Soft tissue sarcomas account for approximately 1% of all new cancer diagnoses. Almost half of all patients diagnosed with the disease eventually die as a result of the cancer. Soft tissue sarcomas can occur anywhere in the body, but most originate in an extremity (41%), the trunk (10%), the retroperitoneum (16%), visceral sites (21%), or the head and neck (12%). Soft tissue sarcomas originate from a wide variety of mesenchymal cell types and include malignant fibrous histiocytoma, liposarcoma, rhabdomyosarcoma, leiomyosarcoma, and desmoid tumors. While the histopathology of these tumors is highly variable, with some exceptions they tend to behave in a fashion dictated by tumor grade rather than the cell of origin.
Most soft tissue sarcomas arise de novo, and rarely do they result from malignant degeneration of a benign lesion. There are several familial syndromes in which patients are genetically predisposed to the formation of soft tissue sarcomas, including Li-Fraumeni syndrome, Recklinghausen disease, and Gardner syndrome. Other proven risk factors exist that may increase the chances of sarcoma formation. External radiation therapy can increase the incidence of sarcomas by 8-fold to 50-fold. Chronic extremity lymphedema also increases the risk for lymphangiosarcoma. A classic example is the development of upper extremity lymphangiosarcomas in the lymphedematous arm of women treated for breast cancer (Stewart-Treves syndrome). Other less clear associations link chronic tissue trauma and occupational chemical exposures with an increased risk for sarcoma formation.
The major features of the staging system for soft tissue sarcomas are the grade of the tumor, its size, and the presence of metastatic disease (Table 44–3). Although the site of the tumor is not considered in staging, patients with retroperitoneal tumors tend to have a worse prognosis. Sarcomas generally metastasize by the hematogenous route, and the metastatic sites of sarcomas are related to the location of the primary tumor. The vast majority of metastases from extremity sarcomas are to the lung, while the majority of retroperitoneal tumors metastasize to the liver. Lymph node involvement is rare with most soft tissue sarcomas, although it may occur with epithelioid sarcoma, clear cell sarcoma, angiosarcoma, rhabdomyosarcoma, or synovial sarcoma.
Table 44–3.AJCC staging system for soft tissue sarcoma. ||Download (.pdf) Table 44–3. AJCC staging system for soft tissue sarcoma.
Primary Tumor (T) https://www.protocols.fccc.edu/fccc/pims/staging/sarcoma.html
TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
T1: Tumor 5.0 cm or less in greatest dimension
T1a: Superficial tumor
T1b: Deep tumor
T2: Tumor more than 5.0 cm in greatest dimension
T2a: Superficial tumor
T2b: Deep tumor
Regional Lymph Nodes (N)
NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis
N1: Regional lymph node metastasis
Distant Metastasis (M)
Histopathologic Grade (G)
GX: Grade cannot be assessed
G1: Well differentiated
G2: Moderately differentiated
G3: Poorly differentiated
|Stage Grouping |
|Stage IA ||T1a-1b ||N0 ||M0 ||G1, GX |
|Stage IB ||T2a-2b ||N0 ||M0 ||G1, GX |
|Stage IIA ||T1a-1b ||N0 ||M0 ||G2, G3 |
|Stage IIB ||T2a-2b ||N0 ||M0 ||G2 |
|Stage III ||T2a, T2b ||N0 ||M0 ||G3 |
| ||Any T ||N1 ||M0 ||Any G |
|Stage IV ||Any T ||Any N ||M1 ||Any G |
The most important prognostic variables for patients with soft tissue sarcoma are the size and grade of the primary tumor. Since grading is based on the cellular architecture and invasive nature of the tumor, FNAB is not a typically useful biopsy technique for the initial diagnosis of a sarcoma. If a tumor is small (< 3 cm) and superficial, excisional biopsy should be performed. All extremity biopsy incisions should be oriented longitudinally, as the biopsy incision scar should be excised in a subsequent definitive resection of the tumor. Core needle biopsies may be performed for large, palpable superficial tumors. For large, deep tumors or those adjacent to vital structures, where core needle biopsy is not advised or failed, incisional biopsy should be considered. The incision should be centered over the mass, tissue flaps should not be raised, and meticulous hemostasis should be ensured, all to prevent the dissemination of tumor cells into adjacent tissue planes.
Treatment of Extremity Sarcomas
MRI is the imaging modality of choice for any suspected extremity sarcoma because it is most accurate in defining the extent of the tumor and invasion of surrounding structures. MRI is also used for follow-up imaging to assess response in patients undergoing therapy, as well as for local and regional recurrence. A chest x-ray or chest CT should be obtained in order to evaluate for pulmonary metastases in patients with high-grade tumors.
Surgery remains the primary therapy for localized extremity sarcomas, but multimodality therapy is recommended to minimize the likelihood of recurrence or the need for amputation. Historically, amputation was the only form of curative surgical therapy for large extremity sarcomas, but multimodality therapy has allowed for a high rate of limb preservation. Today, fewer than 5% of patients with extremity soft tissue sarcoma require amputation, generally reserved for patients whose tumors do not respond to preoperative therapy and cannot be resected adequately, have no evidence of metastatic disease, and have a good prognosis for rehabilitation.
