Pituitary adenomas account for between 10 and 25% of all intracranial neoplasms [3
]. It is well known that primary pituitary adenomas can grow in any direction, and so extension into the sphenoid sinus is expected in about 2–3% of cases [2
]. Extrasellar extensions are often larger than the intrasellar tumors [26
]. At the time of neurosurgery, the hormone function, clinical setting, and imaging findings are known by the endocrinologist, and head and neck and neurosurgeons, respectively, which gives the pathologist an easy setting in which to make the appropriate diagnosis. However, when the pituitary gland is normal, the sella turcica uninvolved, and the patient is presenting clinically with non-specific sinonasal tract symptoms, and a “sphenoid sinus” mass by imaging studies, the clinicians and pathologist are faced with a more daunting task of diagnosis and management. When considering the incidence of ESSPA, based on all surgical pathology cases at one institution, about 0.48% of pituitary adenomas are ectopic; approximately 2.5% of sphenoid sinus lesions are pituitary adenomas; but overall, 0.0000014% of all surgical pathology cases reviewed were ESSPA.
As seen in this clinical series, only one patient presented with a hormonally active tumor: Cushing syndrome as a result of ACTH production. However, the other 97% of this clinical series did not present with hormone-related signs or symptoms. This is in contrast to the literature, where 58% of the patients presented clinically with abnormal hormone production resulting in Cushing syndrome, acromegaly or amenorrhea/galactorrhea. This is probably due to the single case report nature of these patients and reflects publication in primarily clinical and imaging journals, rather than pathology journals (only 11% of cases were reported in pathology journals [12
Retrospective analysis of a specific tumor is a difficult undertaking in modern medicine, and even more so when the entity is rare. However, clinical presentation, gender differences, anatomic site of distribution, size, histologic, and immunohistochemical features, and patient outcome have not been well-characterized by single case reports. The information in this study is combined with that gleaned from the literature (Table ) in an attempt to more fully elucidate the nature of this uncommon tumor.
Combination of current study patients with literature review cases
There were 43 females and 32 males, suggesting a slight female predominance (1.3:1). A broad age range can be affected (2–84 years), but the majority of patients present in the 6th decade (mean, 53.8 years), without a gender difference. There is a trend towards patients presenting at a young age when tumors involve the sphenoid sinus and nasal cavity or nasopharynx, but this was not a statistically significant difference (p
= 0.095). Although the cases reported in the literature tended to present with a symptom complex related to hormone production, the overwhelming majority of cases in this series did not have clinical symptoms related to hormone excess (97%). Overall, patients presented with symptoms which were present for 48.8 months. The majority of symptoms were non-specific and related to the sinonasal tract, including obstruction, sinusitis, rhinorrhea, discharge, drainage, headache, and pain. The symptoms related to visual disturbances (diplopia, visual acuity loss, blurring, proptosis), nerve changes (paresthesia, paresis), and alterations in balance were probably related to a sphenoid sinus tumor expanding into the cavernous sinus or clivus, thereby affecting the corresponding cranial nerves. The patients who presented with symptoms related to hormone excess, were still likely to have symptoms for some time, since hypertension, acne, facial coarsening, hand, foot, nose, jaw and/or forehead enlargement, voice deepening, fatigue, malaise, impotency and amenorrhea are also non-specific, frequently managed medically or symptomatically before additional evaluation is performed. It is also important to remember that ectopic pituitary hormones may also be secreted by bronchial and gastrointestinal neuroendocrine tumors, as well as pulmonary small cell carcinoma and ovarian small cell carcinoma, among other tumor types. Therefore, evaluation of patients with hormone production is not just limited to pituitary and midline sinonasal tract locations. Only three patients presented with epistaxis, but it was not in isolation, and was a symptom which brought the patients to clinical attention after many years of other non-specific symptoms. Finally, about 8% of all patients evaluated were asymptomatic (19% of this clinical study). These tumors were incidentally discovered during evaluation for another reason, most commonly in the setting of metastatic work-up. It is in this latter clinical scenario that the pathologist must be even more vigilant, avoiding the trap of misdiagnosing the tumor as a metastatic neoplasm. Interestingly, in the asymptomatic patients who were being evaluated because of other malignancies, two presented with silent
