Traditional WHO classifications for tumors of endocrine organs and the digestive system conventionally defined MiNEN in which each component comprises at least 30% of the lesion [4]. However, the threshold was set arbitrarily without concrete evidential support [2]. In certain organs, such as the esophagus, stomach, and colorectum, the WHO classification has not established a specific minimum percentage for defining MiNEN [5]. The current case has been diagnosed as MiNEN based on traditional WHO classifications, given that both NEN and non-NEN components each comprise more than 30% of the lesion. Three theories have been proposed to explain the origins of MiNENs, as the pathogenesis remains a subject of debate. The first theory suggests that NEN and non-NEN components develop from distinct cells and eventually merge. The second theory postulates that both components originate from a common pluripotent stem cell progenitor, which undergoes differential differentiation during carcinogenesis. The third theory assumes a shared monoclonal origin for both counterparts, but the NEN counterpart evolves from the non-NEN cells, driven by the progressive accumulation of genetic abnormalities [6]. The findings from our case suggested the third theory, as a part of conventional SCC was considered to obtain undifferentiated morphology and neuroendocrine properties.
Diagnosing MiNEN necessitates a comprehensive evaluation throughout the tumor tissue, given the varied possibilities in proportions of NEN and non-NEN components. Consequently, it is not infrequent to miss the diagnosis on small diagnostic biopsies, only to discover MiNENs on examination of excised samples [2]. Intriguingly, the initial biopsy was able to identify mixed histopathological features in only a third of cases [6]. To confirm the presence of NEN elements with neuroendocrine differentiation, immunohistochemical markers including synaptophysin and chromogranin A are highly recommended. Even though the expression of chromogranin A can be varied from absent to focal in poorly differentiated cases, synaptophysin should be present in these cases [7]. Our case revealed two distinct components that tested positive for neuroendocrine markers, including chromogranin A and synaptophysin, and exhibited marked positivity for squamous cell differentiation markers, cytokeratin 5/6, p63, and p40. These findings led to a diagnosis of MiNEN, comprising large cell NEC, and well-differentiated SCC.
Given the limited number of cases available, uncertainty persists whether the prognosis of MiNEN aligns more closely with that of NEN or its non-NEN constituents. Recent review have proposed that the biological behavior of MiNENs is predominantly influenced by the NEN component, which tends to be poorly differentiated and often found in distant metastatic sites [6]. In the context of head and neck region, the cancer-specific survival (CSS) rates for patients with NEC at 5 years were reported at 43% [8], whereas CSS for patients SCC in the head and neck region stood notably higher at 63% [9]. These findings underscore that the prognosis of NEN, especially NEC, is notably poorer than that of SCC. In our case, the Ki-67% labeling index for the NEC component was approximately 50–60%, whereas the SCC component showed a lower index of 20–30%. This suggests that the biological behavior of the NEN counterpart is more active than its non-NEN counterpart. Notably, patients with MiNEN faced a poorer outcome as compared to those with pure NEC in the small intestine and appendix, although there were no significant survival differences between NEC and MiNEN in other parts of the gastrointestinal system [10]. This raises the possibility that the prognosis of MiNEN may be more aggressive than NEC, though further analysis is necessary to validate this hypothesis. Our case received surgical treatment alone and remained healthy during the 6-year follow-up period.
Since the introduction of MiNEN definition in approximately 2017, reviewing and categorizing these tumors has posed challenges. Prior reports have employed various terms such as coexistence, collision, combined, composite, or mixed, making it more challenging to gather those rare cases. In our investigation, we conducted a review using these aforementioned terms and employed a snowballing technique to identify additional references, ultimately yielding in five cases for inclusion in the review. The cases are summarized in Table 2. Notably, the localization of oral MiNENs displayed remarkable diversity, with reported cases exhibiting unique localization patterns. The age distribution ranged from 32 to 65 years, with an average age of 55.6 years, while the male-to-female ratio was 5:1. The non-NEN elements were predominantly SCC in five cases (83.3%), with one case demonstrating salivary duct carcinoma as the non-NEN counterpart. In three cases, there was a good prognosis even though the Ki-67 labeling index was high (over 50%). This suggests that the proliferation rate may not be the most crucial factor affecting MiNEN prognosis. However, more research is needed to confirm this hypothesis.
Table 2
Clinical and histological features of potential oral MiNEN cases.
| No. | Author, year | Age (year), sex | Site | Biopsy results | NEN components | Non-NEN components | Ki-67 Labeling index | Treatment | Outcomes |
| 1 | Mochizuki et al., 2010 [21] | 62, female | Upper gingiva | NEC | NEC | SCC | > 80% | Partial maxillectomy | 23 months, NED |
| 2 | Yamagata et al., 2016 [22] | 65, male | Oral floor | NET(G2), SCC | NET(G2) | SCC | - | 1st : Chemoradiotherapy 2nd : Tumor excision with neck dissection | 1st : 6 months recurrence only SCC 2nd : 6 months metastasis to lung and mediastinum lymph nodes |
| 3 | Udompatanakorn et al., 2018 [23] | 59, male | Soft palate | SCC | Small cell NEC | SCC | - | Tumor excision with neck dissection | 30 months, NED |
| 4 | Bal et al., 2021 [24] | 32, male | Palate | Carcinoma ex-pleomorphic adenoma, suggestive | Small cell NEC | Salivary duct carcinoma | NEC: 75% | Tumor excision with neck dissection, radiotherapy | 6 months, NED |
| 5 | Archibald et al., 2022 [25] | 53, male | Oral floor, retromolar trigone | Basaloid SCC | Large cell NEC | Basaloid SCC | - | Wide tumor excisiona with neck dissection, | 8 months, NED |
| 6 | Current case, 2023 | 64, male | Lower gingiva | NEC | Medium-to-large cell NEC | SCC | NEC: 50–60% SCC: 20–30% | Partial mandibulectomy | 72 months, NED |
| aThe patient underwent partial glossectomy, segmental mandibulectomy, partial pharyngectomy, tonsillectomy, and tracheostomy. NEC: neuroendocrine carcinoma, NET: neuroendocrine tumor, G2: grade 2, SCC: squamous cell carcinoma, -: no data available, NED: no evidence of disease |
MiNEN associated with SCC have gained recognition across the following anatomical sites: sinonasal tract, oropharynx, larynx, lung, esophagus, cervix/vagina, kidney, and skin [4]g. However, currently, the precise characterization of MiNEN in oral and other head and neck locations have not yet been precisely defined. In addition to our presented case and the cases reviewed, there have been reports of potential MiNEN cases in head and neck, including nasal cavity, sinonasal tract, oropharynx, palatine tonsil, larynx, hypopharynx, and parathyroid [11–19]. Notably, data from these studies consistently point to SCC as the predominant non-NEN component. This observation aligns with the fact that SCC is the most common cancer in the head and neck region, ranking the sixth most common cancer worldwide [20].