Microscopically the normal lymph node architecture was replaced by a disordered vascular proliferation (Fig. 2). The cells were spindled and showed a diffuse fascicular pattern (Fig. 3). Mitotic figures were increased (Fig. 4). Another characteristic was numerous slit-like spaces and regions containing many extravasated red blood cells (Fig. 5). Hyaline globules were also present (Fig. 6).

Immunostains for CD31 and CD34 were positive (Fig. 7). Markers for epithelial (Fig. 7), neural, melanocytic and lymphoid origins were negative.

Diagnosis: “Kaposi Sarcoma”

Christina Martin MSIV, Donald R. Chase MD
Department of Pathology, Loma Linda University and Medical Center, Loma Linda, California
California Tumor Tissue Registry, Loma Linda, California

Discussion: Kaposi Sarcoma (KS) is a locally aggressive endothelial tumor that classically presents with blue-red nodular skin lesions which spread and coalesce into plaques. Lesions may also involve mucosal sites, lymph nodes, and visceral organs. KS is uniformly associated with human herpes virus 8 (HHV-8), and may arise in the context of immunosuppression. It is believed that HHV-8 establishes a latent infection in a number of cell types including B lymphocytes and endothelium, and that reactivation of latent virus is pivotal in the development of KS.

Four epidemiological forms are recognized:

1. Chronic (Classic) KS occurs predominantly in men (90%) during late adult life (peak incidence in 6th and 7th decades) of Mediterranean/Eastern European descent with the classic presentation of purplish, reddish-blue or dark brown plaques, macules, and/or nodules found most often involving the skin of the lower extremities. It is prevalent in certain parts of the world including Poland, Russia, Italy, and equatorial Africa, but rare in the United States, and shows a statistically significant association with a second malignant tumor or altered immune state. The disease is usually indolent with a prolonged clinical course.

2. Endemic (African) KS arises in children and adults in Equatorial Africa who are not HIV infected. It presents primarily as localized or generalized lymphadenopathy, with sparse skin lesions which tend to be truncal. The course of the disease is fulminant, a feature attributed to internal tumor involvement.

3. Iatrogenic KS (i.e. transplant-associated) is well-established in renal transplant patients. Incidence varies based on patient population, suggesting genetic susceptibility. It usually develops several months to a few years after transplant (average 16 months). The extent of the disease correlates directly with the loss of cellular immunity as measured by response to skin testing with phytohemagglutinin (PHA), conconavalin A (Con A), pokeweed mitogen (PWM), and dinitrochlorobenzene (DNCB). Clinical course improves with the patient’s ability to tolerate reduction in immunosuppression and worsens with organ or internal involvement.

4. Acquired immunodeficiency syndrome-associated KS (AIDS KS) occurs in the setting of immunodeficiency caused by HIV-1 infection, which potentiates tumor growth. This form disproportionately involves the male homosexual population with other risk groups including intravenous drug users, sex trade workers and hemophiliacs receiving factor VIII-enriched blood fractions. Presentation is usually in young adults with initially small, flat, pink patches on the skin which later progress to classic blue violet papules, with a predilection for lines of cleavage and mucosal surfaces. It may also metastasize or synchronously involve deep viscera/organs.

Treatment for KS in limited mucocutaneous disease usually consists of local therapy including cryotherapy, intralesional injections and radiation therapy. Mortality is 10-20%. In patients with AIDS, KS responds to highly active antiretroviral therapy (HAART). The mortality rate in AIDS KS has decreased from 90% to less than 50%. AIDS patients with KS, usually die of secondary (opportunistic) infections many times due to pulmonary compromise.

The KS phenotype may be found in other tumors, generally as a minor component:

• Well-differentiated angiosarcoma (AS) has features virtually indistinguishable from early KS skin lesions, however a careful history (lifestyle, immunosuppression, etc) is of great importance. KS also tends to be HHV-8 positive while AS is generally negative.

• Fibrosarcoma can be confused with the advanced lesions of KS. The presence of ectatic slit-like spaces and inflammatory cells at the periphery of the lesions, and hyaline globules point towards KS, as does positivity for HHV-8.

