BACKGROUND: Sialadenoma papilliferum (SP), a rare minor salivary gland tumor, shares morphological and genetic similarities with syringocystadenoma papilliferum. Recent studies have identified BRAF V600E or HRAS mutations in SP, suggesting its neoplastic nature. Despite being uncommon, SP poses diagnostic challenges due to its resemblance to other lesions like squamous papilloma. The emergence of sialadenoma papilliferum-like intraductal papillary tumor (SP-IPT) further complicates its classification, emphasizing the need for thorough investigation.
METHODS: A 50-year-old male presented with a left palatal lesion histologically diagnosed as SP-IPT. Surgical resection revealed characteristic features, including papillary projections into cystically dilated ductal spaces. Immunohistochemistry confirmed positivity for pan-keratin AE1/AE3, cytokeratin 7, SOX10, and BRAF V600E. Whole-exome sequencing identified BRAF V600E and PIK3CA H1047R mutations. No recurrence was observed three months post-excision.
CONCLUSIONS: SP-IPT\'s diagnostic complexity stems from its resemblance to SP without an exophytic papillary component. However, shared BRAF mutations suggest a close relationship between the two entities. Similarities with skin adnexal tumors underscore the importance of molecular markers in tumor classification. The identification of PIK3CA mutation in SP-IPT adds to its molecular diversity, warranting further investigation into its clinical significance.
CONCLUSIONS: This study presents a case of SP-IPT with unique histological and molecular features, highlighting its diagnostic and therapeutic challenges. The co-occurrence of BRAF V600E and PIK3CA H1047R mutations suggests a distinct molecular profile in SP-IPT, necessitating further research to elucidate its biological behavior and clinical implications.

Alpelisib plus fulvestrant is a valid second or advanced line of treatment for patients with metastatic hormone receptor (HR)-positive, HER2-negative breast cancer who harbor an activating PIK3CA mutation. The well-known side effects of alpelisib are hyperglycemia, rash, and diarrhea. Herein, we report a case of a woman who developed diffuse depigmented macules on the face, arms and legs, three months after initiating alpelisib. Both clinical and histopathological findings were consistent with new-onset vitiligo. To our knowledge, this is the first case described in literature which suggests a causal relationship between alpelisib and irreversible dermatological adverse effect.

Triple-negative breast cancer (TNBC) represents about 15% of all breast cancers and is usually characterized by aggressive clinical behavior and a poor prognosis. Four TNBC subgroups have been previously defined with different molecular profiles: (i) luminal androgen receptor (LAR), (ii) mesenchymal (MES), (iii) basal-like immunosuppressed (BLIS) and (iv) basal-like immune-activated (BLIA). Among these, LAR is characterized by the expression of the androgen receptor (AR), and exhibits genomic characteristics that resemble luminal breast cancers, with a still undefined prognosis and clinical behavior. Here, we report a case of a woman affected by recurring LAR TNBC, which underwent phenotypic changes throughout its natural history. After the initial diagnosis of LAR breast cancer, the patient experienced local recurrence with strong expression of the estrogen receptor. Due to this finding, she started treatment with a CDK4/6-inhibitor and an aromatase inhibitor, followed by oral vinorelbine, both with dismal outcomes. Then, she received everolimus and exemestane, which determined temporary disease stabilization. An extensive NGS analysis of tumor tissue showed PIK3CA and HER2 mutations. Our case is consistent with previous reports of LAR breast cancer and underlines the potential utility of re-biopsy and molecular testing in breast cancer (BC), especially in rare subtypes.

BACKGROUND: Squamous cell carcinoma (SCC) is the most common oral malignancy, and somatic mutations in some driver genes have been implicated in SCC development. Clear cell SCC (CCSCC) is a rare histological variant of SCC, and various clear cell neoplasms must be considered in the differential diagnosis of CCSCC in the oral cavity. Based on a limited number of CCSCC cases reported in the oral cavity, CCSCC is considered an aggressive variant of SCC with a poor prognosis; however, its genetic characteristics remain unknown.
METHODS: A maxillary gingival tumor in an 89-year-old female was described and investigated using immunohistochemical staining, special staining, fluorescence in situ hybridization, and next-generation sequencing (NGS) with a custom panel of driver genes, including those associated with SCC and clear cell neoplasm development.
RESULTS: Histopathological examination revealed a proliferation of atypical epithelial cells with abundant clear cytoplasm and enlarged and centrally placed round nuclei. The tumor was exophytic with deep, penetrating proliferation. The atypical clear cells were continuous with the conventional SCC cells. Immunohistochemical analysis showed that the clear cells were positive for CK AE1/AE3 and CK5/6 and nuclear-positive for p63. In contrast, the clear cells were negative for αSMA, S100, HMB45, Melan-A, CD10, and p16. p53 immunoreactivity exhibited a wild-type expression pattern. Additionally, the clear cells were positive for periodic acid-Schiff (PAS) and negative for diastase-PAS, mucicarmine, and Alcian blue. Based on these results, the diagnosis of CCSCC was confirmed. Molecular analysis of the clear cells identified PIK3CA p.E542K (c.1624G>A) and HRAS p.G12A (c.35 G>C) somatic mutations classified as oncogenic. No pathogenic variants were identified in TP53, EWSR1, AKT1, PTEN, BRAF, KRAS, NRAS, RASA1, or MAML2.
CONCLUSIONS: We report a case of CCSCC of the oral cavity with PIK3CA and HRAS mutations. The identification of PIK3CA and/or HRAS mutations is rare in SCC; however, both mutations are important potential targets for antitumor therapy. A detailed analysis of gene mutations in CCSCC may lead to a better understanding of its biological behavior and an improved prognosis, as well as a differential diagnosis from other clear cell neoplasms.

