Histiocytic lymphoma (reticulum-cell sarcoma) Report
of five cases
Robert E. Cl&e, D.D.S.,” La Crosse, Wis. LA
CROSSE
LUTHERAN
HOSPITAL
and Thomas G. Stenger, AND
GUNDERSEN
D.D.S.,
M.S.,*#
CLINIC
The subject of lymphomas is discussed and five cases seen in our Oral Surgery Department are presented. Histiocytic lymphoma, especially of the oral regions, can present with a variety of clinical manifestations. The signs and symptoms, diagnostic modalities, and treatment are discussed and the most recent classification is included.
M
alignant lymphomas are tumors of lymphoreticular tissues. They frequently arise in lymph nodes or in tissues rich with lymphoreticular cells, such as the tonsils, nasopharynx, gastrointestinal tract, spleen, liver, and bone. Less frequently they arise as primary tumors in such tissues as skin, gonads, or brain, pointing to the ubiquitous distribution of these cells. Lymphomas are divided into Hodgkin’s and non-Hodgkin’s groups. There have been reported revisions of the histologic classifications under each group. This paper is based on the most common classification by Rappaport (Tables I and II) .I, 2 Lukes and Collins revised Rappaport’s classification on t.he basis of research in immunobiology in which in vitro functional studies and immunofluorescent techniques resulted in recognition of B and T lymphocytes and of differences in their origin, structure, and function.3-5 A comparison of Lukes’ classification is given in Table III.4 The histologic classification and clinical staging of the disease have provided the clinician with valuable guidelines in treatment and prognosis. It is worth noting that the Rappaport and the Lukes and Collins classifications may not be valid with respect to primary bone lymphomas.22 We report five cases of malignant, lymphoma involving the oral structures, *Formerly **Chief
422
Senior Resident; of Dental Surgery.
now
at the Sheboygan
Clinic,
Sheboygan,
Wis.
Histiocytic
Volume 43 Number 3
lymphoma
423
Table I. Classification of Hodgkin’s lymphomas Nodular Sclerosing Locyte predominance Lvmohocvte deoletion
Table II. Classification of non-Hodgkin’s lymphomas Nodular Lymphocytic Poorly differentiated Well differentiated H$stztic Nodular sclerosing Diffuse Lymphocytic (lymphosarcoma) Poorly differenttated Well djfferentiated l$$cyt~ (rettculum-cell sarcoma) Stem
Table Ill. Comparison of classifications 1
Nodular Undifferentiated-
Rappuporr
1
Lukes and Collins
T\ICC..--Undefined cell
*Large noncleaved -1mmunoblastic sarcoma (B-cell) .Histiocvtic Unclassifiable ‘Lymphocytic
and histiocytic.
nose, and paranasal sinuses. The histologic diagnosis according to Rappaport’s classiflcation was “malignant lymphoma, histiocytic type: diffuse.” All showed intermediate degrees of differentiation (Fig. 1). HISTIOCYTIC LYMPHOMA Histiocytes are primitive cells that normally differentiate into other cell types, including hemocytoblasts, myeloblasts, and lymphocytes. Histiocytes are found in small numbers in normal persons, where they line the sinusoids of lymph nodes and are also found in bone marrow. When a neoplasm of histiocytes develops, they proliferate and no longer differentiate into other cell types. Histiocytic lymphoma is less common than other lymphomas. It occurs pre-
424
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and Stenger
Oral March,
Surg. 1977
dominantly in men, with a ratio of 2 :l.“. 7 The diseasemay involve soft tissue or bone. Primary histiocytic lymphoma of soft tissues appears mainly in the elderly, whereas primary bone involvement is seen more commonly in the younger patient (30 to 50 years of age) .O Early signs of primary soft-tissue involvement include regional enlargement of lymph nodes or prominent extranodal tumors. Later a generalized involvement of many organ systems develops. Common sites of lymphatic origin are the tonsillar, cervical, mediastinal, retroperitoneal, gastrointestinal, or inguinal nodes. At surgery these nodes arc generally found to be discrete, white nodules up to 5 cm. in diameter. The tumor can permeate the capsule of the involved node to destroy the surrounding tissue.8 The disease tends to metastasize to regional lymph nodes rather than have multicentric primaries. Generally, the patient dies of a disseminated disease. Histiocytic lymphoma of soft tissue in the head and neck area usually originates in cervical lymph nodes or Waldeyer’s ring. Occasionally, it is seenin extranodal sites. Histiocytic lymphoma of the pharynx without cervical lymph node or bone involvement is a potentially curable tumor. Primary histiocytic lymphoma of bone has a more favorable prognosis because there is less tendency for the diseaseto metastasize.g Bones frequently involved are the vertebrae, pelvis, femur, ribs, and skull, with only occasional involvement of the maxilla and mandible. Clinical