• Arteriovenous malformations may duplicate the skin lesions of KS and have been termed “pseudo KS” but lack the marked spindling and formation of slit-like lumens of KS. They may present with bruits or by touch, “thrills”.

• Spindle-cell hemangioendothelioma (aka Kaposiform hemangioendothelioma) is often confused with KS. A younger population, without immunosuppression favors SCH, as does cavernous vessels and epithelioid endothelial cells. The preservation of lobules (not found in KS) is also helpful.

Suggested Reading:

Enzinger and Weiss’: Soft Tissue Tumors 5th Ed. Editors Weiss SW, Goldblum JB. Mosby, Inc. pp 722-730, 2008.

World Health Organization Classification of Tumours: Pathology & Genetics Tumours of Soft Tissue and Bone. Editors Fletcher CDM, Unni KK, Mertens F, pp 170-172, 2002.

An unusual cause of a parotid mass in an immunocompetent host: Classic Kaposi’s sarcoma. Pagani D, Bellinvia M, Capaccio P, Scoppio B, Brambilla L, Pignataro L. Tumori. 2009 Mar-Apr; 95(2);248-50.

Kaposi sarcoma in unusual locations. Pantanowitz L, Dezube BJ. BMC Cancer. 2008 Jul 7;8:190. Review.

Lymph nodes involved by multicentric Castleman disease among HIV-positive individuals are often involved by Kaposi sarcoma. Naresh KN, Rice AJ, Bower M. Am J Surg Pathol. 2008 Jul;32(7):1006-12.

Fine needle aspiration cytology determinants of the diagnosis of primary nodal Kaposi’s sarcoma as the first sign of unknown HIV infection: a case report. Morelli L, Pusiol T, Piscioli I, Del Nonno F, Brenna A, Licci S. Acta Cytol. 2007 July-Aug;51(4):602-4.

The tumor showed a peculiar trabecular growth pattern (Fig. 1), consisting of cohesive, small, polygonal to round blue cells, sometimes nested, with a prominent supporting desmoplastic stroma (Fig. 2). At the periphery of the tumor the tumor grew in nests and single files (Fig. 3). A subtle but substantial vascular network was seen (Fig. 3). There were scattered mitotic figures and mild pleomorphism (Fig. 3, 4). The tumor displayed a polyphenotypic immunoprofile and had positive staining for cytokeratin, EMA, CD99, Vimentin and NSE. It was negative for chromogranin, GFAP, S-100 and desmin (Fig. 5).

Diagnosis: “Desmoplastic Small Round Cell Tumor of Abdomen”

Miriam Peckham, 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 20 years ago by Gerald and Rosai, desmoplastic small round cell tumor (DSRCT) is a rare malignant lesion presenting in the abdomen with distension and discomfort. It is usually peritoneal-based. DSRCT is typically found in young males (4:1) and occurs between the ages of 15 and 35. Though this tumor presents most commonly in the abdomen and pelvis, it has also been documented in various non-peritoneal sites including the parotid gland, CNS, pancreas, ovary, and lung.

Because of its lack of a definite visceral origin (though there is substantial evidence that it arises from mesothelial cells), this tumor is virtually undifferentiated and has a microscopic appearance of primitive, small, round, nested blue cells (Zellballen-like) within a desmoplastic stroma. Though this microscopic pattern is noted in a large portion of tumors, the histology may vary significantly. Some DSRCTs may show unusual cytology with spindle, rhabdoid, signet-ring, and pleomorphic cells.

Another diagnostic characteristic of DSRCT is its tendency to immuno-mark for neural, mesenchymal, and epithelial elements. The great majority of DSRCT cases stain positively for epithelial markers such as EMA and cytokeratins, as well as mesenchymal markers such as vimentin and desmin (usually in a dot-like, perinuclear pattern). Desmin positivity, which is frequently considered a diagnostic marker, was not noted in our presentation case. DSRCT has also been shown to have multiple neural antigens with neuron-specific enolase being the most common. Chromogranin and synaptophysin positivity, however, is not common. A more specific characteristic of this lesion is that it expresses WT1 – the Wilms’ tumor gene. This is believed to be a central component of DSRCT’s pathogenesis.

