Skull Invaders: When Surgical Pathology and Neuropathology Worlds Collide

Transcription

1 J Neuropathol Exp Neurol Copyright Ó 2013 by the American Association of Neuropathologists, Inc. Vol. 72, No. 7 July 2013 pp. 600Y613 REVIEW ARTICLE Skull Invaders: When Surgical Pathology and Neuropathology Worlds Collide Hilary S. Serracino, MD and B.K. Kleinschmidt-DeMasters, MD Abstract Skull and dura serve as effective barriers to penetration by most tumors, often preventing masses originating intracranially from extending into the contiguous bone and soft tissues, or those arising in head and neck regions from extending into the dura and brain tissue. We review our 15-year experience with extracranial tumors that had sufficiently invaded adjacent skull, dura, or brain from the outside-in to require a neurosurgeon to participate in the surgical resection and discuss our 40 cases in context with the literature. Sinonasal-origin tumors (n = 17) and cutaneous tumors (n = 10) were the most frequent skull-invaders. Most of the cutaneous tumor types were squamous cell carcinomas (n = 9); diverse sinonasal-origin types included 4 squamous cell carcinomas, 4 adenoid cystic carcinomas, 2 sinonasal undifferentiated carcinomas, 2 sinonasal adenocarcinomas, and single examples each of sinonasal-origin hemangiopericytoma, solitary fibrous tumor, melanoma, mucocele, and teratocarcinoma. There were 9 olfactory neuroblastomas, and middle ear-origin basal cell carcinoma, recurrent glomus jugulare, and orbital malignant hidradenoma were also seen. Unique tumors included a cutaneous cylindroma invasive of skull convexity occurring in familial cylindromatosis and a ganglioneuroma of the middle ear with massive bilateral skull base extension. Convexity dural spread, a seldom-reported pattern of dissemination, was seen in 1 olfactory neuroblastoma and 1 adenoid cystic carcinoma. The ability to show skull/dural invasion did not correlate with specific histopathologic features; even benign tumor types can show skull/dural penetration. Key Words: Adenoid cystic carcinoma, Ganglioglioma of middle ear, Invasive squamous cell carcinoma, Mucocele, Olfactory neuroblastoma. Surgical pathology and neuropathology ordinarily remain relatively separate disciplines, with each specialty possessing a different and characteristic population of neoplasms in their purview. This separation speaks to the effectiveness of the skull and dura in providing an excellent barrier to invasive growth of tumors in either direction. In instances when this partition is breached, it is usually From the Departments of Pathology (HS, BKK-D), Neurosurgery (BKK-D), and Neurology (BKK-D), The University of Colorado Health Sciences Center, Aurora, Colorado. Send correspondence and reprint requests to: B.K. Kleinschmidt-DeMasters, MD, Department of Pathology, Neurology and Neurosurgery, Anschutz Medical Campus, University of Colorado Denver, E. 17th Ave., B216 Aurora, CO 80045; bk.demasters@ucdenver.edu 600 attributable to tumor growth from inside-out, with meningiomas and pituitary adenomas being the most common tumors that cause direct bony invasion. Less often, the invasion proceeds from outside-in and is caused by tumors arising from cutaneous, sinonasal, or middle ear sites developing intracranial invasion due to bony erosion of the skull and dural penetration. These cases are particularly challenging to manage surgically and often require a joint surgical approach by ear, nose, and throat specialists and neurosurgeons to effectively achieve resection. This report is a retrospective review of our 15-year experience with tumors originating in skin, sinonasal, or middle ear sites, and sufficiently invading into the cranium, to require neurosurgical participation in the surgical resection. Cases such as these are often seen at referral centers because of colleagues surgical expertise and thus the potential existed for our experience to be skewed as to types and numbers of cases. Therefore, we compared our experience with several series from the literature (1Y5), although several address surgical resection issues specifically for skull-based tumors (1, 2). In contrast, our series includes tumors that involved skull either at the base or convexity and is confined to those tumors with outside-in directionality. After exclusion of meningiomas, pituitary adenomas, schwannomas, primary bony, and cartilaginous tumors of skull base, chordomas, or metastases to skull boneyall of which are well known to exhibit bony destructionywhat emerges is an interesting series of tumors that heighten awareness of neuropathologists for how surgical pathology and neuropathology worlds may collide. MATERIALS AND METHODS Case Accrual Methods The study included all in-house and outside consultation surgical cases from the University of Colorado at Denver Departments of Pathology and Neurosurgery from 1998 through the end of December 2012 (15 years inclusive), which represented the time frame for which our computer coding and searches were most accurate and reliable. Case accrual was accomplished via computerbased word search of surgical pathology records, using key words bone and skull both alone and paired with squamous cell carcinoma (SCC), basal cell carcinoma, adenoid cystic carcinoma, and neoplasm. Cases with a known high proclivity for skull invasion, such as olfactory neuroblastoma, glomus jugulare/tympanicum paragangliomas, and endolymphatic sac tumors, were further crosschecked by searching our pathology databases for these specific diagnoses and then determining skull-invasive status. In addition, neurosurgical colleagues further validated the search by crosschecking J Neuropathol Exp Neurol Volume 72, Number 7, July 2013

2 J Neuropathol Exp Neurol Volume 72, Number 7, July 2013 records from their departmental databases. Fifteen of the 33 in-house casesinthestudyhadbeenoperatedonby1neurosurgeonatourinstitution, reflecting the specialty nature of skull base neurosurgical practice. Eligible cases included tumors that originated from head and neck regions and developed overt intracranial extension. The presence of intracranial extension was established based on the intraoperative impression, as provided by the neurosurgeon to the pathologist at the time of intraoperative consultation, or by designation of the tissue specimen as having come from the dura or brain and verified by the histologic features. Cases with only skull invasion but no clear-cut intracranial extension were not included. Further verification of the true intracranial extension of these cases was provided by the necessity of having a neurosurgeon as participating in the resection in the first place, sometimes as the sole surgeon but often as a joint procedure