Category: Case of the Month

History: A 48-year-old man noticed an enlarging, freely moveable mass in the left shoulder. The excised specimen consisted of two portions of firm lobulated tan tissue each approximating 2.0 cm in greatest diameter.

The tumor was well-circumbscribed and varied in cellularity (Fig. 1). It microscopically had an eosinophilic stroma consisting of spindled and fibrous cells (Fig. 2a, 2b), myxoid regions (Fig. 3) and chondroid areas (Fig. 4). Clusters and solid sheets of cell-enveloped ducts generally had two layers of cuboidal cells (Fig. 5). There were scattered mitotic figures and mild pleomorphism (Fig. 6). Calcifications and ossification were also present. Immunohistochemical stains for CEA, CK, vimentin and S100 (not shown) were positive.

Diagnosis: “Chondroid Syringoma”

Jonathan Zumwalt, MSIV, and Donald R. Chase, MD
Department of Pathology and Human Anatomy, Loma Linda University and
Medical Center, Loma Linda, California
California Tumor Tissue Registry, Loma Linda, California

Discussion: First described by Billroth in 1859 as “mixed tumor of the skin” the term “chondroid syringoma” (CS) was first used by Hirsch and Helwig in 1961 to describe the same entity which had also been known as mixed tumor, eccrine syringoma, cutaneous mixed tumor, and pleomorphic adenoma of the skin. The lesions also have more recently been sub-classified as apocrine or eccrine, or as a combination “mixed”. The tumor typically presents in mid to late-aged men as a solitary, slowly growing nodule on the head or neck. However, it may occur in either gender, in any skin site, in most any age (range 10-96). It is usually between 0.5-3.0 cm in diameter.

The apocrine mixed tumors are generally well-defined tumors with a background of fibrous, myxoid and/or chondroid stroma. Although most tumors show a mixture of all three elements, it is not uncommon for only two to be present. The stromal areas may contain calcifications or areas of ossification.

The glandular portion of the tumor shows ducts lined by two layers of cuboidal epithelium. Some of the ducts are variably dilated and may have keratinous cysts. Eosinophilic globules composed of collagen (collagenous spherulosis) may be found in both the lumina of the glandular elements and in the stroma. Metaplastic squamous changes may also be present.

The cells of this tumor usually express CEA and CK, while the cells in the outer layer of the tubular structures contain vimentin and S100. The presence of CEA and CK suggest apocrine origin of the intrafollicular ducts. Type IV collagen, tenacin, and fibronectin, are usually found in the mucoid-like or chondroid stroma. Type II collagen is generally found in both the stromal and epithelial compartments; otherwise it is only expressed in cartilage.

A rare variant of CS is the so-called “hyaline cell-rich chondroid syringoma”. This unique tumor is composed of epithelial cells with eosinophilic hyaline that displaces the nucleus and results in a plasmacytoid appearance. Although these tumors may be mistaken for plasmacytomas, they usually show duct formation.

The eccrine mixed CS differs from the apocrine variant in having numerous small syringoma-like ducts within a cartilaginous and myxoid stroma. These ducts express both CEA and CK.

The malignant variant of the CS is quite uncommon, and is initially indolent for months or years and abruptly shows rapid growth. It mostly occurs in women (2:1) usually in the extremities or trunk. The tumor is generally larger than the benign variant (2-3 cm). Microscopic examination shows persistence of the lobules, and infiltration/invasion of the adjacent tissue. Cords of cells with cuboidal or polygonal shapes with glandular differentiation are characteristic. The malignant variant often shows pleomorphism, mitotic figures and invasion into lymphatics. The tumor cells express CK and the cells lining the lumens are CEA positive. Approximately 30-40% metastasize.

Suggested Reading:

A special thanks to Martin Mihm and his 120th CTTR Semi-Annual Pathology Slide Seminar Handout.

Barnett MD, Wallack MK, Zuretti A, Mesia L, Emery RS, Berson AM. Recurrent malignant chondroid syringoma of the foot: a case report and review of the literature. Am J Clin Oncol. 2000 Jun;23(3):227-32.

