6 Pathology of the Skull Base Tumors • Skull base tumors are a diverse group of neoplasms with different clinical, biological, and pathological features. • They vary from benign, clinically indolent lesions to very aggressive malignancies that have a dismal prognosis. • Both the biological behavior and anatomic location of the tumor have to be considered. • Tumors of the skull base can arise from a wide array of tissues and may originate intracranially, extracranially, or from the skull base itself. The skull base can also be involved with systemic neoplasms (hematologic malignancies and metastases) and benign cysts. • Despite this heterogeneity, the differential diagnoses can often be narrowed based on the location of the lesion (Table 6.1). • Immunohistochemistry is a useful tool for differentiating tumors that have a similar morphological appearance (Table 6.2). Pilocytic astrocytoma is a relatively slow-growing, well-circumscribed tumor, World Health Organization (WHO) grade I1, likely of astrocytic origin occurring anywhere along the neuraxis. Table 6.1 Anatomically Based Classification of Skull Base Tumors
Key Points
Definition
Classification
Intracranial Tumors: Tumors of the Nervous System
Pilocytic Astrocytoma (Optic Pathway Glioma)
Anterior Skull Base |
|
Intracranial | Meningioma, optic pathway glioma |
Sinonasal tract | Inverted papilloma, nasopharyngeal angiofibroma, squamous cell carcinoma, adenocarcinoma, adenoid cystic carcinoma, sinonasal undifferentiated carcinoma, esthesioneuroblastoma, mucosal melanoma, sinonasal lymphoma |
Orbit | Cavernous hemangioma, capillary hemangioma, lymphangioma, melanoma, retinoblastoma, lymphoma, optic pathway glioma, optic nerve sheath meningioma, osteoma, orbital rhabdomyosarcoma |
Middle Skull Base |
|
Sellar/suprasellar | Pituitary adenoma, meningioma, craniopharyngioma, germ cell tumors, pilocytic astrocytoma/optic pathway glioma, nasopharyngeal carcinoma, sinonasal carcinomas, (epi)dermoid cyst, Rathke cleft cyst, arachnoid cyst |
Pterygopalatine/infratemporal fossae | Meningioma, schwannoma, lymphoma, ameloblastoma, adenoid cystic carcinoma, juvenile nasopharyngeal angiofibroma, hemangioma, squamous cell carcinoma, chondrosarcoma |
Posterior Skull Base |
|
Petrous apex | Chondrosarcoma, meningioma, chordoma, plasmacytoma, paraganglioma, endolymphatic sac tumor, schwannoma, cholesterol granuloma, mucocele, epidermoid cyst |
Cerebellopontine angle | Schwannoma, meningioma, epidermoid cyst, arachnoid cyst |
Jugular foramen | Paraganglioma, schwannoma, meningioma |
Clivus | Chordoma, chondrosarcoma, meningioma, plasmacytoma |
Foramen magnum | Meningioma, schwannoma, chordoma, chondrosarcoma, fibrous dysplasia |
Craniocervical junction | Meningioma, neurofibroma, chordoma, bone tumors |
Table 6.2 Common Antibodies in Skull Base Tumors168
Antibody | Tumor(s) |
Brain, Neuroendocrine, Meninges |
|
Glial fibrillary acid protein (GFAP) | Astrocytoma, nasal glial heterotopia, schwannoma (variable), esthesioneuroblastoma (variable), endolymphatic sac tumor (variable) |
Synaptophysin | Paraganglioma, esthesioneuroblastoma |
Chromogranin | Paraganglioma, esthesioneuroblastoma |
S100 | Schwannoma, neurofibroma, astrocytoma, chordoma, melanoma, paraganglioma (sustentacular cells), esthesioneuroblastoma (sustentacular cells), meningioma (variable) |
EMA | Meningioma, chordoma, nasopharyngeal carcinoma, adenocarcinoma, sinonasal undifferentiated carcinoma, squamous cell carcinoma (variable), arachnoid cyst |
GH, PRL, TSH, ACTH, LH, FSH, α-subunit | Pituitary adenoma (see text) |
Germ cells |
|
α-fetoprotein | Yolk sac tumor, teratoma (variable) |
β-HCG | Choriocarcinoma |
Human placental lactogen (HPL) | Choriocarcinoma |
Placental alkaline phosphatase (PLAP) | Germinoma, embryonal carcinoma, yolk sac tumor (variable), choriocarcinoma (variable) |
C-kit | Germinoma, teratoma (variable) |
OCT4 | Germinoma, embryonal carcinoma |
Cytokeratins |
|
