Right Upper Lobe Large Cell Neuroendocrine Carcinoma with Atypical Carcinoid Features: Case Report

Lung neuroendocrine tumors (NETs) comprise approximately 20% of all lung cancers. NETs are categorized as one of four distinct types based on defined criteria: typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell lung carcinoma (SCLC). TC and AC tumors are considered well-differentiated NET (WD-NET), while LCNEC and SCLC tumors are considered poorly differentiated NET (PD-NET) [1‒3]. Identification of these tumors is based largely on two factors: neuroendocrine morphology and the expression of at least one neuroendocrine marker through either immunohistochemistry staining (e.g., chromogranin, synaptophysin, or INSM1) or neuroendocrine granules identified by electron microscopy. However, the categorization of WD-NET or PD-NET is based on morphological parameters, namely, the number of mitoses per 2 mm² (equivalent to 10 high power fields [HPFs]) and the presence or absence of necrosis [4]. By definitional criteria, TC has <2 mitoses per 10 HPF and no necrosis, AC has 2–10 mitoses per 10 HPF with or without punctate necrosis, and LCNEC and SCLC have >10 mitoses per 10 HPF usually with abundant necrosis. LCNECs are distinguished from SCLCs based on the larger cell size, greater amount of cytoplasm, and often more prominent nucleoli in the former [1‒4]. Further, WD-NET tumors have distinct genetic abnormalities that are different from those of PD-NET tumors. RB1 and p53 mutations are extremely rare in carcinoid tumors and extremely common in PD-NET [1, 5‒8]. In addition, prior reports have found that tumor mutation burden (TMB) is low in carcinoid tumors and higher in PD-NET [5].

In general, ACs are considered intermediate-grade, well-differentiated tumors, while LCNECs are considered high-grade tumors with a poor prognosis, exhibiting a 5-year survival rate of approximately 15–25% in advanced stages [7]. In terms of clinical presentation, AC patients have an average age in the sixth decade (vs. seventh decade for LCNEC patients), a female predominance (vs. a male predominance for LCNEC), a better prognosis, and a lower likelihood of smoking than LCNEC patients [9]. Histopathologic differences between pulmonary NETs are often subtle, especially in small biopsy specimens or cytologic samples. Notably, because WD-NETs and PD-NETs are recognized as being genetically dissimilar, progression from WD-NET to PD-NET is not a recognized phenomenon. Therefore, this case of NET in the right upper lobe of the lung, which displays features of both AC and LCNEC, is a very unusual presentation.

The patient is an 83-year-old male with a past medical history of chronic obstructive pulmonary disease, esophagitis, hyperlipidemia, transient ischemic attacks, anxiety, and hypertension. Patient denies history of smoking or other drug use. Family history is negative for any malignancies. The patient presented with a 2-day history of hemoptysis and was subsequently admitted to the hospital for diagnosis and management. During his hospitalization, he had a small volume hemoptysis and required supplemental oxygen.

The patient underwent bronchoscopy, which revealed a fungating mass in the right mainstem bronchus protruding medially from the lateral wall with near-complete occlusion of the right mainstem bronchus. The results of pulmonary function tests were normal, and the pulmonary perfusion demonstrated significant left-sided perfusion of 80%. Computerized tomographic imaging demonstrated a right lung mass arising from the right mainstem bronchus with associated right upper lobe consolidation (Fig. 1). Endobronchial ultrasound revealed an obstructing mass at the orifice of the right upper lobe that appeared infiltrative and polypoid. It was unable to be traversed. Biopsy of the bronchial mass revealed an NET, confirmed by expression of synaptophysin and chromogranin A, and exhibited low Ki67 proliferation (∼3%) with a rare single mitosis. Based on these findings, the mass was classified as a carcinoid tumor, NOS. Endobronchial ultrasound of the lymph node stations 4R, 4L, 7, and 11L did not show any malignant cells. There were no identifiable diagnostic challenges.

Based on the diagnosis, surgical resection with bronchoscopy, right upper lobectomy with possible bronchoplasty or sleeve lobectomy, and mediastinal lymph node dissection were recommended given the tumor’s localization in the right upper lobe bronchus, lack of lymph node involvement, and early disease stage. Perioperative expectations were reviewed with the patient, and the possible need for rehabilitation or SNF placement post-operation was discussed.