Bhargava D, Bhusnurmath S, Daar AS. Chondroid syringoma of the nose: report of a case. J Laryngol Otol. 1997 Sep;111(9):862-4.

Kazakov DV, Belousova IE, Bisceglia M, Calonje E, Emberger M, Grayson W, Hantschke M, Kempf W, Kutzner H, Michal M, Spagnolo DV, Virolainen S, Zelger B. Apocrine mixed tumor of the skin (“mixed tumor of the folliculosebaceous-apocrine complex”). Spectrum of differentiations and metaplastic changes in the epithelial, myoepithelial, and stromal components based on a histopathologic study of 244 cases. J Am Acad Dermatol. 2007 Sep;57(3):467-83.

Metzler G, Schaumburg-Lever G, Hornstein O, Rassner G. Malignant chondroid syringoma: immunohistopathology. Am J Dermatopathol. 1996 Feb;18(1):83-9.
Sungur N, Uysal A, Gümüş M, Koçer U. An unusual chondroid syringoma. Dermatol Surg. 2003 Sep;29(9):977-9.

Yavuzer R, BaÅŸterzi Y, Sari A, Bir F, Sezer C. Chondroid syringoma: a diagnosis more frequent than expected. Dermatol Surg. 2003 Feb;29(2):179-81.

Yim YM, Yoon JW, Seo JW, Kwon H, Jung SN. Pleomorphic adenoma in the auricle. J Craniofac Surg. 2009 May;20(3):951-2.

History: A 49 year-old woman presented with a left thigh mass. It was completely excised and found to be well circumbscribed. It weighed 13 grams, and was relatively homogeneous gray-to-tan. It lacked hemorrhage and/or necrosis.

Microscopically, the tumor had well-defined border (Fig. 1, 2) and grew in a whorled lobular or “finger print” pattern (Fig. 3). High density regions of cells were juxtapositioned with lowly cellularity regions (Fig. 4). The cells were polygonal, epithelioid and spindled, with intervening collagen (Fig. 5). The nuclei were bland, and lacked pleomorphism or significant mitotic activity (Fig. 6).

Immunohistochemistry showed strong S100 positivity and negative staining for cytokeratin.

Diagnosis: Cellular neurothekeoma, thigh

Michelle Iverson, PSF, and Donald R. Chase, MD
Department of Pathology and Human Anatomy,
Loma Linda University and Medical Center, Loma Linda, California
California Tumor Tissue Registry, Loma Linda, California

Discussion: Neurothekeoma (NT) is a term used by Gallager and Helwig in 1980 to reference a unique neural tumor. As described, NT is a superficial dermal tumor that typically occurs in the upper extremities of the head and neck, mostly in the first two decades of life. It is comprised of epithelioid cells and spindle cells which arrange into nodules with a whorled or somewhat spiral fascicular pattern. Collagen is often seen in association with the cellularity. Nuclear atypia and mitotic figures are rare, and when they do occur, the clinical significance is uncertain. Treatment consists of excision and clinical monitoring. The tumors are considered low-grade without metastatic potential, although local reoccurrence has been described.

Rosati, in 1986, described a cellular variant of myxoid neurothekeoma. This variant appears morphologically the same as classic neurothekeomas, however the immunohistochemical profile is shows S100 is be negative and NKI-C3 and NSE to be positive.

Although the tumor can usually be diagnosed on its unique growth patterns, mimickers include:

• Nerve sheath myxoma which has a greater myxoid component, and is multilobular with a prominent fibrous periphery. The cells are more spindled and stellate. They are S100 and GFAP positive.

• Melanocytic neoplasms (especially Spitz nevus) show downward growth which is not seen in cellular neurothekeoma. They show epithelioid and spindle cells in a nested pattern.

• Plexiform fibrohistiocytic tumor is a multinodular, biphasic tumor composed of histiocytic cells and osteoclast-like giant cells with fascicles of fibroblastic cells in-between.

