Blood tests to detect antibodies against KSHV have been developed and can be used to determine whether a person is at risk for transmitting infection to their sexual partner, or whether an organ is infected prior to transplantation. However, these tests are not available except as research tools, and, thus, there is little screening for persons at risk for becoming infected with KSHV, such as people following a transplant.

Although KS may be suspected from the appearance of lesions and the patient's risk factors, definite diagnosis can be made only by biopsy and microscopic examination. Detection of the KSHV protein LANA in tumor cells confirms the diagnosis.

In differential diagnosis, arteriovenous malformations, pyogenic granuloma and other vascular proliferations can be microscopically confused with KS.

On conventional radiographs, the most common osseous presentation is a permeative lytic lesion with periosteal reaction. The classic description of lamellated or "onion-skin" type periosteal reaction is often associated with this lesion. Plain films add valuable information in the initial evaluation or screening. The wide zone of transition (e.g. permeative) is the most useful plain film characteristic in differentiation of benign versus aggressive or malignant lytic lesions.

Magnetic resonance imaging (MRI) should be routinely used in the work-up of malignant tumors. It will show the full bony and soft tissue extent and relate the tumor to other nearby anatomic structures (e.g. vessels). Gadolinium contrast is not necessary as it does not give additional information over noncontrast studies, though some current researchers argue that dynamic, contrast-enhanced MRI may help determine the amount of necrosis within the tumor, thus help in determining response to treatment prior to surgery.

Computed axial tomography(CT) can also be used to define the extraosseous extent of the tumor, especially in the skull, spine, ribs, and pelvis. Both CT and MRI can be used to follow response to radiation and/or chemotherapy. Bone scintigraphy can also be used to follow tumor response to therapy.

In the group of malignant small round cell tumors which include Ewing's sarcoma, bone lymphoma, and small cell osteosarcoma, the cortex may appear almost normal radiographically, while permeative growth occurs throughout the Haversian channels. These tumours may be accompanied by a large soft-tissue mass while almost no bone destruction is visible. The radiographs frequently do not shown any signs of cortical destruction.

Radiographically, Ewing's sarcoma presents as "moth-eaten" destructive radiolucencies of the medulla and erosion of the cortex with expansion.

Other entities with similar clinical presentations include osteomyelitis, osteosarcoma (especially telangiectatic osteosarcoma), and eosinophilic granuloma. Soft-tissue neoplasms such as pleomorphic undifferentiated sarcoma (malignant fibrous histiocytoma) that erode into adjacent bone may also have a similar appearance.

The diagnosis of synovial sarcoma is typically made based on histology and is confirmed by the presence of t(X;18) chromosomal translocation.

Two cell types can be seen microscopically in synovial sarcoma. One fibrous type, known as a spindle or sarcomatous cell, is relatively small and uniform, and found in sheets. The other is epithelial in appearance. Classical synovial sarcoma has a biphasic appearance with both types present. Synovial sarcoma can also appear to be poorly differentiated or to be monophasic fibrous, consisting only of sheets of spindle cells. Some authorities state that, extremely rarely, there can be a monophasic epithelial form which causes difficulty in differential diagnosis. Depending on the site, there is similarity to biphenotypic sinonasal sarcoma, although the genetic findings are distinctive.

Like other soft tissue sarcomas, there is no universal grading system for reporting histopathology results. In Europe, the Trojani or French system is gaining in popularity while the NCI grading system is more common in the United States. The Trojani system scores the sample, depending on tumour differentiation, mitotic index, and tumour necrosis, between 0 and 6 and then converts this into a grade of between 1 and 3, with 1 representing a less aggressive tumour. The NCI system is also a three-grade one, but takes a number of other factors into account.

Sarcomas are given a number of different names based on the type of tissue that they most closely resemble. For example, osteosarcoma resembles bone, chondrosarcoma resembles cartilage, liposarcoma resembles fat, and leiomyosarcoma resembles smooth muscle.