features
The patient may initially present with malaise, fever, weight loss, hyperhydrosis, and pruritus. Enlarged lymph nodes are firm, fixed, and discrete.” They are generally not painful, unless there is overlying inflammation. Mediastinal or retroperitoneal nodal involvement may cause back pain or abdominal discomfort. Progressive bone involvement is painful and disability can develop. A systems review will reveal signs and symptoms associated with localized organ involvement. Mediastinal nodal involvement may produce coughing, substernal pain, dysphagia, and paralysis of the recurrent laryngeal nerve.6 Splenomegaly is not as common in histiocytic lymphoma as in the other lymphomas.” Retroperitoneal nodes may become enlarged and produce partial obstruction of the inferior vena cava with edema of the lower extremities.6 Hematologic disorders are uncommon during early stages of histiocytic lymphoma. As the diseaseinvolves ttie peripheral blood and bone marrow, however, associated leukemic disorders develop. 2 Also normochromic anemia may appear with progressive bone marrow failure. lo Viral infections, notably herpes zoster, and fungal infections occur occasionally. Such hematologic factors and infections, combined with systemic manifestations of fever, toxemia, and multiple lesion sites, lead to a poor prognosis. Enlargement of the involved bone is the most constant feature of histiocytic lymphoma of bone. Pain and disability are common and a pathologic fracture can occur with increasing bone destruction. Bone tumors usually remain localized initially without adjacent nodal involvement or early hematologic dissemination 1%21
Histiocytic
Fig. 2. Microscopic (Rematoxylin
Oral
and eosin
appearance of a diffuse stain. Magnification, x40.)
histiocytic
type
of
Zymphoma
malignant
425
lymphoma.
features
Primary histiocytic lymphoma of the soft tissues of the oral cavity is rare. Clinically, it usually manifests itself as a chronic, inflammatory process. It is often confused with periodontal disease, Vincent’s infection, or pericoronitis.12 Such confusion suggests that histiocytic lymphoma should be considered in a differential diagnosis if inflammatory lesions or surgical healing sites do not resolve. If there is paresthesia or anesthesia of the oral regions, a biopsy is definitely indicated. Oral manifestations of patients with histiocytic lymphoma may include herpes zoster, with the pain persisting for weeks or months. Since the nervous system is involved in 10 to 14 per cent of histiocytic lymphomas, cranial nerve palsies, especially with ocular, facial, and trigeminal nerve involvement, may occur.g Oral petechiae and bleeding from mucous membranes occur as a result of thrombocytopenia present in terminal stages of histiocytic lymphoma.s Primary facial bone involvement is also rare. Localized pain and bony destruction in an otherwise healthy patient are the most significant features.lO Gerry and Williams13 reported some cases in which they found pain to be the most prominent finding. Tooth mobility is common, but ulceration of the mucosa over the involved bone is rare. In addition to pathologic fractures of the mandible, local extension leads to involvement of the submandibular and cervical tissues. Extension beyond the maxilla leads to involvement of the maxillary sinuses and nasal cavity. Radiographic
features
Radiographic findings are not pathognomonic for histiocytic lymphoma, but a destructive radiolucency may suggest a malignant process. It is often as long as 3 years before oral radiographs show evidence of the disease.14A mandibular osteolytic lesion may be a direct extension of a primary lesion in soft tissue.