An important step in diagnosing DSRCT is separating it from similar-appearing small round blue cell tumors including rhabdomyosarcoma, PNET, Wilms tumor, lymphoma, neuroblastoma, small cell carcinoma, poorly differentiated carcinoma, malignant mesothelioma, and Merkel cell carcinoma. These tumors can be distinguished from DSRCT based on location (whether intra or extra-abdominal), age group (pediatric to young adult patients), and most convincingly, staining patterns via immunohistochemistry. Because of DSRCT’s characteristic polyphenotypia, an immunostain panel is needed to distinguish this entity from similar appearing tumors.

The most defining diagnostic feature of DSRCT is a reciprocal translocation of chromosomes 11 and 22, more specifically t(11;22)(p13;q12). This translocation exhibits the same genes found in Wilms tumor and Ewings sarcoma – fusion of the WT1 gene, from chromosome 11, and the EWS gene from chromosome 22. Other breakpoints for this translocation have been documented as well. Involvement of the WT1 protein has fueled speculation that its overexpression is related to the expression of both mesenchymal and epithelial markers. The EWS-WT1 chimeric protein has also been found to activate, through transcription factors, insulin-like growth factor 1. This is a possible mechanism for proliferation of tumor cells.

DSRCT behaves very aggressively and has a less than 2 year average survival rate. In the abdominal cavity it progressively fills the region with neoplastic nodules and accompanying ascites. These multiple implants frequently make complete excision impossible. A study done in 1998 followed up on 35 patients with DSRCT and found that 25 of those patients had already died, succumbing to widespread metastasis. The remaining patients lived on for an average of 25.2 months. Though the outlook of this disease is grim, the combination of surgical debulking and multimodality therapy can possibly improve survival. A study done by Lal & Sue, et al, showed a 55%, 3-year-survival in patients undergoing a combination of surgery, chemotherapy, and radiotherapy.

Suggested Reading:

1. Weiss SW, Goldblum JR. Soft Tissue Tumors. Mosby Inc. through Elsevier Inc. Philadelphia. 2008.
2. Neder L, Scheithauer BW, Turel KE, Arnesen MA, Ketterling RP, Jin L, Moynihan TJ, Giannini C, Meyer FB. Desmoplastic small round cell tumor of the central nervous system: report of two cases and review of the literature. Virchows Arch. 454:431-39, 2009.
3. Hiralal, Gamanagatti S, Thulkar S, Rao SK. Desmoplastic round cell tumour of the abdomen. Singapore Med J. 48(1): e19, 2007.
4. Lee Y, Hsiao C. Desmoplastic small round cell tumor: A clinicopathologic, immunohistochemical and molecular study of four patients. J Formos Med Assoc. 106(10):854-60, 2007.
5. Murphy AJ, Bishop K, et al. A new molecular variant of desmoplastic small round cell tumor: Significance of WT1 immunostaining in this entity. Hum Pathol. 39:1763-70, 2008.
6. Rosai J. Proceedings of the 107th California Tumor Tissue Registry semi-annual seminar, syllabus pages 32-33, December 5, 1999.
7. lal DR, Su WT, Wolden SL, et al. Results of the multimodal treatment for desmoplastic small round cell tumors. J Pediatr Surg. 40:251-5, 2005.

Preventive steps have also been taken. Hopefully this will calm things down for awhile.

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Microscopic sections showed the tumor to break out of bone and to involve surrounding tissues with extension up to the deep dermis (Fig. 2). The tumor displayed an osseous matrix consisting mostly of woven and trabecular bone often incorporating cells similar to those in the stroma (Fig. 3). In hypercellular regions that lacked bone formation, the tumor displayed both spindled and epithelioid features (Fig. 4) and had scattered mitotic figures. There were also areas which displayed a lace-like pattern of stromal cells intimately associated with, and incorporated into, osteoid (Fig. 5). Osteoclastic-like giant cells were not seen.