with an otolaryngologist. Cases such as glomus jugulare tumors or endolymphatic sac tumors had to possess definitive intracranial extension, not simply bony invasion of skull base, verified by the need for neurosurgical participation in the surgical resection to be included. Tumors arising intracranially and extending inside-out from the skull (i.e. meningiomas, pituitary adenomas, dural and bony skull-based sarcomas, schwannomas, and gliomas) were excluded. Tumors with invasion of the mandible, maxilla, or other facial bones were also excluded unless they additionally encroached on the cranial vault and brain/dura. Metastatic tumors to the bone that originated from outside the head and neck region but blistered into the dura and skull were excluded. Also excluded were hematopoietic tumors such as secondary/metastatic deposits within the skull of lymphoma and plasma cell myeloma. The resulting cases consisted of a set of cutaneous, sinonasal, middle ear, and rare orbital tumors with intracranial extension. Histologic Methods Tissues were fixed in 10% formalin and processed in routine fashion, with staining for with hematoxylin and eosin (H&E) and for reticulin. Immunostaining was conducted in selected cases, as appropriate to diagnoses, including for bcl-2 (Dako, Carpinteria, CA; 1:200), CD99 (Dako; 1:25), CD34 (Cell Marque, Rocklin, CA; PreDilute), cytokeratin 7 (Dako; 1:800), cytokeratin 20 (BioCare, Concord, CA; 1:200), MIB-1 (Ventana, Tucson, AZ; PreDilute), TP53 (Dako; 1:200), epidermal growth factor receptor (Invitrogen, Carlsbad, CA; 1:400), chromogranin (BioCare; 1:50), synaptophysin (Ventana; PreDilute), S-100 (Ventana; PreDilute), and neuron-specific enolase (Ventana; PreDilute). Details of immunostaining done on the 2 previously published cases are delineated in original reports (6, 7). RESULTS Forty cases were identified; of these, 33 were inhouse cases and 7 were consultation cases (Table). In our practice, tumors originating from cutaneous (n = 10: 9 SCCs and 1 cylindroma) and sinonasal areas (n = 17: 4 SCCs, 4 adenoid cystic carcinomas, 2 sinonasal undifferentiated carcinomas, 2 adenocarcinomas, and 5 more, each of singular histologic type), predominated over olfactory neuroblastomas (esthesioneuroblastomas) (n = 9) and those from middle ear (n = 2), orbit (n = 1), or skull base foramina (glomus jugulare tumor) (n = 1) as skull invaders. Squamous cell carcinomas were the single most common histologic type of tumor to show skull invasion and the most frequent cutaneous skull-invasive tumor type. Squamous Outside-in Skull Tumor Invasion cell carcinomas with skull invasion occurred predominantly in adult males, ranging in age from 53 to 86 years. Most patients with invasive cutaneous SCCs had had multiple cutaneous lesions with persistent disease despite repeated resections, including Mohs surgery, before developing skull invasion. Four SCCs (Patients 10, 11, 12, and 13) arose from the sinuses or nasal cavity. Human papillomavirus testing was performed on 2 of these latter tumors and showed focal positivity (Table). Of the SCCs, anterior skull base was the site of invasion in 5 (Fig. 1a, Case 11), with convexity of skull bony invasion in 8 (Fig. 1b, Case 9). In one instance, the posterior scalp was so eroded by the invasive SCC, that the fungating mass (Fig. 1b) had extended into the underlying dura, which needed to be excised completely (Fig. 1c), requiring extensive skin grafting in this patient. Histologically, most of these 13 cases displayed moderate differentiation (n = 9) with keratinization (n = 3 of 9) (Fig. 1d, Case 13), although there were several cases each that showed well-differentiated features with keratinization (n = 2) or poorly differentiated features (n = 2) (Table). Two of these cases additionally showed acantholytic features and 1 case had focal basaloid histology. Thus, histopathologic features in SCCs did not correlate with the ability of SCC to be skullinvasive. Several cases (n = 3) demonstrated perineural invasion, consistent with the known tropism of SCC for nerves (Table), and this was a likely route of intracranial extension. The single skull-invasive massive cylindroma arose in a patient with an underlying genetic syndrome and was characterized by extensive skull invasion over the vertex of the skull (Fig. 1e, Case 38). This case with familial cylindromatosis has been previously reported in detail (6). The hypercellular, nested tumor invaded through the bone and dura as intact cohesive nests of cells surrounded by a distinct eosinophilic hyaline band (Fig. 1f). Thus, if this study had been confined to skull base regions only, and had not incorporated tumors with convexity skull invasion, a significant number of skull invaders would have been missed. Sinonasal tumors represented the most frequent overall site of origin for skull invasion with 17 cases, although the subtypes were more diverse than for cutaneous-origin skull invaders. Within the sinonasal tumor group, SCCs and adenoid cystic carcinomas of sinonasal cavities were the most common, each with 4 examples. One of the adenoid cystic carcinomas (Case 24) showed rapid growth over a 3-month interval (Fig. 1g, h). Once invasive of the skull and dura, the adenoid cystic carcinomas consisted of 1 high-grade, 1 intermediate-grade, and 2 low-to-intermediate grade based on the presence of solid, cribriform (Fig. 1i), and tubular elements, respectively. Occasionally, invasion of intradural sinuses was seen when the tumor infiltrated the dura (Fig. 1i, arrow). manifested highly undifferentiated phenotypes suggestive of dedifferentiation. A single case of adenoid cystic carcinoma also showed involvement of dural convexity (Fig. 2a, Case 26). Although nodular tumor was identified, the dura was diffusely thickened, as seen on neuroimaging (Fig. 2a), and the resection specimen where the discrete nodule is was surrounded by a thickened lumpy tumor (Fig. 2b, asterisk), as best seen on cross section (Fig. 2c, arrow, and corresponding whole mount Ó 2013 American Association of Neuropathologists, Inc. 601