In addition to being named based on the tissue of origin, sarcomas are also assigned a grade (low, intermediate, or high) based on the presence and frequency of certain cellular and subcellular characteristics associated with malignant biological behavior. Low grade sarcomas are usually treated surgically, although sometimes radiation therapy or chemotherapy are used. Intermediate and high grade sarcomas are more frequently treated with a combination of surgery, chemotherapy and/or radiation therapy. Since higher grade tumors are more likely to undergo metastasis (invasion and spread to locoregional and distant sites), they are treated more aggressively. The recognition that many sarcomas are sensitive to chemotherapy has dramatically improved the survival of patients. For example, in the era before chemotherapy, long-term survival for patients with localized osteosarcoma was only approximately 20%, but now has risen to 60–70%.

Imaging studies such as X-rays, computed tomography scans, or MRI may be required to diagnose clear-cell sarcoma together with a physical exam. Normally a biopsy is also necessary. Furthermore, a chest CT, a bone scan and positron emission tomography (PET) may be part of the tests in order to evaluate areas where metastases occur.

It can be detected by magnetic resonance imaging (MRI), but a biopsy is required for the definitive diagnosis. MRI findings typically show a well-circumscribed mass that is dark on T1-weighted images and bright on T2-weighted images. Central necrosis is often present and identifiable by imaging, especially in larger masses.

The only reliable way to determine whether a soft-tissue tumour is benign or malignant is through a biopsy. There are two methods for acquisition of tumour tissue for cytopathological analysis;

- Needle Aspiration, via biopsy needle

- surgically, via an incision made into the tumour.

A pathologist examines the tissue under a microscope. If cancer is present, the pathologist can usually determine the type of cancer and its grade. Here, 'grade' refers to a scale used to represent concisely the predicted growth rate of the tumour and its tendency to spread, and this is determined by the degree to which the cancer cells appear abnormal when examined under a microscope. Low-grade sarcomas, although cancerous, are defined as those that are less likely to metastasise. High-grade sarcomas are defined as those more likely to spread to other parts of the body.

For soft-tissue sarcoma there are two histological grading systems : the National Cancer Institute (NCI) system and the French Federation of Cancer Centers Sarcoma Group (FNCLCC) system.

Soft tissue sarcomas commonly originate in the upper body, in the shoulder or upper chest. Some symptoms are uneven posture, pain in the trapezius muscle and cervical inflexibility [difficulty in turning the head].

The most common site to which soft tissue sarcoma spreads is the lungs.

Evidence is conflicting on the prognostic significance of chloromas in patients with acute myeloid leukemia. In general, they are felt to augur a poorer prognosis, with a poorer response to treatment and worse survival; however, others have reported chloromas associate, as a biologic marker, with other poor prognostic factors, and therefore do not have independent prognostic significance.

Dermatofibrosarcoma protuberans is diagnosed with a biopsy, when a portion of the tumor is removed for examination. In order to ensure that enough tissue is removed to make an accurate diagnosis, the initial biopsy of a suspected DFSP is usually done with a core needle or a surgical incision.

Definitive diagnosis of a chloroma usually requires a biopsy of the lesion in question. Historically, even with a tissue biopsy, pathologic misdiagnosis was an important problem, particularly in patients without a clear pre-existing diagnosis of acute myeloid leukemia to guide the pathologist. In one published series on chloroma, the authors stated that 47% of the patients were initially misdiagnosed, most often as having a malignant lymphoma.

However, with advances in diagnostic techniques, the diagnosis of chloromas can be made more reliable. Traweek et al. described the use of a commercially available panel of monoclonal antibodies, against myeloperoxidase, CD68, CD43, and CD20, to accurately diagnose chloroma via immunohistochemistry and differentiate it from lymphoma. Nowadays, immunohistochemical staining using monoclonal antibodies against CD33 and CD117 would be the mainstay of diagnosis. The increasingly refined use of flow cytometry has also facilitated more accurate diagnosis of these lesions.

