. [ABSTRACT FROM AUTHOR]

Recently, the term mixed neuroendocrine non-neuroendocrine neoplasms (MiNEN) has been proposed as an umbrella definition covering different possible combinations of mixed neuroendocrine-exocrine neoplasms. Among these, the adenoma plus neuroendocrine tumor (NET) combination is among the rarest and not formally recognized by the 2019 WHO Classification. In this setting, the debate between either collision tumors or true mixed neoplasms is still unsolved. In this report, a pancreatic intraductal papillary mucinous neoplasm (IPMN) plus a NET is described, and the molecular investigations showed the presence in both populations of the same KRAS, GNAS, and CDKN2A mutations and the amplification of the CCND1 gene. These data prove clonality and support a common origin of both components, therefore confirming the true mixed nature. For this reason, mixed neuroendocrine-exocrine neoplasms, in which the exocrine component is represented by a glandular precursor lesion (adenoma/IPMN) only, should be included into the MiNEN family.

Familial atypical multiple mole melanoma (FAMMM) syndrome is a hereditary syndrome characterized by multiple dysplastic nevi and melanoma. Patients with FAMMM may have a heterozygous, inactivating, pathogenic germline variant in the CDKN2A gene, especially the NM_000077.4: c.225_243del19 (p.p75fs) variant, also known as p16 -Leiden variant. Patients with this variant are at high risk for developing melanomas and pancreatic cancer due to somatic inactivation of the wild-type CDKN2A allele. The combination of an inactivating germline CDKN2A mutation and somatic inactivation of the wild-type CDKN2A allele in the same cell results in tumor formation. It has been suggested that carriers of a germline CDKN2A mutation are also at increased risk for several other cancer types, including esophageal cancer. Here, we describe two unrelated patients with the p16 -Leiden variant who developed esophageal squamous cell cancer. Evidence of loss of the wild-type CDKN2A allele was obtained in the tumor tissue of both patients indicating biallelic inactivation of p16 in the tumor cells. These results suggest that these patients developed esophageal squamous cell cancer in the context of FAMMM syndrome. [ABSTRACT FROM AUTHOR]