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An Official Publication of the Indian Association of Oral and Maxillofacial Pathologists


 
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CASE REPORT  
Year : 2017  |  Volume : 21  |  Issue : 2  |  Page : 286-295
 

Small cell neuroendocrine carcinoma of the paranasal sinus with intraoral involvement: Report of a rare case and review of the literature


Department of Oral and Maxillofacial Pathology, Goa Dental College and Hospital, Bambolim, Goa, India

Date of Submission22-Feb-2017
Date of Acceptance23-Jul-2017
Date of Web Publication18-Aug-2017

Correspondence Address:
Shruti U Nagvekar
H. No. 188/2, Ranoi, Aldona, Bardez - 403 508, Goa
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jomfp.JOMFP_205_15

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   Abstract 

The diffuse neuroendocrine system continues to be an enigmatic topic of study in pathology due to its controversial embryologic origins, biology and a variety of tumors engendered. Originally thought to be localized to the classic neuroendocrine organs (pituitary, thyroid, pancreas and adrenal medulla), the neuroendocrine cells are now known to be distributed in every organ system of the body. A number of human diseases have been linked to aberrations in the functioning of the neuroendocrine cells. Neoplasms of the neuroendocrine system can thus occur in myriad primary sites and range in behavior from benign to lethal. Small cell neuroendocrine carcinoma (SNEC) is a high-grade neuroendocrine tumor, rarely presenting in the sinonasal region. This article reports a case of a 68-year-old male patient with primary paranasal SNEC showing intraoral involvement. The diagnosis is based on a thorough clinical, histopathological and immunohistochemical workup to differentiate it from the other small round blue cell tumors.


Keywords: Neuroendocrine tumors, small cell neuroendocrine carcinoma, small round blue cell tumors


How to cite this article:
Spadigam A, Dhupar A, Syed S, Nagvekar SU. Small cell neuroendocrine carcinoma of the paranasal sinus with intraoral involvement: Report of a rare case and review of the literature. J Oral Maxillofac Pathol 2017;21:286-95

How to cite this URL:
Spadigam A, Dhupar A, Syed S, Nagvekar SU. Small cell neuroendocrine carcinoma of the paranasal sinus with intraoral involvement: Report of a rare case and review of the literature. J Oral Maxillofac Pathol [serial online] 2017 [cited 2021 Jul 24];21:286-95. Available from: https://www.jomfp.in/text.asp?2017/21/2/286/213196



   Introduction Top


The neuroendocrine system includes neurons and endocrine cells sharing a common phenotypic program.[1] Initially, considered to be the constitutive cells of the classic neuroendocrine organs (pituitary, thyroid, pancreas and adrenal medulla), the neuroendocrine cells are now known to be present in every organ of the body and referred to as the diffuse neuroendocrine system (DNES).[2]

Neoplasms of the neuroendocrine system are epithelial neoplasms with predominant neuroendocrine differentiation and constitute a rare and heterogeneous group of neoplasms which can occur in myriad sites and characterized by embryological, biologic and histopathological differences, referred to as the “neuroendocrine tumors” (NETs) [Figure 1].[3] Currently, there is no system of nomenclature, grading, or staging for neuroendocrine neoplasms that is common to all anatomic sites. Morphologically similar NETs differ in the terminology and criteria adopted for histologic grading and staging depending on the site of origin.[3] Small cell neuroendocrine carcinoma (SNEC) is a high-grade neoplasm, characterized by proliferation in sheets, cords, or ribbons of small-to-oval cells with hyperchromatic nuclei, sparse cytoplasm and high nuclear/cytoplasmic ratio.[4] The present case of SNEC of the paranasal sinuses was diagnosed using immunohistochemistry after distinguishing it from the other small round blue cell tumors.
Figure 1: Spectrum of neuroendocrine cells and associated tumors

