Miscellaneous Neuroendocrine Tumors of the Neural Type: Olfactory Neuroblastoma and Central Neurocytoma



Miscellaneous Neuroendocrine Tumors of the Neural Type: Olfactory Neuroblastoma and Central Neurocytoma





This chapter covers two of the neuroendocrine neoplasms of neural type that occur very rarely and includes olfactory neuroblastoma and central neurocytoma. They are encountered occasionally in the practice of cytopathology. Their documentation in cytopathology literature amounts to rare case reports only.


OLFACTORY NEUROBLASTOMA

Olfactory neuroblastomas, also known as esthesioneuroblastomas, are malignant neuroectodermal tumors thought to arise from the olfactory neuroepithelium of the sinonasal tract in the upper one-third to one-half of the nasal septum, the cribriform plate, and the superomedial surface of the superior turbinate. With aging, the olfactory epithelium degenerates and is replaced by respiratory epithelium. The olfactory epithelium is composed of bipolar sensory neurons, supporting cells, and the reserve or basal cells. The basal cells are mitotically active and are the presumed progenitor of olfactory neuroblastoma.


CLINICAL FEATURES

Olfactory neuroblastomas are uncommon, representing 2% to 3% of malignant sinonasal tract tumors. There is no gender predilection. It occurs over a wide age range, from 3 years to the ninth decade, with a bimodal peak in the second and sixth decades of life. The presenting symptoms include unilateral nasal obstruction, epistaxis, anosmia, headache, pain, excessive lacrimation, and visual disturbances. The most common sites of occurrence are upper nasal cavity, in the area of cribriform plate and ethmoid sinus. Olfactory neuroblastomas can also occur in paranasal sinuses. The tumor presents as a rapidly growing mass and has a tendency to invade the central nervous system (CNS).

The biologic behavior of olfactory neuroblastoma parallels the histologic grade of the tumor. Metastases occur in 30% of the cases, most often involving the cervical lymph nodes and also the brain, lungs, bones, and viscera.


RADIOLOGIC FINDINGS

CT or MRI demonstrates a sinonasal mass causing opacification with or without bone destruction. MRI shows the presence of a vascular lesion.


GROSS AND MICROSCOPIC FEATURES

Grossly, olfactory neuroblastoma presents as a soft, polypoid mass, covered by glistening mucosa, varying from 1 cm to a mass filling the nasal cavity with possible extension into paranasal sinuses and nasopharynx.

Histologically, olfactory neuroblastomas are classified into four grades, based on differentiation.

Grade I is the most differentiated tumor type, presenting a lobular architecture with communicating lobules consisting of uniform, small cells. Their nuclei are round with coarsely granular chromatin and inconspicuous nucleoli. The cell borders are indistinct. The stromal matrix demonstrates neurofibrillary material (neuropil)
(Figs. 17.1 and 17.2C). Homer-Wright rosettes are often present. The tumor appears monomorphic with no mitotic activity or necrosis. The interlobular stroma is fibrous or can be very vascular. Calcification may be present.

Grade II olfactory neuroblastomas present the same histologic pattern as that of grade I, except for lesser neurofibrillar stroma. The neoplastic cells are more pleomorphic with some mitotic activity.

Grade III olfactory neuroblastomas retain the lobular architecture and are more cellular with numerous mitosis and necrosis. The neurofibrillar component is less and focally present. These less differentiated olfactory neuroblastomas may contain true rosettes (Flexner-Wintersteiner rosettes). Calcification is absent.

Grade IV olfactory neuroblastomas present a diffuse growth pattern. The lobular architecture may be maintained. The neoplasm is undifferentiated and anaplastic, with pleomorphic nuclei, prominent nucleoli, and indistinct cytoplasm. Mitotic activity is brisk and necrosis is very common. The neurofibrillary matrix is absent. True rosettes may be present.


