Lymphomas involving extranodal sites most commonly occur simultaneously with nodal involvement, either at the time of diagnosis or during the course of the disease. Extranodal involvement that occurs as the only initial evidence of lymphoma after staging procedures is referred to as primary extranodal lymphoma. The presence of a tumor or mass outside of the lymph nodes is usually not considered lymphoma until a biopsy is done and the histopathology establishes the diagnosis. On the other hand, solitary extranodal lymphomas can occur in virtually any organ or tissue and should be considered in the differential diagnosis of a solitary mass lesion anywhere. The histopathology of primary extranodal lymphoma is usually either marginal zone lymphoma of MALT or DLBCL. Follicular lymphoma and several other histologic subtypes of lymphoma may also occur. Therapy usually involves a combination of multidrug chemotherapy and a lymphocyte-directed monoclonal antibody, such as rituximab-cyclophosphamide, hydroxydoxorubicin, vincristine (Oncovin), and prednisone (R-CHOP). Selection of the best regimen depends on the histopathologic subtype of lymphoma and the location of the disease. Radiotherapy is used less commonly in the management of lymphoma than in the past because of concerns about induction of secondary malignancies and delayed cardiopulmonary toxicities, although it still has a role in treatment of localized, stages I to II lymphomas, and for consolidation of bulky adenopathy (>10 cm) in selected settings.
An unanswered pathogenetic question concerning primary extranodal lymphoma is the propensity for both sites of paired organs (e.g., ovaries, testicles, breasts, ocular adnexa, adrenal glands, kidneys, and ureters) to be affected simultaneously. It is also curious that several of these sites (e.g., kidney) are normally devoid of significant accumulations of lymphatic tissue. If the transformed lymphocyte arises outside these tissues, it must have a tropism for both paired organs, perhaps because of expression of site-specific adhesion molecules or addressins.147
Primary lymphomas originating in and confined to the leptomeninges,148 brain,149,150,151 or spinal cord152 are uncommon. They almost always are of an aggressive histologic subtype, usually DLBCL.151,153 Spinal cord compression typically presents with back pain, followed by extremity weakness, paresis, and paralysis. Leptomeningeal spread may present with cranial nerve palsies and signs of meningeal irritation, for example, headache and stiff neck. Intracerebral mass lesions may present with headaches, lethargy, papilledema, focal neurologic signs, or seizures. Intracerebral lymphoma increased dramatically after the onset of the human immunodeficiency virus epidemic as a result of the association with AIDS-related aggressive lymphomas (Chap. 81). The incidence of intracerebral lymphoma has slowed in AIDS patients because of more successful antiviral therapy. Primary pituitary (or hypothalamic) extranodal lymphoma may result in hypopituitarism. Diabetes insipidus or anterior pituitary failure may occur. The lesion may invade the sella turcica or other neighboring bone and nervous tissue.154,155,156
Ophthalmic lymphoma, the most common orbital malignancy, includes lymphoma localized to the eyelid, conjunctiva, lacrimal sac, lacrimal gland, orbit, or intraocular space.157,158,159 This location accounts for approximately 7 percent of all extranodal lymphomas.160 The most frequent subtype is extranodal marginal zone lymphoma of MALT. Bilateral involvement occurs in 10 percent of cases. The most common site of ocular lesions is the periorbital soft tissues, particularly the conjunctival mucosal surfaces and the area surrounding the lacrimal gland. These lesions typically have a low-risk of progression and commonly have the histology of a marginal zone lymphoma of MALT or follicular center cell lymphoma and may be associated with C. psittaci (see “Infectious Agents” above). In a Danish study, approximately 50 percent of orbital and ocular adnexal lymphomas were of the marginal zone lymphoma of MALT subtype; DLBCL was the most common intraocularly.91,160 Lymphoma arising in the lacrimal sac was usually DLBCL. There has been a striking increase in incidence rates for lymphoma of the eye over the past 30 years.24,157,158,159,161 Patients with marginal zone lymphoma of MALT of the ocular orbit may relapse or have progression of disease after initial therapy and relapses can be found at extraocular sites.91 Overall survival, however, was not significantly worse for patients with relapse. The frequency of translocations involving the MALT1 and IGH gene loci is low in orbital marginal zone lymphoma of MALT (approximately 5 percent), but may predict increased risk of relapse.160 The therapy for orbital marginal zone lymphoma is usually radiotherapy, which is curative in the majority of patients.157 Anecdotal reports of responses to rituximab or rituximab postradiation suggest that rituximab may have a therapeutic role in low-grade lymphomas involving the eye. In the rare situation where DLBCL involves the periorbital soft tissue, treatment is determined by the distribution of the disease, but R-CHOP chemotherapy either alone or combined with local radiotherapy is standard.