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   Case Report Top


A 68-year-old male patient reported to the Department of Oral and Maxillofacial Pathology with a chief complaint of swelling over the right infraorbital malar region since 20 days. The swelling measured 5 cm × 3 cm in greatest dimensions, intraorally obliterating the upper right buccal vestibule. Right submandibular lymph nodes were palpable and tender. Incisional biopsy of the lesion was performed. Light microscopic examination of the biopsy specimen revealed a homogenous mass of proliferating small, round cells with scanty cytoplasm and hyperchromatic nuclei; few cells showed evidence of nuclear molding. Areas of tissue necrosis and crush artifact were evident [Figure 2]. Tumor cells showed positivity for cytokeratin, chromogranin, synaptophysin and thyroid transcriptional factor-1 whereas negativity for CD45, CD56 and carcinoembryonic antigen [Figure 3]. The patient was thus diagnosed as SNEC, stage D (Morita Modification of the Kadish Staging System) with a grade IV (Hyam's Grading System).
Figure 2: Photomicrograph of small cell neuroendocrine carcinoma showing the presence of (a) uniform population of small round cells (×400), (b) Nuclear molding (×400), (c) Crush artifact (×100), (d) Invasion and destruction of soft tissues (×100)

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Figure 3: Immunohistochemical analysis of various markers in the tumor mass. (a) Thyroid transcription factor 1+ (b) Synaptophysin+, (c) Cytokeratin 20+, (d) Chromogranin+, (e) Carcinoembryonic antigen−, (f) CD56−, (g) CD45− (×100)

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   Discussion Top


The DNES based on its derivation comprises two distinct groups.

  1. Neural crest origin (adrenal medullary cells, melanocytes, paraganglia, sympathetic ganglia, thyroid-C cells)
  2. Neuroendocrine-programmed origin (gastrointestinal, hepatobiliary, lower and upper respiratory tracts, sinonasal tract, pancreatic endocrine cells, parathyroid cells).[5],[6]


The neonatal respiratory tract contains a prominent system of neuroendocrine cells; both dispersed and aggregated into neuroepithelial bodies. Both types decline numerically during childhood. In adults, clusters of these cells are situated in the basal layers of the respiratory epithelium.[7]

The sinonasal tract refers to the paranasal sinuses (maxillary, ethmoid, sphenoid and frontal) and the nasal cavity which is lined by ectodermally derived respiratory (Schneiderian) mucosa, consisting of pseudostratified columnar-ciliated epithelium with interspersed goblet cells and neuroendocrine cells.[6]

Neuroendocrine cells are conventionally described as cells lacking axons and synapses and:

  1. Possessing the ability to produce neurotransmitters, neuromodulators, neuropeptide hormones, or neuropeptide processing enzymes (subtilase-like proprotein convertases)
  2. Containing dense core secretory granules containing a variety of substances (such as fluorogenic amines, aromatic amino acid decarboxylase nonspecific esterases and/or cholinesterases and others).[8]


However, neuroendocrine cells can no longer be defined simply based on their synthesis/content of neuropeptides or chromogranins.[9] When appropriately stimulated, cells of diverse embryologic origins that are neither neural nor endocrine can acquire at least partial neuroendocrine phenotype characteristics that are ascribed to the neuroendocrine cells, including the expression of the various substances mentioned above.[10] This morphological and functional plasticity under the control of hitherto unelucidated genetic switches might help explain many of the apparently aberrant characteristics of neuroendocrine cells under pathological conditions.[8]

Heidenhain (1870) described scattered cells throughout the intestinal mucosa, structurally and functionally different from other cells of the mucosa that showed reactivity for chromium and silver salts.[10],[11] Nicholas (Nikolai) Kultschitzky (1897) in his paper “Zur Frage über den Ban des Darmkanals” mentioned that unlike the mucous-secreting and absorbing cells of the intestinal mucosa, these cells emptied their secretory products toward the basilar pole of the mucosa and possibly into the vessels.[11]