Suggested reading:

Hornick, JL, Fletcher, CDM. Cellular neurothekeoma: detailed characterization in a Series of 133 cases. Am J Surg Pathol 2007; 31:329.

Barnhill, R.L., Mihm M.C. Jr. Cellular neurothekeoma: a distinctive variant of neurothekeoma mimicking nevomelanocytic tumors. Am J Surg Pathol 1990; 14:113.

Calonie, E., Wilson Jones, E., Smith N.P. Cellular ‘neurothekeoma’; an epitheloid variant of pilar leiomyoma? Morphological and immunohistochemical analysis of a series. Histopathology 1992; 20:397.

Fetsch, JF, et al. Neurothekeoma: an analysis of 178 tumors with detailed immunohistochemical data and long-term patient follow-up information. Am J Surg Pathol 2007; 31:1103.

Gallager, R.L., Helwig, E.B. Neurothekeoma-benign cutaneous tumour of neural origins. Am J Clin Pathol 1980; 74:759.

Fetsch, JF, et al. Nerve sheath myxoma: a clinicopathologic and immunohistochemical analysis of 57 morphologically distinctive, S-100 protein- and GFAP-positive, myxoid peripheral nerve sheath tumors with a predilection for extremities and a high local recurrence rate. Am J Surg Pathol 2005; 29:1615.

Angervall, L., Kindblom, L-G., Haglid, K. Dermal nerve sheath myxoma. A light and electron microscopic, histochemical and immunohistochemical study. Cancer 1984; 53:1752.

History: A 76-year-old female presented with a two week history of a 7.1 cm nodular tumor in the buttock. It was violaceous, raised and firm. There was also adenopathy in the groin.
The biopsy showed a large, asymmetrical poorly-confined neoplasm (Fig. 1) extending from the papillary dermis (Fig. 2) into the subcutaneous fatty tissue (Fig. 3). The tumor showed a trabecular pattern with irregularly shaped tumor nodules between the stroma (Fig. 4). The closely packed neoplastic cells showed large, round vesiculated nuclei and inconspicuous nucleoli, aka “small round blue cells” (Fig. 5). Some regions showed hyper- and hypo-dense cell sheets. Scattered throughout the tumor were atypical mitotic figures and necrotic neoplastic cells (Fig. 6).

Diagnosis: “Merkel Cell Carcinoma, Buttock”

Jonathan Zumwalt, PSF, and Donald R. Chase, MD
Department of Pathology and Human Anatomy, Loma Linda University and
Medical Center, Loma Linda, California
California Tumor Tissue Registry, Loma Linda, California

Discussion: First described about in 1972 by Toker as “trabecular carcinoma”, Merkel cell carcinoma was later ultrastructurely shown to have neuroendocrine granules identical to those found in Merkel cells of the epidermis, cells which share similar ultrastructure and biochemistry as the tumor first described by Toker and Friedrich Sigmund Merkel in 1875. They are neural crest derived cells usually located in the DEJ or within adnexal epithelium. They play roles as both mechanoreceptors and endocrine cells for the sensory system: light touch discrimination of shapes and textures.
Merkel cell carcinoma (MCC), an epithelial neuroendocrine cell tumor, is included in the APUD system (amine precursor uptake and decarboxylase system). It is believed that malignant transformation takes place in the cell of origin as a result of chronic exposure to ultraviolet radiation. Molecular alterations found in Merkel cell carcinoma include deletion of the short arm of chromosome 1, trisomy 6 and loss of heterozygosity of chromosome 13.

The clinical presentation of MCC is typically of a small growing firm nodule on the head or neck of patients with sun damage. The average size of the tumor is typically 2.0 cm. MCC can occasionally grow to tremendous proportions up to 20 cm. Checking for lymphadenopathy is critical for the clinician, due to there being metastasis to local nodes 30% at the time of diagnosis.
MCC is most commonly found in older Caucasian men with previous sun damage. The age range of MCC incidence is 40-90; with the most common group in ages 70-80. Fifty per cent of tumors are on the head and neck, 35% are on the extremities and 15% are on the chest, back and abdomen. There is an increased incidence of MCC in patients with HIV, B-cell neoplasms, CLL and HIV, due to the immunosuppression of these diseases.