The patient underwent a right thoracotomy with right upper lobectomy, hand-sewn bronchoplasty, stapled pulmonary artery arterioplasty, intercostal muscle flap, and mediastinal lymph node dissection. The operative time was 4 h and 48 min with a blood loss of 100cc. The lobectomy specimen consists of a lung lobe measuring 17 cm × 10.5 cm × 3 cm and weighing 218 gm. Evaluation of the lobectomy specimen revealed an endobronchial tumor occluding the bronchus and measuring 2.2 cm in greatest dimension. Microscopic examination revealed the tumor was composed of nests of monomorphic cells with occasional rosettes, characteristic of a NET, and large areas of necrosis. The tumor was found to have a variable expression of mitotic activity. In one 2.0 mm² area, there were 22 mitotic figures; in a separate 2.0 mm² area on the same slide, there were no identifiable mitoses (shown in Fig. 2). Other than mitotic activity, the cellular and immunophenotypic features were the same in both areas. Image analysis using QuPath (version: 0.1.2) revealed the area of high mitotic activity had 20.0% expression for Ki67, versus 5.4% expression without any identifiable mitoses (shown in Fig. 3). Based on the mitotic activity and the large areas of necrosis, the tumor was classified as LCNEC.

The margins of the resected lung tissue were negative for tumor involvement, and there was no identifiable evidence of lymphovascular invasion or pleural invasion. All lymph nodes were negative for metastatic tumor, and the disease was staged as pT1cN0, stage IA3 (according to the 8th edition AJCC pathologic Tumor-Node-Metastasis staging system). Lymph nodes were retrieved from level 9, level 7, level 10 (both anterior and posterior), level 4, level 2, and level 11. Subsequent molecular analysis performed at Caris Life Sciences Laboratory in Phoenix, Arizona, revealed PDGFRA gene alteration, high PTEN protein expression (2+ at 90%), and low TMB of 2 mutations/Mb. There were no mutations or deletions detected in the tumor DNA for RB1 or TP53.

No adverse or unanticipated events were detected post-surgery, and hospital stay lasted 4 days. The patient has been followed for 8 months, and his first 6-month surveillance revealed stable lung findings with no concern for recurrence. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000540889).

Pulmonary NETs are a group of rare lung tumors, including lung carcinoid tumors and neuroendocrine lung cancers, that are organized according to guidelines from the World Health Organization (WHO) and the International Association for the Study of Lung Cancer (IASLC) [1]. AC tumors have been found to affect individuals of all ages and both sexes equally, with half of all patients being asymptomatic at the time of diagnosis. AC tumors tend to form a round shape and are usually 2–3 cm in size. AC tumors are most commonly treated with surgical resection and are less responsive to chemotherapy and radiation therapy than PD-NETs [9].

In contrast to AC, LCNEC is strongly associated with current or former smoking history. LCNEC tumors are often peripheral tumors that are typically 3–4 cm in size. Compared to AC patients, LCNEC patients have a significantly lower 5-year survival rate, ranging from 15% to 57% [1, 10].

The annual incidence of lung NETs has increased markedly in recent decades, rising at a rate of 7.0% per year [11]. Among these cases, LCNECs account for approximately 3% of all lung malignancies, while ACs account for less than 1% [2]. Despite the increase in incidence, the diagnosis of neuroendocrine neoplasms remains challenging due to the similarities among categories and the limitations of examining small biopsy specimens. As the frequency of these cases rises, it is important to explore different presentations to better comprehend this tumor type. The diagnosis of NETs requires comprehensive histological, cytological, and immunohistochemistry analyses.

Based on the mitotic activity and large areas of necrosis, this patient’s resected tumor was classified as an LCNEC; however, the genetic analysis of the tumor unexpectedly revealed normal RB1 and TP53 genes and low TMB, which are more consistent with a carcinoid tumor than LCNEC [12]. There is a distinct division between these two NET groups because of differences in clinical presentation, behavior, and genetic alterations. PD-NETs are not thought to arise from preexisting carcinoid tumors. Therefore, the finding of both morphologically WD-NET and PD-NET features in the same tumor is quite unusual.

