Category: Case of the Month

History: A 50 year-old woman presented with a 9 x 7 x 6 cm slowly enlarging, painless upper abdominal mass extending to the flank. A CT scan demonstrated a focally calcified, well-demarcated tumor which completely encompassed and obliterated one rib with involvement of adjacent ribs, as well as extending peripherally into the soft tissues of the thoracic wall (Fig. 1). She subsequently underwent needle biopsy resulting in a small aggregate of gray-tan semi-translucent tissue fragments.

Microscopically, the material varied greatly in cellularity, including fibrous regions, prominent supporting blood vessels, and abundant myxomatous regions incorporating bland round to oval cells with occasional stellate cells (Fig. 2). Mitotic figures were not encountered. The predominant pattern was myxomatous and had no particular growth pattern (Fig. 3 left). There were also regions of necrosis and fibrosis in which were scattered hyphal mycotic organisms (Fig. 3 right). In addition to haphazard growth (Fig. 4 left), several areas showed nodular patterns with groupings of small, hyperchromatic cells residing in lacunae (Fig. 4 right.). Physaliferous cells were not encountered.

Diagnosis: “Myxoid Chondrosarcoma”

Laura Denham MS3, Donald R. Chase, M.D.
Department of Pathology, Loma Linda University and Medical Center
California Tumor Tissue Registry, Loma Linda, California

Discussion: Myxoid Chondrosarcoma (MC) is a rare soft tissue tumor that comprises less than three percent of all soft tissue tumors. It was first described by Stout and Verner in 1953 but not until 1972 did Enzinger and Shiraki elaborate on the clinicopathologic features. MCs have traditionally been divided into skeletal and extraskeletal tumors based on their location of origin, which at times may be difficult to elucidate. It is believed that extraskeletal myxoid chondrosarcoma is a distinct entity whereas skeletal myxoid chondrosarcoma is a separate variant of conventional chondrosarcoma. In 1985 it was discovered that the majority of extraskeletal myxoid chondrosarcomas showed a genetic translocation which was lacking in neoplasms arising from bone. This finding, along with certain histologic and clinical findings, suggests that they are separate entities.

The tumor is grossly characterized as being well circumscribed, lobulated to nodular, and having a gelatinous gray to tan cut surface. There is often hemorrhage, which may be quite prominent. Microscopically, it is usually composed of fairly uniform small round to oval cells with hyperchromatic nuclei edged by eosinophilic cytoplasm. The cells are often arranged in cords, strands and/or nests in a myxoid matrix which may be separated into lobules by fibrous tissue. Occasionally the cells may be arranged in a more diffuse pattern, which is reportedly more common in the skeletal version of myxoid chondrosarcoma. Although somewhat unusual, it is possible to find foci of well-differentiated chondrocytes with typical lacunae in a specimen that has been well sampled, however calcification is rare. Mitoses and fibroblastic cells may also occasionally be found. A cellular variant of myxoid chondrosarcoma is described, characterized by sheets of large cells with prominent nucleoli and a more open, vesicular chromatin pattern and with less myxoid change between cells. Rarely, areas of blue cells reminiscent of Ewings sarcoma/PNET, as well as rhabdoid-like cells with peri-nuclear inclusions have been reported.

Neoplastic cells stain positively for S100 protein in 20-40% of the cases. The decoration is generally weak, but diffuse. Because many of the differential diagnoses also stain strongly for S100 protein, Enzinger and Weiss argue that the usual lack of staining in MC is a useful diagnostic feature. Curiously, MCs occasionally stain positively for cytokeratins, such as EMA and may also stain positively for chromogranin and neuron-specific enolase, suggesting a possible neuroendocrine lineage. Neurosecretory granules seen via electron microscopy also lend support this possibility. Other ultrastructual and histochemical findings such as dilated rough endoplasmic reticulum, prominent mitochondria, diastase sensitive PAS positive intracytoplasmic material and hyaluronidase resistance tend to support chondroid lineage.

Genetic studies show approximately 70% of extraskeletal myxoid chondrosarcomas have a t(9; 22) (q22; q12) translocation. This balanced translocation combines the EWS gene with the CHN (known as NOR1 in rodents). Other translocations have also been described, however, to date similar translocations have not been found in the skeletal myxoid chondrosarcoma.

Differential Diagnosis:

• Chondromyxoid fibroma – Typically the tumor cells are arranged in fused lobules, with a fibrous band surrounding the lesion. The periphery of a lobule tends to be more cellular, with more pleomorphic and fibroblastic cells, while the center of the lobule is usually more myxomatous and may show lacunae formation. It is not unusual to find multinucleated giant cells, especially in areas with bland cells. Occasional foci of calcification or ossification may also be present. An area of well-vascularized connective tissue separates lobules from each other, as well the neoplasm from adjacent bone.

• Ossifying Fibromyxoid Tumor of Soft Parts (OFMT) – Grossly the tumor is surrounded by a thick fibrous capsule and is separated into lobules by fibrous tissue with an underlying shell of lamellar bone in the majority of cases. The uniform round to spindled cells are rimmed by pale cytoplasm and are found in nests, cords or sheets within a myxoid to collagenous matrix. There may be areas of cartilage formation, as well as intricate vasculature often with perivascular hyalinization, both of which are rare in myxoid chondrosarcomas. Furthermore, the majority of OFMTs are S100 positive.

• Myxoid liposarcoma – Grossly these tumors are gelatinous and may be multinodular. The round to spindled cells are characteristically denser around the periphery and are suspended in a myxoid matrix, which is sensitive to hyaluronidase. Lipoblasts are normally present in varying numbers, usually at the periphery of a tumor lobule. A distinct plexiform “chicken-wire” vasculature is a common feature, which helps to differentiate this tumor from myxoid chondrosarcomas. There may also be foci of high cellularity which may or may not have round cell differentiation and little myxoid stroma.