MCC acts very aggressively, and wide local excision is the treatment of choice after simple excision. Wide local excision decreases locoregional relapse of tumor by 3 fold (89% to 27%) and increases 2-year survival by 3 fold (28% to 86%) as compared to simple excision. The tumor is radiosensitive, but tends to reoccur after treatment. Radiation alone is usually used for palliative care. 10-year survival rates range from 30-70% depending on staging.

One of the most recent finding with MCC is its origin. In 2008, Drs. Chang and Moore at the University of Pittsburgh found a virus associated with the tumor. The virus coined, Merkel Cell Polyomavirus, is found in 80% of MCC tumors. The virus is infects most healthy humans by age 15 and infection is asymptomatic. Testing of healthy human tissue shows occasional infection of the virus. The virus is under the papovaviridae family, which includes the HPV (warts), BK (upper respiratory infection) and JC (progressive multifocal leukoencephaolopathy) viruses. The virus is non-transmissible after integration into the host genome, due to the truncation of the DNA during integration and the virus is only monoclonal after integration. Some researchers are even looking into a vaccine.
MCC has shown to regress spontaneously. This unique phenomenon has been documented 22 times in the literature. It accounts for 1.5% of the reported MCC cases. It is thought that the immune system is able to identify and eliminate the MCC virus. Similar to the mechanism in which the body is able to spontaneously dispose of skin warts.

There are three histologic subtypes of Merkel cell carcinoma:
– Trabecular Pattern: composed of ribbons of uniform cells with nuclear molding.
– Intermediate type formed by nodules and sheets of basophilic cells that show pale vesicular nuclei containing a small nucleolus.
– Small cell type: with small “oat cells” usually displaying crush artifact.

MCC is unique to other neuroendocrine tumors due to its immunohistochemical profile. The tumor expresses both epithelial and neuroendocrine markers. The most unique marker is cytokeratin 20, which usually stains with a typical perinuclear “dot-like” pattern. High molecular cytokeratins such as CAM 5.2 are also commonly expressed.
The cells may also show a spindled appearance. There is usually an elevated mitotic rate. Also, necrotic cells may be scattered throughout the tumor. Lymphatic and vascular invasion are commonly present (30%) and must be investigated due to prognostic factors and staging.
Sometimes the tumor shows epidermotropism. Additional epidermal findings include actinic keratosis and/or squamous cell carcinoma in situ. Fully developed adjacent squamous cell or basal cell carcinomas have also been described.

Differential Diagnosis:
Basal Cell Carcinoma: Basal cell carcinoma (BCC) is the most common mimicker of MCC. BCC differs in that is shows retraction between the stroma and tumor. BCC nuclei are also hyperchromatic and tend to palisade around the periphery of nests.

Melanoma: The small cells of neuroendocrine carcinoma of the skin can be initially interpreted as lymphoid or nevoid melanoma, especially considering that MCC can present with epidermotropism. Immunohistochemistry will readily exclude a lymphoma or a melanoma from the differential diagnosis.

Small Cell Carcinoma of the Lung may appear almost identical to MCC due to it being a neuroendocrine tumor and the age groups of the patients. The tumor is characterized by poor circumscription, and the extremely smudged interface between cells as well as a tendency for the distortion of the cells during preparation to form elongated basophilic strings. Small cell carcinoma is positive for TTF1 and CK7 staining.

Ewing Sarcoma: Ewing sarcoma usually occurs in a younger population and is rare in an adult. Extraskeletal Ewing’s sarcoma has cells that are less closely packed and the neoplasm is often large and deep-seated. The tumor stains positively for CD99.
Thanks

A special thanks to Martin Mihm and his 120th CTTR Semi-Annual Pathology Slide Seminar Handout.