Masson (1914) demonstrated argentaffin positivity in these cells.[10] Later studies demonstrated that these cells with similar histochemical properties were not restricted to the intestinal mucosa but were diffusely distributed in the body. They were identified in the bronchopulmonary tract, thymus, thyroid gland, skin, pancreatic islets, parathyroid glands, endocrine cells of the breast and the genitourinary tract.[10],[12],[13]

These cells were recognized independently by several other investigators and were given different terminologies, such as “enterochromaffin cells,” “argentaffin cells,” “clear cells,” “enteroendocrine cells,” “Kultschitzky cells,” and “paraneurons.”[9],[11]

In 1938, Feyrter identified the Helle Zellen cells (clear cells) and grouped these endocrine cells located in various organs and dispersed throughout the body into the DNES.[14] Due to his extensive work in this field, he has been referred to as the “Father of Neuroendocrinology.”[14] With the detection of similar biogenic amines and peptide hormones in neurons and in the dispersed endocrine system, Pearse (1966) developed the amine precursor uptake and decarboxylation (APUD) concept.[8]

The term “APUD cell” has fallen into disuse because embryological studies have conclusively demonstrated that neither all neuroendocrine cells have amine-synthesizing ability nor are all cells with neuroendocrine characteristics derived from the neuroectoderm.[8],[9] The current concept of a neuroendocrine cell does not support a neuroectodermal origin.[9] The term “neuroendocrine” is used to denote the shared phenotype characterized by the expression of the endocrine and neural features and highlights one of the important facts in biology that the developmental regulation of genetic expression is not necessarily related to cell lineage.[10] The neuroendocrine-programmed cell is therefore identified by cell markers expressed by different genes ranging from cell surface markers, constituents of secretory granule matrix and membranes, hormone-synthesizing enzymes, enzymes related to cellular energy metabolism and cytoskeletal elements.[6],[8]

Cell identity is defined by molecular properties and phenotypic characteristics linked to germ layer derivation. As markers not associated with neuroendocrine cells have been detected within tumors of neuroendocrine origin, it follows that the genetic switches that control the expression of neuroendocrine markers, viz., neuropeptides/chromogranin by tumor cells, have been turned on resulting in the acquisition of a neuroendocrine phenotype rather than being of true embryonic neuroectodermal origin.[8]

The general function of the neuroendocrine system is in maintaining homeostasis.[9],[11],[15] The neuroendocrine cells of the respiratory tract exert multiple effects on airway function which include contraction of airway smooth muscle; mucus secretion; vasodilation and plasma extravasation; stimulation of mast cells, macrophages, lymphocytes, eosinophils, chemotaxis and vascular adhesion of neutrophils.[7],[15] Neuroendocrine cells may also play a role in stimulation of growth of sensory and sympathetic nerves in addition to its role in stimulating the sensory nerves to release neuropeptides.[9],[11],[15]

Specific causes of altered neuroendocrine function are still not fully elucidated. Neuroendocrine dysfunction may manifest as temperature lability, disturbances in appetite, weight fluctuations, hypothalamic disorders, pituitary disorders, disorders of fluid regulation, hypertension or hypotension, fatigue, increased anxiety, depression, memory failure, cognitive deficiencies, reduced bone and muscle mass and immunologic disorders and has been associated with various chronic diseases.[16]

Tumors arising from the neuroendocrine cells or the neoplasms showing prominent neuroendocrine differentiation constitute a heterogeneous group of epithelial neoplasms referred to as the NETs.[16]

Neuroendocrine neoplasms or NETs are classified into well differentiated (typical), moderately differentiated (atypical carcinoids) and poorly differentiated (small and nonsmall cell types). Well and to a lesser extent, moderately differentiated NETs tend to carry better prognosis with low metastatic rates and better survival, while poorly differentiated NEC (SNECs) are characterized by rapid growth and fatal outcome prognosis. Treatment recommendations for this entity vary considerably largely due to a lack of consensus and variable pathological classifications.[17]