A pseudocapsule composed of tumor cells surrounds sarcomas, and local invasion along fascial planes and neurovascular structures is common. It is important not to dissect along the pseudocapsule, which is associated with high local recurrence rates, but rather obtain a wide (2-cm) margin of normal tissue. This may need to be compromised in the immediate vicinity of functionally important neurovascular structures. If the tumor involves these structures, nerve grafts and arterial reconstruction with autologous or prosthetic conduits may be required. Large soft tissue defects often require the construction of myocutaneous flaps to improve function and cosmesis. Soft tissue sarcomas rarely invade bone or skin, and wide resections of these structures are infrequently necessary.
Following wide local excision, metal clips should be placed at all margins of the resection in order to guide subsequent radiotherapy. For patients with T1 tumors located superficially in an area where it is not difficult to obtain widely negative margins, postoperative radiation therapy may not be necessary. For most other lesions, postoperative radiation is almost always recommended, with either external beam radiation or brachytherapy. Radiation should be started 4-8 weeks after surgery, as delay can result in a lower local control rate. Preoperative radiotherapy may have some advantages in patients with large tumors. Lower doses can be delivered to an undisturbed tumor bed, which may also have better oxygenation, and larger tumors may decrease in size, allowing for limb-sparing procedures. Preoperative radiation is associated with an increase in short-term wound complications but a decrease in long-term tissue fibrosis and edema. The optimal mode and sequence for treatment has yet to be defined and often requires a multidisciplinary approach.
Adjuvant chemotherapy remains controversial. Chemotherapy can be given either preoperatively or postoperatively. The three drugs most effective in sarcoma are doxorubicin, dacarbazine, and ifosfamide. Preoperative chemotherapy is sometimes recommended because in addition to the early treatment of micrometastatic disease, it allows for assessment of tumor response, which helps avoid prolonged therapy in patients not responding. However, while disease-free survival may be improved, there are conflicting data on overall survival. A recent meta-analysis of randomized trials suggested there may be a small survival benefit for extremity sarcomas, and so its use has increased.
The vast majority of localized recurrences in soft tissue sarcomas occur in the first 2 years after resection, necessitating close follow-up during that period. A local recurrence is not indicative of systemic disease and, in the absence of evidence of metastases, should be treated aggressively in the same manner as a primary tumor. The resection of pulmonary metastases should be considered in patients who have fewer than four radiographically detectable lesions and who have achieved apparent local control following resection of the primary tumor. In such circumstances, disease-free survival can approach 25%-35%.
Treatment of Retroperitoneal Sarcomas
Retroperitoneal sarcomas comprise approximately 15% of all soft tissue sarcomas, with liposarcoma, malignant fibrous histiocytoma, and leiomyosarcoma the three most common types. They usually present as a large abdominal mass. Nearly half are over 20 cm in size at diagnosis. Once they compress or invade contiguous structures, they can cause symptoms such as abdominal pain or nausea and vomiting. Workup should include CT of the abdomen and pelvis to evaluate the mass as well as CT of the lung and liver to look for metastases. CT-guided core biopsy is the sampling technique of choice, with open or laparoscopic incisional biopsy reserved for inconclusive core biopsies.
As with extremity sarcomas, surgery represents the primary treatment, with the goal being en bloc resection with a rim of normal tissue. Although retroperitoneal tumors are generally large at presentation and often invade vital structures, the majority of these tumors are resectable. Retroperitoneal sarcomas rarely invade surrounding organs, but an intense desmoplastic reaction makes it difficult to assess the extent of tumor, so often these organs need to be resected rather than risk positive margins. The kidney, colon, pancreas, and spleen are the most commonly resected organs.
While adjuvant radiation therapy is standard in extremity sarcoma, evidence supporting its use in retroperitoneal sarcoma is less convincing. Because of the low tolerance to radiation of the abdominal and retroperitoneal organs, delivery of adequate radiotherapy is often difficult. There is encouraging evidence for intraoperative radiation therapy to the tumor bed, but this technique is still considered investigational and can be performed only in select centers. Although complex, preoperative radiation may be beneficial because it uses lower radiation doses, is less injurious to the small bowel, and can increase respectability by shrinking the tumor and creating a thickened capsular structure around the lesion.
JR, eds: Enzinger and Weiss’s Soft Tissue Tumors, 5th ed. Mosby, St. Louis, MO 2008.
SL: Sarcomas of soft tissues and bone. In: Scientific Principles and Practice, 5th ed. Mulholland
et al. Lippincott Williams & Wilkins, Philadelphia, PA 2011.
The incidence of melanoma is unfortunately rising. The reasons for this rise are not clear but are most likely related to an increased exposure to ultraviolet radiation from sunlight. Individuals whose first sunburn occurred at an early age, or have had three or more sunburns before age 21 have an increased incidence of melanoma, as do individuals who use tanning beds. Other risk factors include freckles, a fair complexion, reddish or blond hair, blue eyes, a first-degree relative with melanoma, and the presence of multiple or dysplastic nevi.