AE1/AE3 | Wide panel that stains most epithelium (does not include cytokeratins [CK] 8 and 18) |
CAM5.2 | Panel that includes CKs 8, 18, and 19; used with AE1/AE3 in screening panel |
CK5/6 | Low molecular weight keratins that are positive in squamous cell carcinoma (not adenocarcinoma) |
Soft tissue |
|
CD34 | Hemangiopericytoma, normal endothelium |
Desmin | Muscle differentiation, including rhabdomyosarcoma |
Vimentin | Most mesenchymal cells; soft tissue tumors, meningioma |
Myogenin | Rhabdomyosarcoma |
CD99 | |
Hematopoietic |
|
CD45 | Lymphocytes but not plasma cells |
CD20 | B-cells (and related lymphomas) |
CD3 | T-cells (and related lymphomas) |
CD56 | NK cells, NK/T-cell lymphoma |
CD79a | B cells (and lymphomas) and plasma cells (and myeloma) |
CD138 | Plasma cells, myeloma/plasmacytoma |
Melanocytic |
|
HMB-45 | Melanoma |
Melan-A | Melanoma |
Abbreviations: ACTH, adrenocorticotropic hormone; EMA, epithelial membrane antigen; FSH, follicle-stimulating hormone; GH, growth hormone; HCG, human chorionic gonadotropin; LH, luteinizing hormone; NK, natural killer; PRL, prolactin; TSH, thyroid-stimulating hormone.
• Relevant to the skull base, pilocytic astrocytomas commonly occur along the optic pathway (optic nerve, chiasm, hypothalamic region), and hence are termed optic pathway gliomas (OPGs).
• In children, the optic pathway is the most common supratentorial site. Overall, 25% involve only the optic disk and nerve, but 40 to 75% involve the chiasm. Of these, 33 to 60% also involve the hypothalamus or third ventricle.2
Epidemiology
Pilocytic astrocytomas account for 3 to 5% of childhood intracranial tumors.3
• Typically, the mean age of onset is 9 years, but OPGs have been reported in patients up to 79 years of age; males and females are affected equally.4
• Optic pathway gliomas are seen in 11 to 30% of individuals with neurofibromatosis type 1 (NF1).5
Pathology
Pilocytic astrocytomas are soft, gray, and generally well circumscribed; often they are cystic.1 OPGs involving the optic nerve show fusiform enlargement and kinking. Microscopically, the tumor shows a biphasic pattern of growth, consisting of compacted bipolar cells with Rosenthal fibers and looser multipolar cells with microcysts and eosinophilic granular bodies. Tumors exhibit either perineural or intraneural growth, with sporadic cases favoring the latter and NF1 patients the former.4
Diagnostic Criteria for Neurofibromatosis Type 16
Two or more of the following:
• Six or more café-au-lait spots ≥ 5 mm in diameter in prepubertal individuals and ≥ 15 mm in postpubertal individuals
• Axillary or inguinal freckles
• Two or more typical neurofibromas or one plexiform neurofibroma
• Optic pathway glioma
• Two or more iris hamartomas (Lisch nodules)
• A distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex, with or without pseudarthrosis
• First-degree relative with NF1 by above criteria
Prognosis
Generally, the prognosis is favorable, as OPGs are slow growing and low grade.
• The presence of NF1 and an anterior location are favorable factors, whereas younger age at presentation confers a poorer prognosis.7
• Optic pathway gliomas involving the chiasm, hypothalamus, or third ventricle fare worse than those involving the anterior visual pathway or the optic nerve alone and tend to have higher rates of recurrence.8
Schwannoma
Schwannoma is a benign encapsulated tumor, WHO grade I9, arising from the Schwann cells that support peripheral nerves.
• Schwannomas are the main peripheral nerve sheath tumor that should be considered in the skull base, usually from the vestibular divisions of cranial nerve (CN) VIII (90%).10
• Less commonly, they can also be associated with the CNs V (second most common),11 VII (third most common),12 IX, X, XI, and XII. Very rare localizations are CN IV (probable origin of some of the described tentorial schwannomas), greater superficial petrosal nerve, ethmoidal nerves (the latter as the probable cause of the “anterior skull base” schwannomas).