Literature reveals multiple site-specific systems of nomenclature and classification. In the absence of a classification system for NETs involving the sinonasal tract, the classification scheme of the laryngeal NECs has been extended to the sinonasal NETs.[18],[19]

Differentiation is the extent to which a neoplasm recapitulates the features of the nonneoplastic cellular components, whereas grade refers to the inherent biological aggressiveness of a neoplasm.[16] The grade of NETs is a fundamental predictor of outcome, and grading parameters are part of the most classification systems [Table 1].[3],[16],[18] Thus, the well-differentiated NECs (G1/G2 NETs) retain the morphological similarities with nonneoplastic neuroendocrine cells, grow in nesting, trabecular and organoid forms and express markers of neuroendocrine differentiation; mitosis and necrosis are infrequent. However, the poorly differentiated (G3 NETs) bears little resemblance to normal neuroendocrine cells, grow in less organized pattern, with frequent necrosis and mitosis.[16]
Table 1: Classification systems of neuroendocrine tumors (European Neuroendocrine Tumor Society, gastroenteropancreatic)

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Although there is a standardized grading system (European NET Society [ENETS]/WHO grading system) for the NETs for the gastroenteropancreatic system, no such system has been developed for the sinonasal NETs due to the rarity of such lesions in the sinonasal tract.[16],[19] And as such, the Hyam's Grading System which was originally devised for esthesioneuroblastoma has been extrapolated to the sinonasal NETs [Table 2].[20]
Table 2: Grading system for the sinonasal neuroendocrine tumors

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Although the ENETS and American Joint Committee on Cancer (AJCC) staging systems have been prognostically used to stage tumors of the gastrointestinal and pancreatic NETs, it cannot be applied to the sinonasal NETs.[16] The Kadish system, Morita Modification of the Kadish Staging System and the 2009 AJCC system for nasal cavity and paranasal sinus tumors have been commonly applied to the sinonasal NETs [Table 3].[19],[20],[21]
Table 3: Staging systems for the sinonasal neuroendocrine tumors

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SNEC is a poorly differentiated NET. Within the head and neck region, NEC most commonly occurs in the larynx, followed by the salivary glands and sinonasal region.[4] Paranasal NEC is rare and accounts for approximately 5% of malignancies of this site, with maxillary sinus being the most frequently involved paranasal sinus (60%).[22],[23] Head and neck SNECs show a slight male predominance.[24]

The clinical features are nonspecific similar to other sinonasal tumors and could be grouped into rhinological symptoms, ophthalmic signs and other signs suggestive of locoregional invasion.[24],[25] Nasal obstruction, rhinorrhea and epistaxis are the common rhinological symptoms. The ophthalmic signs include exophthalmos, loss of visual acuity and limitation of eye mobility.[25]

Because of the thin bony partitions between the nasal cavity, sinuses, orbit and cranial vault, invasion into the adjacent structures is common.[24] Locoregional invasion can be suspected in the presence of local pain, anosmia, or any tender swelling over the nose or paranasal sinuses.[25]

Paraneoplastic syndromes due to ectopic hormone production also occur.[24] However, clinical evidence of endocrine overactivity in the head and neck tumors is rarely detected.[26] Kameya et al. have reported cases with increased levels of adrenocorticotrophic hormone and calcitonin.[27]

Metastasis to the lungs, liver and bone is fairly common.[28] Metastatic cervical lymph nodes have also been described.[22],[25] As the tumor can metastasize to different sites, diagnosis of secondary small cell carcinoma should be kept in mind.[29] Majority of the patients present with an advanced stage tumor.[19]