The best approach to melanoma is to prevent it from occurring, through sun avoidance and sun protection with sunscreens with a sun protection factor (SPF) of 30 or higher. Second to prevention, the most significant impact on melanoma comes from early recognition and diagnosis. The prognosis of melanoma is inversely and dramatically related to the depth of invasion at diagnosis (Breslow thickness), emphasizing the importance of early diagnosis of this disease. Lesions that are suspicious for melanoma can be identified by their clinical characteristics, often referred to as the ABCDs of melanoma (Table 44–4). Diagnosed early, well over 90% of primary melanomas can be cured with surgical excision alone. Patients presenting with thicker lesions or regional nodal metastases have a significantly poorer prognosis. The AJCC staging system is presented in Table 44–5.
Table 44–4.Clinical characteristics of melanoma (ABCDs). ||Download (.pdf) Table 44–4. Clinical characteristics of melanoma (ABCDs).
A- Asymmetry: Asymmetric shape, color, or contour
B- Borders: Irregular or ill-defined borders
C- Color: Color variation within the lesion
D- Difference: Any lesion that has changed in size, shape, or color
Table 44–5.AJCC staging system for melanoma. ||Download (.pdf) Table 44–5. AJCC staging system for melanoma.
|TNM Classification |
|T1a ||≤1 mm ||without ulceration and mitoses < 1/mm2 |
|T1b ||≤1 mm ||with ulceration or mitoses ≥ 1/mm2 |
|T2a ||1.01-2.0 mm ||without ulceration |
|T2b ||1.01-2.0 mm ||with ulceration |
|T3a ||2.01-4.0 mm ||without ulceration |
|T3b ||2.01-4.0 mm ||with ulceration |
|T4a ||> 4.0 mm ||without ulceration |
|T4b ||> 4.0 mm ||with ulceration |
|N0 ||No regional metastases detected || |
|N1a ||Micrometastasis in 1 node || |
|N1b ||Macrometastasis in 1 node || |
|N2a ||Micrometastasis in 2-3 nodes || |
|N2b ||Macrometastasis in 2-3 nodes || |
|N2c ||In-transit met(s)/satellite(s) without metastatic nodes || |
|N3 ||≥ 4 metastatic nodes, or matted nodes, or in-transit met(s)/satellite(s) with metastatic nodes || |
|M0 ||No detectable evidence of distant metastases || |
|M1a ||Metastases to skin, subcutaneous, or distant lymph nodes with normal serum LDH || |
|M1b ||Metastases to lung with normal serum LDH || |
|M1c ||Metastases to all other visceral sites or any distant metastases with an elevated serum LDH || |
|Stage Groupings |
|IA ||T1a N0 M0 || |
|IB ||T1b N0 M0, T2a N0 M0 || |
|IIA ||T2b N0 M0, T3a N0 M0 || |
|IIB ||T3b N0 M0, T4a N0, M0 || |
|IIC ||T4b N0 M0 || |
|IIIA ||T1-4a, N1a or N2a, M0 || |
|IIIB ||T1-4b, N1a or N2a, M0 || |
| ||T1-4a, N1b, N2b or N2c, M0 || |
|IIIC ||T1-4b, N1b, N2b or N2c, M0 || |
| ||Any T, N3, M0 || |
|IV ||Any T, Any N, M1 || |
There are several distinct categories of melanoma; the four most common are superficial spreading, nodular, lentigo maligna, and acral lentiginous melanoma.
Superficial spreading melanoma is the most common presentation, accounting for nearly 70% of all melanomas. These usually occur in sun-exposed areas of the body or in individuals with multiple dysplastic nevi. They generally arise in preexisting nevi and can occur at any age after puberty. The superficial spreading subtype tends to grow in a radial pattern during the earlier stages and converts to a vertical growth pattern during the later stages of development.
Nodular melanomas account for between 15% and 25% of all melanomas. These tend to occur in older individuals and are more common in men. Nodular melanomas generally develop de novo, not in a preexisting nevus. They usually are dome shaped with distinct borders and often resemble a blood blister. Nodular melanomas occur most commonly on the head, neck, and trunk. They lack a significant horizontal growth phase and tend to be deep at the time of diagnosis.
Lentigo maligna melanoma has less propensity to metastasize and thus has a more favorable prognosis relative to the other subtypes. However, it can be locally aggressive, with high recurrence rates after excision. These lesions account for 4%-10% of melanomas and occur in an older population. Lentigo maligna lesions almost always develop in sun-exposed areas. They have a long horizontal growth phase and often have very convoluted borders.
Acral lentiginous melanomas account for between 2% and 8% of melanomas in Caucasians but for 30%-60% of melanomas in blacks, Asians, and Hispanics. These lesions do not occur in sun-exposed areas; instead, they occur on the sole of the foot, the palm, beneath the nail beds, and in the perineal region. Acral lentiginous melanomas are often large, with an average diameter of 3 cm at the time of diagnosis. They develop relatively rapidly over the course of months to several years and tend to behave very aggressively. The clinical characteristics of these melanomas are often unmistakable, with variegations in color and convoluted borders. Ulceration of these lesions is common.