lactotroph adenomas; one with a functional lactotroph adenoma; and one unclassified, plurihormonal adenoma. This is different from patients with intrasellar tumors who also have another primary: in this latter group, the tumors are usually functional somatotroph adenomas (GH), with colonic primaries the most likely finding [48
Laboratory investigation for elevated pituitary hormones, with and without stimulation or suppression testing, is recommended, as the current classification is based on functional status. Even though the patient may not yet have a symptom-complex related to hormone excess, it is important to document serologic elevation of hormones. The old pneumonic of “FLAG TOP” may help in performing the necessary evaluation, including FSH, LH, ACTH, GH, TSH and PRL. Oxytocin is produced by the posterior pituitary (neurohypophysis), which is embryologically distinct from the anterior pituitary, and therefore is not associated with sphenoid sinus tumor development. Axiomatic, the term “silent” adenoma should not really be used unless there is no evidence clinically or biochemically of an abnormality. This is often difficult to achieve by the pathologist, since an inadequate or incomplete clinical work-up should not be the reason to render the diagnosis of a “silent” adenoma. Therefore, in this series, where the exact clinical evaluation was not always known to the pathologist, it is possible that the term “silent” was used just to pigeon-hole the case instead of implying there was truly a silent lesion.
It is most important that appropriate imaging studies are performed as part of the evaluation of these ectopic tumors. Part of the definition for an ESSPA is that the sella turcica is uninvolved and that the pituitary gland is normal. Intraoperative assessment of the sella and pituitary can be performed, but pre-operative imaging evaluation will yield the most clinically useful information. Not only will imaging studies document a normal pituitary and sella turcica, but they will also highlight the size of the tumor, give information about the margins and extent of the tumor, and allow for appropriate surgical planning [19
]. It is most important to exclude an invasive pituitary adenoma into the sphenoid sinus, a much more common finding than the ectopic pituitary adenoma. CT and MRI studies can detect abnormalities that are greater than 3 mm within the pituitary gland [48
], with MRI reported to be more sensitive for pituitary gland evaluation and giving precise information about the relationship to the sphenoid sinus. Specifically, the imaging studies demonstrate a well-defined tumor margin, often with bony sclerosis, distinct and separate from the normal, uninvolved intrasellar pituitary gland. Bone destruction with expansion into the cavernous sinus was a frequent finding. MRI shows mild to moderate heterogenous contrast-enhancement, without a unique T1- or T2-weighted image intensity. Non-enhanced CT shows tumors that are iso- to hypo-dense to grey matter, showing modest enhancement in post-contrast studies [26
Most tumors affected the sphenoid sinus alone, but it was not uncommon to have expansion into the adjacent nasopharynx or nasal cavity. Tumors were generally large for the anatomic site, with an average size of 2.9 cm for all cases evaluated. The tumors usually filled the sphenoid sinus. There was no difference in tumor size between males or females (p = 0.312). As expected, as the tumors expanded into adjacent structures, the average size increased, a finding which was statistically significant (p = 0.015). The macroscopic appearance of the tumors was non-specific and usually described as multiple fragments of tissue, ranging from firm to gelatinous and vascular.
An intact respiratory surface epithelium was present in most cases. Although absent in several, the surface epithelium was not destroyed or affected by the neoplasm. This may help in separating ESSPA from other neoplasms in the differential diagnosis, such as neuroendocrine carcinoma (NEC) and sinonasal undifferentiated carcinoma (SNUC), which frequently destroy the surface epithelium. Olfactory neuroblastoma is usually separate from the surface epithelium, but arises from the ethmoid sinus, associated with the cribriform plate. Melanoma may involve the surface epithelium with a “junctional” component, but more often than not, the surface epithelium is ulcerated and lost due to the neoplastic growth.