Diagnosis: “High-grade Conventional Osteosarcoma, Osteoblastic Type”

(Material donated by the Archdiocesan-Diocesan Health Services in Accra-Koforidua, Africa.)

Miriam Peckham, 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: Osteosarcoma (OS) is a tumor of atypical mesenchymal tumor cells which are able to produce immature bone or osteoid. It is the most common malignant primary osseous neoplasm (20%) and has a bimodal age distribution. Most cases occur in the second decade of life. Less common are those which present over the age of 40.

Though the clinical course of this lesion is comparable in younger patients and patients over 40 years of age, there are different associations. In patients over 40, OS has been found to be secondary to radiation exposure, various chemical agents, viral infection or areas of pre-existing osseous Paget’s disease. In younger patients, no precursor conditions have been elucidated. There is, however, an association with previous trauma. OS has a male dominance (3:2).

Our presentation case is most unusual in that it occurred in the toe. Osteosarcoma arising in a small bone has only been documented five times in the literature, with the last case being reported in August of 2000. Although most cases of osteosarcoma present in the metaphyses of long bones (most commonly in the proximal tibia and distal femur), in patients over the age of 50, there is a higher occurrence in the flat bones and axial skeleton. In both age groups, however, occurrence in the digital bones of the hands and feet is fleetingly rare.

Osteosarcoma can be divided into three histologic subtypes based on the most prominent matrix material. These subtypes are “osteoblastic osteosarcoma,” “fibroblastic osteosarcoma,” and “chondroblastic osteosarcoma.” In rare cases with abundant giant cells, the tumor may be referred to as “giant cell osteosarcoma”.

Metastatic dissemination of OS is mostly hematogenous, with lung being involved in 80% of cases that metastasize. Standard treatment for OS has traditionally been amputation of the affected limb, however the success of pre-operative chemotherapy has enabled use of limb-salvage techniques. With amputation only, the 5 year survival rate is from 5-23%, but with the pre-surgical chemotherapy, the overall rate jumps to 50-65%. Differential diagnoses include osteoblastoma, chondrosarcoma, Ewing sarcoma, pleomorphic sarcoma (MFH), giant-cell tumor of bone, and exuberant fracture callus.

1. Osteoblastoma (OB) can resemble osteosarcoma due to the presence of bony trabeculae. However, the trabeculae in OB are more uniform and there is less nuclear atypia, unlike osteosarcoma which generally grows larger (>5cm) and has a destructive pattern of growth which can engulf preexisting trabeculae. Most helpful is that the sites of presentation for these two tumors are quite different with OB preferring the sacrum, vertebral column, and craniofacial bones, locations that are very rare in OS.

2. Chondrosarcoma (CS) is usually distinguished from OS through radiologic, clinical and pathologic studies. Its presenting location differs from OS by showing preference for the truncal bones. There may be morphologic overlap between variants of CS and OS, especially chondroblastic OS compared to a CS with enchondral ossification. When confronted with this dilemma, factoring in the location of the tumor, the age of the patient and any preexistent or concurrent conditions may be of help.

3. Ewing Sarcoma (ES) can be confused with an OS composed primarily of small cells. It may also be mimicked by other small, round-cell neoplasms including lymphoma, and even some rhabdomyosarcomas. However, none of these tumors form a stromal matrix and each has its own unique immunohistochemical profile.

4. Pleomorphic Sarcoma (PS, Malignant Fibrous Histiocytoma) has more atypism and pleomorphism than OS, and does not form an extra-cellular matrix. An OS with limited osteoid production has considerable morphologic overlap with PS, in fact, before PS was seen as an entity, it had been previously classified as “osteolytic, anaplastic type of osteosarcoma.”

5. Giant-cell tumor of bone may be confused with osteoclast-like giant cell osteosarcoma. However, giant-cell bone tumors most often occur in the epiphyses while osteosarcomas are most commonly found in the metaphyses. GCT usually has a uniform distribution of giant cells, while osteoclastic osteosarcoma shows region to region variation in the number of multinucleated cells.