Treatment of Primary Melanoma
Any suspected melanoma should be removed by punch or excisional biopsy. Given the importance of Breslow thickness, shave or curette biopsies are contraindicated. If the biopsy specimen reveals melanoma, a formal excision with adequate margins is required. Because microscopic tumor cells frequently surround primary melanomas, excision with narrow margins is associated with an unacceptably high rate of local recurrence. The current standard for lesions less than 1 mm in depth is excision with 1-cm margins. Melanomas between 1 and 2 mm in thickness should be excised with 2-cm margins, but a smaller margin (10-15 mm) may be acceptable in areas where it is difficult to get 2 cm without the need for a skin graft or exceptionally tight closure. Melanomas deeper than 2 mm should be excised with a 2-cm margin. The resection should be carried down to the underlying fascia, although the fascia need not be excised.
Melanomas generally metastasize by the lymphatic route in a predictable and orderly fashion. Any palpable nodes must be considered suspicious for metastatic involvement, easily verified with an FNAB. About 5%-10% of patients have clinical evidence of nodal metastases upon initial presentation and should undergo a therapeutic lymph node dissection at the time of their wide excision. Many patients will have microscopic disease in the lymph nodes that will not be apparent on physical examination. In the past, substantial controversy surrounded elective lymph node dissection of the draining nodal basin for melanoma. The practice gained dramatic acceptance, however, with the advent of the sentinel lymph node biopsy, which is based on the anatomic concept that lymphatic fluid from defined regions of skin drains specifically to an initial node or nodes (“sentinel nodes”) prior to disseminating to other nodes in the same or nearby basins. Sentinel node biopsy allows for a more detailed histologic examination of the sentinel lymph nodes and helps avoid the morbidity of lymph node dissection in patients who are pathologically node negative. Patients with a negative sentinel node are over six times more likely to survive than those with a positive sentinel lymph node, making the predictive impact of sentinel node status much greater than any other prognostic factor. Evidence also suggests that early removal of micrometastatic disease from the lymph nodes, as compared with waiting for regional recurrence to perform a lymph node dissection, may improve survival.
The sentinel lymph node biopsy has become the standard of care in the staging and treatment of melanoma and should be performed at the time of the wide excision for primary melanomas thicker than 1.0 mm. It should be selectively applied for tumors between 0.75 and 1.0 mm when other worrisome features are present, such as ulceration, angiolymphatic invasion or a mitotic rate >1. Melanomas less than 0.75 mm are very unlikely to have regional metastases and do not require sentinel lymph node biopsy. The dominant drainage basins can be identified by lymphoscintigraphy, which involves intradermal injection of technetium-99m (99mTc) sulfur colloid in the area around the tumor and a gamma camera to image the sites of lymph node drainage. In the operating room, blue dye (isosulfan or methylene) is injected in a similar fashion. Any lymph nodes that have evidence of 99mTc uptake on a handheld gamma probe, have evidence of blue dye, or are clinically suspicious should be excised. After removal of the nodes, they are analyzed by serial thin-sectioning, routine H&E staining, and immunohistochemical staining. Using these methods of analysis, the pathologist is able to detect even minute numbers of metastatic melanoma cells in the sentinel node. Patients with a positive sentinel lymph node biopsy should undergo formal lymph node dissection of the entire drainage basin, although the benefit of this is being examined in the prospective randomized Multicenter Selective Lymphadenectomy Trial-II (MSLT-II).
Traditional chemotherapy regimens have proved largely ineffective in the treatment of melanoma; however, the cytokine IFN alpha-2b (Intron A) has been shown to improve disease-free and overall survival in high-risk patients with no evidence of systemic metastases. This treatment is not without controversy, however, as the duration of therapy is long (12 months), the toxicities are substantial, and some of the data regarding the overall survival benefit are conflicting. An alternate approach to high-dose IFN alpha-2b is pegylated interferon alpha-2b. This has a longer half-life and can be administered subcutaneously with fewer side effects, albeit for a longer period of time (5 years). Finally, another consideration for adjuvant therapy is biochemotherapy, which combines IL-2, IFN alpha-2b, cisplatin, vinblastine, and DTIC. This regimen has significant toxicity but is shorter (9 weeks) and was shown in a prospective randomized trial to improve relapse-free survival compared with high-dose interferon, although there was no improvement in overall survival. All patients with high-risk melanoma (node-positive melanoma or thick, ulcerated, node-negative melanoma) should have a balanced discussion of the potential risks and benefits of adjuvant therapy. While melanoma is relatively radioresistant, there may be some benefit to regional control after node dissection with radiation in patients with gross extracapsular extension or multiple involved lymph nodes.
Local Recurrence & In-transit Metastasis
Although rare with appropriate surgery, an isolated local recurrence can be treated with a repeat wide excision with 2-cm margins. Approximately 2%-3% of melanoma patients will develop in-transit metastasis, which is the appearance of metastasis along the path from the primary tumor to its regional nodal basin, and is lymphatic in nature. The management of in-transit metastasis is dictated by the number and the size of the lesions. If few in number, surgical excision with a margin of surrounding normal cutaneous and subcutaneous tissue is appropriate; however, this becomes unlikely with multiple lesions. Intralesional therapy with granulocyte-macrophage colony-stimulating factor can result in significant regression of melanoma deposits but requires multiple injections and is not always effective. Although melanoma is relatively radiation resistant, this therapy can provide palliation in unresectable lesions in many cases. Radiation therapy should be considered in those patients with a smaller volume of cutaneous or subcutaneous metastases.