Intraocular lymphomas are a rare presentation of lymphoma of the eye. Most cases are DLBCL. The diagnosis is established by a vitrectomy. There is an approximately 50 percent chance that the disease will be bilateral and the disease is frequently associated with brain or leptomeningeal involvement. The mainstay of therapy in the past has been local radiotherapy or intraocular injections of methotrexate or rituximab, but most patients treated in this manner relapse within the eye or brain. Standard chemotherapeutic agents administered intravenously (e.g., R-CHOP) typically do not penetrate the eye or brain, rendering these regimens ineffective. In recent years, many neuro-oncologists have advised treating intraocular lymphomas similarly to primary DLBCL of the brain with high-dose methotrexate based-chemotherapy with or without intrathecal treatment and/or whole-brain and eye radiotherapy. A large study conducted at 17 European centers has not confirmed the expected efficacy of this aggressive approach for vitreoretinal lymphoma, however.158
Localized NHL involving the nasal cavity and/or paranasal sinuses may be DLBCL, T-cell lymphoma, or NK/T-cell lymphoma.74,162,163,164,165,166,167,168 The nasal cavity is the predominant site of involvement in T-cell and NK/T-cell lymphoma, whereas sinus involvement without nasal disease is common in B-cell lymphoma. Systemic B symptoms are more frequently observed in NK/T-cell lymphoma. Based on in situ hybridization studies, there is a strong association of EBV with NK/T-cell lymphoma. These lymphomas may involve the frontal, maxillary, ethmoid, and sphenoid sinuses and typically involve bone. They present with local pain, upper airway obstruction, rhinorrhea, facial swelling, or epistaxis. They may extend into the periorbital area causing proptosis, visual loss, or diplopia. These lymphomas typically are DLBCL in the United States and Western Europe and more often T- and NK-cell lymphomas in Asia. Nasal NK/T lymphomas are typically treated with combination chemotherapy including l-asparaginase plus radiotherapy.162,169 In contrast, patients with primary sinus lymphoma usually have DLBCL. A series of 80 patients with primary sinonasal DLBCL treated with R-CHOP chemotherapy demonstrated a long-term progression-free survival rate of 50 to 60 percent, with only a single patient experiencing CNS relapse.170
The three main types of cutaneous B-cell lymphomas are primary cutaneous marginal zone B-cell lymphoma, primary cutaneous follicular center lymphoma, and primary cutaneous large B-cell lymphoma (leg type) as defined by the WHO–European Organization for Research and Treatment of Cancer.171 Primary cutaneous marginal zone B-cell and primary cutaneous follicle center lymphoma are indolent types with an excellent prognosis that should be treated primarily with nonaggressive therapies, including simple excision, glucocorticoid injections or local radiotherapy. Primary cutaneous large B-cell lymphoma (leg type) is a diffuse dermal infiltrate of neoplastic B cells with extension to both the papillary dermis and the subcutaneous fat.172,173 It typically presents as a solitary soft-tissue mass and mimics a soft-tissue sarcoma until biopsy clarifies the diagnosis. It is an aggressive lymphoma that should be treated primarily with aggressive chemotherapy (Chap. 98). Chap. 103 discusses classical T-cell cutaneous lymphomas, particularly mycosis fungoides.