6. Exuberant Fracture Callus may mimic OS by having a high mitotic rate, atypical osteoblasts and the production of osteoid. A distinguishing factor between the two entities is the more uniform histologic progression of healing that is present in callus but is lacking in OS. For example, the trabeculae in a callus are usually arranged in parallel, a pattern that differs from OS in which a haphazard deposition predominates. Also, the history of trauma and/or the presence of a hematoma is supportive of a reparative process.

Suggested Reading:

1. Gangadharan VP, Ramachandran K, Elizabeth SK, Preetha S, Chithrathara K, Elizabeth KA. Primary Osteosarcoma of Metatarsal Bone. Am J Clin Oncol-Canc; 23(4):429-30, 2000.
2. Dorfman HD, Czerniak B. Bone Tumors. Mosby, Inc. St. Louis,1998.
3. Rozeman LB, Cleton-Jansen AM, Hogendoorn PCW. Pathology of primary malignant bone and cartilage tumours. Int Orthop; 30(6):437-44, 2006.
4. Gassiamis A, Tsakonas G, Soukouli G, Mylonakis N, Karabelis A, Kosmas C. Diffuse calcification of metastases after intensive multiagent chemotherapy in widespread osteosarcoma leading to death in a 18-year-old male. Med Oncol; 23(4):455-62, 2006.
5. Marulanda GA, Henderson ER, Johnson DA, Letson GD, Cheong D. Orthopedic surgery options for the treatment of primary osteosarcoma. Cancer Control; 15(1):13-20, 2008.
6. Weiss SW, Goldblum JR. Soft Tissue Tumors. Mosby Inc. through Elsevier Inc. Philadelphia. 2008.
7. Wafaa E, Abdelhalim F, Chase DR. A 34 y/o male with a trauma-related mass in the right arm. California Tumor Tissue Registry, www.cttr.org, Case of the Month, vol 8(12), September, 2006.

Microscopically, the mass was composed mostly of thick, hypocellular collagenous tissue (Fig. 1). It was well-circumbscribed and minimally associated with adjacent soft tissue (Fig. 2). Widely interspaced within the collagen were stellate to spindle-shaped cells resembling fibroblasts and myofibroblasts (Fig. 3, 4). The tumor lacked pleomorphism and did not display mitotic figures.

Diagnosis: Desmoplastic fibroblastoma (Collagenous fibroma)

Miriam Peckham, 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: Described first by Evans in 1995, desmoplastic fibroblastoma (DFB) is a rare, benign fibrous soft tissue mass that occurs most commonly in the skeletal muscle and subcutaneous tissue of adult males (5:1). This tumor presents most often in the fifth and sixth decades (mean 57 years) as a slow-growing, mobile, painless mass. The most common presentation sites include the upper and lower extremities, with the head and neck regions affected less frequently. The size of this tumor is normally less than 4 cm, but has been reported up to 20 cm.

Microscopically DFB is characterized by thick collagenous to myxocollagenous stroma with interspersed spindle and stellate-shaped fibroblasts/myofibroblasts. There are rare to absent mitotic figures and virtually no necrosis, hemorrhage or cellular atypia. Though DFB has the low-power appearance of a well-demarcated lesion, fat entrapment and infiltration of the surrounding soft tissues are commonly seen. Immunohisto- chemically, DFB positively marks for vimentin, and focally, expresses muscle-specific actin and alpha-smooth muscle actin. The tumor is generally negative for desmin, S-100 protein, and CD34.

Tumor behavior is usually indolent, with a slowly expanding soft tissue mass, which, when adequately excised, has limited capacity for local recurrence. To date, metastases have not been reported. This has led to question the nature of DFB and it has been reported that the tumor has a specific breakpoint at 11q12, supporting the notion that is a neoplastic process rather than a reactive one. Differential diagnoses include:

1. Nuchal fibroma: An uncommon lesion, nuchal fibroma most commonly occurs in the back of the neck of adult males. This lesion has a 30-40% association with diabetes and may recur after excision, most likely due to its persistent inciting cause. Histologically, its appearance is very similar to desmoplastic fibroblastoma in that it is made up of hypocellular collagen strands. Also seen are entrapped fat cells and an increased amount of small nerves. This morphology also overlaps with Gardner fibroma.