CYTOPATHOLOGIC FEATURES

The specimens for cytologic diagnosis represent either fine needle aspiration biopsies of the nasal cavity mass or crush preparations of biopsy specimens performed during intraoperative consultation. Scrapings of the mass lesion have been described. The cytologic presentation depends on the grade of the tumor (Table 17.1; Figs. 17.2 and 17.3). In low-grade neoplasms, the smears are usually cellular consisting of monomorphic population of small round cells, dispersed or in loosely cohesive groups. The cells have poorly defined cell borders, indistinct cytoplasm, and high N/C ratios. Their nuclei are round with granular chromatin and nucleoli are not prominent. Rarely carrot-shaped elongated nuclei are present. There may be slight nuclear molding. Homer-Wright rosettes and fibrillary matrix can be appreciated in low-grade tumors. In high-grade olfactory neuroblastomas, the cells are more pleomorphic and contain prominent nucleoli. Their cytoplasm is scant. The fibrillar matrix is inconspicuous (Fig. 17.3).


IMMUNOPROFILE

Olfactory neuroblastomas are reactive to neuroendocrine markers such as neuron-specific enolase synaptophysin and variably reactive to chromogranin, CD56, and CD57. Variable reactivity is also seen with glial fibrillary acidic protein, neurofilament protein, S100 protein, and epithelial membrane antigen (EMA). Some demonstrate positive reactivity to cytokeratin. Olfactory neuroblastomas are nonreactive to CD99, a differentiating feature from primitive neuroectodermal tumor (PNET).


ULTRASTRUCTURE

Ultrastructure reveals secretory granules, neurofilaments, neurotubules, and Schwann-like cells.


DIFFERENTIAL DIAGNOSES

The differential diagnoses of olfactory neuroblastomas include several high-grade lesions consisting of smallsized cells that either arise primarily in sinonasal area or metastasize to sinonasal region. The differential diagnostic considerations differ in different age groups. In pediatric and adolescent age groups, metastatic neuroblastoma, PNET/Ewing sarcoma, malignant lymphoma, rhabdomyosarcoma, and pituitary adenoma must be included in the differential diagnoses. In adults, sinonasal undifferentiated carcinoma, small cell neuroendocrine carcinoma, metastatic poorly differentiated adenocarcinoma/squamous carcinomas, nasopharyngeal carcinoma, PNET/Ewing sarcoma, malignant lymphoma, solitary plasmacytoma, pituitary adenomas, metastatic Merkel cell carcinoma, and small cell type malignant melanoma enter the differential diagnoses. Many of these diagnostic entities have been discussed in Chapter 13 in the section Sinonasal Small Cell Neuroendocrine Carcinoma and will not be repeated. However, they are summarized in Table 17.2 and illustrated in Figures 17.4,17.5,17.6,17.7,17.8,17.9,17.10,17.11,17.12 and 17.13.



Olfactory Neuroblastoma (Figs 17.1,17.2 and 17.3)






Fig. 17.1: Histologic sections of an olfactory neuroblastoma in a 51-year-old woman with a large mass at the base of the skull and also involving the sphenoid sinus and cavernous sinuses. A: Lowpower view showing lobular masses of loosely cohesive small cells (H&E). B: Higher magnification showing neurofibrillar stroma separating neoplastic cells (H&E). C: Different case of olfactory neuroblastoma, depicting tumor arising from the olfactory epithelium and involving the subepithelial area. The neoplasm shows a diffuse growth pattern and is composed of small round cells with high N/C ratios. The nuclear chromatin is granular with micronucleoli. Neurofibrillar stroma is seen in focal areas. Note the olfactory mucosa (arrow) (H&E).






Fig. 17.2: Intraoperative Consultation. Crush preparation of an olfactory neuroblastoma. A, B: These smears depict loosely cohesive small round cells with poorly defined cell borders, scant stroma, and high N/C ratios. Neurofibrillary stroma is not conspicuous (H&E).







Fig. 17.2: (continued) C: Histologic section of this tumor showing a solid growth pattern formed by uniform small cells. Note occa sional rosettes and focal neurofibrillary stroma (H&E).