426
Cline and Xtenger
Oral March,
Surg. 1977
Roentgenographic examination of long bones in patients with histiocytic lymphoma is a more valuable adjunct to diagnosis than roentgenographs of the jaw bones.14 Radiographic examination of primary histiocytic lymphoma of the mandible often reveals periosteal elevation, an increased radiolucency of the bone, and some soft tissue en1argement.15 Pathologic fracture and fragmentation of the cortex due to expansion of bone can result. Worth14 described the mandibular lesion as similar to a myxoma without the definitive margins of a benign tumor. When there is little osteoblastic reaction and lack of well-delineated boundaries, a mottled appearance can be present. Sinus tumors may show dense opacity, although their bony walls may show little or no destruction. Histopathology
Microscopically, there is a diffuse growth of histiocytes with obliteration of normal structures. The cells vary in shape and are pleomorphic with oddly shaped, elongated pseudopods of the nucleus and cytoplasm.* The cells are larger than lymphocytes with abundant and faintly acidophilic cytoplasm and large nucleoli that are somewhat vacuolated. I6 The nucleus is often twice the size of that of a lymphocyte and is frequently kidney shaped.16The rate of mitotic activity is great and numerous mitotic figures can be seen permeating the capsules of lymph nodes and invading the surrounding tissues, including walls of veins. Multinucleated cells are common and on occasion resemble the Reed-Sternberg ce11.7 Histiocytic lymphoma may stimulate fibroblastic production of reticulin, which can be detected by special silver impregnation.* Reticulin is abundantly laid down between individual-and clusters of-histiocytes. When bone is involved, the tumor is almost always of the nodular type, and reticulin formation is a prominent feature. This latter fact may be lacking in histiocytic lymphoma of the soft tissues. An increase in reticulin is not found in lymphoblastomas and carcinomas. The histopathology of primary histiocytic lymphoma of bone is very similar to that of soft tissue, except for the reticulin formation. Many times the tissues overlying the involved bone can be confused with an inflammatory lesion,7,I7 which adds to the difficulty in diagnosis. Microscopically, Hodgkin’s disease, plasmacytoma, and Ewing’s sarcoma have also been mistaken for histiocytic lymphoma.i, 9, I8 Because the identification of the histiocyte is difficult, Lukes and Collins revised Rappaport’s classification. Their classification of malignant lymphomas is based on the B- and T-cell systems and changes in lymphocytic transformation (B cell-bursal equivalent-thymic independent or humoral immunity ; T cellthymic dependent-or cellular immunity) .4 According to their classification most of the histiocytes (reticulum cells) cannot be differentiated from transformed lymphocytes. Retrospective studies have shown this to be true. As noted from the classification (Table III), the majority of lymphomas (nodular and diffuse non-Hodgkin’s) have the cytologic features of the follicular center cell (FCC).”
Volume Number
Histiocytic
43 3
Zymphoma
427
The lymphomas of FCC are divided according to the cell size type: (1) small cleaved, (2) small noncleaved, (3) large cleaved, (4) large noncleaved. DIAGNOSIS
Microscopic examination is required to establish the diagnosis of histiocytic lymphoma. However, early in the course of the disease histologic changes may not be distinctive. Radiographs, thorough history, clinical examination, and lymphangiography are valuable adjuncts to determine the extent of the disease and the subsequent treatment. ** Hematologic studies, including complete blood count (CBC) and platelet count, along with bone marrow smears, can help determine the extent of the disease, especially if a leukemic transformation is suspected. Histiocytic lymphoma has also been reported to develop in renal transplant patients on long-term immunosuppressives and in patients on immunocytotoxic agents from rheumatoid arthritis and lupus erythematosus.” Although similar histologically to soft-tissue lesions, there are primary lesions of bone as pointed out and differentiated from Ewing’s sarcoma in 1939 by Parker and Jackson.ls When the tumor is of bony origin, the patient can remain in good health even though the tumor has reached a fairly good size. The long bones, especially the femur, are more commonly affected, but there can be involvement of ribs, scapula, mandible, maxilla, and parts of the vertebral co1umn.2o An SMA-12 is routinely obtained, which generally shows an increase in enzymes such as alkaline phosphatase and a hypercalcemia. Bone