• Terms such as acoustic neurinoma or neuroma are incorrect.
Epidemiology
Schwannomas represent 8% of intracranial tumors and 85% of cerebellopontine angle (CPA) tumors.10
• Approximately 4% are in the setting of neurofibromatosis type 2 (NF2) and in 5% are multiple but not associated with NF2.13 Men and women are affected equally, usually in the fourth to sixth decades.9
Pathology
Schwannomas appear as globoid masses measuring a few centimeters in size, sometimes with cystic or hemorrhagic components.
• Microscopically, neoplastic cells have a characteristic histology that falls into two intermixed patterns:
Antoni A pattern is composed of compact, elongated cells with occasional nuclear palisading (Verocay bodies), although this is less common with intracranial schwannomas.
Antoni B areas are less cellular, with loosely textured cells, indistinct process, and variable lipidization (the most typical in the CPA schwannomas).9
• Cystic and hemorrhagic degeneration may be present.
• A bizarre nuclear appearance, cytoplasmic-nuclear inclusions, and occasional mitotic figures are known as “ancient” changes and are not features associated with malignancy.
• Thick-walled, hyalinized blood vessels may be present.
• Variants of the classic morphology include cellular (hypercellular with predominant Antoni A tissue), plexiform (plexiform or multinodular growth pattern, which is not common in intracranial schwannomas as this usually involves a nerve plexus), and melanotic (pigmented cells containing melanosomes).
• Immunohistochemistry: tumor cells strongly express S100 and may focally express glial fibrillary acid protein (GFAP). All tumor cells possess a surface basal lamina, which can be stained using collagen IV or visualized by electron microscopy.
• Malignant change in schwannoma is exceptionally rare14
Treatment and Prognosis
Schwannomas are benign and slow-growing tumors. Cellular schwannomas tend to recur more commonly (30–40%).15
Neurofibroma
Neurofibroma is a tumor consisting of a mixture of cell types (Schwann cells, perineurial-like cells, fibroblasts) either growing in a well-circumscribed intraneural or diffusely infiltrative extraneural fashion. It occurs in peripheral nerves/plexus, skin, and, more rarely, orbit, spinal roots, or cranial nerves.
Schwannomas and Neurofibromatosis Type 2
• Schwannomas are one of the tumors associated with NF2, an autosomal-dominant syndrome that occurs much less frequently than NF1, with a prevalence of 1 in 50,000.16
• NF2 is a tumor suppressor and its mutation results in loss of expression of its protein product merlin.17,18
• Patients may have benign and hamartomatous lesions of Schwann and meningothelial cells.
• The presence of bilateral vestibular schwannomas is a diagnostic feature of this syndrome.
• NF2-associated schwannomas are similar to their sporadic counterparts, but there are some special features: earlier presentation, higher proliferative indices, and increased entrapped facial nerve fibers
Diagnostic Criteria for Neurofibromatosis Type 216
• Bilateral vestibular schwannomas
• A first-degree relative with NF2 AND
Unilateral vestibular schwannoma OR
Any two of: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities
• Unilateral vestibular schwannoma AND
Any two of: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities
• Multiple meningiomas AND
Unilateral vestibular schwannoma OR
Any two of: schwannoma, glioma, neurofibroma, cataract
• Multiple or plexiform neurofibromas are associated with the neurofibromatosis type.
Epidemiology
Neurofibroma is sporadic or associated with NF1. It has no sex predilection, and all ages are affected.
Pathology
Solitary neurofibromas are well circumscribed and fusiform.
• Plexiform neurofibromas have a “bag of worms” appearance (NF1).
• Microscopically, neurofibromas are composed mostly of Schwann cells with spindled nuclei and fibroblasts, on a background of collagen and myxoid material that may appear in bundles (“shredded carrots”).
• Immunohistochemistry: invariably positive for S100.
Prognosis
Tumors of major nerves or of a plexiform pattern may transform to malignant peripheral nerve sheath tumors.
Meningothelial and Dural-Based Tumors
Meningioma
Meningiomas arise from arachnoid cap cells and usually appear grossly as a well-demarcated solid mass with broad dural attachment.19
• Invasion of the dura is common, sometimes with hyperostotic changes in the overlying skull.