Suggested Reading:
Albores-Saavedra J, Batich K, Chable-Montero F, Sagy N, Schwartz AM, Henson DE. Merkel cell carcinoma demographics, morphology, and survival based on 3870 cases: a population based study. J Cutan Pathol. 2009 Jul 21.

Andea AA, Coit DG, Amin B, Busam KJ. Merkel cell carcinoma: histologic features and prognosis. Cancer. 2008 Nov 1;113(9):2549-58.

Bichakjian CK, Coit DG, Wong SL. Radiation versus resection for Merkel cell carcinoma. Cancer. 2010 Apr 1;116(7):1620-2.

Calder KB, Smoller BR. New insights into merkel cell carcinoma. Adv Anat Pathol. 2010 May;17(3):155-61.

Craig PJ, Calonje JE, Harries M, Stefanato CM. Incidental chronic lymphocytic leukaemia in a biopsy of Merkel cell carcinoma. J Cutan Pathol. 2009 Jun;36(6):706-10.

Ciudad C, Avilés JA, Alfageme F, Lecona M, Suárez R, Lázaro P. Spontaneous regression in merkel cell carcinoma: report of two cases with a description of dermoscopic features and review of the literature. Dermatol Surg. 2010 May;36(5):687-93. Epub 2010 Apr 1.

D’Agostino M, Cinelli C, Willard R, Hofmann J, Jellinek N, Robinson-Bostom L. Epidermotropic Merkel cell carcinoma: a case series with histopathologic examination. J m Acad Dermatol. 2010 Mar;62(3):463-8.
Duncavage EJ, Le BM, Wang D, Pfeifer JD. Merkel cell polyomavirus: a specific marker for Merkel cell carcinoma in histologically similar tumors. Am J Surg Pathol. 2009 Dec;33(12):1771-7.

Foulongne V, Dereure O, Kluger N, Molès JP, Guillot B, Segondy M. Merkel cell polyomavirus DNA detection in lesional and nonlesional skin from patients with Merkel cell carcinoma or other skin diseases. Br J Dermatol. 2010 Jan;162(1):59-63. Epub 2009 Jul 6.

Heath M, Jaimes N, Lemos B, Mostaghimi A, Wang LC, Peñas PF, Nghiem P. Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: the AEIOU features. J Am Acad Dermatol. 2008 Mar;58(3):375-81.

Heymann WR. Merkel cell carcinoma: insights into pathogenesis. J Am Acad Dermatol. 2008 Sep;59(3):503-4.

History: A 51 year-old man with a medical history significant for hypertension, renal stones, and chronic kidney disease (with 66% function of the right kidney and 33% function of the left kidney) presented with a complex cystic mass of the left kidney. The lesion was discovered incidentally in October of 2006 and followed radiologically. The mass slowly increased in complexity and size, evolving from a radiologic Bosniak II to a Bosniak III lesion. The patient declined surgical intervention until there was a rapid, 1 cm increase in size between May and December of 2009. The patient subsequently underwent laparoscopic nephrectomy.

On CT scan, performed shortly before excision, the lesion measured 10.3 x 12.9 x 11.4 cm and showed multiple internal septations with mild calcifications along the upper aspect of some septations (Fig. 1, 2).

The white-tan multi-cystic mass appeared to have arisen from the mid-renal pole and pelvis (Fig. 3, gross photo from similar case). It was partially encapsulated and compressed residual normal kidney. The multiple cystic spaces were filled with transparent amber-colored fluid and delineated by smooth, thin septa (Fig. 4). The cysts were seen microscopically to be either confluent with other spaces or individual without communication (Fig. 5). The lining was by a single layer of flattened epithelium with eosinophilic cytoplasm and bland hyperchromatic nuclei (Fig. 6). Scattered regions had a hobnail morphology (Fig. 7). The fibrous elements were of dense fibrous tissue with frequent areas showing ovarian-like stroma. Rare regions had a hypocellular, myxoid morphology. The cyst walls lacked renal tubules, primitive blastema, and glomeruli.