3 Serracino and Kleinschmidt-DeMasters J Neuropathol Exp Neurol Volume 72, Number 7, July 2013 TABLE. Skull Invaders Case Number/ Years of Surgery Age/Sex Pathologic Diagnosis Location Squamous cell carcinomavcutaneous origin 1 / /M Invasive SCC, well differentiated, keratinizing 2 / /M Invasive SCC, well differentiated, keratinizing 3/ /M Invasive SCC, moderately differentiated 4 / 2008, /M Invasive SCC, moderately differentiated, keratinizing 5 / /M Invasive SCC, moderately differentiated, focally keratinizing 6 / 2011, /M Invasive SCC, moderately differentiated 7 / /M Invasive SCC, moderately differentiated, keratinizing 8 / /F Invasive SCC, moderately differentiated 9 / /M Invasive SCC, moderately differentiated Squamous cell carcinomavsinonasal origin 10 / /M Invasive SCC, moderately differentiated 11 / 2011, /M Invasive SCC, poorly differentiated, nonkeratinizing 12 / /F Invasive SCC, poorly differentiated Parietal, with extension into the bone and sagittal sinus Right frontal scalp with skull and frontal sinus involvement Preoperative Dx and Significant Clinical Findings 12-year history of recurrent cutaneous malignancy of the vertex of head, s/p multiple excisions, liquid nitrogen and radiation therapy. Presumed SCC 1 year before presentation for skull invasion (no records available) s/p multiple excisions including Mohs surgery and radiation therapy. Right temporal scalp Basal cell carcinoma excised È3.5 years before presentation for skull invasion s/p multiple excisions and radiation therapy. Frontal scalp and left temporal bone Right parietal region with extension into the underlying bone and brain Left posterior frontal scalp extending into the underlying bone and dura Vertex scalp extending into bone overlying the superior sagittal sinus and the underlying dura Posterior biparietal and bioccipital bone invading into the underlying dura and right parietal lobe Right scalp with invasion of the bone and dura Right frontal sinus with invasion into right frontal lobe Nasal extending into anterior skull base Left nasal cavity extending through the anterior frontal sinus and medial left orbit with frontal lobe invasion History of SCC and recurrent basal cell carcinoma s/p multiple excisions. History of SCC È2.5 years before presentation for skull invasion, which was excised and then treated with radiation therapy. Developed recurrence and underwent resections 2. Suffered simple partial seizure È1 week before presentation. Recurrent disease s/p multiple resections and radiation therapy. SCC removed from back of head (with reportedly negative margins) 1 year before presentation with skull invasion. Minor trauma to back of head (scrap on tree branch followed by hit on car door which failed to heal) 18 months before presentation with skull invasion. SCC of skin above right ear, s/p multiple resections. Increasing confusion and sinus headaches. History of left-sided congestion and bleeding from left nare 4 months before presentation for skull invasion. Distant history of Hodgkin disease (30 years ago) treated with radiation with cobalt. Noticed lump above left eye 5 months before presentation with skull invasion that enlarged despite treatment with antibiotics. Additional Pathologic/ Molecular Findings Perineural invasion Acantholytic features, focal keratinization, perineural invasion Focal necrosis, vascular invasion Acantholytic type with lymphovascular invasion Focal basaloid features, lymphovascular and perineural invasion. Extensive necrosis. EGFR=1+to2+in50%of tumor cells. Positive high-risk HPV (rare cells). 602 Ó 2013 American Association of Neuropathologists, Inc.

4 J Neuropathol Exp Neurol Volume 72, Number 7, July 2013 Outside-in Skull Tumor Invasion 13 / /F Invasive SCC, moderately to poorly differentiated Olfactory neuroblastoma 14 / /M Olfactory neuroblastoma, Hyams Grade II 15 / 2001, /M Olfactory neuroblastoma, 16 / 1994, 1994, 2003, 2009, 2013 Hyams Grade III at the time of intracranial invasion 43/F Olfactory neuroblastoma, Hyams Grade III at the time of intracranial invasion 17 / 2006, /M Olfactory neuroblastoma Hyams Grade II at the time of intracranial invasion 18 / /F Olfactory neuroblastoma, Hyams Grade II at the time of intracranial invasion 19 / /M Olfactory neuroblastoma, Hyams Grade II at the time of intracranial invasion 20 / /M Olfactory neuroblastoma, Hyams Grade II at the time of intracranial invasion 21 / /F Olfactory neuroblastoma with extensive epithelial differentiation (neuroendocrine carcinoma), Hyams Grade II 22 / /M Olfactory neuroblastoma, Hyams Grade III at the time of intracranial invasion Nasal cavity extending into the right orbit and through the cribriform plate 2-year history of inflammation, tearing, and bone sensitivity in the upper nose and cheeks. Focal necrosis. EGFR = 1+ to 2+ in 40% of tumor cells. Positive for high-risk HPV, focal. Suprasellar/intranasal mass Hyponatremia Ethmoid sinuses and middle turbinate with intracranial extension Left ethmoid and maxillary sinus extending into the left temporal lobe with involvement of the falx cerebri Cribriform plate and bilateral subfrontal area Anterior cranial base and paranasal sinuses Ethmoid region and cribriform plate with extension into the nasal cavity Progressive loss of smell and episodes of epistaxis before presentation with skull invasion Tumor initially presented as nasal polyp È9 years before presentation with skull invasion Late convexity metastasis, 9 y after original tumor Increased nasal and sinus pressure L9R Negative EGFR and Her2/neu Left-sided nasal obstruction Skull base/orbital extension È3-year history of progressive nose and sinus symptoms Skull base/orbital extension Nasal and anterior skull base Recurrent right sided epistaxis Skull base/nasal extension Nasal mass involving left ethmoid and extending into the cranial vault Nasopharynx extending through the skull base into the base of the bilateral frontal lobes as well as into the orbits, frontal sinuses, and through the frontal bone into the scalp and maxillary sinuses Adenoid cystic carcinoma 23 / 2005, /M Adenoid cystic carcinoma Medial left temporal lobe and left cavernous sinus Esthesioneuroblastoma initially diagnosed 2 years before presentation for skull invasion when the patient presented with recurrent sinus infections. Underwent cranial facial surgery followed by radiation therapy at that time. 8-year history of anosmia and several months of history of diplopia in right eye History of left parotid tumor s/p resection and chemoradiotherapy approximately 1 year before presentation with skull invasion Extensive epithelial differentiation Tumor in the leptomeningeal and dural areas High grade with mostly solid growth (some areas with cribriform architecture). MIB-1 nearly 100%. Foci of cells positive for high-level amplification of EGFR. Rare cells positive (2+) for amplification of HER-2. Highly complex karyotype. (Continued on next page) Ó 2013 American Association of Neuropathologists, Inc. 603