ESSPA are frequently associated with bone invasion or involvement, a function of their anatomic site rather than necessarily biologic aggression. Necrosis can also be seen in about 25% of cases. When present, other histologic features would need to be used to help separate the tumor from other lesions in the differential diagnosis. A richly-vascularized stroma is a common finding, separating the tumor nests into a variety of different patterns of growth. However, many cases show a heavily collagenized and sclerotic fibrosis. The neoplastic cells are often difficult to see in this pattern of growth. Therefore, when evaluating samples from the sphenoid sinus that seem to be “fibrosis only,” careful high-power examination should be performed in order to make certain isolated neoplastic cells are not entrapped in the fibrosis. Invariably, small collections of neoplastic cells are present, but only discovered after diligent high-power review. Immunohistochemistry studies could be performed to highlight the cells, realizing that both a keratin and neuroendocrine marker would need to be performed to make certain the cells are captured. Perineural and lymph-vascular invasion were not identified in these tumors. This is a very helpful feature in the differential diagnosis, especially when one considers that significant lymph-vascular invasion and midline destruction can be caused by other tumors in the differential diagnosis.
Whenever there are many patterns of growth within a tumor, a neuroendocrine neoplasm should quickly rise to the top of the differential diagnostic considerations. While one pattern may dominate, there are usually several different patterns of growth in a pituitary adenoma. Even though described as “solid,” there is still a very rich, albeit delicate fibrovascular stroma separating the tumor into smaller nests or islands. A true “lobular” pattern is not usually appreciated. Pseudorosettes, especially as they are arranged around vessels in a palisaded appearance, are seen in about one-third of cases. The glandular architecture, with a lumen, can cause some diagnostic difficulty. Secretions or concretions may also be seen. However, this is usually an isolated finding, and not one that is dominant. In general, the tumors have a low to moderate cellularity. This means there is quite a bit of space between nuclei of the neoplastic cells: at least the width of two nuclei or at least the nuclei are approximating one another. When there is nuclear overlapping and crowding, then a high cellularity is identified (but this was not common among our cases). Again, in this setting, the differential diagnoses need to be carefully considered and excluded.
Most tumors contained small polygonal to plasmacytoid cells with a low nuclear to cytoplasmic ratio and ample cytoplasm surrounding the nuclei. The Golgi space adjacent to the nucleus was frequently easy to see, helping to suggest the neuroendocrine nature of the lesion. Although quite variable throughout a tumor, a delicate salt-and-pepper nuclear chromatin distribution was present. A delicate, even nuclear chromatin distribution with focally vesicular change was also noted. When the chromatin was open, nuclear grooves and folds became easier to detect. Nucleoli were usually inconspicuous to small. Large, irregular nucleoli were uncommon, and when present, suggested other tumors in the differential diagnosis. When the cells were smaller, a more hyperchromatic appearance was seen. Intranuclear cytoplasmic inclusions were identified in the majority of cases. This finding can also be seen in mucosal melanoma and meningioma, but in general the other histologic features are quite different and so the appearance of this feature can aid in correct diagnosis. Fibrous bodies in the cytoplasm were detected in three cases, but were not specifically correlated to a tumor type (prolactin; multiple hormones). Tumor multinucleation was also frequent. Tumor giant cell formation could be seen too (endocrine organ atypia), but the multinucleation of several small nuclei is different from several other tumors in the differential diagnosis. Finally, mitoses were usually inconspicuous, infrequent, and never atypical. Therefore, when evaluating a sphenoid sinus tumor, the lack of mitoses or identification of only isolated mitoses may help in making an accurate diagnosis.
There are approximately 14 recognized primary pituitary adenoma subtypes, with a very specific morphologic, immunohistochemical, ultrastructural and biologic classification scheme [47
]. More recent classifications separate tumors based on symptoms and blood hormone levels, neuroimaging and intraoperative data, tumor size, histologic criteria, immunohistochemistry, and ultrastructure [49
]. Furthermore, many immunohistochemistry markers obviate the need for ultrastructural examination, except in the most unusual of circumstances [3
]. Therefore, in general, tumors are separated into “functional” and “non-functional”, with additional separation into specific families based on immunohistochemistry findings, while the terms “microadenoma” and “macroadenoma” are employed if the tumors are <1 or >1 cm, respectively. The non-functioning tumors are referred to as “silent” adenomas, and encompass all six hormones normally produced by the adenohypophysis (GH, TSH, PRL; ACTH; FSH, LH). Again, the term “silent” should only be accurately applied when a full work-up (clinically and biochemically) is negative—perhaps difficult for a pathologist to assess at the original diagnosis.