Megalencephaly-capillary malformation syndrome (MCAP, OMIM # 602501) is caused by hyperactivity of the thephosphoinositide-3-kinase (PI3K)-Vakt murine thymoma viral oncogene homolog (AKT)-mammalian target of rapamycin (mTOR) pathway, which results in megalencephaly, capillary malformations, asymmetrical overgrowth, and connective tissue dysplasia. Herein, we report the case of a 7-month-old girl with MCAP due to a PIK3CA somatic mosaic variant who presented with atrial tachycardia, finally diagnosed as pulmonary arterial hypertension (PAH). Oxygen therapy and sildenafil decreased pulmonary blood pressure and improved atrial tachycardia. Previous studies reported an association between the PI3K/AKT/mTOR pathway and abnormal pulmonary arterial smooth muscle cell proliferation, which may be associated with PAH. PAH should be considered a potentially lethal complication in MCAP patients, even when no structural cardiac abnormalities are identified in the neonatal period.

Kaposiform hemangioendothelioma (KHE) is an extremely rare, locally aggressive vascular neoplasm. The etiopathogenesis of KHE is still poorly understood. In the present study, we found a new mutation in KHE (c.685delA, p.Thr229fs). The KHE patient with the PIK3CA mutation showed complete regression after sirolimus treatment. We propose that the presence of the PIK3CA mutation in KHE may correlate with good response to sirolimus.

Cavernous malformations (CM) have long been considered congenital of central nervous system, while the mechanism of CMs detailed development process associated with genetic factors remains unclear. We reported an uncommon case which suffered spinal cord cavernous malformations. In this work, representative samples were obtained, and the sequenced results were described for the first time. A 9-year-old boy was found oblique shoulder with slightly weakness of left limbs; MRI indicated spinal cord cavernous malformations (CMs) located at the C4-C6 vertebral level. On genetic analysis, a shared mutation of PIK3CA (p.H1047R) in CMs and associated developmental venous anomalies (DVAs) was detected, with a different abundance (2% and 7%, respectively), and a somatic mutation of MAP3K3 (p.I441M) was detected in the CM tissue samples. This case provides better knowledge of the formation history and genetic triggers of the DVA-associated CMs. This evidence allows us to speculate the developmental history of the CM lesion: The DVA with PIK3CA mutation might be genetic precursor, and then the associated CM could be derived from terminal cell population of the DVA by acquiring a somatic mutation in MAP3K3.

Congenital infiltrating lipomatosis of the face (CILF) is a rare, congenital, nonhereditary facial overgrowth due to post-zygomatic activating mutations in PIK3CA gene. It is unilateral and involves hypertrophy of both the soft and hard tissue structures on the affected side of the face. This commonly results in early eruption of the teeth, hypertrophy of the facial bones, macroglossia, and proliferation of the parotid gland. Less than 80 cases of CILF have been reported in the literature so far. Treatment modalities include liposuction and surgical excision. However, since the hallmark of CILF is mutation in the PIK3CA gene, PI3K inhibitors may play a therapeutic role in CILF. We report a case of an 8-year-old boy with recurrent CILF of the scalp and nose, with PIK3CA H1047R mutation. We discuss the differential diagnoses, clinical outcomes, and management of this rare entity.

Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer death among women in the United States. In clinical practice, the standard method to confirm metastatic disease and tailor treatment is to biopsy a metastatic site. Bone is the most common metastatic site, occurring in up to 70% of patients with advanced breast cancer. Standard-of-care management includes a needle biopsy with histopathological analysis to confirm tumor status and to evaluate for mutations. However, bone biopsies can be technically challenging and are oftentimes painful for patients. Given the challenges in acquisition and analysis of bone samples in metastatic breast cancer (mBC), a liquid biopsy is a less invasive alternative that can reveal clinically relevant alterations. Here, we report two cases of bone-dominant hormone-positive (HR+) mBC, in which circulating tumor DNA (ctDNA) was extracted from blood samples using two different next-generation sequencing (NGS) platforms to identify molecular targets for FDA approved treatment. In both patients, PIK3CA mutations were detected and subsequently started on alpelisib along with aromatase inhibitor or fulvestrant treatment. These cases demonstrate a feasible real-world clinical application to liquid biopsies.

P40 and thyroid transcription factor-1 (TTF-1) dual expression in non-small cell lung cancer (NSCLC) is a rare occurrence. However, the presence of EML4-ALK and PIK3CA gene mutations in this type of cancer is unknown. The present study describes the case of a 38-year-old male patient who had never smoked. A 4.5-cm mass adjacent to his right upper mediastinum was detected by a computed tomography (CT) scan of the chest. Biopsy of the level four lymph nodes in the right mediastinum revealed microscopic morphological features typical of high-grade NSCLC. Immunohistochemical findings resembled those reported previously for several cases of NSCLC with the dual expression of P40 and TTF-1 markers. In addition, echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit a (PIK3CA) gene mutations were detected using high-throughput next-generation sequencing. To the best of our knowledge, this is the first report of NSCLC with the expression of P40 and TTF-1 as well as EML4-ALK and PIK3CA gene mutations. The presence of this type of tumor should be considered in patients with NSCLC who have never smoked and may have unique clinicopathological features.