Sustentacular cells in pulmonary neuroendocrine tumours

AIMS: To determine the prevalence of sustentacular cells across the range of pulmonary neuroendocrine tumours: typical and atypical carcinoid tumours and large cell and small cell neuroendocrine carcinomas. METHODS AND RESULTS: Sustentacular cells were sought in 80 pulmonary neuroendocrine tumours by immunolabelling for S100 protein, nerve growth factor receptor and glial fibrillary acidic protein. Intratumoural macrophages and Langerhans cells were identified with the KP 1 (CD68) and CD1A antibodies. S100-positive sustentacular cells were present in 25 of 30 typical carcinoids, 200 of 25 atypical tumours, six of 10 large cell carcinomas and six of 15 small cell lesions. They were most numerous in the typical carcinoids but very few in the small cell carcinomas, their prevalance being clearly related to grade of differentiation and, in particular, to the degree of architectural organization. CONCLUSIONS: Sustentacular cells are often found in pulmonary neuroendocrine tumours, especially better-differentiated lesions with a well-developed architecture. their prevalence clearly reflecting the degree of structural organization. Whether their prevalence is a useful prognostic indicator within a particular group of such tumours, such as the atypical carcinoids or the large cell carcinomas, as appears to be the case with paragangliomas, is unclear.     

Adrenocorticotropin-producing pulmonary tumorlets with lymph node metastasis

A case of pulmonary tumorlets with ectopic adrenocorticotropin (ACTH) production and lymph node metastasis in a bronchiectatic patient is reported. A 65-year-old man underwent right lower lobe lobectomy because of a sudden attack of cough and hemoptysis. Histological study revealed multiple discrete uniform small nests of tumor cells surrounding dilated bronchioles. Tumor nests were also found in the hilar lymph node. Immunohistochemically, the proliferating cells were confirmed to be neuroendocrine in origin with ectopic ACTH production, despite being clinically silent. The findings in the present case suggest that the clinical behavior of pulmonary tumorlets may be like a carcinoid, and need to be treated as tumor-like lesions. Ectopic hormonal production in the present case suggests pulmonary tumorlets should be considered in the differential diagnosis of Cushing's syndrome.     

Differential expression of neural-cadherin in pulmonary epithelial tumours

Aims:  Neural (N)-cadherin belongs to a group of transmembrane molecules with a crucial role in tissue morphogenesis and maintenance of an epithelioid phenotype and increased N-cadherin expression is implicated in tumour progression and dedifferentiation. The aim was to determine whether evaluation of N-cadherin in pulmonary tumours might assist in identifying lesions with more aggressive potential.
Methods and results:  One hundred and fifty-five pulmonary lesions were analysed for N-cadherin expression using immunohistochemistry, including neuroendocrine hyperplasia ( n  = 3), typical carcinoid ( n  = 59), atypical carcinoid ( n  = 12), small cell lung carcinoma ( n  = 11), large cell neuroendocrine carcinoma ( n  = 12), adenocarcinoma ( n  = 35) and squamous cell carcinoma ( n  = 23). Lymph node status was correlated with immunohistochemical expression. N-cadherin expression was demonstrated in all cases of neuroendocrine hyperplasia, 96% of typical carcinoids, 83% of atypical carcinoids, 63% of the small cell lung carcinomas and 32% of large cell neuroendocrine carcinomas. Over 90% of the adenocarcinomas and 100% of the squamous cell carcinomas were negative. Increased N-cadherin expression in typical carcinoids was associated with negative lymph node status ( P  < 0.001).
Discussion:  N-cadherin is differentially expressed in pulmonary tumours and is predominantly observed in neuroendocrine lung lesions with high expression in typical and atypical pulmonary carcinoids. The level of expression of N-cadherin between types of lung tumours does not appear to indicate malignant potential or aggressive behaviour.     