Given the wide variety of classifications employed, a modification is presented to categorize ESSPA (Table ). Although a new classification scheme cannot possibly be suggested without pituitary transcription factor evaluation in addition to other ancillary studies, this model may be useful in future classifications of these tumors. In this system, tumors are classified as functional and nonfunctional. Functional tumors are defined by symptoms related to a specific hormone production, or evidence of serologic hormone elevation. Nonfunctional tumors are defined as not producing serologic hormone elevation, but producing immunohistochemical evidence of a specific hormone. Then the tumors are separated into specific families based on similarities of histologic appearance, immunohistochemistry, or ultrastructural features. When more than one hormone is produced, excluding the combination of PRL and GH (which is given a specific designation based on laboratory findings), then the tumor is placed in the “unclassified, plurihormonal adenoma” category. For the combined PRL and GH producing adenomas, they are separated into nonfunctional and functional, with the latter further separated into lactotroph or mammosomatotroph group depending on which serologic value dominates clinically. Tumors which were tested for all six hormones and were negative were referred to as unclassified, silent adenomas. However, this is not a true “null-cell” category. It is well-known that current pituitary transcription factors can be employed in these cases to yield a specific subtype when other techniques have failed. However, in this retrospective review study with only limited material, definitive classification could not always be reached. As can be seen from the cases in this study combined with the literature, the majority of cases fell into the GH-Prolactin-TSH family of adenomas, with two-thirds functional and one-third clinically silent
. The next largest group were the unclassified adenomas, with plurihormonal adenomas (n = 12) and silent
adenomas (n = 13) comprising this group (see explanation above). Similar to intrasellar primaries, prolactinomas and unclassified silent adenomas are the most common subtypes [3
]. Even though we only had a single child in the series, this ESSPA was a corticotrophinoma, known to be the most common pituitary tumor in pre-pubertal children [2
Categorization of ectopic sphenoid sinus pituitary adenomas
In general, the immunohistochemistry profile of ESSPA is identical in distribution and pattern to their intrasellar counterparts. It is most important to realize that the evaluation of ESSPAs is nearly always driven by the differential diagnosis with other tumors of this area. Therefore, a primary pituitary hormone panel, to include pituitary transcription factors, is not usually performed up-front. It is not the intention of this paper to suggest that a more thorough evaluation of these ectopic tumors not be undertaken by performing these additional studies. The thrust of this description is to make sure that a diagnosis of pituitary adenoma is rendered instead of the other diagnoses in the differential. A variety of neuroendocrine markers can be used, with synaptophysin and CD56 providing the most sensitive results. Chromogranin and NSE are positive in 70.8 and 76.5%, respectively. There was only 1 case in which NSE and chromogranin were reactive in which synaptophysin was negative (all hormones were also negative in this case); and there was 1 case that was negative with CD56, that was positive for synaptophysin and NSE, while negative for chromogranin and all hormone markers. Therefore, when evaluating a tumor which may represent an ESSPA, the neuroendocrine markers should include synaptophysin and CD56.
The tumors generally showed a keratin reaction, with pan-keratin reactive in 78.6%, increased to 85.8% if CAM5.2 was also performed. The presence of a Golgi dot-like pattern in 45% of cases was an additional helpful feature in the diagnosis, since most of the tumors in the differential diagnosis do not usually show this pattern of reaction. There is no reaction with CK5/6 or CK7, findings that are most helpful in the differential diagnosis. Likewise, S100 protein was negative in nearly all cases tested. There was neither sustentacular arrangement (as would be seen in olfactory neuroblastoma) nor a diffuse cytoplasmic reaction (as expected in mucosal melanoma).