scanning with radioisotopes can be a helpful adjunct. Coley, Higinbotham, and Groesbeck’Ooutlined a clinical and roentgenographic differential diagnosis for histiocytic lymphoma of bone that includes: osteogenic sarcoma, Ewing’s sarcoma, secondary bone involvement by lymphosarcoma, chronic osteomyelitis, metastatic carcinoma, eosinophilic granuloma, metastatic neuroblastoma, malignant giant-cell tumor, myeloma, and Paget’s diseaseof bone. Soft-tissue biopsy of oral lesions can be confused with inflammatory lesions such as periodontitis, Vincent’s infections, and ulcer formation. Further investigation, including repeated biopsies, is necessary if an extraction site does not heal. Anesthesia or paresthesia of the lips or gingiva along with intra- or extraoral swelling may be the only clinical manifestations present. Treatment
and
prognosis
Treatment for early stages of the diseaseis best managed by irradiation. Because there is good local control rate with megavoltage radiotherapy, surgical treatment is unnecessary in the majority of cases.2oA dosage of 4,500 to 5,000 rads over 4 to 5 weeks should bring resolution of the tumor.ll The more curable lesions are those of the tonsils, nasopharynx, or bone.6y21If the white blood count falls below 2,000 or platelets below 50,000, treatment should be temporarily interrupted.O Radiographs of irradiated bone show new bone forming, but the trabecular pattern is altered from that of normal bone.14 Chemotherapy is used when systemic manifestations are severe and the disease widespread. Treatment generally involves radiation therapy to destroy the obvious lesions followed by chemotherapy to maintain remission. Alkylating
420
Fig. extracted widening
Cline
and Stenger
8. Case 1: Arrows point to the left canine several weeks prior to biopsy in the same of the periodontal ligament.
Oral March,
tooth (Panorex radiograph) area for histiocytic lymphoma;
Surg. 1977
which note
was the
agents, vincristine and cyclophosphamide (Cytoxan), can be used with fairly good results, although response rates are lower than in Hodgkin’s diseaseor lymphosarcoma.I* Chemotherapy usually brings remission in 6 to 8 weeks.‘l Cyclophosphamide. has several toxic manifestations, including hair loss, nausea, vomiting, and hematuria. Vincristine is useful for remission and is used when other alkylating agents have lost their effectiveness.G There can be side effects such as toxic neuropathy and paresthesia of t,he deep tendon reflexes.G As with other lymphomas, adrenal corticosteroids (prednisone) have a lympholytic effect and also are used to alleviate autoimmune hemolytic anemias and thrombocytopenia. One possible chemotherapeutic regimen is cyclophosphamide (15 mg. per kilogram per week), vincristine (0.025 mg. per kilogram intravenously per week), and prednisone (0.6 mg. per kilogram orally per day) administered over 6 weeks.” Prognosis depends on the stage of the diseaseand whether there is soft tissue or bone involvement. Histiocytic lymphoma of bone doeshave a higher curability rate than that of soft tissue. In all stages, the prognosis for women is better than for men.ll Histiocytic lvmphoma, as with other non-Hodgkin’s lymphomas, can be staged under the sa& classifications as Hodgkin’s disease.But unlike Hodgkin’s disease, prognosis can be correlated better according to the histopathologic subtype rather than clinical staging.2” The Ann Arbor reclassification for Hodgkin’s is as follows :24 Stage I: Disease limited to one anatomic region or a localized extralymphatic organ or site. Stage ZZ: Disease in two or more anatomic regions on the same side of the diaphragm or solitary involvement of an extralymphatic organ or site of
Histiocytic Table IV. Clinical data of five patients sarcoma) of the head and neck region Pr. 1 Anesthesia Swelling
Radiolucency
Abscessed teeth or periodontitis Pain Fever Trismus Ulceration Inflammation
with histiocytic
Pt. 2
Yes (area of No. Ill Yes r
lymphoma
lymphoma
Pt. 3
429
(reticulum-cell
Pt. 4
Pt. 5
Yes
No
No
No
Yes (Right cheek)
Yes (lumps on both sides of neck and swelling of nose) No thickening 0 r sinus lining)
Yes (left side of face)
Yes (right side of face)
Yes
Yes (pathologic fracture; alveolar bone destruction)
Yes
No
Yes
No; edentulous
No
Yes
Yes No No Yes (ulcer-like lesion on midline of palate) Yes
Yes
E No
Yes No Yes No
Yes No Yes Yes (fungating lesion of left alveolar ridge) Yes
No-except widening /?eg$$al cloudy Yes Yes
for of
No
sinus
ii: No Yes