5 Serracino and Kleinschmidt-DeMasters J Neuropathol Exp Neurol Volume 72, Number 7, July 2013 TABLE. (Continued) Case Number/ Years of Surgery Age/Sex Pathologic Diagnosis Location 24 / 2003, 2003, /M Adenoid cystic carcinoma Midline frontal skull and right supraorbital region Preoperative Dx and Significant Clinical Findings History of frontal sinus adenoid cystic carcinoma s/p anterior skull base resection È4 years before presentation with skull invasion. 25 / 2011, /F Adenoid cystic carcinoma Nasal, anterior skull base 11-year history of intermittent left-sided epistaxis 26 / /M Adenoid cystic carcinoma Dural-based tumor in the left frontoparietal region Sinonasal undifferentiated carcinoma (SNUC) 27 / 2011, /M SNUC Intranasal with involvement of the left medial orbit and anterior skull base Recurrent adenoid cystic carcinoma s/p radiation therapy. First diagnosed with adenoid cystic of parotid 16 years before presentation. 28 / 2011, /F SNUC Nasal, anterior skull base Rapid vision loss approximately 6 months before presentation Sinonasal teratocarcinosarcoma 29 / /M Midline tumor that invaded the frontal and ethmoid sinuses with small focus of dural invasion and intradural extension as well as sphenoid sinus invasion Sinonasal invasive adenocarcinoma 30 / /F NonYsmall cell carcinoma with focal gland formation and brain invasion 31 / /M Invasive mucinous adenocarcinoma Sinonasal melanoma 32 / 2011, /F Poorly differentiated malignant neoplasm Hyponatremia, increasing headaches, mild inabilitytoperform upward gaze Additional Pathologic/ Molecular Findings Low-to-intermediate grade with tubular and cribriform patterns. CD117/C-Kit = 1Y2+ in approximately 80%Y90% of cells. EGFR = 1Y2+ in approximately 30% of cells. Her-2/Neu = negative. Low-to-intermediate grade, tubular, and cribriform Dural involvement over convexity. Intermediate grade, cribriform IHC = 2+ EGFR and 3+ CKIT. EGFR, HER2, and KIT = negative by molecular testing. Left facial/sinus/left eye pressure Predominantly high-grade olfactory neuroblastoma component (975% of tumor), with more differentiated neuroblastoma areas (È15%) and craniopharyngioma histology (È10%). Sinuses extending to frontal lobe Increased intracranial pressure Poorly differentiated Superior aspect of nasal fossa with intracranial extension through the cribriform plate and extension into both orbits 2- to 3-month history of nasal obstruction, loss of sense of smell, epistaxis Invasive mucinous adenocarcinoma with signet ring features Nasal, anterior skull base 6-month history of left-sided epistaxis Immunohistochemically consistent with malignant melanoma Sinonasal hemangiopericytoma 33 / /F Hemangiopericytoma Nasal, anterior skull base, sella Right-sided nasal congestion and epistaxis Sinonasal solitary fibrous tumor 34 / /F Solitary fibrous tumor Nasal, anterior skull base 4- to 5-month history of left retro-orbital headache and progressive proptosis Hemangiopericytoma Classic solitary fibrous tumor histology 604 Ó 2013 American Association of Neuropathologists, Inc.

6 J Neuropathol Exp Neurol Volume 72, Number 7, July 2013 Outside-in Skull Tumor Invasion Mucocele 35 / /F Mucocele Extradural mass, left orbit with communication with the frontal sinus Basal cell carcinoma (BCC) of the ear 36 / /M BCC Left ear canal and temporal bone With muscular dystrophy and history of weakness opening her left eye Previous history of BCC involving the external auditory canal and ear excised È30 years before presentation with postoperative radiation therapy (s/p multiple reexcisions including Mohs). Ganglioneuroma of ear 37 / 2011, /F Ganglioneuroma Anterior skull base History of ganglioneuroma of the right ear that was partially resected È5 years Cylindroma 38 / 2006, 2010, 2010 before presentation. Also noted to have temporal bone fibrous dysplasia. Mucocele with intense chronic inflammation and bony erosion Classic BCC histology BRAF = negative, KIT = negative (exons 11 and 17) 59/M Cylindroma Left frontoparietal region History of familial cylindromatosis Classic cylindroma histology Invasive high-grade adnexal tumor 39 / 2003, 2004, 70/F Malignant hidradenoma Right medial orbital mass 2004, 2004 with intracranial extension Paraganglioma 40 / 2005, /M Paraganglioma, WHO Grade I, clinically recurrent glomus jugulare tumor Temporal bone with intracranial extension Progressively enlarging mass with obstruction of the lacrimal system. Intranasal biopsy showed nodular hidradenoma with atypical features. Paraganglioma of middle ear È6 years before presentation, failed to follow up now subsequent progressive tumor growth. EGFR = positive (2+) and Her2/neu = negative Classic paraganglioma histology BCC, basal cell carcinoma; Dx, diagnosis; EGFR, epidermal growth factor receptor; F, female; HPV, human papillomavirus; M, male; SCC, squamous cell carcinoma; s/p, status-post. Ó 2013 American Association of Neuropathologists, Inc. 605

7 Serracino and Kleinschmidt-DeMasters J Neuropathol Exp Neurol Volume 72, Number 7, July 2013 FIGURE 1. (A) Coronal magnetic resonance (MR) imaging study, T1-weighted, with contrast, illustrates a squamous cell carcinoma (SCC) occupying the left nasal cavity and directly invading the skull base and extending intracranially. Case 11. (B) Preoperative picture showing a massive cutaneous fungating SCC occupying most of the posterior scalp of a 72-year-old woman. Picture was taken intraoperatively, immediately before the start of surgical resection, courtesy Dr. Allen Waziri. Case 9. (C) Intraoperative photograph after resection of the cutaneous fungating SCC and the massively involved underlying dura, exposing the superficial brain tissue; note the congested leptomeningeal vasculature. This patient required extensive skin grafting. Case 9. (D) Photomicrograph of the SCC taken from this same patient shown in panels B and C that was extensively invasive of dura (the dense eosinophilic collagenous background). Note the varying-sized islands of invasive cancer, including small islands (arrow) and larger ones with focal keratinization (arrowhead). Case 9. Hematoxylin and eosin (H&E); original magnification: 200. (E) Coronal MR imaging study, T1-weighted with contrast, showing the bulky extracranial and intracranial tumor burden in the patient with a cylindroma. Note the dark signal representing edema in the underlying brain as a result of the intracranial extension. Case 38. (F) Photomicrograph of the benign cylindroma composed of irregularly shaped islands of basaloid cells surrounded by a distinct eosinophilic hyaline band. H&E; original magnification: 200. (G, H) Coronal MR imaging studies, T1-weighted with contrast, are taken from the same patient with invasive adenoid cystic carcinoma at a 3-month interval between panels G and H, illustrating how rapidly this tumor progressed. Case 24. (I) Photomicrograph of the adenoid cystic carcinoma invasive of the dura from the same patient shown in panels G and H. Note the cribriform pattern in the lower part of the field, as well as the invasion of dural venous sinuses by the tumor (arrow). Case 24. H&E; original magnification: Ó 2013 American Association of Neuropathologists, Inc.