• Myoepithelioma – This mixed tumor may be composed of a mixture of epithelioid, clear, spindled or physaliferous cells found in cords, nests or sheets. The stromal component is also variable and may be myxoid, chondroid or focally osteoid. If ductal differentiation is not present, it may be difficult to differentiate between this entity and myxoid chondrosarcoma. However, in contrast to myxoid chondrosarcomas, these tumors typically co-express S100 and epithelial markers such as EMA and cytokeratin, and may express smooth muscle actin as well.

• Myxoma – A fairly common neoplasm, myxomas are essentially avascular, consisting of widely-spaced, bland spindled to stellate cells with round to oval nuclei in an abundant myxoid matrix with varying amounts of reticulin fibers. There may also be infiltration of the neoplasm into the surrounding skeletal muscle. Myxomas are much less cellular than myxoid chondrosarcomas and tend to have a haphazard spindled pattern rather than a lobular chondrocyte-type pattern.

• Myxoid variant of Extraskeletal (Soft Part) Chondroma – These multinodular lesions are composed of chondrocytes, which tend to be more differentiated toward the periphery of the lesion. The cells may be surrounded by stippled calcification and may occasionally have foci of multinucleated giant cells. Although they are usually less cellular than myxoid chondrosarcoma, the two entities may be difficult to differentiate. However, myxochondromas may be distinguished from myxoid chondrosarcomas based on their predilection for hands and feet, their propensity to form mature hyaline cartilage, and their unique peri-cellular granular calcification pattern.

• Chondroid Lipoma – This rare tumor is generally smooth, well circumscribed and consists of hibernoma-like cells with vacuolated, often granular cytoplasm. The cells are in cords or nests with surrounding myxoid stroma. Although some cells may resemble chondroblasts, this benign neoplasm can be distinguished from myxoid chondrosarcomas by the intracytoplasmic vacuoles, rounded, less lobular appearance, greater vascularity and more consistent positive staining of S100 protein.

Clinically, myxoid chondrosarcomas are mostly found in the deep tissues of the lower extremities, especially buttock and thighs, as well as in the proximal upper extremities such as shoulders or neck. Both skeletal and extraskeletal forms of MC are characterized by slow growth. However, despite its bland morphology and slow growth pattern extraskeletal myxoid chondrosarcoma has a propensity for metastases, most commonly to the lung. Furthermore, recurrences are very common in this entity and may often be multiple. Both chemotherapy and radiation have little role in the eradication of disease, and early total surgical extirpation is the preferred treatment.

Suggested Reading:

1. Enzinger FM, Skiraki M. Extraskeletal myxoid chondrosarcoma: an analysis of 34 cases. Hum Pathol. 3:421-435, 1972.

2. Meis-Kindblom JM, Bergh P, Gunterberg B, Kindblom LG. Extraskeletal myxoid chondrosarcoma: a reappraisal of its morphologic spectrum and prognostic factors based on 117 cases. Am J Surg Pathol 23:636-50, 1999.

3. Atonescu CR, Argani P, Erlandson RA, healey JH, Ladanyi M, Huvos AG. Skeletal and extraskeletal myxoid chondrosarcoma: a comparative clinicopathologic, ultrastructural and molecular study. Cancer 83:1504-21, 1998.

4. Rubin BP, Fletcher JA. Skeletal and extraskeletal myxoid chondrosarcoma: related or distinct tumors? Adv Anat Pathol 6:204-212, 1999.

5. Meis JM, Enzinger FM. Chondroid lipoma: a unique tumor simulating liposarcoma and myxoid chondrosarcoma. Am J Surg Pathol 17(11): 1103-1112, 1993.

6. Rahimi A, Beabout JW, Ivins JC, Dahlin DC. Chondromyxoid fibroma: a clinicopathologic study of 76 cases. Cancer 30:726-736, 1972.

7. Kilpatrick SE, Hitchcock MG, Kraus MD, Calonje, E, Fletcher C. Mixed tumors and myoepitheliomas of soft tissue: a clinicopathologic study of 19 cases with a unifying concept. Am J Surg Pathol 21(1):13-22, 1997.

8. Mackenzie DH. The myxoid tumors of somatic soft tissues. Am J Surg Pathol 5(5): 443-458, 1981.

9. Smith TA, Easley KA, Goldblum JR. Am J Surg Pathol 20(20):171-180, 1996.

10. Enzinger FM, Weiss SW, Liang CY. Ossifying fibromyxoid tumor of soft parts: a clinicopathological analysis of 59 cases. Am J Surg Pathol 13(10) 817-827, 1989.

11. Enzinger and Weiss, Soft Tissue Tumors, 5th edition.

History: A 31 year-old trauma patient underwent a splenectomy to remove a lacerated spleen. The organ was enlarged, weighing 500 grams and had overall diameters of 19.5 x 10.5 x 3.5 cm. The parenchyma was uniformly firm and red with indistinct follicular and trabecular markings. No focal lesions were identified.

Microscopically, the red pulp was expanded, largely by a macrophage infiltration (Fig. 1). These cells had bubbly, vacuolated cytoplasm giving the cytoplasm a “clear cell” appearance (Figs. 2,3). Special stains included:

CD68 Positive
PAS (+/- diastase) Faintly positive
Giemsa Rare ceroid-containing (‘sea blue’) histiocytes
Iron Negative
AFB Negative

Diagnosis: Lipid Storage Disease, Consistent With Niemann-Pick Disease

Melissa Skaugset, MSIV and Donald R Chase MD
Department of Pathology, Loma Linda University and Medical Center, and
California Tumor Tissue Registry, Loma Linda, California

Discussion: Niemann-Pick disease is a disorder of lipid metabolism and storage that causes accumulation of sphingomyelin in tissue macrophages (histiocytes) due to a deficiency of acid sphingomyelinase. Patients can be classified both by clinical features and by genetic mutation. Four types have been identified. Types A and B are associated with a defect in the SMPD1 (acid sphingomyelinase) gene with type A being the neuronopathic form and B the non-neuronopathic form. Mutations in both the NPC1 and NPC2 genes cause so-called type C disease. All forms have autosomal recessive inheritance.