• In 2 to 9% of cases, the meningioma appears en plaque, showing flat, plate-like growth.20
• Multiple meningiomas occur in less than 10% of cases, often in association with NF2.21
Epidemiology
Overall, meningiomas are the most common primary intracranial tumor with an incidence of 13 per 100,000 and occur mainly in middle-aged to elderly patients.19 They are more common in women (2:1).
Location
Intracranial meningiomas occur most commonly over the convexities, sometimes parasagittal in association with the falx. Other common sites include the anterior skull base (olfactory groove, planum sphenoidale), sphenoid wing, sellar/suprasellar region, optic nerve sheath, petrous ridge (CPA), tentorium, and posterior fossa.
• Higher grade meningiomas may metastasize outside the central nervous system (CNS), with the most common sites of involvement being the lung, pleura, bone, and liver.22
Pathology
Microscopically, meningiomas have diverse histological appearances and can fall into WHO grades I to III.19
• 80% grade I; 15–18% grade II; 2–5% grade III.19,23
• Common immunohistochemical markers for meningiomas include epithelial membrane antigen (EMA), vimentin, and progesterone receptor.
• Proliferative marker Ki-67 is also a useful indicator of aggressiveness but currently not part of the WHO grading criteria. A proliferative index < 5% is generally seen in grade I tumors, but there are no specific cut-offs delineating the different grades.
• Cytokeratins and S100 are variably positive.
• On electron microscopy, interdigitating cell membranes with desmosomes are a characteristic feature.
Meningioma Subtypes by Grade (2007 WHO Classification)19
WHO Grade I
• Meningothelial
• Fibrous (fibroblastic)
• Transitional (mixed)
• Psammomatous
• Angiomatous
• Microcystic
• Secretory
• Lymphoplasmacyte-rich
• Metaplastic
WHO Grade II
• Atypical
• Chordoid
• Clear cell
• Any WHO grade I histology with brain invasion
WHO Grade III
• Anaplastic
• Papillary
• Rhabdoid
WHO Grade I
• Meningothelial: lobules and whorls formed by largely uniform tumor cells (closely resembling the normal arachnoid cap cells) with oval nuclei that occasionally show clearing or “pseudoinclusions.” Lobules are demarcated by thin collagenous septa.
• Fibrous (or fibroblastic): spindle cells forming a network of bundles and fascicles in a collagen-rich matrix.
• Transitional (or mixed): coexistence of the features of the two previous patterns.
These first three subtypes are the most common.
• Psammomatous: predominance of psammoma bodies, which are round collections of calcium. Tumor cells usually have a transitional appearance with whorl-formation.
• Angiomatous: predominance of blood vessels of variable size and wall thickness. Vessel walls usually show marked hyalinization. The differential diagnosis includes vascular malformations and hemangioblastomas. Cerebral edema may be seen on imaging.
• Microcystic: tumor cells with long thin processes and intercellular microcysts containing eosinophilic mucinous fluid. This can result in edema.
• Secretory: Focal epithelial differentiation results in formation of pseudopsammoma bodies, which contain periodic acid-Schiff (PAS)-positive, eosinophilic fluid. These structures stain for carcinoembryonic antigen (CEA).24 Due to its secretory nature, significant peritumoral edema can be seen on imaging.25
• Lymphoplasmacyte-rich: the rarest variant, characterized by extensive inflammatory infiltration that may leave the meningothelial component difficult to appreciate. Abnormal systemic hematology may be a clinical finding.26
• Metaplastic: Mesenchymal components (bone, cartilage, fat) may be present. Care must be taken to distinguish these from meningiomas exhibiting bone and/or soft tissue invasion.
WHO Grade II
• Higher grades are more likely to recur and take a more aggressive clinical course. They are also more likely to metastasize.
Chordoid: cords or trabeculae of eosinophilic and often vacuolated cells in mucoid matrix, similar to chordomas. These areas are often contained with more meningothelial elements.27
Clear cell: Growing in no specific pattern, there is abundant glycogen in tumor cell cytoplasm, giving it a clear appearance, and abundant interstitial and perivascular collagen deposition. The glycogen-rich cytoplasm is PAS positive. Most commonly, clear cell meningiomas occur in the CPA and cauda equina, which can result in cerebrospinal fluid (CSF) seeding.