8 J Neuropathol Exp Neurol Volume 72, Number 7, July 2013 Outside-in Skull Tumor Invasion FIGURE 2. (A) Coronal magnetic resonance (MR) imaging study, T1-weighted with contrast, from another patient with adenoid cystic carcinoma, this time with the far more uncommon convexity dural spread. Note the nodule on the patient s left (right of photograph) as well as the irregular dural enhancement and thickening due to more massive dural spread. Case 26. (B) Photograph of the dural surgical resection specimen from the same patient illustrated in panel A. Note the discrete subdural nodule but the more subtle, lumpy, raised, glistening diffuse dural involvement nearby (asterisk). Case 26. (C) Cross section of the dural surgical specimen (top) with corresponding the low-power whole-mount, Hematoxylin and eosin (H&E)Ystained section (bottom, from area with arrow) showing that the dural involvement is transdural, not simply subdural. Scale bar = 1 cm (top); original magnification: 20 (bottom). (D) Photomicrograph of the surgical specimen from a third case of adenoid cystic carcinoma showing perineural invasion by the tumor within the soft tissue near the site of the tumor origin. The close juxtaposition of tumor with nerve is best seen on highest power in the inset. Case 23. H&E; original magnification: 100; inset: 600. (E, F) Another sinonasal tumor type that invaded the skull and dura included a mucinous adenocarcinoma, seen here in the coronal MR imaging study, T1-weighted with contrast, invading the skull base and laterally displacing the left globe. Case 31 (E). Photomicrograph of the skull baseyinvasive mucinous adenocarcinoma showing abundant, faint gray-blue mucin surrounding the tumor within the bone (F). Note the eosinophilic bone spicules and the well-formed glands in this specimen. Case 31. H&E; original magnification: 600. (G) Photomicrograph of the other skull baseyinvasive sinonasal adenocarcinoma, this 1 more poorly differentiated although with focal gland formation as well. Case 30. Immunostaining for cytokeratin 7 with light hematoxylin counterstain; original magnification: 200. (H) Photomicrograph of the same, more poorly differentiated sinonasal adenocarcinoma with parenchymal brain invasion; note the lack of gland formation in this part of the tumor and the nearby reactive astrocytes (arrow). Case 30. H&E; original magnification: 400. (I) Sagittal MR imaging study, T1-weighted with contrast illustrating extensive subfrontal intracranial extension of an olfactory neuroblastoma. Note the displacement of the orbital regions of the inferior frontal lobe. Case 14. Ó 2013 American Association of Neuropathologists, Inc. 607

9 Serracino and Kleinschmidt-DeMasters J Neuropathol Exp Neurol Volume 72, Number 7, July 2013 section). Occasionally, extensive perineurial tumor involvement was identified in the soft tissue portions of the resection specimens near the site of tumor origin (Fig. 2d, arrow, and inset, Case 23). Other sinonasal tumors identified included 2 sinonasal undifferentiated carcinomas, 2 adenocarcinomas, 1 melanoma, 1 hemangiopericytoma, 1 solitary fibrous tumor, and 1 sinonasal teratocarcinoma. The adenocarcinomas showed neuroimaging features indistinguishable from the skull-invasive SCCs, often with lateral displacement of the globe (Fig. 2e, Case 31). One case infiltrating the skull base and dura had copious mucin (Fig. 2f, skull base bony invasion). The other adenocarcinoma was poorly differentiated, highly necrotic, but focally formed glands immunoreactive for cytokeratin 7 (Fig. 2g, Case 30). This case was immunonegative for synaptophysin and also showed brain parenchymal invasion (Fig. 2h). Tumors arising in the olfactory placode (i.e. olfactory neuroblastomas [esthesioneuroblastomas]) were the second most frequent single tumor type of skull invader (Table). Skullbased invasion is well known to occur in this tumor type (8Y10) and could be quite massive (Fig. 2i, Case 14). One of the cases with multiple recurrences over a 9-year period developed dural involvement of a convexity site on the most recent recurrence (Fig. 3a, Case 16), which was discrete and hyperemic at the time of surgical resection (Fig. 3b). This secondary dissemination within dura is less well appreciated (11). Histologically, at the time of intracranial involvement, there were 6 Hyams Grade II and 3 Hyams Grade III olfactory neuroblastomas. No single Hyams grade predominated in the olfactory neuroblastomas once they were skull invasive. Once the tumor invaded the dura and skull, the nested pattern could be disrupted, although the essential histologic features were preserved, including the presence of closely packed small blue tumor cells with scant cytoplasm, often minimal fibrillar processes (Fig. 3c), and synaptophysin immunoreactivity (Fig. 3d, tumor within dura). There were only 2 tumors originating from the middle ear: a basal cell carcinoma that originated in the left ear canal and temporal bone and a ganglioneuroma. Although several of the rare endolymphatic sac tumors identified in our search showed bony invasion, as expected, none showed definitive intracranial extension to dura or brain and thus were not included. The patient with basal cell carcinoma of the external auditory canal had a tumor that had been excised and treated with postoperative radiation therapy approximately 30 years before his presentation with intracranial extension. He had had at least 2 reexcisions for recurrent disease, including Mohs surgery. Three weeks before his presentation with skull invasion, he noticed swelling above his external auditory canal in the temporal bone area, which was initially treated as a Staphylococcus aureas infection before biopsy showed recurrent basal cell carcinoma. The ganglioneuroma of middle ear arose in a 15-yearold girl (Case 37) who originally presented in 2006 with her primary tumor in right ear that was partially resected. She also had polyostotic fibrous dysplasia. She was followed on a yearly basis until 5 years later when she began noticing blurring in her right eye, due to expansion of her sphenoorbital ridge fibrous dysplasia. Her tumor at that time