It is difficult to specifically give guidance on the pituitary hormones to evaluate, since they should all be tested in an ideal setting to give a correct classification based on the proposed system in Table . Prolactin is the most frequently identified hormone, but GH, ACTH, LH, FSH, and TSH are all variably present. It is important to note that more dilute antibody titers may decrease the perceived plurihormonal results. By this we mean, if the concentration of the FSH and TSH were decreased (made more dilute), it is possible that the analyte would not be detected. Therefore, the monoclonal antibody used and dilution are critical in interpretation. If more than one hormone is identified when the six have been tested, then the classification system allows for a specific subclassification. In many cases, the patient symptoms or serologically elevated hormone levels dictated which immunohistochemistry to perform on the tumor. However, it is important to note that serologic elevation of a hormone may not be the only hormone identified in the tumor by IHC. Therefore, it is prudent to perform the battery of pituitary hormone studies for exact classification and potential management decisions. Specifically, pituitary transcription factors, such as Pit-1, T-pit, SF-1, ER-α, and GATA-2 can be performed to help yield a specific classification. Needless to say, since many of the cases in this series did not have sufficient material to perform these studies, there is, no doubt, a significant number which are placed in the “null-cell” or “silent” category that would otherwise have been placed into a specific classification were material available.
The finding of calcitonin is unique. Laryngeal neuroendocrine tumors are known to express calcitonin [53
]. However, pituitary neoplasms are not known to produce calcitonin. A calcitonin gene-related peptide or m-CEA could not be performed to confirm this finding.
ESSPA is a very commonly misdiagnosed tumor. In 22 of 25 cases in which a diagnosis was postulated by the contributing pathologist, the diagnosis was incorrect. The most frequent misclassification was olfactory neuroblastoma, followed by neuroendocrine carcinoma (NEC), sinonasal undifferentiated carcinoma (SNUC), melanoma, meningioma, nasopharyngeal carcinoma, paraganglioma, metastatic “carcinoid” (submitted diagnosis), and lymphoma. The pattern of growth and immunohistochemistry findings would immediately eliminate lymphoma from further consideration.
Olfactory neuroblastoma (ONB) is a neuroectodermal-derived neoplasm, which is the most commonly misdiagnosed category for ESSPA. Clinically, nearly all of the tumors are hormonally silent, with non-specific clinical signs and symptoms. By imaging studies, the tumors are centered within the ethmoid
sinus, nearly always involving the cribriform plate. The tumors show a significant intracranial expansion in many cases, giving a “dumb-bell” shaped tumor mass across the cribriform plate. The tumors are typically arranged in a lobular configuration (although a lobular and diffuse pattern can be seen), showing pseudorosettes or true rosettes in about 30% of all cases. There is often a neural matrix background. The lesional cells are usually small with scant cytoplasm. The nuclei may show a salt-and-pepper nuclear chromatin distribution. Nucleoli are inconspicuous and mitoses are rare in the low-grade tumors. While high-grade tumors may present a more difficult diagnosis, low-grade tumors are usually quite straight forward. The tumor cells are reactive with neuroendocrine markers, including synaptophysin, chromogranin, NSE, and CD56. However, there is a delicate S100 protein sustentacular supporting framework reactivity. It is known that pituitary adenoma within the sella can show a sustentacular reaction with S100 protein due to folliculostellate cells, which are modified glial cells [54
]. However, this is an uncommon phenomenon. Keratins are negative in 95% of ONB cases. When keratin is reactive, it is limited to isolated cells and is not in a dot-like distribution. The specific anatomic site, lobular architecture, and unique immunohistochemical profile should allow for an accurate separation [55
]. The distinction from ESSPA is important, since the management for ONB may involve major, destructive bi-craniofacial surgery (trephination) and possible additional potentially toxic radiotherapy and/or chemotherapy, with a very different prognosis. Endoscopic management is used in some cases, but surgery is still the main treatment.