Atypical: Tumors can meet criteria for the “atypical” category independent of morphological subtype. The criteria, which correlate with an eightfold increase in recurrence rate, are increased mitotic activity (≥ 4 mitoses/10 high-power fields) or three or more of the following: increased cellularity, small cell morphology with high nuclear/cytoplasmic ratio, prominent nucleoli, patternless or sheet-like growth, and foci of “spontaneous” or “geographic” necrosis.
Pathology Pearl
The presence of brain invasion in a tumor with grade I histology is associated with increased rate of recurrence, and so this feature is sufficient to warrant classification as grade II.19
WHO Grade III
• These highest grade meningiomas are rare, with an incidence of 0.17 per 100 000 persons10 and a median survival time of < 2 years.28
Rhabdoid: Sheets of rhabdoid (muscle-like) cells, with eccentric nuclei, prominent nucleoli, and prominent eosinophilic cytoplasm, are present. They are highly proliferative and often contain another histological hallmark of malignancy.
Papillary: A perivascular pseudopapillary (finger-like) pattern composes most of the tumor. This tends to occur mainly in younger patients, and local and/or brain invasion is present in the majority of cases.
Anaplastic (or malignant): These tumors demonstrate the histological features of malignancy in excess of what is seen in atypical meningiomas. These features include obvious malignant cytology resembling carcinoma, melanoma, or high-grade sarcoma, or a highly elevated mitotic index, i.e., ≥ 20 mitoses/10 high-power fields.
Meningioma Metastasis
Metastases to outside the CNS can be seen in an estimated 0.15 to 0.76% of all meningiomas,29,30 usually in higher grades. Lungs/pleura (37%), bones (16.5%), intraspinal (15%), and liver (9%)22 are the most common sites, with sporadic reports in other locations as well.
• Metastases into meningiomas by systemic neoplasms have also been reported. In cases with a high index of suspicion, even benign-appearing meningioma specimens should be submitted in toto and examined carefully because the presence of a systemic micrometastasis would significantly alter the prognosis.31
Meningioma Mimics32
Neoplastic
• Dural-based metastasis
• Schwannoma (CPA)
• Hemangiopericytoma/solitary fibrous tumor
• Lymphoma, plasmacytoma
• Melanocytic neoplasms
Nonneoplastic
• Rosai-Dorfman disease
• Neurosarcoidosis
• Hypertrophic pachymeningitis
Hemangiopericytoma/Solitary Fibrous Tumor
Recent evidence suggests that hemangiopericytoma (HPC) and solitary fibrous tumor (SFT) represent morphological variants of the same tumor type, with HPC being the cellular variant and SFT the less cellular variant.33
• Classically, HPC is a very cellular and vascularized mesenchymal tumor, with dural attachment and high tendency to recur (almost invariably) or to metastasize (bones, lung, liver).34
• Hemangiopericytoma is WHO grade II, with an anaplastic variant that is WHO grade III.
• Hemangiopericytomas are usually solitary and generally radiologically indistinguishable from meningioma. However, edema is usually present in the underlying brain parenchyma and it lacks the calcifications sometimes seen in meningiomas.
Epidemiology
Hemangiopericytomas are rare, accounting for 0.4% of all primary brain tumors, and they are more frequent in men than in women, with mean age of onset in the fifth decade.35
Pathology
Grossly, HPCs are solid and well-demarcated tumors that have a tendency to bleed.
• Microscopically, tumor cells are monomorphous and closely packed, arranged randomly, and with little intervening collagen.
• Nuclei are round to oval and sometimes spindled.
• There is a rich vasculature with slit-like vessels lined by flattened endothelium and thin-walled branching vascular spaces known as “stag-horn” vessels.
• Infiltration into adjacent brain or bone (without hyperostosis seen in meningiomas) can occur.
• Anaplastic (grade III) tumors show high mitotic activity (≥ 5 mitoses/10 high-power field) or necrosis, and two or more of the following: hemorrhage, moderate to high nuclear atypia, and cellularity.34
• Immunohistochemistry: HPCs stain for vimentin and CD34. They are negative for EMA, progesterone receptor (usually positive in meningioma), and CD31.