Hyperthermic isolated limb perfusion (HILP) is a way of isolating the blood circuit to the extremity and administering chemotherapeutic agents regionally at a concentration 15-25 times higher without resulting in systemic side effects. Melphalan has been used as a standard drug for hyperthermic isolated limb perfusion secondary to its efficacy and low regional toxicity. While this has not been shown to improve survival, the use of hyperthermic isolated limb perfusion provides a significant palliation of locoregional symptoms when other options are not available. Less complicated, but also effective, is isolated limb infusion (ILI). This involves using minimally invasive techniques to access the vessels along with a tourniquet to minimize systemic uptake.
Regional and systemic recurrence of melanoma can be latent, and recurrence 10 years after the original diagnosis is not uncommon. This fact necessitates close lifelong follow-up of these patients. Patients with a past history of melanoma have a dramatically increased risk of developing a second primary lesion and require diligent screening for other lesions.
et al.: Cutaneous Melanoma, 5th ed. Quality Medical Publishing, St. Louis, MO 2009.
CK: Cutaneous neoplasms. In: Scientific Principles and Practice, 5th ed. Mulholland
et al.. Lippincott Williams & Wilkins, Philadelphia, PA 2011.
Lymphomas are malignant neoplasms that originate from the lymphoid tissues. Two distinct categories of lymphoma exist: Hodgkin and non-Hodgkin. The two types not only have different morphologic characteristics but differ also in their clinical behavior and their response to various therapeutic regimens. It is not possible to differentiate Hodgkin and non-Hodgkin lymphoma on clinical grounds; surgical biopsy is necessary. In the diagnosis of a suspected lymphoma, excisional biopsy of the entire lymph node or nodes is imperative, as the architecture has a bearing on the diagnosis and the subsequent treatment of the tumor.
Hodgkin lymphoma may occur at any age but is generally a disease of young adults. Prevalence in women peaks in the third decade and then falls, while it remains fairly constant in men after this time. The diagnosis of Hodgkin lymphoma is based on the finding of Reed-Sternberg cells in an appropriate cellular background of reactive leukocytes and fibrosis. It is the pattern of the lymphocytic infiltrate that determines the classic subtypes of Hodgkin disease (see Table 44–6). All subtypes of classical Hodgkin lymphoma are presently treated in the same way, and modern therapy has allowed for cure of over 70% of patients with this malignancy.
Table 44–6.Classic subtypes of Hodgkin lymphoma. ||Download (.pdf) Table 44–6. Classic subtypes of Hodgkin lymphoma.
|Subtype ||Characteristics |
|Lymphocyte-predominant ||Uncommon (6% of Hodgkin lymphomas), diffuse lymphocytic infiltrate with few Reed-Sternberg cells, excellent prognosis |
|Lymphocyte-depleted ||Rare (2% of Hodgkin lymphoma), abundant Reed-Sternberg cells, paucity of lymphocytes, occurs in older males, aggressive clinically |
|Mixed cellularity ||Common (20%-25% of Hodgkin lymphoma), histologically intermediate between above two forms, often presents with disseminated disease |
|Nodular sclerosis ||Most common form (70% of Hodgkin lymphoma), fibrosis with Reed-Sternberg and lymphoid cells, more common in young women, presents with cervical or mediastinal disease |
The cause of Hodgkin disease is not well understood; however, epidemiologic studies have revealed certain patterns of disease clustering. The incidence appears to be higher with a lower number of siblings, early birth order, siblings with Hodgkin disease, a decreased number of playmates, certain HLAs, single-family dwellings, and patients who have undergone tonsillectomy. The incidence is increased also in persons with immunodeficiencies and autoimmune disorders. This pattern suggests that an oncogenic virus may cause Hodgkin disease. Nuclear proteins of the Epstein-Barr virus have been detected in about 40% of classical Hodgkin lymphoma, and alternative lymphotropic viruses may be involved in the pathogenesis of cases negative for Epstein-Barr virus.
Most patients present with enlarged but painless lymph nodes, typically in the lower neck or supraclavicular region. On occasion, mediastinal masses are associated with cough or dyspnea or discovered on routine chest x-ray. About 25% of patients will have systemic symptoms, called B symptoms, including weight loss, pruritus, fever, and drenching night sweats.
With regard to therapy, the most important prognostic factor in Hodgkin lymphoma is the disease stage. The AJCC staging system for Hodgkin and non-Hodgkin lymphoma is shown in Table 44–7. The Ann Arbor staging system is also commonly used, which further subclassifies the stages into A and B categories: B for those with weight loss, fever, night sweats, or other constitutional symptoms, and A for those without such symptoms.