Clinically, presentation varies with type of disease, with Type A showing the most severe impairment characterized by hepatomegaly, jaundice, failure to thrive, seizures, and mental retardation in infancy. Children with Type A disease rarely survive past 18 months. Type B disease has no neural involvement, so patients typically present later, most commonly in late childhood/early teens. These children present with poor growth, hepatosplenomegaly, recurrent lung infections, and may have lab abnormalities, including elevated lipids and cholesterol and thrombocytopenia.

Type C disease differs significantly from A or B disease in both pathologic mechanism and clinical presentation. The defect in the NPC gene causes failure of a transporter in the endosomal-lysosomal system of cells, causing a buildup of cholesterol and glycolipids in lysosomes. The clinical presentation of Type C disease varies widely. In children who manifest disease, progressive neurological deficits develop which may or may not be associated with hepatosplenomegaly or jaundice. Neurologic disease is diffuse and has been documented to include dysphagia, dysarthria, ataxia, seizures, gaze palsies, ptosis, dystonia, hypotonia, psychiatric disorders, and dementia. Types A, B, and C are increased in Ashkenazi Jews.

A fourth form exists, occurring mostly in a population from Yarmouth County, Nova Scotia. This Type D or “Nova Scotian” form has been demonstrated to also have a defect in the NPC1 gene. Interestingly, it seems that those with Type D disease share common ancestry with Joseph Muise (born in Nova Scotia in 1679) and his wife Marie Amirault (born in Nova Scotia in 1684), making one or both of them the likely carrier of original mutation causing disease in this population. It is unclear why what may be a new mutation in either Joseph or Marie resulted in such a high carrier rate, but close communities (this is seen in the Acadian population of Nova Scotia) with the resultant limitation in genetic diversity may have played a role. Once a high carrier rate was achieved, it became possible for this autosomal recessive disease to manifest as children of dual carrier parents who were homozygotic for the disease causing gene, therefore having clinical disease. Similar patterns of emergence of rarer genetic diseases have been seen in populations such as the Old Order Amish (Ellis-Van-Crevald syndrome), French Canadian Chicoutimi (hereditary tyrosinemia). More recently there has been an emergence of fumarase deficiency noted in the Fundamentalist Church of Jesus Christ of Latter Day Saints particularly at the Arizona-Utah border, that shows similar patterns. This is also and autosomal recessive disorder and in a community is able to definitively trace its ancestry to a limited group of church/community leaders, however it has not yet been elucidated when the defective gene was found in the founding members or introduced to the community at a later date.

Pathologic specimens from patients with Niemann-Pick disease may be limited to bone marrow biopsies if the diagnosis is suspected clinically. These are used to confirm disease and to help guide additional biochemical and genetic testing. When surgical specimens are available, gross findings include enlarged spleens and livers, with diffuse involvement of the liver and spleen evident on cut sections. Expansion of the cordal macrophages gives a firm texture to the cut surface of the spleen. The tissue is frequently pale and homogeneous on cross section. The normal markings of the spleen are made less distinct by the proliferation of histiocytes. Later findings in hepatic involvement include nodular fibrosis of the liver.

Histologically, Niemann-Pick cells are enlarged with accumulation of small vacuoles containing sphingomyelin (Figs 2,3). These give the cells a foamy or bubbly appearance and make them lighter in color than the similar appearing Gaucher cells. Niemann-Pick cells are CD-68 positive histiocytes. PAS staining is only faintly positive, but Sudan Black B and Oil Red O are positive, indicating that neutral fat contained in the vacuoles. These lipid deposits are birefringent and have yellow-green fluorescence in UV light. Electron microscopy shows lamellated structures in the lysosomes (similar to myelin figures) and may also demonstrate “zebra bodies”, parallel lamellated structures in the cytoplasm. Giemsa staining can highlight “sea blue” histiocytes containing ceroid, most common in Type C disease.

Many of the congenital enzyme deficiencies cause accumulation of material within the histiocytes of the spleen, liver, and CNS, causing enlargement of the parenchyma and the clinical manifestations of the disease. Many cases are diagnosed using tests for enzyme activity, but histologic diagnosis is often the mainstay of initial evaluation. Histology allows for guidance of enzymatic and/or genetic testing by helping differentiate the cells noted in different metabolic diseases. The cells of Gaucher disease are identified by their “crinkled tissue paper” cytoplasm, seen best on touch imprints. Niemann-Pick histiocytes have bubbly, multi-vacuolated cytoplasm, as do the gangliosidoses and mucopolysaccharidoses (i.e. Tay-Sachs, Hunter’s, or Hurler’s disease), however the latter with ballooned cells makes it distinct from the former. Fabrys, Wolmans, and von Gierkes disease all have foamy appearing histiocytes. Hermansky-Pudlak syndrome causes ceroid accumulation, leading to sea blue colors in the cells, though it should be noted that ceroid containing histiocytes are also seen on other, more common diseases (and in fact were noted in this case) and should therefore be considered somewhat non-specific. Evaluation by of enzyme activity is required for more precise classification of disease.

Because treatment regimens are very limited, patient prognosis depends more on the type of disease, rather than on the treatment. Type A disease almost invariably ends in infantile death. Type B patients may live significantly longer, but have significant morbidity, particularly due to lung involvement. Bone marrow transplantation has been used in Type B patients with some success. It is thought that Types C and D may benefit from a low cholesterol diet, though this has not been demonstrated in clinical studies. The prognosis for Types C and D is widely variable, with some childhood deaths. The less severely affected patients may live into adulthood. An ongoing clinical trial of enzyme replacement therapy uses a recombinant human acid aphingomyelinase, and to date, this protocol shows the greatest promise for improving outcomes in the most severe forms of the disease.

Suggested reading:

Hopkin, R.J., Grabowski, G.A. Lysosomal Storage Diseases (Ch. 341). In: Kasper, D., Fauci, A., Longo, D., Braunwald, E., Hauser, S., and Jameson, J. Harrison’s Principles of Internal Medicine, 16th Ed. New York: McGraw-Hill (2005). pp2315-2319.

Neiman, R., Orazi, A. Disorders of the Spleen, 2nd ed. Philadelphia: W.B. Saunders Company (1999). pp167-175.