was also 608 identified as showing skull base invasion with extensive bony and dural involvement on the right side near the tumor origin, but also extending to the opposite skull base (Fig. 3e). This tumor was completely benign, with large dysmorphic ganglion cells, some binucleated, embedded within the neuroma background (Fig. 3f). Cells were synaptophysin-immunopositive (Fig. 3f). Despite the benign histologic features, there was massive bony and dural involvement. The other histologically benign lesion encountered as a skull invader was a mucocele of the frontal sinuses that eroded bone (Fig. 3g, Case 35) and extended as a cohesive ball-like mucin-filled mass into the cranial vault (Fig. 3h). Histologically, this showed pseudostratified epithelium with extensive squamous metaplasia and massive lymphoplasmacytic infiltrates in the underlying submucosa (Fig. 3i). One tumor arose from the orbit, a high-grade adnexal tumor (a malignant hidradenoma). Although 23 glomus jugulare/glomus tympanicum paragangliomas had been operated on at our institution during the study period, only 1 showed definitive massive intracranial extension and was included (Table). DISCUSSION After excluding meningiomas, sarcomas, pituitary adenomas invasive of skull base, and metastases, our cases show good agreement with previously published series with respect to the types of tumors seen (1Y3, 5, 12), suggesting that our institutional experience coincides with that of other centers. The otolaryngology series by Batra et al (1) on minimally invasive endoscopic resection of anterior skull base neoplasms included 6 cases of SCC, 5 of esthesioneuroblastoma, 5 of mucosal melanoma, and 4 sinonasal undifferentiated carcinomas. The surgical series by Ducic and Coimbra (13), also restricted to skull base tumors, included 3 SCCs, 3 esthesioneuroblastomas, and 1 each of adenocarcinoma and adenoid cystic carcinoma. Squamous cell carcinomas also predominated in the series of Manolidis et al (5), which included only tumors invasive of the temporal bone and lateral skull,base and in the 1994 series of Irish et al (3). Squamous Cell Carcinoma Whereas SCC was the most common cutaneous type of tumor to invade skull in our series, it is the second most common cutaneous malignancy after basal cell carcinoma. Although no single histologic type of SCC was exclusively associated with skull invasion in our series, moderately differentiated invasive SCC with keratinization was the most frequent histologic pattern. Previous literature has addressed the issue of which factors might be associated with skull invasion in cutaneous tumors. Cernea et al (14) investigated p53 expression in basal and SCCs with skull base invasion, compared to control groups with good outcomes, in an attempt to correlate tumor protein expression with tumor aggressiveness. The TP53 gene encodes for the p53 protein, which functions to maintain the integrity of the genome by arresting the cell cycle in mutated or stressed cells and/or initiating apoptosis in cases of irreparable damage; therefore, TP53 functions as a tumor suppressor gene and TP53 mutations are often implicated in tumorigenesis. Because tumors with TP53 somatic Ó 2013 American Association of Neuropathologists, Inc.

10 J Neuropathol Exp Neurol Volume 72, Number 7, July 2013 Outside-in Skull Tumor Invasion FIGURE 3. (A) Coronal magnetic resonance (MR) imaging study, T1-weighted with contrast, from a patient with olfactory neuroblastoma showing the rare spread of tumor over the vertex of the head and attached to dura. Note the very small dural tail. This spread occurred after multiple recurrences over the skull base over a 9-year period. Case 16. (B) Intraoperative photograph of the lesion illustrated in panel a showing the discrete nature of this metastasis and hyperemic appearance. Case 16. (C) Photomicrograph of the dural olfactory neuroblastoma metastasis showing characteristic, closely packed, small blue tumor cells with scant cytoplasm and minimal fibrillar processes embedded within the dura. Case 16. Hematoxylin and eosin (H&E); original magnification: 400. (D) Photomicrograph of the dural olfactory neuroblastoma metastasis immunostained for synaptophysin showing diffuse immunoreactivity. Note the more irregular configuration of the nests when embedded in the dura. Immunostaining for synaptophysin, with light hematoxylin counterstain; original magnification: 600. Case 16. (E) Axial MR imaging study, T1- weighted with contrast, showing the bony and dural extension of a benign ganglioneuroma of the right middle ear in a teenaged girl. This lesion produced massive bony skull base and bilateral dural extension. Although the tumor is more bulky on the same side as the original ear lesion (arrow), dural and bony tumor was also present on the left side (arrowhead). Case 37. (F) Photomicrograph of the benign ganglioneuroma, immunostained for synaptophysin, showing a binucleated ganglion cell at the far left, a strongly immunoreactive large ganglion cell at the top right and the bone at the bottom of the figure. Case 37. Immunostaining for synaptophysin with light hematoxylin counterstain; original magnification: 600. (G) Coronal computed tomographic scan of a patient with the mucocele showing the rounded, bony, destructive left-sided mucocele (arrow) extending intracranially from the frontal sinus. Case 35. (H) Coronal T1-weighted MR imaging delineating how discrete and anterior the lesion is. Case 35. (I) Photomicrograph of the mucocele showing the benign squamous metaplasia and underlying lymphoplasmacytic infiltrate in the submucosa. Case 35. H&E; original magnification: 400. Ó 2013 American Association of Neuropathologists, Inc. 609