• As mentioned previously, HPC and SFT exist on a spectrum as they share a genetic mutation that results in a STAT6-NAB2 fusion protein. This results in constitutive activation of STAT6 and its aberrant localization to the nucleus, which can be detected by immunohistochemistry and distinguishes it from histological mimics.36,37
Prognosis
The median survival for grade II hemangioperycitomas is 216 months versus 142 months for grade III tumors.38
Pituitary Tumors
Pituitary Adenoma
Pituitary adenoma accounts for 10 to 15% of all intracranial tumors, and have been found in almost 20% of the general population at autopsy.39
• They are rare in the pediatric population, accounting for 2% of pituitary tumors.
• Although considered benign, as many as 25 to 55% of pituitary adenomas are invasive40–42 and may have clinically aggressive behavior.43,44
Classification
Adenomas can be classified by size as microadenomas (diameter < 10 mm), macroadenomas (≥ 10 mm), or giant adenomas (> 4 cm).
• Clinically, they are also divided into functional (two thirds of cases) and nonfunctional (or silent) by the presence of symptomatic endocrinopathy or elevated serum levels of a circulating hormone.45
• In contrast, the histological classification of pituitary adenomas is based on the cell of origin (somatotroph, lactotroph, corticotroph, thyrotroph, gonadotroph), mainly by the use of immunohistochemistry for hormone(s) and specific transcription factors expressed. Each cell type can give rise to a tumor that is either clinically functional or nonfunctional.46
Functional Adenomas
Growth Hormone–Producing Adenoma47
Growth hormone–producing adenoma accounts for 25 to 30% of surgically removed pituitary adenomas but 11 to 13% in clinical series (due to medical management),48 and it manifests as growth hormone (GH)/insulin-like growth factor (IGF)-1 excess, mass effect, or tumor-induced adenohypophyseal dysfunction.
• Microadenomas are well circumscribed, but macroadenomas have been known to invade the meninges, cavernous sinus, bone, and sphenoid sinus.
• The pseudocapsule, composed mainly of fibroblasts and collagen, distinguishes adenoma from a normal pituitary gland. It may contain tumor cells, and its resection may result in higher rates of remission.49
• Growth hormone–producing adenomas can be monohormonal somatotroph adenomas, bihormonal mammosomatotroph adenomas, or plurihormonal adenomas that produce thyroid-stimulating hormone (TSH) and α-subunit of glycoprotein as well.
• Somatotroph adenomas can be densely granulated or sparsely granulated.
Densely granulated somatotroph adenoma is characterized by medium-size, round acidophilic cells with granular cytoplasm. It stains for GH in a strong, uniform, and diffuse manner. Half of these tumors also stain for α-subunit of glycoprotein hormones.
The sparsely granulated somatotroph adenomas are cellular chromophobic tumors composed of small, round irregular cells with a round nucleus and prominent nucleolus. The cytoplasm often contains a “fibrous body” that causes peripheral displacement of the nucleus. Immunoreactivity for GH is often scant or negative. Fibrous bodies are reactive for low molecular weight keratins (e.g., CAM 5.2).
The electron microscopic characterization in densely and sparsely granulated tumors is clinically relevant. Sparsely granulated GH-adenomas may show resistance to long-acting somatostatin analogues (54% acute GH reduction and 7% long-term IGF-1 reduction vs 87% and 52%, respectively, for densely granulated).50,51
• Mammosomatroph adenoma is a rarer entity, containing both GH and prolactin.
• Plurihormonal adenomas can produce β-TSH, and sometimes β-follicle-stimulating hormone (FSH) and β-luteinizing hormone (LH), in addition to GH, prolactin (PRL), and α-subunit.
• Pit-1 transcription factor, localized in somatotrophs, lactotrophs, and thyrotrophs, is expressed in all these tumors.46
• Pituitary tumor transforming gene (PTTG) has been found to have highest expression in GH-producing adenomas52; in other studies, it is an emerging biomarker for aggressive behavior.53,54
Prolactin-Producing Adenoma55
Prolactin-producing adenoma accounts for 11 to 26% of pituitary adenomas in surgical series, but represents ~ 50% of all adenomas. Medical management is the mainstay of treatment.48 Onset usually occurs in young adulthood, with a female predominance.
• Prolactin-producing adenomas fall into either sparsely granulated (most common) or densely granulated lactotroph categories. A rarer entity known as acidophil stem cell adenoma is variably classified as a subtype of either GH-producing adenoma or PRL-producing adenoma.