Vanier, M.T., Kinuko, S. (1998). Recent Advances in Elucidating Niemann-Pick C Disease. Brain Pathology. 8: 163-174.

Winsor, E.J.T., Welch, J.P. (1978). Genetic and Demographic Aspects of Nova Scotia Niemann-Pick Disease (Type D). Am J Genet. 30: 530-538.

History: A 45-year-old gravida 0 woman presented with frequent menometrorrhagia. Transabdominal sonography and computerized tomography revealed a large multi-loculated cystic mass in the left ovary, multiple nodules in the myometrium, and pelvic lymphadenopathy. The patient was treated with total abdominal hysterectomy, bilateral salphingo-oophorectomy, and limited pelvic lymph node dissection.

The excised uterus and adnexa weighed 2450 grams and contained a multicystic 34.5 x 21.0 x 9.5 cm left ovarian mass dominated by thin and thick-walled cysts filled with mucoid material. The outer surface was smooth. The uterus was 8.0 × 4.5 × 2.5 cm and had unremarkable endometrium and multiple intramural leiomyomata up to 0.8 cm. Both oviducts were normal as was the right ovary. Multiple enlarged pelvic lymph nodes up to 1.5 cm in diameter were present having grey and pink homogeneous cut surfaces. The omentum was unremarkable.

Microscopically, the dominant left ovarian mass had cystic spaces lined by mucin-secreting columnar calls (Fig. 1). Minimal stratification was seen and neither complex microvilli nor marked nuclear pleomorphism were encountered. Stromal invasion was not seen.

In addition to focal adenomyosis and benign leiomyomata, the uterus was found to have a 3-4 mm superficial tumor in the myometrium consisting of confluent nodules of blunt-ended spindled and epithelioid cells growing in short fascicles around mildly dilated entrapped endometrial glands (Fig. 2). The neoplastic nuclei were round or oval, mildly hyperchromatic and displayed small nucleoli (Fig. 3). Tumor marked for HMB-45 (Fig. 4) as well as for actin, but was negative for CD10. A desmin stain highlighted the surrounding myometrium but was negative in the tumor (Fig. 5). Mitotic figures were only rarely seen (<1/10 HPF). Two pelvic lymph nodes were involved by a proliferation of bland spindled cells surrounding endothelium-lined spaces reminiscent of a pericytoma pattern. Most of the cells had moderate clear to eosinophilic with partially vacuolated cytoplasm (Figs. 6a & 6b). The cells were HMB-45 positive (Fig. 7) and also marked for smooth muscle actin.

The patient had an uneventful postoperative recovery. Additional clinical investigation uncovered stigmata of the tuberous sclerosis complex (TSC). A postoperative Tc99m bone scan showed a solitary focus of increased activity in the upper pole of the left kidney suspicious for angiomyolipoma (AML).

Diagnosis: “Perivascular Epithelioid Cell Tumor (‘PEComa’) of
the Uterus Associated with Lymphangioleiomyoma of the Pelvic Lymph Nodes (another ‘PEComa’) and Cystic Mucinous Tumor of the Ovary”

Mingyi Chen MD, Craig Zuppan MD, and Donald R. Chase MD
Department of Pathology, Loma Linda University and Medical Center, and
California Tumor Tissue Registry, Loma Linda, California

Discussion: The histogenesis of angiomyolipoma, lymphangioleiomyomatosis, and clear cell sugar tumor has long been controversial. The concept of a common cell origin for this collection of neoplasms was first advanced by Bonetti et al. in a letter published in the American Journal of Surgical Pathology in 1992, in which the authors noted that both angiomyolipoma (AML) and clear cell ‘‘sugar’’ tumor of the lung (CCST) were immunoreactive with melanocytic markers and exhibited an epithelioid appearance with clear-acidophilic cytoplasm, usually in a perivascular distribution. In 1996, Pea et al proposed the perivascular epithelioid cell (PEC) as the cell of origin of these tumors and noted that due to the pleuri-immunohistochemical potential of the PEC, that tumors of this type may express varying degrees of melanocytic, muscle, pericytic, and perivascular epithelioid differentiation. Since then, the World Health Organization has broadly defined PEComas as ‘‘mesenchymal tumors composed of histologically and immunohistochemically distinctive perivascular epithelioid cells.’’

The PEComa family of tumors is now recognized to include angiomyolipoma (AML), lymphangioleiomyomatosis (LAM), clear-cell “sugar” tumor of the lung (CCST), and clear-cell myomelanocytic tumor of the falciform ligament/ligamentum teres. The PEC is also found in other clear-cell tumors such as “abdominopelvic sarcoma of perivascular epithelioid cells”, “primary extrapulmonary sugar tumor,” and “extra-renal epithelioid AML”.

PEComas have been reported in almost every body site, and the growing list includes gynecological sites, genitourinary and gastrointestinal locations, extremities, skin, as well as isolated reports in the heart, breast, oral cavity, orbit, and skull base. The uterus is the most commonly reported site of a PEComa.

Although the clinical significance is unclear, Vang and Kempson have divided uterine PEComas into two types based on morphology and immunohistochemical characteristics:
• Type A tumors show a tongue-like growth pattern and are composed of cells with clear to eosinophilic pale granular cytoplasm, diffuse HMB-45 expression, and focal smooth muscle reactivity.
• Type B tumors are composed of epithelioid cells with less prominent clear cell features, only a few of which are HMB-45 positive. In addition, these cells demonstrate extensive muscle marker expression and a lesser degree of tongue-like growth pattern.

The PEC does not have a known normal histologic counterpart. Morphologically it is somewhat spindled, yet epithelioid with clear to granular cytoplasm, a round to oval centrally located nucleus and an inconspicuous nucleolus. Immunohistochemically, PEC proliferations co-express both myogenic markers (actin and desmin) and melanocytic markers such as HMB45, HMSA-1, MelanA/Mart1, and microophthalmia transcription factor (MiTF). It minimally decorates for vimentin. Ultrastructure shows PEC tumors to contain microfilament bundles with electron-dense condensations, numerous mitochondria and membrane-bound dense granules.