As a group of tumors, neuroendocrine carcinoma (NEC) of the sinonasal tract are very poorly understood and classified. Without going into an extensive discussion of this group of lesions, small cell carcinoma, neuroendocrine type (SCCNET) and large cell undifferentiated neuroendocrine carcinoma (LCUNC) generally present in the upper nasal cavity with maxillary and ethmoid sinus involvement. Patients often present with epistaxis. There is generally a destructive pattern of growth. Histologically, either tumor usually has a very high grade appearance, showing nuclear molding, smudging and crush artifact. The appearance is similar to histologic counterparts in the lung. There are many mitoses, including atypical mitoses. There is no neurofibrillary matrix material. These tumors express keratin in a dot-like pattern, and have neuroendocrine marker reactivity; however, specific pituitary peptide markers are not present, with rare exceptions showing ACTH and antidiuretic hormone. While ESSPA may have pleomorphism, the pattern of growth and destruction is not the same as NECs. Furthermore, NEC will frequently have metastatic disease at presentation, with an associated high mortality rate. The separation is obviously important, as the patient management with combination radiation and chemotherapy, combined with their toxic side effects and dismal outcome is remarkably different [29
]. Metastatic neuroendocrine tumors (previously used to include carcinoid) may be considered in the differential diagnosis, but in general, these tumors will have increased mitoses, a high proliferation index, a known history of a primary tumor elsewhere, and would probably not have pituitary hormone expression. We hasten to add, however, that inappropriate expression of selected pituitary hormones (ACTH, CRH, GHRH) can be seen in neuroendocrine tumors from other body sites, and so this differential may require additional clinical and imaging correlation. A variety of tumors in the sinonasal tract can co-express neuroendocrine markers, including sinonasal adenocarcinomas, sinonasal undifferentiated carcinoma, melanoma, and desmoplastic round cell tumor, among others. However, it is always important to realize that positive neuroendocrine markers in a tumor do not always confer upon the tumor a different diagnosis or a different diagnostic category. Melanomas are known to express neuroendocrine markers since melanocytes are of neural crest origin, while sinonasal undifferentiated carcinoma may also show immunophenotypic heterogeneity and plasticity along with lineage infidelity. Therefore, strict adherence to histologic criteria, focused immunohistochemical evaluation that may encompass several overlapping markers, with targeted molecular studies should help to keep categories more pure and reproducible.
Paraganglioma of the sinonasal tract is a vanishingly rare neoplasm, with only isolated cases reported. They would be keratin negative, similar to a few ESSPA cases. The zellballen architecture would be highlighted by an S100 protein reaction, a feature not seen in ESSPA. Furthermore, paraganglioma would be positive with tyrosine hydroxylase, while negative for both pituitary hormones and pituitary transcription factors [60
Sinonasal undifferentiated carcinoma (SNUC) presents with a rapid clinical onset of obstruction, epistaxis, proptosis, facial pain and CN involvement. The imaging features demonstrate extensive infiltration of many different sites within the sinonasal tract, resulting in significant destruction. The tumors are not usually centered on the sphenoid sinus. The tumors are high grade neoplasms, perhaps showing surface dysplasia or carcinoma in situ. The cells are generally large, showing a high nuclear-to-cytoplasmic ratio and variable amounts of poorly-defined cytoplasm. The nuclei range from hyperchromatic to vesicular, with variably present nucleoli. Mitoses are greatly increased and include atypical forms. Confluent tumor necrosis is usually easily seen. Lymph-vascular and perineural invasion is seen in most cases. Rosettes and neurofibrillar matrix are absent, as are areas of squamous or glandular differentiation. These tumors are strongly positive with pan-cytokeratin and CK7, while non-reactive with CK5/6 and CK13. Occasional cases may show neuroendocrine markers (such as chromogranin, synaptophysin, CD56 or CD57), but reactivity is usually weak and limited. Pituitary hormone and transcription factors are negative [63
]. Again, the management with multimodality therapy is very different from the management for ESSPA, with a very different prognosis and outcome.