Pulmonary paraganglioid carcinoids and bcl-2 oncoprotein expression

Bcl-2 protein immunoreactivity was examined in 10 pulmonary carcinoid tumors with abundant S-100 protein-positive sustentacular cells (SCs) diagnosed as paraganglioid carcinoids. Its positivity in the mentioned tumors was compared with that of neoplasms formed of neuroendocrine cells only (30 pulmonary carcinoids), and with another group of 30 lesions consisting of neuroendocrine and sustentacular elements, i.e., paragangliomas (11 paragangliomas of the glomus caroticum and 9 jugulotympanic paragangliomas [JPTGs]), pheochromocytomas (5 cases), and a rare form of pulmonary tumorlets (PTUs) with a high frequency of SCs (5 cases). Bcl-2 protein was found in all 70 examined cases, and its expression showed no difference between the examined groups. On the basis of these results, bcl-2 protein expression was not found to be an indicator for either survival or useful for the differential diagnosis of pulmonary carcinoid tumors.     

Metastatic medullary thyroid carcinoma or calcitonin‐secreting carcinoid tumor of lung? A diagnostic dilemma in a patient with lung mass and thyroid nodule

Calcitonin‐secreting neuroendocrine tumors are rare and have been reported in literature as case reports or case series in various organs including lung, pancreas, larynx, bladder, and ovary. These tumors have similar cytologic features and immunohistochemical profile to medullary thyroid carcinoma and thus it is difficult to distinguish them, especially when calcitonin‐secreting neuroendocrine tumors are intermediate or higher grade and there is a mass lesion in the thyroid gland. Here, we report a rare case of calcitonin secreting atypical carcinoid tumor of the lung in a patient with thyroid nodule. However, after extensive ancillary studies on the thyroid gland, no tumor was detected and subsequent resection specimen revealed a pulmonary atypical carcinoid tumor with metastasis to level 11 lymph node. Being aware of this entity has significant clinical, diagnostic, and therapeutic implications and can prevent unnecessary thyroidectomies with subsequent possible morbidities.     

MELF invasion in endometrial cancer as a risk factor for lymph node metastasis

Pavlakis K, Messini I, Vrekoussis T, Panoskaltsis T, Chrysanthakis D, Yiannou P & Voulgaris Z
(2011) Histopathology  58 , 966–973
MELF invasion in endometrial cancer as a risk factor for lymph node metastasis Aim: To investigate whether the microcystic, elongated and fragmented (MELF) pattern of myometrial invasion encountered in certain endometrioid endometrial carcinomas can be considered as a risk factor for lymph node metastasis. Methods and results: A total of 351 cases of total abdominal hysterectomy and bilateral salpingo‐oophorectomy with/without lymphadenectomy or lymph node sampling, performed for endometrioid endometrial adenocarcinoma, were included in this study. The existence of MELF invasion, vascular invasion, fibromyxoid stromal reaction and lymph node metastasis were recorded. Immunohistochemistry for endothelial and epithelial markers was performed on selected cases. MELF invasion was identified in 20 (10.81%) and 13 cases (13.13%) treated without and with lymphadenectomy, respectively. All these cases were either well or moderately differentiated carcinomas, stages IA–II (without considering lymph node status). Positive lymph nodes were detected in seven of 13 MELF‐positive (53.84%) and six of 86 MELF‐negative cases (6.97%) This observation was statistically significant. Of the seven MELF‐positive tumours with lymph node metastasis, three cases exhibited intravascular tumour emboli while four showed a fibromyxoid stromal reaction. Conclusion: MELF pattern invasion was found to be related statistically to lymph node metastasis. Nevertheless, further studies are needed in order to evaluate the clinical significance of this observation.     