Primary pulmonary lymphoma may present as a pulmonary nodule or mass and may be associated with hilar lymph node enlargement. The histopathology is usually marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue or DLBCL, though lymphomatoid granulomatosis may also present in this fashion.174,175 Lung biopsy is usually required to make a definitive diagnosis. Pleural effusions may occur as a result of either central lymphatic obstruction or pleural seeding.
Primary chest wall lymphoma may present as local pain or may be accompanied by fever, sweating, and dyspnea. These masses usually require excisional or incisional biopsy. They may be associated with pleural effusions and involvement of neighboring ribs.176
Primary endobronchial lymphoma is a rare occurrence and may follow lung transplantation. It can lead to airway obstruction as an early sign.
Primary cardiac lymphoma may involve the heart or pericardium or both. Patients may present with dyspnea, edema, arrhythmia, or pericardial effusion. The effusion may result in cardiac tamponade. Lymphomatous masses may be found in the right atrium (most common), pericardium, right ventricle, left atrium, or left ventricle. Most cases are a B-cell lymphoma; less than 5 percent are of T-cell lineage.177,178,179
Gastrointestinal lymphoma is the most common form of extranodal lymphoma, accounting for one-third of cases.180 The most commonly involved site is the stomach, followed by the small bowel, ileum, cecum, colon, and rectum. Lymphoma of the stomach typically causes dyspeptic symptoms and sometimes anorexia or early satiety. Hemorrhage is unusual but if present suggests a high-grade lymphoma. Diagnosis typically is made by endoscopic biopsy.180,181 H. pylori infection has been implicated in the pathogenesis of MALT gastric lymphoma.88 At endoscopy, mild to severe gastritis is common. Multiple biopsies are important to obtaining adequate material to determine the presence of H. pylori. MALT lymphoma is common, but DLBCL also may arise de novo or may be found in the background of a MALT lymphoma.181 If both subtypes of lymphoma are present, the treatment should be directed at the large B-cell lymphoma.
In the bowel, the small intestine, rectum, and colon may be involved, in that order of frequency.88,182 The intestinal location most often involved is the ileocecal region followed by small bowel, large bowel, and multiple intestinal sites.182 Primary esophageal lymphoma is rare.183 Primary colonic lymphoma is associated with symptoms of diarrhea, lower gastrointestinal bleeding, and nausea and vomiting secondary to low-grade obstruction. The most common disease location is the cecum, followed by the right colon, and the sigmoid colon.184
Rare cases of lymphoma may be confined to the liver. Right upper quadrant pain is the most common symptom. In about half of cases there is a history of previous inflammatory liver disease, such as hepatitis C.185,186,187,188
Primary extranodal lymphoma of the pancreas may present with abdominal pain, nausea, vomiting, obstructive jaundice, and weight loss, and very rarely signs of pancreatitis.189,190,191
The gallbladder may be the site of primary extranodal lymphoma and may present with right upper quadrant pain or other symptoms and signs consistent with cholecystitis.192,193 It may extend into the bile ducts with jaundice and other signs of bile duct obstruction.194
Primary lymphoma of the testes typically presents as a painless enlargement of the testis in an older man (Fig. 95–5). A hydrocele may also be present.195,196,197,198 The histologic type usually is a DLBCL. At presentation, two-thirds of cases are localized to the testicle or to the testicle and pelvic or abdominal lymph nodes. After orchiectomy has established the diagnosis, patients are staged with a special focus on the remaining testicle. If sonography of the remaining testicle demonstrates a solid mass, it should be assumed to be lymphoma. Patients presenting with testicular lymphoma have historically experienced a poorer prognosis compared to patients with other presentations of DLBCL, with relapses commonly occurring in either the CNS or contralateral testicle.199 The current international standard of care consists of orchiectomy, R-CHOP chemotherapy given every 21 days for six cycles, intrathecal methotrexate, and locoregional radiotherapy to the contralateral testicle.195,196 This combined modality approach has been shown to render an excellent 5-year progression-free survival rate of 74 percent.196
Primary extranodal diffuse large B-cell lymphoma in a testicular mass. A. Uninvolved area of testes. B. Area of testes replaced by an abnormal lymphocyte population. C. High-power view of the lymphoma cells. D. Positive immunohistochemistry staining for CD20. (Used with permission from Raymond Felgar, University of Pittsburgh Medical Center.)