Many PEComas have been reportedly associated with the tuberous sclerosis complex (TSC). TSC is an inherited disorder characterized by mutations of TSC1 and TSC2, two tumor suppressor genes located on chromosomes 9q34 and 16p13.3, respectively. This chromosomal imbalance has been demonstrated both in TSC and in PEComa. The TSC1 gene produces hamartin, whereas the TSC2 gene produces tuberin, these two proteins being responsible for the regulation of multiple intracellular signaling pathways of cell growth control. Inherited or acquired loss of heterozygosity at the TSC1 and TSC2 loci leads to uncontrolled cell proliferation and the development of hamartomas and tumors. Activation of the mTOR signal pathway through loss of inhibition by TSC1/2 likely occurs in most, if not all PEComas.

PEComas Versus Uterine Smooth Muscle Cell Tumors (U-SMTs). PEComas may be confused with true smooth muscle neoplasms with both spindled and epithelioid morphology. On microscopic examination, PEComas show overlapping features with epithelioid U-SMTs, as they have cells with abundant clear or eosinophilic cytoplasm and round to oval nuclei arranged in sheets, small solid nests, or cords separated by scant hyalinized stroma. Features that will favor the diagnosis of PEComa over an epithelioid U-SMT include the association with tuberous sclerosis and lymphangiomyomatosis, the presence of multinucleated giant cells and ‘‘spiderlike’’ cells in PEComas, and the expression of melanocytic markers such as HMB-45, Melan A, and MiTF. Other helpful clues include the absence of delicate capillary networks in epithelioid SMT and the frequent keratin and EMA expression in epithelioid U-SMTs but none in PEComas.

PEComas Versus Uterine Tumor Resembling an Ovarian Sex Cord Tumors (UTROSCT). UTROSCTs are rare stromal tumors showing prominent sex cord–like differentiation. On microscopic examination, the neoplastic cells show an epithelioid appearance with indistinct eosinophilic (sometimes vacuolated) cytoplasm and oval to round nuclei and grow in tight nests, cords, and sheets. Sometimes, spindle-shaped cells are present, and the stroma is generally sparse with some hyaline strands. The epithelial differentiation in UTROSCTs is more pronounced than in PEComas, with tubular formation, retiform differentiation, or prominent vacuolated cytoplasm, as seen in the luteinized cells of sex cord stromal tumors of the ovary. The presence of sex cord stromal markers (inhibin and calretinin) in UTROSCTs is helpful in this differential diagnosis.

PEComas Versus Placental Site Trophoblastic Tumor and Epithelioid
Trophoblastic Tumor. Microscopically, placental site trophoblastic tumors (PSTTs) and epithelioid trophoblastic tumors (ETTs) are composed of mononucleated round or polyhedral intermediate trophoblastic cells with abundant eosinophilic to clear cytoplasm frequently associated with a diffuse or nested growth. Features favoring a diagnosis of trophoblastic tumor include history of recent pregnancy or abortion and an elevated serum human chorionic gonadotropin level, an infiltrative growth of single cells or small aggregates of cells dissecting individual muscle fibers (PSTT), prominent vascular involvement with associated fibrinoid change (PSTT), islands or nests of cells surrounded by extensive necrosis or a hyaline-like matrix (ETT), as well as immunoreactivity for inhibin, human placental lactogen, and p63 (ETT), with negativity for myomelanocytic markers.

PEComas Versus Endometrial Stromal Sarcoma. Cells with abundant dense eosinophilic cytoplasm have been rarely described in endometrial stromal tumors, and this finding may lead to a differential diagnosis of a PEComa, especially in small samples. In these cases, the distinct immunohistochemical features (CD10 vs HMB-45) are helpful clues for the diagnosis.

PEComas Versus Melanoma. Although unusual, conventional clear cell sarcoma (melanoma of soft tissue) or metastatic melanoma from other genital or extragenital sites could involve the uterus and should always be in the differential diagnosis of PEComas. Diffuse positivity for S100, HMB-45, and Mart-1, and negative expression of smooth muscle markers will favor the diagnosis of melanoma. Identification of the t(12; 22) (EWS-ATF1) translocation is diagnostic for CCS.

Our presentation case shows a most interesting combination of two PEComas in the setting of the tuberous sclerosis complex and points to the possibility of “PEComatosis”, a condition that is likely under-reported and therefore under-studied. Literature supports the existence of malignant PEComas that have metastasized, but to date, no uterine primary tumor has been described with this behavior, and virtually all metastasizing lesions have been malignant angiomyolipomas (Pea M, et. al, and Vip SK, et. al). For this reason, we interpret the multicentricity of these two PEComas as being synchronous primaries.

It has been suggested that HMB-45 immunostaining should be performed on uterine mesenchymal tumors with lymphangiomyomatous pattern or with clear and epithelioid features to identify PEC tumors, and that the diagnosis of a PEComa warrants the examination of the patient for TSC.

Although most uterine PEComas follow a benign course, they should be viewed as having uncertain malignant potential particularly those larger than 8 cm with marked hypercellularity, cytological atypia, high mitotic activity (including atypical forms), coagulative necrosis and/or an infiltrative growth pattern. The mainstay of treatment of conventional uterine PEComas is wide excision or hysterectomy. A recent pilot study from the Dana-Farber Cancer Institute suggests that malignant PEComas may show responses to mTOR Inhibitor (Sirolimus) treatment.

Suggested Reading:

Martignoni G, Pea M, Reghellin D, Zamboni G, Bonetti F. PEComas: the past, the present and the future. Virchows Arch. 2008 Feb;452(2):119-32.

Folpe AL, Mentzel T, Lehr HA, Fisher C, Balzer BL, Weiss SW. Perivascular epithelioid cell neoplasms (PEComas) of soft tissue and gynecologic origin: a clinicopathologic study of 24 cases. Mod Pathol 2005;18:48A.

Folpe AL. Neoplasms with perivascular epithelioid cell differentiation (PEComas) In: Fletcher CDM, Unni KK, Epstein J, Mertens F (eds). Pathology and Genetics of Tumours of Soft Tissue and Bone. Series: WHO Classification of tumours. IARC Press: Lyon, 2002, pp. 221-222.