one or more lymph node regions on the same side of the diaphragm. Spleen may be involved in case of localization below diaphragm. Stage III: Disease in anatomic regions on both sides of the diaphragm, may be accompanied by involvement of spleen or by localized involvement of an extralymphatic organ or site or both. Stage IV: Diffuse or disseminated involvement of one or more extralymphatic organs or tissues with or without associated lymph node involvement. CASE REPORTS CASE
1
A 66-year-old man presented with mobility of the left maxillary canine, anesthesia, and localized swelling in the anterior maxillary mucobuccal fold. Periapical and Panorex films were unremarkable except for some widening of the periodontal membrane around the canine (Fig. 2). The tooth was extracted because of its extreme mobility. Biopsy was not considered necessary at this time (see Table IV). The patient returned in 4 weeks with persistent swelling in the area and was evaluated in the otolaryngology department for possible chronic sinusitis. Straw-colored fluid was aspirated from the left antrum. A culture and sensitivity tests were done. Alpha-streptococcus and Neiaseria were cultured, and the patient was placed on appropriate antibiotics. Two weeks later the swelling remained, and a firm left parotid mass was noted. Biopsy of the left maxillary antrum revealed histiocytic lymphoma (reticulum-cell sarcoma). Additional investigation showed that the lymphoma involved the left ethmoid labyrinth, left parotid and submaxillary glands, and cervical nodes. Radiation therapy was started, but during this time the patient continued to deteriorate. One month after the therapy, a low-grade fever, mucositis, bilateral levator veli paralysis, fatty stools, and bloody emesis developed. Anemia developed (hemoglobin 7.1; hematocrit 21 per cent), and esophagoseopy and gastroscopy revealed infiltrative histocytic lymphoma (reticulum-cell sarcoma). Because of the systemic nature of the disease, only supportive measures were taken. The
430
Cline and Stenger
Fig. 8. Case 2: Panorex biopsy
was taken
patient adrenal CASE
for
died 4 months glands, kidneys,
histiocytic
Oral March,
radiograph, lymphoma.
after the and lungs.
diagnosis
essentially
was
unremarkable,
made
with
showing
metastatic
the
involvement
area
Burg. 1977
where
of
the
2
A 72-year-old woman presented to the clinic 5 weeks after the mandibular right premolar was extracted by her local dentist. Her initial complaint was numbness and pain in the mandibular right extraction site. Other than some minor protuberances of buccal bone around the extraction site, results of the intraoral examination were normal. At her next visit, she complained of persistent discomfort in the extraction area. There was extreme tenderness of the alveolar crest distal to the site with protrusion of a small mass of yellowish tissue. A biopsy was performed under local anesthesia, and the report showed chronic inflammation and fibrosis. Three succeeding visits followed within the next 4 months, and the last one revealed a diffuse swelling involving the right submandibular and right buccal space. A Panorex film was essentially unremarkable except for several remaining periodontally involved teeth (Fig. 3). A diagnosis of cellulitis subsequent to periapical pathology was made, and the patient was placed on penicillin. An intraoral incision and drainage (I & D) was done with only a minimal amount of purulent discharge. The culture and sensitivity report revealed alpha-streptococcus sensitive to penicillin. Throughout the next month, the numbness of the right lower lip persisted, and a firm swelling remained on the lateral border of the right mandible. A developing osteomyelitis was considered at this time. Radiographs demonstrated no osteolytic activity. Seven months .after her initial presentation to the clinic and 3 weeks after her last visit, she again presented with persistent swelling and numbness. Radiographs showed possible elevation of periosteum at the inferior border of the right mandible. No evidence of fluctuance was noted. The white blood count at this time was 5,100. The patient WBS subsequently taken to the operating room where a through-and-through drainage was done. Culture and sensitivity revealed alpha-hemolytic streptococcus, and the patient was maintained on antibiotics. Soft tissue and bone biopsy in the right mandibular region revealed inflammatory granulation tissue and sclerotic bone consistent with healed osteomyelitis. Her course continued to improve for the next 2 months with decreasing trismus and anesthesia of the right lower lip. On her return visit, swelling was noted in the right mandibular area. An I & D was performed at this time under local anesthesia, and a considerable amount of necrotic tissue was biopsied. The findings revealed histiocytic lymphoma (reticulum-cell sarcoma).