Mucosal malignant melanoma (MMM), when it is non-pigmented, may present with a pattern of growth similar to pituitary adenoma. However, MMMs are usually large tumors centered within the nasal cavity or paranasal sinuses, usually not presenting with sphenoid sinus tumor only. The tumors are very cellular, show a remarkable variety of growth patterns and may have necrosis. The presence of intranuclear cytoplasmic inclusions, prominent nucleoli, plasmacytoid growth, and tumor cell multinucleation may give findings similar to an ESSPA. However, the application of the selected, pertinent immunohistochemistry panel would help with separation, as melanoma will show S100 protein, HMB-45 or Melan-A reactivity, while negative with keratins and pituitary hormones or transcription factors, and nearly always negative for neuroendocrine markers (chromogranin, synaptophysin, CD56) [58
A meningothelial pattern is not seen in ESSPA, but the presence of intranuclear cytoplasmic inclusions, a sheet-like to packeted growth, and isolated psammoma calcifications can raise the differential diagnosis of meningioma. However, meningioma is usually positive with EMA and CK7 (in a pre-psammoma body like pattern), while negative with neuroendocrine and pituitary hormone markers [68
Nasopharyngeal carcinoma (NPC) may be raised in the differential diagnosis of ESSPA with nasopharyngeal extension. The syncytial epithelial architecture, especially when the inflammatory element is prominent, is not a pattern seen in ESSPA. Occasionally, the epithelioid appearance with prominent nucleoli may result in incorrect diagnosis. However, NPC are strongly immunoreactive with pan-cytokeratin, CK5/6, p63, and nearly all cases are reactive with Epstein Barr virus-encoded RNA (EBER). There is a lack of neuroendocrine tumor markers as well as pituitary hormones [70
In summary, the following considerations will greatly aid in the appropriate classification of ESSPA: (1) The anatomic site: Sphenoid sinus. As soon as the anatomic site is known, ectopic pituitary adenoma must be considered and actively excluded; (2) Imaging findings: The specific location and presence or absence of pituitary gland or sphenoid sinus involvement will help. Specifically, there is a lack of significant nasal cavity destruction; (3) The histologic appearance shows a variety of patterns of growth, nearly always associated with a very delicate fibrovascular stroma. Necrosis can be seen, and should not dissuade from the diagnosis. The presence of intranuclear cytoplasmic inclusions, tumor multinucleation, isolated pleomorphism, and a plasmacytoid appearance can considerably narrow the differential diagnosis; (4) The immunohistochemistry evaluation must include pan-keratin, a couple of neuroendocrine markers (synaptophysin and CD56), S100 protein, and then, depending on these results, a panel of pituitary hormone markers and/or transcription factors. Finally, in selected cases only where the tumor is a true “null-cell” neoplasm, without hormone or transcription factors present, electron microscopy can be used to disclose the specific features seen in true silent pituitary adenomas, such as silent subtype III adenomas and acidophil stem cell adenomas.
Treatment and Prognosis
Surgical removal is the treatment of choice for ESSPA. Specifically, during surgery additional evaluation of the roof of the sinus and the sella turcica can be performed to help guide additional management. Margins are not usually assessed for these tumors, since they are usually removed in pieces. Various medical therapies have been employed, with bromocriptine (a dopamine agonist) used most frequently for PRL secreting tumors, effectively reducing their size [4
]. However, medical management is not a cure, with drug effects identified only while medical therapy is ongoing. Therefore, when medication is stopped, the tumor may regrow. Therefore, if a dopamine agonist is employed, it should be continued for the patient’s life [46
]. There are potential benefits of initial medical therapy in an attempt to reduce the size of the tumor, but frequently the pre-operative diagnosis is not correct, limiting medical therapy to the post-operative setting.
Radiotherapy has been employed for these tumors in selected cases. Radiation was used in five patients in this series: 3 at the time of initial diagnosis, and 2 at the time of recurrence. There are well-known risks of radiation to this area, including macular ischemia, vasculopathy and even optic neuropathy. Furthermore, radiotherapy is not very effective in tumor control for tumors of the pituitary fossa [50
], and so likewise, is probably not effective in ectopic foci either. Therefore, in selected cases, if the tumors are large or incompletely excised, post operative radiotherapy may be indicated for tumor control, although not cure [4