11 Serracino and Kleinschmidt-DeMasters J Neuropathol Exp Neurol Volume 72, Number 7, July 2013 mutations show increased nuclear labeling with p53 immunohistochemistry, because of the defective degradation of mutant p53, immunohistochemistry for the protein can serve as a surrogate marker for mutational status. Cernea et al (14) found that p53 protein expression was more common in basal cell carcinomas with skull base invasion. Squamous cell carcinomas, in contrast, showed decreased p53 protein expression, although the difference was not statistically significant compared to the controls. We did not have the original tumors before skull invasion in our hospital system to validate or refute the findings of Cernea et al, but we were able to identify no other studies in the literature that might further contribute to this question. Thus, to our knowledge, there is currently no reliable marker that the pathologist can assess to predict predilection for skull invasion in SCCs of the head and neck. Other case reports and surgical series have focused on cutaneous carcinomas with skull invasion, including a surgical series of 25 patients reported by Soma et al (12). They note that some of their cases occurred in patients where initial scalp lesions are not appropriately diagnosed or their extent is underestimated by the doctor/patient. Outcome was excellent in their series, although a multidisciplinary approach by surgeons from several specialities (combined plastic surgery/ neurosurgery procedure and neuro-oncological management) was required. Their series included 8 SCCs and 12 basal cell carcinomas, differing from our series by the predominance of basal cell carcinomas. Our predominance of SCCs better correlates with that of Manolidis et al (5). Although that series was restricted to temporal bone invasion and included tumors excluded from our study (e.g. chordomas and skull base sarcomas), they had 26 SCCs, 10 adenoid cystic carcinomas, and 4 basal cell carcinomas in their cohort (5). They also identified 4 acinic cell carcinomas and 3 carcinomas arising from pleomorphic adenomas Y tumor types not found in our group. of our cases arose as postburn SCCs. Etlik et al (15) described a rapidly progressive, destructive SCC in a 15-year-old girl arising from a postburn scar of the scalp with deep cerebral extension. Tumors originating in areas of chronicinjurysuchasburnscars(alsoknownasmarjolin ulcer) are usually SCCs and are known for their more aggressive biology (15). Basal Cell Carcinoma We identified only a single example of basal cell carcinoma, which was included with middle ear neoplasms because it arose in the auditory canal. In several series, this type of cutaneous malignancy represents the second most common tumor type to produce skull penetration. In the series by Irish et al (3), 29 SCCs were identified, with 10 basal cell carcinomas, whereas Manolidis et al (5) reported only 4 basal cell carcinomas in their cohort. Basal cell carcinomas are the most common cutaneous malignancy, and most cases occur in the head and neck region. Although skull invasion may be seen with a variety of subtypes, some patterns, notably the sclerosing (morpheic) pattern, have been associated with especially aggressive behavior (16). Fortunately, most cases of basal cell carcinoma pursue an indolent course, with the typical tumor requiring years before metastasis to local lymph nodes (17). The rate of intracranial spread is correspondingly low, with estimates of 0.03% in the literature (18). Despite these reassuring numbers, the literature contains no shortage of case reports that exemplify the destructive consequences of long-standing tumor, either because of obstinate growth despite repeated treatments (as in our case) or because of patients neglect of their tumor. When skull invasion occurs, basal cell carcinoma usually erodes the bone and accesses the cranium via direct extension of tumor (17, 19Y24). Studies also document an especially aggressive breed of tumor with a swift course of invasion that seems to preferentially affect younger adults (16, 17). Finally, as previously mentioned, p53 protein expression seems increased in basal cell carcinomas with skull base invasion (14). Cylindroma Our case of cylindroma with intracranial extension has been previously detailed (6). Cylindromas are benign adnexal tumors of sweat gland origin, characteristically occurring on the head and neck of middle-aged women, that may be sporadic (usually solitary) or in association with autosomal dominant familial cylindromatosis (Brooke-Spiegler syndrome), a syndrome characterized by loss of heterozygosity at the CYLD gene locus on chromosome 16q (25, 26). Clinically, the tumors manifest as dome-shaped pink nodules, which can enlarge and coalesce to disfigure and ensheathe the scalp. The cylindroma in our series affected a middle-aged man as part of familial cylindromatosis. Diagnosis of malignant cylindromas requires increased nuclear pleomorphism and anaplasia, loss of peripheral palisading with stromal invasion, and increased mitotic activity (6, 27). These malignant features were not seen in our patient; instead, invasiveness was likely attributable to prior surgeries with subsequent loss of bony skull integrity, as well as some degree of patient neglect and disinclination to seek medical care (per the patient s neurosurgeon). We are aware of only 1 other report of a benign cylindroma with skull invasion (28). Other rare types of cutaneous malignancies we identified in the literature as skull invaders, but not seen in our series, include Merkel cell carcinoma (29), dermatofibrosarcoma protuberans (30Y32), and eccrine adenocarcinoma (33). Olfactory Neuroblastoma The second single most frequent tumor type to display skull invasion in our series was olfactory neuroblastoma, seen in 9 cases. Olfactory neuroblastomas (esthesioneuroblastomas) arise from the olfactory mucosa and make up approximately 2% to 3% of sinonasal tract tumors (34). They are staged according to the 3-tiered Kadish system, whereby Stage A disease is confined to the nasal cavity, Stage B disease involves the nasal cavity as well as the paranasal sinuses, and Stage C disease indicates local or distant spread. Thus, local extension, including into the skull base and dura, is well known (8, 9). Prognosis correlates with the tumor stage, although intracranial invasion may or may not influence the prognosis (34Y36). Histologically, tumors are graded by Hyams grading system, which classifies the tumors into 4 grades based Ó 2013 American Association of Neuropathologists, Inc.