• Sparsely granulated lactotroph adenomas have a diffuse or rarely papillary growth pattern and contain relatively large and elongated tumor cells. The cytoplasm is chromophobic or slightly acidophilic. PRL is positive in the cytoplasm exhibiting an extremely rare paranuclear pattern, and α-subunit is usually negative.
• Densely granulated lactotroph adenoma is distinguished by stronger cytoplasmic acidophilia and strong, diffuse PRL staining.
• The transcription factors Pit-1 and Estrogen Receptor (ER) are positive in PRL-producing adenoma.46
Thyroid-Stimulating Hormone–Producing Adenoma56
Thyroid-stimulating hormone–producing adenomas are rare tumors accounting for about 1% of pituitary adenomas, the rarest cause of hyperthyroidism. Age of onset was found to be 20s to 60s with a female predominance in a small series.
• At the time of presentation, most tumors are macroadenomas.
• Thyrotroph adenoma is composed of chromophobic cells with indistinct cell borders, growing in a solid or sinusoidal pattern. Stromal fibrosis is a common finding. Cytoplasmic globules representing lysosomes stain strongly with PAS. Tumor cells are immunoreactive for α-subunit and β-TSH.
Adrenocorticotropic Hormone (ACTH)-Producing Adenoma57
Adrenocorticotropic hormone (ACTH)-producing adenoma is the cause of Cushing’s disease and occurs at a rate of 1 to 10 cases per million per year; it accounts for 10 to 15% of pituitary adenomas. The peak incidence is in the fourth decade and is much more prevalent in women (8:1).
• Corticotroph adenomas contain monomorphic round cells in a diffuse pattern with a characteristic sinusoidal pattern around capillaries. The cells are basophilic and PAS-positive. Immunoreactivity is positive for ACTH, β-lipo-tropic pituitary hormone (LPH), and β-endorphin, which are cleavage products of the precursor molecule pro-opiomelanocortin.
• Crooke cell adenoma is another subtype that may produce ACTH. It is clinically aggressive and distinguished by prominent cytoplasmic cytokeratin filaments.58–60
• Crooke’s hyaline change refers to nonadenomatous corticotrophs with a zone of glassy agranular cytoplasm (accumulation of keratin filaments) around its nucleus and is indicative of glucocorticoid excess (corticotroph adenoma, ectopic ACTH secretion, adrenocortical hyperplasia, or exogenous source)46
Plurihormonal Adenoma61
These tumors are defined as those having immunoreactivities for more than one pituitary hormone, which are not explained by normal developmental mechanisms. Hence, they do not include combinations of GH, PRL, and TSH or of FSH and LH.
• Microscopically, these tumors tend to be chromophobic and negative for PAS.
• Combinations of hormone reactivities commonly found include TSH, FSH, and GH or PRL and TSH, although any combination is possible.62
Nonfunctional Adenomas
Nonfunctional adenomas are those that do not present with clinical or biochemical evidence of a hormone excess syndrome. Most commonly, these are gonadotroph adenomas.46,63
Gonadotropin-Producing Adenoma63
Functional gonadotropin (FSH, LH)-producing adenomas are uncommon and are usually diagnosed in men more than in women.
• Gonadotroph adenomas are usually clinically silent.46
• At the time of diagnosis, the tumor is often a macroadenoma and can show significant sellar/suprasellar invasion.
• The tumor can grow in several histological patterns, which can occur in combination.
• The majority consists of uniform, tall, polar cells forming a sinusoidal pattern with perivascular pseudorosettes. Papillary growth is another pattern, although less common. A minority shows diffuse growth. This histological variability is also reflected in its immunohistochemical profile. There is often patchy, uneven staining with α-subunit, β-FSH, and β-LH.
• These tumors are also positive for the transcription factor Steroidogenic Factor 1 (SF1).46
α-Subunit of Glycoprotein Hormones64
The hormones human chorionic gonadotropin (HCG), LH, FSH, and TSH consist of an α- and β-subunit. The α-subunits of these hormones (expressed in certain pituitary adenomas) are nearly identical, whereas the β-subunits confer specificity.
Silent Corticotroph Adenomas
There are two types of silent corticotroph adenomas: subtype 1 and subtype 2.57
• Subtype 1 very closely resembles functional corticotroph adenomas seen in Cushing disease.
• Subtype 2 has smaller than average polyhedral cells and sparse, irregular secretory granules on electron microscopy. It resembles sparse corticotrophs.