Fig. 17.3: FNA of an Intranasal Mass. A-F: These six images represent a marginally cellular specimen showing small- to medium-sized cells with ill-defined cell borders, pleomorphic nuclei, and prominent nucleoli. The chromatin is coarsely granular. Their cytoplasm is pale and variable. The tumor histologically confirmed as olfactory neuroblastoma.







Fig. 17.3: (continued)








TABLE 17.1. CYTOPATHOLOGIC FEATURES OF OLFACTORY NEUROBLASTOMA

































Cellularity

Variable, can be marked


Presentation

Dispersed pattern frequent, cells in loosely cohesive groups with pseudorosettes, fibrillar stroma


Cells

Small, round, monomorphic in low-grade tumors, mild-to-marked pleomorphism in higher grades; high N/C ratios


Nucleus

Round to oval; chromatin coarsely granular with typical salt-pepper appearance in low grade; coarsely granular chromatin with parachromatin clearing, occasional carrot-shaped nuclei; nucleoli prominent in high-grade tumors


Cytoplasm

Scant to indistinct


Background

Neurofibrillar stroma; necrosis +/-; mitoses +/-


Immunoprofile

Positive reactivity to neuroendocrine markers; S100 protein, neurofilament proteins; occasionally reactive to cytokeratin


Ultrastructure

Neurosecretory granules, neurofilaments, neurotubules, and Schwann-like cells


Differential diagnoses

In pediatric and adolescent age groups: Metastatic neuroblastoma Ewing sarcoma/PNET Rhabdomyosarcoma Malignant lymphoma Pituitary adenoma

In adults:


Sinonasal neuroendocrine carcinoma Sinonasal undifferentiated carcinoma Nasopharyngeal carcinoma Malignant lymphoma Malignant melanoma Pituitary adenoma Ewing sarcoma/PNET Basaloid squamous carcinoma Rhabdomyosarcoma











TABLE 17.2. DIFFERENTIAL DIAGNOSES OF OLFACTORY NEUROBLASTOMA

























































Diagnostic Entity

Cytopathologic Features

See Figure(s)


Olfactory neuroblastoma

Monomorphic, small, round cells; dispersed cell pattern; pseudorosettes; uniform nuclei with salt-pepper chromatin pattern; nucleoli seen in high-grade tumors; carrot-shaped nuclei +/-; neurofibrillar stroma; immunoreactive to neuroendocrine markers, S100 protein (Schwann cells in stroma); neurofilament protein, protein gene product (pgp) 9.5 and occasionally to cytokeratin; CD99 –

Figures 13.20A,B; 17.1,17.2 and 17.3


Neuroblastoma

Monomorphic, small, round cells; dispersed cell pattern; Homer-Wright rosettes +; uniform nuclei with salt-pepper chromatin pattern; nucleoli seen in highgrade tumors; ganglionic differentiation +/-; neurofibrillar stroma (neuropil) +; immunoreactive to neuroendocrine markers, S100 protein (Schwann cells in stroma), pgp 9.5; negative to cytokeratin and CD99 –

Figures 13.16; 16.3,16.4,16.5 and 16.6; 17.4A, B


Ewing sarcoma/PNET

Dispersed cell population; syncytial tissue fragments; Homer-Wright rosettes frequent; small to slightly larger cells; poorly defined cell borders; high N/C ratios; unipolar cytoplasmic tags or processes +/-; spindle forms in 10%-20% of the cases; round to oval; smooth to irregular nuclear membranes; chromatin fine to coarsely granular, salt-pepper type; micronucleoli +; mitoses +/-; molding +/-; scant, cytoplasm; CD99 +; neuroendocrine markers +; pgp 9.5 +; reciprocal translocation between the long arms of chromosomes 11 and 22 (t[11:22]q24:q12)

Figures 13.28; 17.5A-C; 16.22,16.23 and 16.24


Rhabdomyosarcoma

Cellular smears; small- to medium-sized uniform cells with poorly defined cell borders; scant cytoplasm with high N/C ratios; granular chromatin with nucleoli; no nuclear molding; strap cells +/-; Desmin and muscle-specific actin +; neuroendocrine markers -; CD99 -; specific translocation: t(2;13)(q35; q14) for alveolar type