Vang R, Kempson RL. Perivascular epithelioid cell tumor (‘PEComa’) of the uterus: a subset of HMB-45-positive epithelioid mesenchymal neoplasms with uncertain relationship to pure smooth muscle tumors. Am J Surg Pathol 2002;26:1-13.

Pea M, Bonetti F, et. al. Apparent renal cell carcinomas in tuberous sclerosis are heterogeneous; the identification of malignant epithelioid angiomyolipoma. Am J Surg Pathol 1998:22:180-187.

Vip SK, Sim CS, Tan BS. Liver metastasis and local recurrence after radical nephrectomy for an atypical angiomyolipoma. 2001:J Urol 165:898-899.

History: A 35-year-old woman presented with persistent post-coital bleeding. Examination revealed a coarsely granular, tan mass protruding from the cervical os. Following multiple cervical biopsies, the patient underwent a hysterectomy with bilateral salpingo-oophorectomy. A 6.6 x 2.5 x 0.8 cm well-circumbscribed, exophytic tumor was removed from the region of the transition zone.

Microscopically, the mass was mostly exophytic (Fig. 1), involved the squamo-columnar junction (Fig. 2), and only superficially invaded the underlining cervical tissue. It was uniformly papillary with long thin branching papillae that were lined by endocervical-type epithelium. Occasional mucin-filled cysts were present at the base (Fig. 3). The lining cells showed minimal cytologic atypia and displayed mild nuclear stratification. Although papillary and micropapillary regions dominated (fig. 4), some areas were “adenomatous” resembling tubular adenomas of the colon. Most of the cells had abundant eosinophilic cytoplasm and had nuclei with finely granular chromatin and small but distinct nucleoli (Fig. 5, 6). Occasional cells showed discrete vacuoles, suggestive of some degree of mucinous differentiation. Mitotic figures were rarely seen. Neither lymphovascular nor perineural invasion was present.

Diagnosis: “Well Differentiated Papillary Adenocarcinoma of Cervix / Villoglandular Adenocarcinoma”

Jin Guo, MD, and Donald R. Chase, MD
Department of Pathology, Loma Linda University and Medical Center,
Loma Linda, California
California Tumor Tissue Registry, Loma Linda, California

Discussion: First reported in 1989, villoglandular adenocarcinoma (VGA) is a rare tumor of the uterine cervix with just over 100 cases in the literature. It mostly arises in young women (often <40 years) without known risk factors. Patients usually present with vaginal bleeding and/or abnormal cervical smears. Although VGA generally carries a good long-term prognosis, it may be locally invasive. There are also scattered reports of metastases and rarely death from the tumor. VGA may be grossly visualized during pelvic examination as an exophytic polypoid cervical mass. It grows as complex papillae varying from long, delicate, fingerlike projections to short, broad, complex and branching excrescences. The fibrovascular cores are covered with stratified endocervical, endometrial or intestinal-type tall columnar epithelium. Generally, the cells have abundant eosinophilic cytoplasm and elongated hyperchromatic mildly atypical nuclei. Mucin production is variable. The deeper regions of the papillae may show adenocarcinoma in situ or superficial invasion. Interpretation of an initial, superficial biopsy is often challenging largely because the tumor usually lacks host desmoplasia, shows minimal atypia, and only occasionally shows invasion. For these reasons deferment of the diagnosis is suggested pending full examination of a cone biopsy or hysterectomy specimen. VGA, having a relatively good prognosis, needs to be distinguished from several conditions including cervical implant(s) from conventional or papillary endometrial adenocarcinoma, serous papillary adenocarcinoma of the cervix, as well as hyperplastic reactive glands. Unlike most endometrial adenocarcinomas, VGA occurs mainly in young women at the cervical transitional zone, and may decorate for HPV. Traditional endometrial adenocarcinomas usually arise in the uterine fundus or ovaries of postmenopausal women and tend to be HPV negative. Serous papillary adenocarcinoma (SPA) of the cervix is rare and resembles serous papillary carcinoma of the ovary or endometrium. Although the growth patterns of SPA and VGA are similar, SPA is less glandular, rarely displays mucinous differentiation, and is highly invasive of both stroma and lymphatics. Unlike VGA, SPA may present with distant metastasis to pelvic and/or periaortic lymph nodes. There is also more cytologic atypia and increased mitotic activity. Reactive, hyperplastic glands do not show the profound villoglandular architecture and lack the degree of cellular atypia of VGA or SPA. VGA usually marks positively for B72.3, Ca-125, carcinoembryonic antigen, keratin 7, and p16 protein. It is usually negative for vimentin, P53, and estrogen and progesterone receptors. Molecular studies with PCR amplification of tumor DNA may reveal a positive signal for HPV-DNA but not for HSV-DNA. Villoglandular adenocarcinoma of the cervix is usually suspected by microscopic examination of tissues from a cervical biopsy and/or a cervical cone. Careful review of this material will show if any further surgery is needed. A completion hysterectomy is usually reserved for residual/recurrent disease, or in those cases showing unequivocal adenocarcinoma, significant invasion, atypical squamous features, and/or high grade glandular dysplasia. Cone biopsy is curative in most cases and also gives the potential benefit of preserving fertility. Suggested reading:

R.H. Young and R.E. Scully. Villoglandular papillary adenocarcinoma of the uterine cervix. A clinicopathologic analysis of 13 cases, Cancer, 63:1773–1779, 1989.

Heather Stanley-Christian, Bradley K. Heim, Jeffrey F. Hines, Kevin L. Hall, Gerald D. Willett and Willard A. Barnes. Villoglandular Adenocarcinoma of the Cervix: A Report of Three Cases and Review of the Literature. Gyn Oncol, 66(2):327-330, 1997.

R.D. Macdonald, J. Kirwan, K. Hayat, C.S. Herrington and H. Shawki. Villoglandular adenocarcinoma of the cervix: Clarity is needed on the histological definition for this difficult diagnosis. Gyn Oncol 100(1):192-194, 2006.