Table 44–7.AJCC staging system for Hodgkin and Non-Hodgkin lymphoma. ||Download (.pdf) Table 44–7. AJCC staging system for Hodgkin and Non-Hodgkin lymphoma.
|Stage ||Prognostic Groups |
|I ||Involvement of a single lymphatic site (ie, nodal region, Waldeyer ring, thymus, or spleen) (I). |
| ||OR |
| ||Localized involvement of a single extralymphatic organ or site in the absence of any lymph node involvement (IE) (rare in Hodgkin lymphoma) |
|II ||Involvement of two or more lymph node regions on the same side of the diaphragm (II) |
| ||OR |
| ||Localized involvement of a single extralymphatic organ or site in association with regional lymph node involvement with or without involvement of other lymph node regions on the same side of the diaphragm (IIE). The number of regions involved may be indicated by a subscript Arabic numeral, for example, II3 |
|III ||Involvement of lymph node regions on both sides of the diaphragm (III), which also may be accompanied by extralymphatic extension in association with adjacent lymph node involvement (IIIE) or by involvement of the spleen (IIIS) or both (IIIE, IIIS). Splenic involvement is designated by the letter S |
|IV ||Diffuse or disseminated involvement of one or more extralymphatic organs, with or without associated lymph node involvement |
| ||OR |
| ||Isolated extralymphatic organ involvement in the absence of adjacent regional lymph node involvement, but in conjunction with disease in distant site(s). Stage IV includes any involvement of the liver or bone marrow, lungs (other than by direct extension from another site), or cerebrospinal fluid |
As discussed earlier, excisional lymph node biopsy is essential to the diagnosis of Hodgkin lymphoma. Once the diagnosis is made, disease staging begins with a detailed history and physical examination, with attention to all lymph node beds, B symptoms, and symptoms related to extranodal involvement. CT of the chest, abdomen, and pelvis is the major means of staging intrathoracic and intra-abdominal disease. Bone marrow biopsy is also part of the staging evaluation of patients with bony symptoms or cytopenias. Fluorodeoxyglucose F 18 (FDG-PET) scan significantly adds to the staging of Hodgkin lymphoma and has become a standard staging tool both before treatment and at completion. In the past, a staging laparotomy (splenectomy, wedge liver biopsy, and dissection of the para-aortic, iliac, splenic hilar, and hepatic portal lymph nodes) was used to determine the extent of disease in the abdomen. Given the improved imaging studies and the inclusion of chemotherapy for patients even with favorable stage I disease, staging laparotomies are rarely, if ever, performed.
Hodgkin lymphoma has changed from a uniformly fatal disease to one that is curable in almost three-quarters of patients. Treatment is guided by both the stage of disease as well as stratification into favorable and unfavorable prognosis. This has allowed for less intensive therapy in patients with a favorable prognosis, with no compromise in outcome. The definition of favorable disease differs with different groups, but takes into account stage and extent of disease, age, ESR, and symptoms. For patients with favorable prognosis stage I-II disease, treatment typically involves a combination of ABVD chemotherapy (doxorubicin, bleomycin, vinblastine, dacarbazine) in combination with involved field irradiation. For patients at risk of long-term complications from radiation, 4 to 6 cycles of ABVD without radiation can be considered, although there are higher recurrence rates compared with combined modality therapy. Patients with unfavorable stage I-II disease are treated with more cycles of AVBD in combination with irradiation.
While ABVD remains the standard regimen for stage III-IV Hodgkin lymphoma (advanced stage), newer regimens include escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) and Stanford V (doxorubicin, vinblastine, mechlorethamine, vincristine bleomycin, etoposide and prednisone). Consolidation radiotherapy may be considered with ABVD or BEACOPP, but is an essential component of the Stanford V protocol. The response rates, toxicity and patient comorbidities must be weighed when deciding on a regimen.
Approximately 5%-10% of patients are refractory to initial therapy, and 10%-30% will relapse after complete remission. In this case, salvage therapy typically involves an alternate chemotherapy regimen. High-dose chemotherapy and autologous hematopoietic cell transplantation (HCT) should be considered for patients with early relapse (within 12 months), second relapse or a generalized systemic relapse, even after 12 months. For patients who fail this approach or are not candidates for high-dose chemotherapy with HCT, there are unfortunately few good treatment options.
Non-Hodgkin lymphoma encompasses a wide spectrum of lymphoid-derived tumors. This heterogeneous group of diseases includes more than 10 distinct tumor subtypes with variable biologic behavior and responses to treatment. As opposed to Hodgkin lymphoma, the prevalence of non-Hodgkin lymphoma rises with age. The incidence has been rising steadily over the past 20 years by about 3%-5% per year, for unknown reasons. Several risk factors have been identified that predispose patients to the development of disease. Patients with congenital disorders such as ataxia-telangiectasia, Wiskott-Aldrich syndrome, and celiac disease have an increased incidence of lymphoma. Certain acquired conditions also predispose patients to lymphoma, including prior chemotherapy or radiotherapy, immunosuppressive therapy, Epstein-Barr infection, HIV infection, human T-cell lymphoma virus [HTLV]-1 infection, Helicobacter pylori gastritis, Hashimoto thyroiditis, and Sjögren syndrome.
Non-Hodgkin lymphoma may originate from B cells, T cells, or histiocytes. Morphologically, the tumors may appear as nodular clusters or diffuse sheets of lymphoid cells.