Diagnosis: “Cystic Nephroma (CN)”
Cassie L. Booth, MD and Donald R. Chase, MD
Department of Pathology and Human Anatomy, Loma Linda University and Medical Center, Loma Linda, CA
California Tumor Tissue Registry, Loma Linda, CA

Discussion: Cystic nephroma (CN), also known as a “multilocular renal cyst” was first described by Dr. Walter Edmunds in 1892. It is a benign process, without reported metastases and is cured by simple excision. Adult CN is to be distinguished from pediatric CN which is considered to be part of the spectrum of Wilms tumor. In adults, CNs are usually incidental findings in middle-aged women (female:male predominance of 7:1). The lesions are solitary and unilateral by definition, and typically arise from the upper pole of the kidney.

CN is usually encapsulated and although it may compress the adjacent kidney, the remaining renal parenchyma is otherwise normal. The cysts are usually non-communicating, filled with serous (or rarely hemorrhagic) fluid, and lined by a single layer of epithelial cells. This lining is usually flattened, cuboidal, or columnar, but areas of hobnail morphology are considered characteristic. Atypical cytologic features such as hyperchromasia may be seen, but are not prominent. The septa between the cysts typically consist of dense fibrous connective tissue without nephrogenic or blastemal elements. Ovarian-like stromal differentiation is also characteristic of this lesion and these areas often are immunoreactive for estrogen, progesterone, inhibin, CD10, and calretinin. Myxoid regions and scattered loose fascicles of smooth muscle may also be present.

Differential Diagnosis:
• Multilocular Cystic Renal Cell Carcinoma/Clear Cell Renal Cell Carcinoma with Prominent Cysts comprise less than 5% of clear cell RCCs. These tumors are well circumscribed with non-communicating cysts and thick fibrous septa with nodules of clear cells in some portion of the cyst wall. The lining epithelium is markedly thin or absent. Thick walls with friable material on the cyst surface and/or hemorrhage within the cyst are characteristic of carcinoma with cystic degeneration. Identification of clear cell aggregates is the hallmark in distinguishing a cystic RCC from CN (benign multilocular cysts).

• Non-neoplastic/Acquired Cystic Disease are entities which show remnants of nephrons within the septal walls and abnormal renal architecture.

• Primary Renal Synovial Sarcoma consists of monomorphic, plump spindle cells frequently interspersed with large cysts. The cysts are lined by bland, mitotically inactive epithelial cells. The spindle cells are immunoreactive for EMA, CD56, and sometimes CD99 but never ER (which is frequently expressed by the ovarian-like stroma of CNs). The tumor is also characterized cytogenetically by translocation t(X;18)(p11.2/q11.2) resulting in a distinctive SYT-SSX fusion gene.

• Tubulocystic carcinoma has only recently been described and did not appear in the 2004 WHO classification. It has a distinctive gross appearance usually of a spongy off-white cut surface composed of clear fluid-filled cysts which appear to be uniform in size. But microscopically the cysts show considerably size variation, some as small as a renal tubule. The cysts are separated by thin fibrous septa and are lined by a single layer flattened, cuboidal, or hobnail carcinoma cells with spherical nuclei and prominent nucleoli. Necrosis is rare and mitotic figures are infrequently encountered.

• Mixed Epithelial and Stromal Tumor (MEST) is perhaps the most controversial differential for CN, as there are many striking similarities in their clinical behavior, morphologic features, and immunohistochemical properties. Both are benign, biphasic tumors with epithelial and stromal components typically arising in middle-aged/peri-menopausal women. MESTs are well-circumscribed but lack a thick fibrous capsule, however compressed renal tissue may form a pseudocapsule. Unlike CNs which are diffusely cystic, MESTs are composed of cystic and solid areas and the septa between the cysts are typically thicker than that of CNs. The larger cysts may be lined by cuboidal or columnar epithelium with occasional papillary tufts while the smaller cyst linings resemble that of CNs. Like CNs, the stroma consists of a variably cellular spindle cell population ranging from myxoid-like areas to cellular, mesenchymal ovarian-stroma like tissue. These ovarian-stroma like regions are typically more pronounced in MESTs and more frequently immunoreactive for estrogen and progesterone. Recent publications also indicate that MESTs and CNs have similar molecular characteristics. Although these entities are classified separately in the most recent edition of the WHO (2004), there is evidence that they may in fact be opposite ends of a morphologic spectrum for a single neoplasm and the term renal epithelial and stromal tumor (REST) has been proposed as a unifying term.