Primary lymphoma of the ovary is often bilateral and presents as an abdominal mass with abdominal pain or palpation of a mass on physical examination.200,201,202,203,204,205
Uterus, Cervix, Genitalia
Cases of lymphoma limited to the uterus,206,207,208 uterine cervix,209,210 vagina, or vulva211 can occur. Uterine and cervical lymphoma usually presents with an abdominal mass or vaginal bleeding. Lymphoma can develop within a uterine leiomyoma.208
Lymphomatous involvement of both kidneys usually presents with renal insufficiency, which can be reversed with multidrug chemotherapy, or radiotherapy. Bilateral enlargement of the kidneys without obstruction and other organ or nodal involvement and absence of other causes of renal failure are characteristic of primary renal lymphoma.212,213,214,215,216 The origins of the lymphoma are perplexing as the kidney is thought to be devoid of lymphoid tissue. Both careful staging and postmortem examination have verified the absence of lymphoma in other sites. An increased association of renal cell carcinoma and primary renal lymphoma may exist.215 Rarely, the lymphomatous involvement, although still solely extranodal, involves only the perirenal space.217
Ureter, Bladder, Prostate
Bilateral ureteral involvement with obstructive renal failure may occur.218 Primary lymphoma of the bladder may rarely extend to the kidney. Usually it is localized and responds well to treatment.219,220,221 Primary extranodal lymphoma may involve the prostate.222,223
Primary splenic lymphoma is rare.224,225 Concomitant marrow involvement is present in most cases. When primary to the spleen, the lymphoma may be principally confined to the red pulp and is usually consistent histopathologically with DLBCL or marginal zone lymphoma.224 In the absence of lymph node involvement or splenic white pulp involvement at the time of diagnosis or during the course of the disease, it can be considered an “extranodal” splenic lymphoma.225
Primary bone lymphoma may involve any bone but usually affects the long bones.226,227,228,229 The presentation is usually bone pain and the lesions are usually lytic when imaged.226,228 When the skull is involved the lymphoma may invade the central nervous system.227 Most patients exhibiting skeletal involvement are due to aggressive lymphomas, particularly DLBCL. Management generally involves R-CHOP chemotherapy with consolidative radiotherapy.226
The clinical presentation of primary lymphoma of the female breast often mimics carcinoma of the breast. A small proportion of cases may be bilateral. The pathologic diagnosis is DLBCL in approximately 85 percent of cases.230 BCL-2 expression is frequently present in the tumor cells. Small lymphocytic lymphoma, follicular lymphoma, and marginal zone lymphoma of mucosa-associated lymphoid tissue may also be the histopathologic diagnosis.231,232 Staging may uncover either nodal involvement, marrow involvement or other extranodal sites with lymphoma in as many as half of cases. Approximately 10 percent of cases of primary breast lymphoma relapse in the central nervous system.230,232
Primary adrenal lymphoma usually present bilaterally and thus may lead to adrenal insufficiency. In the latter case, the presenting symptoms may be fatigue, asthenia, and other signs of hypoadrenocorticism.233,234,235,236 Primary thyroid lymphoma often occurs in a gland afflicted by Hashimoto thyroiditis. Thus, it occurs more frequently in women than men. The patient may present with an enlarged thyroid (goiter) or have symptoms as a result of tracheal compression.237,238,239 The histopathology may be DLBCL or marginal zone B-cell MALT lymphoma. Primary pituitary lymphoma is discussed under “Central Nervous System” above.