Classically, non-Hodgkin lymphoma presents as nontender enlargement of lymph nodes, but nearly one-third of all cases originate outside the lymph nodes. These extranodal malignancies develop in organs that normally have nests of lymphoid tissue (mucosal surfaces, bone marrow, and skin).
The goal of the staging evaluation is to distinguish patients who have localized disease from those with disseminated disease. After pathologic diagnosis, the staging evaluation for non-Hodgkin lymphoma consists of a detailed history and physical examination, routine laboratory tests, a bone marrow biopsy, and a CT scan of the neck, chest, abdomen, and pelvis. Evaluation of the cerebrospinal fluid should be considered in patients with diffuse large-cell non-Hodgkin lymphoma with bone marrow involvement, a high lactate dehydrogenase (LDH) level, or multiple extranodal sites of disease. It should also be considered in patients with high-grade lymphomas, HIV-related lymphomas, primary central nervous system lymphomas, and posttransplantation lymphoproliferative disorders. Finally, FDG-PET scans provide whole-body images that allow a comprehensive assessment of disease extent and, in conjunction with CT, provides complementary staging information. A pretreatment PET scan is often obtained so that PET can be used for monitoring of response to treatment. Normal PET at the end of therapy correlates with a highly favorable prognosis, while persistent abnormalities mandate close follow-up or biopsy to rule out residual disease.
The staging system for Hodgkin lymphoma is also used in non-Hodgkin lymphoma. Although helpful in assessing the anatomic extent of disease, the Ann Arbor system is of minimal clinical value in non-Hodgkin lymphoma. The international prognostic index (IPI) uses patient age, Ann Arbor stage, LDH level, number of extranodal sites, and ECOG performance status to categorize aggressive non-Hodgkin lymphoma. However, this system does not clearly stratify indolent lymphomas, so another prognostic factor model was devised for follicular lymphoma. The follicular lymphoma international prognostic index uses patient age, Ann Arbor stage, hemoglobin level, number of nodal areas, and serum LDH level to stage patients.
Scientists have made countless attempts to develop a universal, clinically relevant classification system for the subtypes of non-Hodgkin lymphoma, and the merits of the various classifications are an area of hot debate. The most widely accepted classification system is the Revised European-American Lymphoma/World Health Organization (REAL/WHO) classification (Table 44–8).
Table 44–8.Revised European-American lymphoma/World Health Organization (REAL/WHO) classification of lymphoma. ||Download (.pdf) Table 44–8. Revised European-American lymphoma/World Health Organization (REAL/WHO) classification of lymphoma.
|B-cell neoplasms |
|I. Precursor B-cell neoplasm |
| Precursor B-lymphoblastic leukemia/lymphoma (B-ALL/LBL) |
|II. Mature (peripheral) B-cell neoplasms |
B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma
B-cell prolymphocytic leukemia
Splenic marginal zone lymphoma (+/− villous lymphocytes)
Hairy cell leukemia
Plasma cell myeloma/plasmacytoma
Extranodal marginal zone B-cell lymphoma of MALT type
Mantle cell lymphoma
Nodal marginal zone B-cell lymphoma (+/− monocytoid B cells)
Diffuse large B-cell lymphoma
|T-cell and NK-cell neoplasms |
|I. Precursor T-cell neoplasm |
| Precursor T-lymphoblastic lymphoma/leukemia |
|II. Mature (peripheral) T-cell neoplasms |
T-cell prolymphocytic leukemia
T-cell granular lymphocytic leukemia
Aggressive NK-cell leukemia
Adult T-cell lymphoma/leukemia (HTLV1+)
Extranodal NK/T-cell lymphoma, nasal type
Enteropathy-type T-cell lymphoma
Hepatosplenic gamma/delta T-cell lymphoma
Subcutaneous panniculitis-like T-cell lymphoma
Mycosis fungoides/Sezary syndrome
Anaplastic large cell lymphoma, primary cutaneous type
Peripheral T-cell lymphoma, unspecified
Angioimmunoblastic T-cell lymphoma
Anaplastic large cell lymphoma, primary systemic type
|Hodgkin disease/lymphoma |
Lymphocyte-rich classic Hodgkin disease
In determining the therapeutic approach to patients with non-Hodgkin lymphoma, a simpler classification system can be utilized. For treatment purposes, these lymphomas can be functionally divided into two groups: indolent (low-grade) and aggressive (high-grade) lymphomas. Smaller, differentiated cells characterize the indolent lymphomas, and this class tends to have a follicular architecture. Although the course of these lymphomas is not very aggressive and they have a long median survival, they are not usually curable in advanced clinical stages. The natural history of indolent lymphomas often involves progression of the tumor cells to a more aggressive subtype. This progression is sometimes heralded by the onset of B symptoms and portends a dismal prognosis.
The aggressive lymphomas behave differently from the indolent ones and demand a different therapeutic approach. Histologically, the aggressive lymphomas spread more diffusely throughout the lymph nodes and consist of larger, less differentiated cell types. This class of lymphomas demonstrates a very rapid growth rate and an increased rate of early mortality. Despite this malignant behavior, this class of non-Hodgkin lymphoma is more often curable. The extranodal lymphomas develop outside of the lymph nodes and are not amenable to conventional classifications, so they are generally regarded as a separate entity. They can involve any organ but most commonly affect the oropharynx, paranasal sinuses, thyroid, gastrointestinal tract, liver, testicles, skin, and bone marrow.