Why did they change that? Practical implications of the evolving classification of neuroendocrine tumours of the gastrointestinal tract

Neuroendocrine neoplasms (NENs) of the gastrointestinal tract (GIT) comprise neuroendocrine tumours (NETs) and neuroendocrine carcinomas (NECs). During the last decade the classification and grading of GIT NENs has undergone significant changes, culminating in the World Health Organisation (WHO) 2019 classification. These changes, some of which are attributable to an only partially successful attempt to achieve uniform nomenclature among different organs, include: slight changes to the cut‐off used for the Ki‐67 proliferative index to distinguish grade 1 from grade 2 NETs; an emphasis on the distinction between grade 3 NETs (low‐grade NETs with a high proliferative rate) and NECs which, by definition, are all high grade; classification of tumours with mixed non‐neuroendocrine and neuroendocrine differentiation as MiNENs; and replacement of the term ‘goblet cell carcinoid’ with ‘goblet cell adenocarcinoma’. While some of these changes seem minor, even semantic, each was made for very specific reasons which reflect an improved understanding of neuroendocrine neoplasia. The changes have definite implications for pathologists in clinical practice, not all of which may be readily apparent. This review is an attempt to explain the background behind each of the recent changes to the classification of neuroendocrine neoplasms of the gastrointestinal tract and summarise their impact on surgical pathologists – including a guide on how to approach certain recurrent difficulties encountered with the WHO 2019 system in routine clinical practice.     

肺类癌型微小瘤的临床病理及其形态发生分析

目的 描述肺类癌型微小瘤的病理特征和免疫表型,探讨其发生的形态学基础。方法 对3例支气管扩张症(支扩)伴发微小瘤进行临床病理学观察,另11例支扩和2例正常肺作对照;应用免疫组织化学En Vision法检测其特异性标志物和标记气道上皮内神经内分泌细胞(NECs)。结果肺类癌型微小瘤多为散发多灶性镜下结节,呈簇状、巢状或索团状,分布于支扩受损的支气管壁旁、细小支气管周围和瘢痕化的组织中;由短梭形或小圆形细胞构成,核呈圆形、椭圆或长椭圆形,染色深;胞质弱嗜酸性;细胞嗜银性强;强表达神经元特异性烯醇化酶(NSE)、嗜铬素、降钙素、胃泌素等神经内分泌性标志物,小灶性表达绒毛膜促性腺激素(HCG)、促肾上腺皮质激素(ACTH)、5-羟色胺(5-HT),弱表达细胞角蛋白(CK)、上皮膜抗原(EMA)、S-100。微小瘤旁气道黏膜上皮NECs明显增生,比不伴微小瘤的支扩肺和正常肺气道黏膜上皮内NECs计数的差异均具有统计学意义(P值均＜0．001)。结论肺微小瘤具有周围型典型性类癌的病理特征和免疫表型,可能是典型性类癌发生的早期阶段。它的发生可能与肺慢性损伤导致慢性缺氧刺激NECs增生有关。     

Nuclear pleomorphism in typical carcinoid tumours of the lung: problems in frozen section interpretation

Pulmonary typical carcinoid tumours are generally easy to diagnose with their uniform cells, carcinoid growth pattern and lack of mitoses. However, nuclear pleomorphism, which is common in other neuroendocrine tumours, is not emphasized in pulmonary carcinoid tumours. Three cases of typical carcinoid tumours, because of marked nuclear pleomorphism on frozen section, were misdiagnosed as non-small cell carcinomas.     

Sustentacular cells occur frequently in the familial form of medullary thyroid carcinoma

The presence and distribution of S-100-immunoreactive sustentacular cells were investigated by immunohistochemistry in 67 medullary thyroid carcinomas (MTCs). The familial or sporadic status of the tumours was assessed by clinical data and confirmed by the identification of RET germline mutations using the polymerase chain reaction–single-strand conformation polymorphism (PCR–SSCP) and restriction analysis. Sustentacular cells were detected in 19 tumours (28·3 per cent). They were found significantly more frequently in the familial (15/24, 62·5 per cent) than in the sporadic MTCs (4/43, 9·3 per cent). The results indicate that sustentacular cells are commonly found in familial MTC and their presence in any MTC may be regarded as an indirect indicator that the tumour might be of the familial type. © 1998 John Wiley & Sons, Ltd.     