DSRCT is frequently misdiagnosed. Adult patients should always be referred to a sarcoma specialist. This is an aggressive, rare, fast spreading tumor and both pediatric and adult patients should be treated at a sarcoma center.

There is no standard protocol for the disease; however, recent journals and studies have reported that some patients respond to high-dose (P6 Protocol) chemotherapy, maintenance chemotherapy, debulking operation, cytoreductive surgery, and radiation therapy. Other treatment options include: hematopoietic stem cell transplantation, intensity-modulated radiation Therapy, radiofrequency ablation, stereotactic body radiation therapy, intraperitoneal hyperthermic chemoperfusion, and clinical trials.

ASPS is an extremely rare cancer. While sarcomas comprise about 1% of all newly diagnosed cancers, and 15% of all childhood cancers, ASPS comprises less than 1% of sarcomas. According to the American Cancer Society, about 9530 new cases of soft tissue sarcoma will be diagnosed in the USA in 2006. This predicts under 100 new cases of ASPS. Such low numbers of occurrence seriously impede the search for a cure by making it hard to gather any meaningful statistics about the disease. As a result, finding the best treatment option often involves making a lot of educated guesses.

Although ASPS displays a relatively indolent course, the ultimate prognosis is poor and is often characterized by late metastases.

Undifferentiated pleomorphic sarcomas are, by definition, "undifferentiated", meaning (as the name implies) that they do not bear a resemblance to any normal tissue.

The histomorphology, otherwise, is characterized by high cellularity, marked nuclear pleomorphism, usually accompanied by abundant mitotic activity (including atypical mitoses), and a spindle cell morphology. Necrosis is common and characteristic of high grade lesions.

Because this is a rare tumor, not many family physicians or oncologists are familiar with this disease. DSRCT in young patients can be mistaken for other abdominal tumors including rhabdomyosarcoma, neuroblastoma, and mesenteric carcinoid. In older patients DSRCT can resemble lymphoma, peritoneal mesothelioma, and peritoneal carcinomatosis. In males DSRCT may be mistaken for germ cell or testicular cancer while in females DSRCT can be mistaken for Ovarian cancer. DSRCT shares characteristics with other small-round blue cell cancers including Ewing's sarcoma, acute leukemia, small cell mesothelioma, neuroblastoma, primitive neuroectodermal tumor, rhabdomyosarcoma, and Wilms' tumor.

Treatment depends upon the site and the extent of the disease. Clear cell sarcoma is usually treated with surgery in the first place in order to remove the tumor. The surgical procedure is then followed by radiation and sometimes chemotherapy. Few cases of clear cell sarcoma respond to chemotherapy. Several types of targeted therapy that may be of benefit to clear cell sarcoma patients are currently under investigation.

VAS appears as a rapidly growing firm mass in and under the skin. The mass is often quite large when first detected and can become ulcerated or infected. It often contains fluid-filled cavities, probably because of its rapid growth. Diagnosis of VAS is through a biopsy. The biopsy will show the presence of a sarcoma, but information like location and the presence of inflammation or necrosis will increase the suspicion of VAS. It is possible for cats to have a granuloma form after vaccination, so it is important to differentiate between the two before radical surgery is performed. One guideline for biopsy is if a growth is present three months after surgery, if a growth is greater than two centimeters, or if a growth is becoming larger one month after vaccination.

X-rays are taken prior to surgery because about one in five cases of VAS will develop metastasis, usually to the lungs but possibly to the lymph nodes or skin.

The differential for OSSN includes pterygium, pingueculum, papilloma, solar keratosis, lipoma, lymphoma, chronic blepharoconjunctivitis, inflammation, melanoma, ocular pannus, pyogenic granuloma, kaposi sarcoma, keratocanthoma, mucoepidermoid carcinoma, pseudoepitheliomatous hyperplasia, and adenocarcinoma. While confocal microscopy can be used for diagnosis, biopsy is considered the standard, especially before treatment with a cytotoxic medication.