Michael S. Ballo, M.D., Steven G. Silverberg, M.D., and Mary K. Sidawy, M.D. Cytologic Features of Well-Differentiated Villoglandular Adenocarcinoma of the Cervix. Acta Cytol, 40:536-540, 1996.

Fadare Oluwole, Wenxin Zheng. Well-differentiated papillary villoglandular adenocarcinoma of the uterine cervix with a focal high-grade component: is there a need for reassessment? Virch Archiv, 447:883-887, 2005.

Giovanna Giordano, Tizsiana D’Adda, Letizia Gnetti, Carla Merisio, Marzio Gabrielli, Mauro Melpignano. Villoglandular adenocarcinoma of the cervix: two new cases with morphological and molecular study. Int J Gynecol Pathol, 26(2):199-204, 2007.

Richard J Zaino M.D. Glandular Lesions of the Uterine Cervix. Mod Pathol, 13(3):261-274, 2000

Young RH, Scully RE. Villoglandular papillary adenocarcinoma of the uterine cervix: a clinicopathologic analysis of 13 cases. Cancer, 63(9):1773–1779, 1989.

Al-Nafussi A, Obafunwa J, Jordan LB, Fulton I, Martin C, Beattie G. Cervical implant from villoglandular endometrial adenocarcinoma masquerading as cervical villoglandular adenocarcinoma. Int J Gynecol Cancer, 12(3):308-11, 2002.

History: A 70-year-old male presented with a one year history of nasal obstruction, facial pain, occasional epistaxis, and headache. A CT scan of the head found a 5.0 x 3.0 cm heterogeneous mass in the left frontal lobe. A biopsy was performed.

Microscopically, the lesion consisted of irregular nests and sheets with fibrovascular stroma (Fig. 1) consisting of uniform small cells containing scant cytoplasm and round to ovoid nuclei with indistinct nuclear membranes, punctuate chromatin and indistinct nucleoli. A fibrillary or reticular background was seen in some areas with others demonstrating more diffuse sheets of cells with a little intervening stroma (Fig. 2). Rosettes of variable size with delicate neurofibrillary stroma and palisading tumor cells were identified with and without lumens (Fig. 3). Immunohistochemically, the tumor cells were positive for S100 and NSE and negative for chromogranin. The rosettes stained positively for keratin but were GFAP negative, while occasional tumor cells and adjacent glial cells were positive for GFAP.

Diagnosis: “Olfactory Neuroblastoma”

Jin Guo, MD, Amita Mistry MD and Donald R. Chase, MD
Department of Pathology, Loma Linda University and Medical Center,
Loma Linda, California
California Tumor Tissue Registry, Loma Linda, California

Discussion: Olfactory neuroblastoma (esthesioneuroblastoma) is a rare malignant tumor of neuroectodermal origin accounting for 1 to 5% of malignant neoplasms in the nasal cavity. Occurring in all age groups (3-88 years) with bimodal peaks in the second and fifth decades, there is no gender predilection. Fewer than 1,000 cases have been reported in the literature since the tumor was first described more than 75 years ago. The tumor is thought to arise from the specialized sensory neuroepithelial (neuroectodermal) olfactory cells in the superior one third of the nasal cavity, including the cribriform plate of the ethmoid sinus as well as the superior turbinate. Almost all olfactory neuroblastomas involve the cribriform plate to some degree, and even when the bulk of a tumor lies intracranially, as in the current case, it is often still attached to the cribriform plate. Patients often present with nonspecific symptoms such as unilateral nasal congestion or obstruction (70%), recurrent epistaxis (50%) and, less commonly, facial pain, headache, anosmia, visual disturbances and/or diplopia. Because of the nonspecific nature of the presenting symptoms, the diagnosis is often missed during its early stages and may not be made until an advanced stage.

Morphologically, olfactory neuroblastoma is characterized by lobular architecture with circumscribed islands or nests of primitive neuroblastoma cells in a vascularized fibrous and fibrillary stroma. The tumor cells are small and round with a blue appearance and a high nucleus-to-cytoplasm ratio. Small and uniform nuclei have an even distribution of granular chromatin and often contain inconspicuous nucleoli. Nuclear pleomorphism, increased mitotic figures and necrosis are uncommon, but may be present in the high grade tumors. Tumor cells are often arranged in a syncytial pattern forming epithelial tubules or rosettes which sometimes resemble that of an ependymoblastoma. Immunohistochemically, the tumor cells stain positive for neuron-specific enolase, synaptophysin, chromogranin, neurofilament, catecholamines and S100 (sustentacular distribution), while staining negatively for EWS-FL1, CD99, EMA and desmin. Since chromogranin can be negative, alone it neither proves nor disproves the diagnosis of neuroblastoma. GFAP positivity is often restricted through active gliosis and occasional GFAP positivity in the tumor cells may indicate the presence of some degree of glial differentiation. The diagnosis of olfactory neuroblastoma is often established through histopathology accompanied by clinical and demographic findings, and then confirmed with pertinent immunohistochemical studies.

The degree of differentiation combined with the presence or absence of a neural stroma, mitotic figures and necrosis determines the grade (I through IV) of an olfactory neuroblastoma. Higher-grade tumors are poorly differentiated and characterized by more pleomorphic nuclei with coarser chromatin, increased mitoses, and necrosis. Pseudorosettes and fibrillar stroma are less commonly seen. Histological grade correlates with the prognosis, although not as closely as tumor stage. Stage A tumors are limited to the nasal cavity, stage B tumors involve the nasal cavity and paranasal sinuses, and stage C tumors extend beyond these structures. At presentation, approximately one-half of all olfactory neuroblastomas are stage C tumors.