Suggested Readings:

1. Antic T, Perry KT, Harrison K, et al. Mixed Epithelial and Stromal Tumor of the Kidney and Cystic Nephroma Share Overlapping Features: Reappraisal of 15 Lesions. Arch Pathol Lab Med. 130:80-85, 2006.
2. Eble JN SG, Epstein JI, Sesterhann IA. Classification of Tumours. Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. Lyon, France: IARC Press; 2004.
3. Moch H. Cystic Renal tumors: New Entities and Novel Concepts. Adv Anat Pathol 12(3):209-214, 2010.
4. Mohanty SK, Parwani AV. Mixed Epithelial and Stromal Tumors of the Kidney: An Overview. Arch Pathol Lab Med 133:1483-1486, 2009.
5. Murphy WM, Grignon DJ, Perlman EJ. Tumors of the Kidney, Bladder, and Related Urinary Structures. Washington, DC: Armed Forces Institute of Pathology; 2004.
6. Turbiner J, Amin M, Humphrey PA, et al. Cystic Nephroma and Mixed Epithelial and Stromal Tumor of Kidney: A Detailed Clinicopathologic Analysis of 34 Cases and Proposal for Renal Epithelial and Stromal Tumor (REST) as a Unifying Term. Am J Surg Pathol 31(4):489-500, 2007.

History: A 44 year old man with a seven year history of persistent right nasal congestion and right facial paresthesia was found to have a mass in the right maxillary sinus. A CT scan demonstrated a 4.0 x 3.8 x 3.2 cm well-circumscribed lesion with focal cystic change and palatine extension. The excised specimen consisted of a 23 gm aggregate of firm, variegated yellow and white hemorrhagic soft tissue fragments.

Microscopically, the tumor consisted of spindle cells with wavy nuclei in cellular and hypocellular regions (Fig. 1). The cellular regions contained short fascicles with nuclear palisading (Fig. 2). Frequently seen were mildly enlarged hyperchromatic atypical nuclei, however; mitoses were not identified (Fig. 3). The hypocellular areas were less ordered and had a loose matrix (Fig. 4). Also present were foamy histiocytes, hyalinized vessels, cyst-like spaces, a mixed inflammatory infiltrate and hemorrhage as well as increased fibrous tissue (Fig. 5). Necrosis was not seen.

Diagnosis: “Schwannoma with Degenerative Change/Ancient Schwannoma”, Maxillary Sinus

Adam Stelling, PSF, MS3, Donald R. Chase MD
Department of Pathology and Human Anatomy, Loma Linda University and Medical Center, Loma Linda, California
California Tumor Tissue Registry, Loma Linda, California

Discussion: Ancient schwannoma is a rare benign peripheral nerve sheath tumor felt to derive from a long standing schwannoma. The lesion occurs most commonly in patients between 20 and 50 years of age. The classic schwannoma is an encapsulated perineural mass consisting of highly cellular Antoni A areas with Verocay bodies and less cellular myxoid Antoni B areas. They are most often found in the head and neck, flexor surfaces of the extremities, paraspinal areas as well as the retroperitoneum. Schwannomas make up approximately 8% of intracranial tumors with the vestibulocochlear nerve most commonly involved followed by the trigeminal and facial cranial nerves. Tumors with “ancient change” demonstrate the same behavior as a classic schwannoma and tend not to recur following excision.