Poorly differentiated NEC or SNEC consists of sheets, cords and ribbons of small- or intermediate-sized cells with poorly defined cell borders.[24],[26] Nuclei are round to oval and contain dense or finely granular delicate chromatin.[24],[26],[30] It may have scanty or moderate eosinophilic or amphophilic cytoplasm.[24],[26] Mitotic figures and areas of necrosis are frequent. Necrosis varies from scattered, individual necrotic cells to confluent “geographic” areas of necrosis producing the “crush artifact.”[26],[31] The “Azzopardi effect” (smudged hematoxylinophilic deposits in blood vessel walls) may be present.[32] Lymphatic, perineural and soft tissue invasion is common.[19],[26],[33]

Immunohistochemical markers of neuroendocrine differentiation include neuron-specific enolase (protein 14-3-2), protein gene product 9.5 (PGP9.5), chromogranins, secretogranins, secretory granule proteins, synaptic vesicle protein 2 and neural cell adhesion molecules.[10] Electron microscopy shows limited neuroendocrine differentiation in the form of sparse membrane-bound dense core neurosecretory granules; tonofilaments may be present occasionally. Cell junctions are absent but could show the presence of well-formed desmosomes.[31]

Paucity of randomized studies on these uncommon tumors has led to a lack of consensus on the management protocol.[34] Chang et al., Qian et al. and Likhacheva et al. have suggested that combined treatment strategy based on surgery has a better disease-free survival and overall survival as compared to treatment without surgery, irrespective of differentiation status of the tumor.[35],[36],[37] Somatostatin analogues and immunotherapeutic agents (interferon alpha) have been recently introduced for the systemic treatment of disseminated disease.[38]

The sinonasal SNEC represents the poorly differentiated form of NET and needs to be differentiated from a group of neoplasms referred to as the “small round blue cell tumors” of the sinonasal area.[39] It is a group of undifferentiated neoplasms showing little or no evidence of differentiation that share the common light microscopic appearance of being composed of relatively small, round to round-spindled, monotonous cells.[31],[32]

Final diagnosis of such neoplasms rests on the immunohistochemical evaluation as well as on genetic analysis.[31],[32],[40] Such an undifferentiated tumor could either represent a metastasis of unknown origin or a primary neoplasia without obvious cell line of differentiation exhibiting pleomorphic to anaplastic appearance.[40] They lack any particular morphologic features that make diagnosis solely based on light microscopic examination difficult.[32]

However, minor differences between the different tumors encompassing the group are provided in [Table 4].[31],[39],[41],[42]
Table 4: Histopathological features of small round blue cell tumors

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From a therapeutic point of view, it is critical to determine whether an undifferentiated neoplasm is epithelial, mesenchymal, or hematopoietic; and as such, a broad lineage differentiation of an undifferentiated tumor is important. Bahrami provided a practical algorithmic approach for the immunohistochemical dissection of such tumors.[40]

It should be emphasized that each tumor requires an “individually constructed panel” composed of carefully selected antibodies that recognize all reasonable diagnostic possibilities in the context of the tumor's morphology, anatomic site and clinical/radiologic findings.[40]

A screening panel to demonstrate the expression of markers of major lineages (i.e., epithelial, mesenchymal, lymphoid and melanocytic) often provides the first clue to the nature of an undifferentiated tumor.[40]

The immunohistochemical and cytogenetic features of the small round blue cell tumors are summarized in [Table 5],[31],[39],[43],[44] and the algorithm for the immunohistochemical differential diagnosis is provided in [Table 6].[39],[40]
Table 5: Immunohistochemical and cytogenetic features of small round blue cell tumors

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Table 6: Algorithm for the immunohistochemical diagnosis of small round blue cell tumors

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   Conclusion Top


The NETs can occur in any region of the body and pose diagnostic difficulties. Knowledge of its histopathology, immunohistochemical as well as ultrastructural features can provide important clues to the diagnosis. Although recently, international consensus groups have attempted to standardize the classification, grading and staging systems of gastroenteropancreatic NETs, little progress has been made in terms of NETs of miscellaneous sites, in particular the head and neck region. In view of the increasing number of NETs in the sinonasal complex, a site-specific system of classification, staging and grading would help in the formulation of precise management protocols.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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