Patients with localized disease, although this is the minority, can be treated with radiation therapy only with curative intent. Most patients have disseminated disease, which tends to be chronic relapsing and remitting. The current therapies for systemic indolent lymphomas are rarely curative, and the goal of treatment is generally directed at palliation of symptoms. At present, a “watch and wait” approach to treatment is recommended for asymptomatic patients. After diagnosis, asymptomatic patients are followed up clinically until they progress to more aggressive disease, major symptoms, or organ dysfunction. Withholding chemotherapy does not reduce survival in patients with non-Hodgkin lymphoma, and it probably improves quality of life.
For patients who have symptoms, a combination of rituximab and alkylator chemotherapy has high response rates and can alleviate symptoms. Rituximab is a monoclonal antibody that binds to the B-cell surface antigen CD20. CD20 is a cell-surface protein involved in the development and differentiation of normal B cells. It is found on the vast majority of B-cell lymphomas. Rituximab is well tolerated and has remission rates of 40%-50% when used as single-agent therapy for relapsed indolent lymphoma. In younger patients with systemic indolent disease, or patients who had a short response to first-line treatment, high-dose chemotherapy with HCT may be considered, although the chance of cure should be balanced against the mortality of treatment, which can approach 10%.
Despite their aggressive nature, these lymphomas have a better chance for cure than their more indolent counterparts. The treatment is typically guided by the prognostic factors (IPI score). Patients with low-risk lymphoma respond well to CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy plus rituximab. Radiotherapy may be used after chemotherapy for areas of bulky disease. Patients with high-risk lymphoma benefit from more intensive regimens of chemotherapy and rituximab and potentially high-dose therapy with HCT. This approach should also be considered for patients who relapse or fail to enter remission after induction chemotherapy. A promising immunotherapy is tositumomab, an anti-CD20 monoclonal antibody bound to 131I (Bexxar). It can kill cells by antibody-mediated cellular cytotoxicity, activation of complement-mediated tumor cell lysis, and the tumor-specific delivery of radiation. Bexxar is currently indicated for the treatment of patients with CD20 antigen-expressing relapsed or refractory non-Hodgkin lymphoma.
There is no consensus about the proper management of localized nonlymphoid lymphomas because large-scale studies of therapy for this disease have not been conducted. With few exceptions, nonlymphoid disease is managed somewhat in the same way as systemic aggressive lymphomas, using combination CHOP therapy.
The CHOP regimen has the disadvantage of poor penetration of the blood-brain barrier and is thus ineffective in the treatment of primary central nervous system lymphomas. These lymphomas rarely metastasize, remaining localized to the central nervous system. Current regimens utilize steroids and whole-brain radiation with some form of adjuvant chemotherapy. Methotrexate is the most common adjuvant treatment in this patient population, and it can be effective when delivered either systemically or intrathecally. This can be combined with whole brain radiation therapy. Central nervous system lymphomas have a poor prognosis, with approximately 20% 5-year survival rates in treated patients. The combined modalities, while providing modest survival benefits, have significant neurotoxicities, and as many as 50% of patients develop severe dementia. Given this morbidity, clinicians often use chemotherapy as the sole modality in the treatment of patients with primary central nervous system lymphomas. Extranodal lymphomas that have a predilection for metastases to the central nervous system, such as testicular, paranasal, and AIDS-related lymphomas, require systemic CHOP therapy combined with prophylactic intrathecal methotrexate treatments.
The treatment of gastric lymphomas has been controversial. Mucosa-associated lymphoid tissue–type gastric lymphomas (MALT-type gastric lymphomas) typically have an indolent behavior, and the most widely accepted initial therapy is the eradication of H. pylori using regimens combining antibiotics and proton pump inhibitors. For patients with MALT-type gastric lymphoma who are H. pylori negative or do not respond to antibiotic/proton pump inhibitor therapy, radiation therapy to the stomach and perigastric lymph nodes obtains high complete response rates and excellent long-term survival. While surgery had previously been used in the treatment of gastric lymphomas, there is now sufficient data to suggest nonoperative management permits a better quality of life with no impact on overall survival. When the disease has spread, the use of chemotherapy is similar to that used for other indolent, advanced lymphomas.
High-grade gastric lymphoma is treated with aggressive polychemotherapy, usually combined with rituximab. Again, surgery used to play a more prominent role but has greatly diminished. It was assumed that the increased risk of perforation and bleeding with chemotherapy could be prevented by pretreatment gastric resection, but modern series have failed to demonstrate that benefit and actually show a high degree of postsurgical complications that may delay the start of chemotherapy. Surgery is limited to patients who have complications or who cannot be managed by standard regimens.
Splenectomy in patients with lymphomatous splenic involvement has not demonstrated therapeutic benefit and should be reserved for patients with symptomatic splenomegaly, pain from recurrent splenic infarctions, and hematologic depression from hypersplenism.
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