Figures 13.27; 16.13; 17.6A,B


Pituitary adenoma

Highly cellular; small round to polygonal cells; cell borders well to poorly defined; nuclei round, uniform with smooth nuclear membranes; coarsely granular chromatin; nucleoli -; mitoses absent; cytoplasm variable, scant to abundant; no cell processes; no necrosis; may form cords, ribbons or papillary structures, richly vascularized; granular background; neuroendocrine markers +

Figures 10.2,10.3,10.4,10.5,10.6 and 10.7


In adult population:


Sinonasal neuroendocrine carcinoma

Small cells, with scant indistinct cytoplasm, occur singly and in syncytial tissue fragments without any architectural patterns; nuclear molding +; deepstaining compact chromatin; nucleoli not appreciated; mitoses +; necrosis +; neuroendocrine markers +; thyroid transcription factor (TTF-1) +; cytokeratin +;

Figures 13.18A-C; 17.9A,B


Sinonasal undifferentiated carcinoma

Highly cellular, small- to medium-sized cells, discrete, in loosely cohesive groups and in syncytial tissue fragments; poorly defined cell borders; scant cytoplasm with high N/C ratios; granular chromatin with parachromatin clearing; nucleoli distinct; no nuclear molding; neuroendocrine markers -; cytokeratin +; EMA +

Figures 13.19A-E; 17.8A,B


Nasopharyngeal carcinoma

Malignant cells isolated, in groups and in syncytial tissue fragments without any architectural patterns; the neoplastic cells are medium sized with granular chromatin, parachromatin clearing and nucleoli; non-neoplastic lymphoplasmacytic infiltrate +/-; Immunoprofile: CK +; neuroendocrine markers -; Epstein-Barr virus (EBV) +

Figure 17.10A,B


Basaloid squamous carcinoma

Small basaloid cells either loosely cohesive or in syncytial tissue fragments with closely packed small cells, poorly defined cell borders, scant stroma and high N/C ratios; deep-stained nuclear chromatin; no nuclear molding; neuroendocrine markers -; cytokeratin +; p53 +

Figure 17.11A-C


Malignant non-Hodgkin lymphoma 1) B-cell type 2) peripheral T-cell type 3) extranodal NK/T-cell type

Depends on the type; 1) B-cell or T-cell types; highly cellular; cells isolated; 2-1/2 to 3 times the size of normal lymphocytes; round nucleus; nuclear membrane irregularity +/-; granular chromatin; nucleoli prominent; mitoses +; cytoplasm scant; no cell processes; necrosis +; background may contain reactive astrocytes; lymphoid markers +; monoclonal population; cytokeratin and neuroendocrine markers – Extranodal natural killer (NK)/T-cell type; shows a polymorphous cell population composed of normal-appearing small lymphocytes, plasma cells, immunoblasts and atypical lymphocytes, mitoses +; Immunoprofile: CD56 +; EBV +; CD3+

Figure 10.10


Malignant melanoma

Primary mucosal malignant melanoma, may present an undifferentiated small cell pattern; also present a pleomorphic cell pattern with spindle, plasmacytoid, epithelioid type cells+/-; melanin pigment +/-; Immunoprofile: strong reactivity with HMB 45, S100 protein and Melan-A; negative reactivity to neuroendocrine markers

Figures 17.12 and 6.11C


Paraganglioma

Monomorphic cell pattern; cells discrete, or in loosely cohesive groups; neoplastic cells small to medium with occasional giant forms; round to plasmacytoid, uniform, round, eccentric nuclei; granular chromatin with salt-pepper appearance; sometimes compact; intranuclear inclusions +/-; cytoplasm variable; may be drawn into delicate process; eosinophilic cytoplasmic granules with Romanowsky stain; mitoses absent; neuroendocrine markers +; S100 protein +

Figures 15.6; 15.7; 17.13A, B

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Jul 17, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Miscellaneous Neuroendocrine Tumors of the Neural Type: Olfactory Neuroblastoma and Central Neurocytoma

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