Desmoplastic stromal reaction in papillary thyroid microcarcinoma

Koperek O, Asari R, Niederle B & Kaserer K
(2011) Histopathology  58 , 919–924
Desmoplastic stromal reaction in papillary thyroid microcarcinoma Aims: To evaluate the value of a desmoplastic stromal reaction (desmoplasia) as an indicator of metastasis in papillary thyroid microcarcinoma. Methods and results: One hundred and nine cases of papillary thyroid microcarcinoma from the pathological archive of the Medical University of Vienna, Austria were analysed for the presence of desmoplasia in relation to other morphological and clinicopathological parameters. Eighty‐one of 109 papillary microcarcinomas showed a desmoplastic stromal reaction. The desmoplasia was significantly associated with lymph node metastases (P = 0.001) and tumour diameter (P < 0.001). In addition, ‘invasive parameters’, such as peritumoral and vascular invasion, were associated with the presence of a desmoplastic stromal reaction (P < 0.001 and P = 0.006, respectively), and all pT3b tumours according to the UICC classification of 2002 (i.e. with perithyroidal infiltration) showed desmoplasia. Of all morphological parameters, the best indicator of lymph node metastasis was tumour calcification (P < 0.001). Conclusions: Our data indicate that a desmoplastic stromal reaction seems to be an indicator of invasive behaviour of papillary thyroid microcarcinomas significantly associated with lymph node metastases. Papillary microtumours without signs of invasion, e.g. desmoplasia, should not be regarded as invasive carcinoma, as they are more likely to be thyroidal intraepithelial neoplasias.     

Typical laryngeal carcinoid tumor with recurrence and lymph node metastasis: a case report and review of the literature

Typical carcinoid tumor of the larynx is an extremely rare lesion which arises from neuroendocrine cells scanning in the laryngeal mucosa or submucosal glands. Conventionally, it is a well-differentiated neuroendocrine carcinoma, conservative surgery represents the treatment of choice, and the patient usually has a good prognosis with rarely recurrence and metastasis. In this report, we present a case of typical laryngeal carcinoid tumor with recurrence and lymph node metastasis. The patient was a 58-year-old man, complaints of intermittent burning pain in his both ears for 2 years, and for the recent one month the pain turn to continuous accompanied with a mild discomfort in the throat, he had neither hoarseness, dysphagia, nor any otorrhea and hearing loss. The patient was scheduled to undergo a tracheotomy and then a biopsy under supporting laryngoscopy. During the operation, the frozen section diagnosis from the first and the second time both indicated that the biopsy specimens originated from musculo-epithelia, it couldn’t be differed from malignant to benign. So the mass was simply removed under supporting laryngoscopy. The histopathology from paraffin sections revealed typical carcinoid of the larynx and the second procedure consisted of supraglottic laryngectomy with clear margins, the otalgia resolved and the patient had no difficulty with phonation or swallowing. After 1 year follow-up, the patient was found a mass on his right neck with symptom free, B-ultrasonography indicated several enlargement lymph nodes with some merged on both sides of the neck, the patient was scheduled to undergo a “total-laryngectomy with radical neck dissection on the left side and an elective neck dissection on the right side”. The specimens were positive for cytokeratin, chromogranin A and synaptophysin, a final diagnosis of typical carcinoid was made for the recurrence lesion and the metastasis of the lymph nodes. Though the post-operative recovery was uneventful, the prognosis was not good, the patient died six months later. Here, we review the pertinent references on this subject, and discuss the main managements for typical carcinoid tumor of the larynx.     