Silent Subtype 3 Adenoma65
A nonfunctional plurihormonal adenoma, the silent subtype 3 adenoma tends to occur in women between 20 and 35 years of age, but it has no age predilection in men.66 Often, it is a macroadenoma at the time of diagnosis. It is composed of spindle cells and fibrous stroma and may show positivity for GH, PRL, and TSH, and other hormones.
Null Cell Adenoma67
These tumors have no hormone immunoreactivity or any other markers of differentiation along a particular adenohypophysial lineage. They occur often in elderly individuals. They are immunopositive for synaptophysin and chromogranin, providing evidence that they are pituitary tumors.
• Microscopically, tumor cells are usually chromophobic and round or polyhedral in shape. There is usually diffuse or papillary growth pattern, with pseudorosette formation.
• These tumors are PAS negative, and they stain for adenohypophyseal hormones and transcription factors.
Pathology Pearl
Pituitary adenomas are defined as “atypical” when they show high mitotic activity, Ki-67 labeling ≥ 3% of cells, and extensive p53 immunoreactivity.
Pituitary Carcinoma
It is defined as a tumor of adenohypophyseal cells that exhibits cerebrospinal and/or systematic metastasis.68 It accounts for 0.2% of pituitary tumors.
• More than 75% of pituitary carcinomas are functional, with PRL and ACTH as the most common tumors.69
Other Tumors of the Pituitary
• Spindle cell oncocytoma of the adenohypophysis is a benign sellar tumor, WHO grade I,70 consisting of granular, mitochondria-rich spindle cells.
• Pituicytoma is a rare neurohypophyseal tumor, WHO grade I,71 composed of spindle cells arranged in fascicles.
• Granular cell tumor is a sellar/suprasellar tumor of the neurohypophysis or infundibulum, WHO grade I.72 It is composed of large, eosinophilic, lysosome-rich cells.
• Spindle cell oncocytoma consists of a folliculostellate mass. Other findings suggest that these tumors are all derived from pituicytes, the modified glial cells of the neurohypophysis.73
• Pituitary blastoma is a rare embryonal pituitary tumor affecting children < 2 years of age. Microscopically, it shows glandular structures resembling Rathke epithelium, clusters of large secretory pituitary cells, and small undifferentiated cells.74
Craniopharyngioma
Craniopharyngiomas are benign, often totally or partially cystic, epithelial tumors, WHO grade I,75 purported to arise from Rathke’s pouch. They occur almost exclusively in the suprasellar region with a minor intrasellar component.
Epidemiology
Craniopharyngiomas account for 1.2 to 4.6% of all intracranial tumors, with an incidence of 0.5 to 2.5 cases per 1 million.75 They are the most common nonneuroepithelial brain tumor in children (5–10%)76. Men and women are affected equally.
Classification
There are two subtypes of craniopharyngioma: adamantinomatous and papillary.
• Although adamantinomatous craniopharyngiomas have a bimodal age distribution with peaks at the ages 5 to 15 and 45 to 60,77 the papillary subtype occurs nearly exclusively in adults.76,78
Adamantinomatous Craniopharyngioma
Adamantinomatous craniopharyngioma appears as a lobulated solid mass with a variable cystic component that contains a dark green-brown liquid resembling machinery oil. Calcification is common.
• Microscopically, it is composed of squamous epithelium organized in cords and lobules, bordered by palisaded columnar epithelium. These dense areas merge with looser areas of squamous cells known as stellate reticulum. “Wet keratin” nodules are another feature, composed of remnants of pale nuclei embedded within an eosinophilic keratinous mass. Flattened epithelium lines the cystic cavities and is filled with squamous debris.79
• At the brain–tumor interface, piloid gliosis with Rosenthal fibers is commonly seen and may be mistaken for pilocytic astrocytoma at frozen section or in small biopsies.75
Papillary Craniopharyngioma
Papillary craniopharyngioma is generally a solid tumor, without or with scarce cysts, and without cholesterol-rich machinery oil. Calcifications are uncommon.
• Microscopically, it consists of well-differentiated squamous epithelium arranged in pseudopapillae or papillae around a fibrovascular core.80
Prognosis
Approximately 60 to 90% of patients are recurrence-free at 10 years; the overall 10-year survival is likewise about 60 to 90%.78,81,82 The most important factor in determining the risk of recurrence is the extent of resection.75

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