The degenerative component of an ancient schwannoma creates a heterogeneous gross appearance with calcification and cystic change within a firm grey, yellow and tan cut surface. Beware that sinonasal schwannomas are often unencapsulated. Microscopically, large irregular hyperchromatic nuclei are a hallmark feature and should not be confused with malignancy. Absent mitotic figures and an appropriate histologic background make this finding most consistent with degenerative atypia. Other common features include histiocytic infiltrates with xanthomatous change and hyalinized vascular walls. Varying amounts of non-specific degenerative changes such as edema, myxoid change, hemorrhage, inflammation and fibrosis are seen.

The single most influential tool in differentiating ancient schwannoma from its mimics is the highly sensitive expression of S-100 protein. Uniform strong positive staining in both Antoni A and B areas supports the notion that the tumor is made up of a single population of neoplastic Schwann cells: a hypothesis confirmed by ultrastructural EM studies.

Differential diagnoses:
Neurofibroma – This unencapsulated benign peripheral nerve sheath tumor has wavy spindled nuclei in a background of prominent collagen in a “shredded carrot” pattern. Prominent cellular or myxoid areas may be present. Wagner-Meissner bodies are a classic feature, particularly in diffuse forms. S-100 positivity is only seen in a subset of cells thought to be of schwannian origin. Typically, neurofibromas do not contain degenerative changes, however; malignant change, more commonly seen in patients with neurofibromatosis type 1, manifests as nuclear atypia.

MPNST – The malignant peripheral nerve sheath tumor has alternating cellular and myxoid areas creating a so called “marble-like” pattern. This lesion contains wavy spindle cells that can palisade, as well as exhibit pleomorphism. Key distinguishing features include necrosis, mitoses, heterologous elements and only weak focal S-100 reactivity in spindled areas. Look for invasion, especially perineural, to confirm malignancy.

Leiomyosarcoma – In contrast to peripheral nerve tumors, smooth muscle tumors tend to have blunt ended “cigar-shaped” spindle nuclei. A fascicular growth pattern and focal hyalinization as well as nuclear palisading and pleomorphism are common, but S-100 is negative. Desmin, calponin and smooth muscle actin are typically positive. Leiomyosarcomas commonly demonstrate increased mitotic activity and necrosis.

Myxoid MFH – The prominent myxoid appearance in this lesion may resemble Antoni B regions of an ancient schwannoma. Other areas that still resemble the classic spindled storiform MFH may palisade yet should not have wavy nuclei. S-100 is negative in this tumor.

Calcifying aponeurotic fibroma – This lesion typically presents in the hands and feet of children and adolescents. This tumor contains palisading spindle cells as well as calcification or cartilage formation. The age of the patient, location of the tumor and S-100 negativity can aid in excluding this differential.

Suggested Reading:

Bruner, J. M. “Peripheral Nerve Sheath Tumors of the Head and Neck.” Semin Diagn Pathol. 4.2 (1987): 136-49. PubMed. Web. 13 May 2010.

Dodd, L. G., E. M. Marom, R. C. Dash, M. R. Matthews, and R. E. McLendon. “Fine-needle Aspiration Cytology of “ancient” Schwannoma.” Diagn Cytopathol. 20.5 (1999): 307-11. PubMed. Web. 13 May 2010.

Fletcher, C. D. “Distinctive Soft Tissue Tumors of the Head and Neck.” Mod Pathol 15.3 (2002): 324-30. www.nature.com/modpathol Web. 13 May 2010.

Hennigan, T. W., A. C. Branfoot, and N. A. Theodorou. “Ancient Neurilemmoma of the Pelvis.” J R Soc Med 85.7 (1992): 416-17. PubMed. Web. 17 May 2010.

Weiss, S. W., J. M. Langloss, and F. M. Enzinger. “Value of S-100 Protein in the Diagnosis of Soft Tissue Tumors with Particular Reference to Benign and Malignant Schwann Cell Tumors.” Lab Invest. 49.3 (1983): 299-308. PubMed. Web. 12 May 2010.

Weiss, Sharon W., John R. Goldblum, and Franz M. Enzinger. Enzinger and Weiss’s Soft Tissue Tumors. Philadelphia, PA: Mosby Elsevier, 5th ed. 2008.