Rectal adenocarcinoid with lymph node metastasis

We describe a case of a rare variant of a rectal carcinoid tumor that showed mucous gland differentiation accompanied by a lymph node metastasis with a histological appearance similar to that of the primary site. The tumor consisted of a typical argyrophilic carcinoid component and of goblet cell glands. The carcinoid component was positive for neuron-specific enolase, chromogranin A and synaptophysin. The goblet cells stained positively with periodic acid-Schiff (PAS) and alcian blue, and expressed carcinoembryonic antigen, but were negative for neuroendocrine markers. This case suggests that carcinoid tumor can differentiate towards mucus glands, which can also be found in the metastatic site.     

Multicentric metachronous pulmonary and intravagal paraganglioma: a case report with immunohistochemical findings

An unprecedented presentation of multicentric paraganglioma in a 48-year-old man is described. One of the paragangliomas, originally diagnosed as a carcinoid tumor, presented as a lung mass and was removed. Four years later, an intravagal paraganglioma was discovered. The lung and intravagal tumors had identical morphologic and immunoreactive characteristics. Both tumors consisted of chief cells (type 1) and sustentacular cells (type 2). The chief cells were immunoreactive with neuroendocrine markers (synaptophysin and chromogranin), but nonreactive with epithelial markers (CAM 5.2, high- and low-molecular-weight keratins, epithelial membrane antigen, and carcinoembryonic antigen). The sustentacular cells were positive for S100 protein. Although pulmonary carcinoids may mimic paragangliomas and occasionally contain sustentacular cells, the diagnosis was rejected because the tumor cells did not demonstrate reactivity with epithelial markers.     

A retrospective analysis of histological prognostic factors for the development of lymph node metastases from auricular squamous cell carcinoma

Clark R R, Soutar D S & Hunter K D (2010) Histopathology 57 , 138–146
A retrospective analysis of histological prognostic factors for the development of lymph node metastases from auricular squamous cell carcinoma Aims: Squamous cell carcinoma (SCC) of the auricle has a high risk of metastatic spread, which is associated with high mortality. Identification of patients with a high risk of lymph node metastases would allow prophylactic treatment to the draining lymph nodes, but there are no established clinical or histopathological criteria to predict which tumours have a high risk of metastasis. The aim was to determine such criteria. Methods and results: The study was a retrospective analysis of the clinical and histological features of 229 cases of SCC of the auricle, with a minimum of 2 years’ clinical follow‐up. Overall, lymph node metastases were present in 24 cases (10.5%). Of the patients with metastatic disease 66.7% died, despite multi‐modality treatment. Tumours with a depth of invasion >8 mm or a depth of invasion between 2 and 8 mm in conjunction with evidence of destructive cartilage invasion, lymphovascular invasion or a non‐cohesive invasive front had a high risk of metastasis (56% and 24%, respectively). Conclusions: Patients with high‐risk tumours, as assessed histopathologically, should be considered for prophylactic therapy to or staging of the regional lymph nodes.     

PAX-5 expression in pulmonary neuroendocrine neoplasms: its usefulness in surgical and fine-needle aspiration biopsy specimens

The World Health Organization classification of lung tumors recognizes 4 histologic subtypes of pulmonary neuroendocrine carcinomas (NECs), which include typical carcinoids (TCs), atypical carcinoids (ACs), small cell carcinomas (SCCs), and large cell NECs (LCNECs). These tumors can be misclassified owing to morphologic parallels, indicating the necessity for adjunctive tests for correct classification. We evaluated immunohistochemical expression of PAX-5 in histologic and fine-needle aspiration (FNA) specimens of pulmonary NECs. Staining was stratified by intensity (0 to 3+) and percentage of cells stained as focal (<10%) or diffuse (=10%). PAX-5 expression was present in 29/37 (78%) of high-grade NECs (22/26 SCCs, 1/2 LCNECs, and 6/9 combined tumors) and none of 51 TCs and ACs; FNA specimens showed concordant staining. This study confirmed that PAX-5 is a useful marker in FNA and surgical specimens for the discrimination of low- to intermediate-grade NECs from high-grade NECs with 100% specificity and 79% sensitivity in surgical specimens.