In general, treatment for soft-tissue sarcomas depends on the stage of the cancer. The stage of the sarcoma is based on the size and grade of the tumor, and whether the cancer has spread to the lymph nodes or other parts of the body (metastasized). Treatment options for soft-tissue sarcomas include surgery, radiation therapy, and chemotherapy.

- Surgery is the most common treatment for soft-tissue sarcomas. If possible, the doctor will remove the cancer and a safe margin of the healthy tissue around it. It is important to obtain a margin free of tumor to decrease the likelihood of local recurrence and give the best chance for eradication of the tumor. Depending on the size and location of the sarcoma, it may, rarely, be necessary to remove all or part of an arm or leg.

- Radiation therapy may be used either before surgery to shrink tumors or after surgery to kill any cancer cells that may have been left behind. In some cases, it can be used to treat tumours that cannot be surgically removed. In multiple studies, radiation therapy has been found to improve the rate of local control, but has not had any influence on overall survival.

- Chemotherapy may be used with radiation therapy either before or after surgery to try to shrink the tumor or kill any remaining cancer cells. The use of chemotherapy to prevent the spread of soft-tissue sarcomas has not been proven to be effective. If the cancer has spread to other areas of the body, chemotherapy may be used to shrink tumors and reduce the pain and discomfort they cause, but is unlikely to eradicate the disease.

Castleman disease (CD) is a lymphoproliferative disorder of unknown cause. CD is associated with an increased risk of B-cell lymphoma.

Human herpesvirus 8 (HHV-8), also known as Kaposi sarcoma-associated herpesvirus (KSHV) has been found in some cases of multicentric Castleman disease (MCD). The HHV8 can give rise to an increased number of plasmablast cells within the mantle zone of B-cell follicles. These plasmablasts express IgM-immunoglobulin light chains, most often of lambda subtype. These plasmablasts can give rise to a spectrum of abnormalities including progression to microlymphoma (microscopic clusters of plasmablast cells) or clinical lymphoma.

This type of lymphoma is predominantly seen in acquired immunodeficiencies, including acquired immunodeficiency syndrome (AIDS) but it can also occur in immunosuppression such as with organ transplantation or the elderly. The plasmablasts do not show rearranged immunoglobulin genes, and typically lack EBV infection.

The disease predominantly affects lymph nodes and the spleen, a pattern dissimilar to plasmablastic lymphoma of the oral cavity of AIDS which is not associated with HHV-8 infection. Despite traditional chemotherapy with CHOP (cyclophosphamide, doxorubicin, prednisone, vincristine), and the possible addition of antiviral therapy and inhibition of specific cellular targets including the use of rituximab, the prognosis in this lymphoma has been poor.

This lymphoma subtype has sometimes been confused with plasmablastic lymphoma in the literature, although that is a dissimilar specific entity. Similarly, this subtype is considered distinct from other lymphomas which have a plasmablastic immunophenotype such as primary effusion lymphoma, ALK+ large B-cell lymphoma, and extracavitary HHV–8-positive lymphoma.

HHV8 is also associated with Kaposi's sarcoma and with another subtype of lymphoma, primary effusion lymphoma, previously called body cavity-based lymphoma.

Tissue biopsy is the diagnostic modality of choice. Due to a high incidence of lymph node involvement, a sentinel lymph node biopsy is often performed. A common characteristic of epithelioid sarcoma (observed in 80% of all cases) is the loss of function of the SMARCB1 gene (also termed BAF47, INI1, or hSNF5). Immunohistochemical staining of INI1 is available and can be used for the diagnosis of epithelioid sarcoma. MRI is the diagnostic modality of choice for imaging prior to biopsy and pathologic diagnosis, with the primary role being the determination of anatomic boundaries.