12 J Neuropathol Exp Neurol Volume 72, Number 7, July 2013 on several microscopic features, including mitosis, necrosis, rosettes, and neurofibrillary matrix. Fukushima et al (34) demonstrate a direct correlation between MIB-1 and Bcl-2 labeling and tumor grade; however, clinical and prognostic import of these findings remains to be determined. Specifically, which of these histopathologic features might influence skull invasion has not been determined. In our series of 9 skull-invasive olfactory neuroblastomas, 6 were Hyams Grade II and 3 were Hyams Grade III at the time of intracranial involvement. Yu et al (10) described 3 types of direct intracranial extension by computed tomography and magnetic resonance imaging: cranio-orbital-nasal communication, cranio-nasal communication, and orbital-nasal communication. Far less appreciated is the dissemination to lateral convexity dura, which was seen in 1 of our cases (Fig. 3a, b). A case of diffuse subdural recurrence was recently reported by Capelle and Krawitz (11), thereby underscoring the rarity of this occurrence. Dissemination to convexity dura might represent dissemination through dural venous sinuses once access to dura by direct extension has occurred. Dural venous sinus invasion was identified in a few of our cases (Fig. 2i). Adenoid Cystic Carcinoma There were 4 cases of adenoid cystic carcinoma with skull invasion. In all patients, there was a previous history of resection and radiation therapy (combined with chemotherapy in the 42-year-old patient; Table). These patients typify the usual disease course for adenoid cystic carcinoma, which is known for its slow-growing yet relentless progression with a notorious propensity to track and infiltrate along nerves. Adenoid cystic carcinoma of the head and neck most commonly arises from the major and minor salivary glands, although it may also involve the lacrimal glands, upper respiratory tract, breast, or uterine cervix. It preferentially spreads hematogenously and rarely metastasizes to lymph nodes. Adenoid cystic carcinomas only comprise approximately 1% of head and neck malignancies; however, the literature estimates the incidence of intracranial involvement by adenoid cystic carcinoma to be somewhere between 4% and 22% (37, 38). Thus, literature searches readily yield over a hundred such examples of adenoid cystic carcinoma invading the skull (37). This invasion usually takes 1 of 3 forms: 1) direct extension, 2) perineural spread, and 3) hematogenous deposition from a distant site (37). Somewhat common scenarios include invasion from the lacrimal gland and nasopharynx or tumors of the anterior skull base mimicking a meningioma complete with a dural tail sign on imaging (39Y42). In addition, there have been a handful of reports of so-called primary intracranial adenoid cystic carcinoma where there is no evidence of tumor outside the cranium (43Y45). Again, of our 4 cases, 1 was high grade, 1 intermediate grade, and 2 were low-to-intermediate grade. One of the most interesting cases in our series was Case 26, which showed diffuse dural dissemination to the lateral convexity, in a pattern also seen with olfactory neuroblastoma, as noted above. Increased solid growth pattern places adenoid cystic carcinoma into a high-grade category and portends a worse prognosis (46, 47). More recently, an aggressive variant of adenoid cystic carcinoma called adenoid cystic carcinoma Outside-in Skull Tumor Invasion with dedifferentiation or adenoid cystic carcinoma with highgrade transformation has been described (48Y51). These tumors occur slightly more commonly in male patients, display distinct histologic features including loss of biphasic appearance (i.e. the myoepithelial layer), and have an increased rate of lymph node metastasis (51). of our 4 tumors manifested dedifferentiation. Although adenoid cystic carcinomas were first described in the mid 1800s, understanding of the molecular alterations in the tumor remains limited (46). Whereas studies have characterized frequent chromosomal alterations including t(6;9) translocation, gains in chromosome 8 and 22, and losses in chromosome 1p, 6q, and 12q, researchers have yet to firmly establish prognostic value for any of these changes other than the fact that more genetic abnormalities in general seem to be associated with a more aggressive tumor (46, 51Y57). In sum, the search for prognostic markers as well as biomarkers that might invite targeted drug therapy in adenoid cystic carcinomas continues, explaining why resection with radiation therapy (with or without neck dissection in cases with high-grade transformation) remains the mainstay of treatment. Not surprisingly, in view of recurrent growth and late metastases, survival at 5 years averages 75% to 80%, but at 10 years, the survival declines to approximately 35% (46). Other sinonasal lesions invasive of skull in our series included 2 cases of sinonasal undifferentiated carcinomas, 2 cases of adenocarcinoma, and single examples of hemangiopericytoma, solitary fibrous tumor, and sinonasal teratocarcinoma. We have previously reported the case of sinonasal teratocarcinoma with massive intracranial extension and unusual craniopharyngioma component (7). Literature search of sinonasal tumors with skull invasion disclosed a report of basaloid SCC arising from the sphenoid sinus and presenting as a sellar mass (58). Our United StatesYbased patient population explains the absence of cases of skull-invasive Epstein-Barr virusydriven nasopharyngeal carcinoma in this series, which are more common in China and Southeast Asia. The incidence of skull base and intracranial invasion in this variant of SCC has been reported at 12% to 31% of patients from endemic geographic regions (59). In these cases, along with traditional SCC, invasion seems to proceed via direct extension; however, there is likely a role for lymphatic and perineural spread as well (59). The most interesting sinonasal lesion with intracranial extension in our series was that of a mucocele. This occurrence is rare, although it has been described in the neurosurgical and otolaryngology literature (60Y62). Mucoceles are benign cysts that can progressively distend the bony and compress nearby structures including orbit, but massive intracranial extension, such as in our case, is rare (62). The surgical literature usually advocates minimally invasive endoscopic endonasal surgery (60, 61) and marsupialization (62); hence, substantiative pathologic specimens are seldom attained from these cases unless the preoperative diagnosis is unclear. The case included and from our cohort (Fig. 3gYi) underscores for pathologists the potential for skull invasion in these lesions. The most unique case in the series was that of a skullinvasive ganglioneuroma of the middle ear in a young girl, Ó 2013 American Association of Neuropathologists, Inc. 611