2. Gardner fibroma: Most commonly presenting in childhood, this lesion occurs mostly in the trunk with a predilection for the paraspinal region. The majority of patients with this lesion have familial adenomatous polyposis (FAP), with the fibroma preceding polyp formation. The correlation of this lesion with FAP makes the proper diagnosis of this fibroma of increased importance. These lesions are poorly demarcated and may recur as desmoid fibromatosis. Histologically, these fibromas show hypocellular collagen bands with artifactual cleft spaces. The cells within the mass have a bland, fibroblast-like appearance and there is frequently entrapment of surrounding soft tissue, all of which is similar to desmoplastic fibroblastoma. These masses stain positively for beta-catenin (similar as desmoid fibromatosis).

3. Neurofibroma: This lesion is characterized by wavy cells embedded within a myxocollagenous stroma. However, unlike desmoplastic fibroblastoma, they usually stain positive for S-100 protein.

4. Fibromatosis: This can be differentiated from desmoplastic fibroblastoma by its increased cellularity and its infiltrative nature. Another difference is this lesions characteristic cellular arrangement into broad fascicles.

5. Low-grade fibromyxoid sarcoma: This tumor is more cellular and more myxoid than DFB. It also tends to form whorls of spindled cells with a prominent fibromyxoid background.

6. Calcifying fibrous pseudotumor: This lesion affects a younger age group than DFB which is usually found in the fifth and sixth decades. This pseudotumor also shows a characteristic lymphoplasmacytic infiltrate, as well as multiple psammomatous calcifications located throughout its stroma.

7. Elastofibroma: This mass occurs mostly on the upper back in the region of the scapula. It is felt to be degenerative in nature, possibly due to repetitive motion. It diagnostically contains wavy elastic fibers which are absent in desmoplastic fibroblastoma.

8. Fibrous hyperplasia: Unlike desmoplastic fibroblastoma, this reparative inflammatory lesion presents with a history of trauma. The size of this lesion is also significantly smaller, ranging up to 1.5 cm.

9. Nodular fasciitis: This pseudosarcoma is more cellular, particularly in its early proliferative phase, and contains increased mitotic activity. It also shows rapid growth, contrasting with DFB which is indolent. A characteristic feature of NF is the mucinous separation of the tumor cells, resembling tissue paper that is being torn apart. The resolution stage of NF may mimic DFB, but is more cellular, mimicking benign fibrous histiocytoma.

Suggested Reading:

1. Watanabe H, Ishida Y, Nagashima K, Makino T, Norisugi O, Shimizu T. Desmoplastic fibroblastoma (collagenous fibroma). J Dermatol. 35(2):93-7, 2008.
2. Weiss SW, Goldblum JR. Soft Tissue Tumors, 5th Edition. Mosby Inc. through Elsevier Inc. Philadelphia. 2008.
3. Takahara M, Ichikawa R, Oda Y, Uchi H, Takeuchi S, Moroi Y, Kiryu H, Furue M. Desmoplastic fibroblastoma: a case presenting as a protruding nodule in the dermis. J Cutan Pathol. 35:70-3, 2008.
4. Walker KR, Bui-Mansfield LT, Gering SA, Ranlett RD. Collagenous fibroma (desmoplastic fibroblastoma) of the shoulder. AJR Am J Roentgenol. 183(6):1766, 2004.
5. Dagli M, Eryilmaz A, Acar A, Kulacoglu S, Akmansu H. Collagenous fibroma (desmoplastic fibroblastoma). Yonsei Med J. 45(5):941-3, 2004.
6. Shimoyama T, Horie N, Ide F. Collagenous fibroma (desmoplastic fibroblastoma): a new case originating in the palate. Dentomaxillofac Radiol. 34(2):117-9, 2005.
7. Fletcher, CDM. Diagnostic Histopathology of Tumors, 3rd Edition. Elsevier Limited. Philadelphia. 2007.