Owing to the “small, round, blue-cell” morphology of this neoplasm, the differential diagnosis is quite extensive:

• Neuroendocrine carcinomas of the nasal cavity and nasal sinuses are especially uncommon and thought to originate from the glandular epithelium of the exocrine glands found in normal olfactory mucosa. Often occurring in older patients (mean age 50 years), these tumors seldom involve the cribriform plate and are composed of sheets and nests of small to intermediate-sized cells with a high nuclear-cytoplasmic ratio, hyperchromatic nuclei, and high mitotic rates.
• Sinonasal undifferentiated carcinomas were first recognized as a distinct entity in 1986, and are comprised of medium-sized cells arranged in nests and sheets with wide trabeculae, extensive necrosis and vascular permeation. Prognosis is considerably less favorable than for olfactory neuroblastoma.
• Pituitary tumors involving the paranasal sinuses frequently arise secondary to invasion from an intrasellar tumor rather than from an ectopic focus. These neoplasms share the wide histological spectrum of other pituitary adenomas, ranging from lesions with neuroendocrine features to those resembling poorly differentiated carcinomas. Sinonasal pituitary adenomas in general may be more aggressive than regular pituitary adenomas because they are commonly more invasive macroadenomas.
• Lymphomas arising from the paranasal sinuses are distinctly less common in Western than in Asian populations, accounting for less than 1% of all extranodal malignant lymphomas. Virtually every subtype of lymphoma can occur in the paranasal sinuses with B-cell lymphomas and natural killer/T-cell lymphomas more regularly encountered. There is an increased male to female ratio with most cases occurring in the sixth to eighth decades of life.
• Sinonasal melanoma, which migrates from the neuroectoderm, is an uncommon tumor constituting 4.8% of all neoplasms in this region. It is composed of a variable morphology of cells that may be round, oval, polygonal, epithelioid, or spindle shaped. Predominantly developing in patients in their fifth through eighth decades of life, these tumors are aggressive with a 5-year survival rate of 36%.
• Despite that facial rhabdomyosarcoma is relatively uncommon, it should be considered in the presence of a rapidly growing facial swelling which is unresponsive to antibiotics. Histologically, the tumor consists of solid sheets of small cells with scattered foci lining alveola-like spaces. Immunohistochemical studies demonstrate the presence of desmin and myoglobin, and absence of pre-keratin, neuron-specific enolase, and leukocyte common antigen (LCA).
• Ewing sarcoma and primitive neuroectodermal tumors (PNET) have a characteristic profile with diastase sensitive PAS positivity, and positive staining for CD99, FLI1 protein NSE, and CD57. Negative staining is seen for S100, LCA, muscle and vascular markers. These tumors routinely share the cytogenetic translocation t (11;22) (q24;q12). Though morphologically similar, it is controversial whether olfactory neuroblastoma and Ewing’s sarcoma/PNET carry the same cytogenetic translocations.
• Plasmacytomas and paragangliomas should also be considered as part of the differential investigation. The distinction of high-grade olfactory neuroblastoma from other poorly-differentiated neoplasms arising in the nasal cavity is challenging and essential to determining patient management and prognosis. A future potential diagnostic marker could be based upon the human achaete-scute homologue (hASH1) gene which is critical in olfactory neuronal differentiation and expressed in immature olfactory cells.

Even though diagnostic and treatment modalities have improved over the past two decades, limited data exists with respect to optimum management strategies due to the rare nature of olfactory neuroblastomas. The natural history of the disease, which may range from slow progression to aggressive local recurrence and distant metastasis, has yielded various treatment protocols and recommendations. Current consensus recommendation for treatment of primary low to moderate-grade tumors is radical craniofacial resection followed by radiotherapy with the addition of chemotherapy for patients with advanced, recurrent, or metastatic disease. Approximately 15% of patients acquire cervical lymph node metastasis, and 10% develop a distant metastasis at some point during the course of their disease. The 5-year survival rate varies from 45 to 80% based on different studies with a local recurrence rate of 30%. Overall negative prognostic factors include age (greater than 50 years at presentation), advanced stage or grade, tumor recurrence, and metastasis.

Suggested reading:

Porter AB, Bernold DM, Giannini C, Foote RL, Link MJ, Olsen KD, Moynihan TJ, Buckner JC. Retrospective review of adjuvant chemotherapy for esthesioneuroblastoma. J Neurooncol. 90(2):201-4. 2008.

Bumm K, Grizzi F, Franceschini B, Koch M, Iro H, Wurm J, Ceva-Grimaldi G, Dimmler A, Cobos E, Dioguardi N, Sinha UK, Kast WM, Chiriva-Internati M. Sperm protein 17 expression defines 2 subsets of primary esthesioneuroblastoma. Hum Pathol. 36(12):1289-93, 2005.

Zvi R. Cohen, M.D., Eric Marmor, M.D., Gregory N. Fuller, M.D., Ph.D., and Franco Demonte, M.D. Misdiagnosis of Olfactory Neuroblastoma. Neurosurg Focus. 2(5). 2002.

Dulguerov P, Allal AS, Calcaterra TC. Esthesioneuroblastoma: A metaanalysis and review. Lancet Oncol. 2:683-90. 2001.

Miyamoto RC, Gleich LL, Biddinger PW, Gluckman JL. Esthesioneuroblastoma and sinonasal undifferentiated carcinoma: impact of histological grading and clinical staging on survival and prognosis. Laryngoscope. 110:1262-1265. 2000.

Eriksen JG, Bastholt L, Krogdahl AS, et al. Esthesioneuroblastoma — what is the optimal treatment? Acta Oncol. 39:231-235. 2000.

Mezzelani A, Tornielli S, Minoletti F, Pierotti MA, Sozzi G, Pilotti S. Esthesioneuroblastoma is not a member of the primitive peripheral neuroectodermal tumour-Ewing’s group. Br J Cancer. 81:586-591. 1999.

Broich G, Pagliari A, Ottaviani F. Esthesioneuroblastoma: a general review of the cases published since the discovery of the tumour in 1924. Anticancer Re. 17:2683-2706. 1997.

Hirose T; Scheithauer BW; Lopes MB; Gerber HA; Altermatt HJ; Harner SG; VandenBerg SR. Olfactory neuroblastoma. An immunohistochemical, ultrastructural, and flow cytometric study. Cancer. 1;76(1):4-19. 1995.

Whang-Penn J. Translocation t (11:22) in esthesioneuroblastoma. Cancer Genet Cytogenet. 1:155-159. 1987.

Thompson L. Olfactory neuroblastoma. Ear Nose Throat J. 85(9):569-70. 2006.