Interestingly, previous research has found that carcinoid morphology with an increased mitotic index (exceeding 10 mitoses per 2 mm²) resembles LCNEC but may carry a better prognosis [13], suggesting that the presence of some AC morphology in an LCNEC neoplasm might contribute to a better prognosis. Kasajima et al. [6] examined the clinical and pathologic features of lung carcinoid tumors with a Ki67 index >20. They evaluated 59 cases of WD-NETs (39 TC, 20 AC) and 185 PD-NETs (58 LCNEC, 127 SCLC). For WD-NETs, individuals with Ki-67 scores ≤20% demonstrated an average of 1 mitosis with a range from 0 to 7 mitoses; individuals with Ki67 scores >20% demonstrated an average of 6 mitoses with a range from 1 to 10 mitoses. PD-NETs averaged 77 mitoses with a range from 0 to 204 total mitotic counts. When available, p53 and Rb1 genetic alteration data were also included. Based on these data, p53 alterations were found in 0 of 48 WD-NETs and 65 of 135 PD-NETs, while Rb1 alterations were found in only 2 of 21 WD-NETs and 69 of 80 PD-NETs, indicating that the presence of p53 or Rb1 alterations is highly specific to PD-NETs versus WD-NETs. The current case showed no alterations in p53 or Rb1 which favors the WD-NET genotype; however, it is important to note these markers are more specific than sensitive and do not confirm the diagnosis of PD-NET.

The presence of the PDGFRA gene alteration is a nonspecific finding. Liang et al. found PDGFRA mutations in 12.5% of LCNEC, and Centonze et al. found PDGFRA mutations in less than 10% of AC tumors [14, 15].

Marchiò and colleagues analyzed proliferation indices in 239 carcinoid tumors and found 61.5% of cases had Ki67 scores of <4%, 25.1% of cases had 4–9% proliferation, and 13.4% of cases had proliferation scores ≥10%. Mitotic count and genetic alterations were not included in the data. This study included only pathologically defined TC and AC and found a statistically significant association between both >10% proliferation and AC histology and worse survival [16]. The current case has proliferation indices of 20.0% in the area of high mitotic activity and 5.4% in the area of lower activity. This finding, along with genotype results, is most consistent with AC (WD-NET).

In a case similar to the one reported here, Inafuku et al. examined 2 cases of lung neuroendocrine carcinoma with carcinoid morphology that showed mitotic counts of 15 and 13 per HPF, respectively. Both cases were categorized as SCLCs based on the WHO classification criteria, and the Ki67 proliferation indices were 40% and 27%, but genetic analysis was not included [17].

The patient expressed a very high level of satisfaction with his surgical care and described a full recovery, noting that his preceding symptoms of hemoptysis and wheezing ceased following surgery, and he no longer needed to use supplemental oxygen. He also reported that postsurgical pain at the incision site had abated. The patient described his care as “truly life changing.”

Based on the findings at the time of resection, the tumor was classified as LCNEC, but the later genetic diagnostic findings indicated that the tumor was likely an AC tumor with LCNEC features. Because of the rarity of this tumor type, the differences in the behavior and best treatment approaches between LCNEC and AC with LCNEC features are not known. Therefore, when treating a patient with a tumor with both WD-NET and PD-NET features, it may be necessary to rely on genetic analysis to inform the final diagnosis.

The patient underwent surgical resection. Although the tumor was an early stage and identified as an AC tumor, its LCNEC features may place it at a higher risk of recurrence after surgery. Given the aggressive nature of LCNEC, and as this AC tumor as LCNEC features, close follow-up and regular evaluations will be critical for this patient. Reporting this uncommon case of a tumor that exhibits traits of both AC and LCNEC may be a crucial step in refining carcinoid tumor diagnoses.

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. Ethics approval is not required for this study in accordance with local or national guidelines.

The authors report no potential conflicts of interest.

The authors received no financial support for the research, authorship, and/or publication of this article.

All authors Y.L., R.R., W.W., and S.W. contributed to the original drafting and reviewing of this manuscript.

William Dean Wallace and Sean C. Wightman contributed equally to this work.

The data that support the findings of this study are not publicly available due to their containing information that could compromise the privacy of our patient but are available from the corresponding author [S.W.].