Histiocytic
Fig. the right
4. Case maxillary
Treatment cyclophosphamide of 3% years. CASE
3: Water’s view sinus region.
was
irradiation and prednisone.
of
sinus
revealing
increased
(5,000 rads over 5 weeks) She has had no recurrence
cloudiness
followed by and is well
lymphoma
and
radiopacity
431
in
chemotherapy of with a remission
3
A 72-year-old woman came to the clinic with complaints of lumps on both sides of her neck and difficulty in breathing through the right nostril of approximately 6 weeks’ duration. The patient had a weight loss of 2.6 kilograms over this period, and a local physician had diagnosed her condition as mumps. The nose appeared swollen and erythematous. Removal of her upper denture disclosed a necrotic, ulcerlike lesion on the midline of the palate. Panorex films and tomograms revealed a thickened lining and two pedunculated masses of the right maxillary sinus along with cloudiness of the right ethmoid sinus (Fig. 4). There was no evidence of bone destruction. Differential diagnosis at this time included midline lethal granuloma, Wegner’s granuloma, histiocytic lymphoma, lymphoepithelioma, and squamous-cell carcinoma. A biopsy of the maxillary sinus showed histiocytic lymphoma (reticulum-cell sarcoma). The patient was placed on radiation therapy for histiocytic lymphoma of the nasopharynx, right antrum, hard and soft palates, and lymph nodes of the anterior cervical chain bilaterally. Because of metastases to the breast and parts of the maxilla, chemotherapy consisting of vincristine, cyclophosphamide, and prednisone was instituted. The patient has been in remission for 3% years. CASE
4
An do-year-old man came to the clinic in January, 1970, with swelling of the left side of the face of several weeks’ duration. One week earlier, his physician had placed him on tetracycline because of the purulent material draining from the sinuses. Panographic films and oral examination revealed a horizontally impacted left maxillary
432
Oral March,
Chine and Stenger
Fig. 5. Case 4: Horizontally impacted graph. Note the radiolucency around the root
left maxillary of the canine
canine tooth.
as seen on Panorex
Surg. 1977
radio-
canme and massive swelling in the maxillary left labial sulcus (Fig. 5). The tooth was removed along with extensive amounts of heavy fibrous-type scar tissue. The biopsy of the surrouzfding tissue revealed histiocytic lymphoma (reticulum-cell sarcoma). Further radiographs, including Water’s sinus, lateral skull, and periapical films, showed destruction of bone in the floor of the left maxillary antrum and a large tissue mass on the medial wall of the sinus. Tomograms revealed destruction on the lower rim of the left orbit. The patient received cobalt therapy (4,440 to 5,370 rads over 35 days) to the left cheek, left nares, and left ethmoid labyrinth.After completion of the radiotherapy, no further treatment was indicated. Follow-up was maintained, and in March, 1971, the patient returned with a lesion of softball size in the pectoralis region of the left axilla. Supraclavicular nodes were also noted to be enlarged. Chemotherapy was initiated with vincristine, cyclophosphamide, and Allopurinol. The patient did not maintain his follow-up visits. When the patient returned, his maintenance dose of cyclophosphamide was increased. The patient died in September, 1972, with generalized metastasis. CASE
5
A
79-year-old woman was brought from a nursing home for evaluation of right facial and mandibular swelling. Her oral appearance showed a nonfluctuant swelling of the right midface, extending from the infraorbital area to the inferior border of the mandible. Intraorally, the patient was edentulous and a large mass was noted on the right side of the mandible along the crest of the ridge, obliterating the vestibule. The lesion was covered with mucosa except for two small round areas on top of the ridge that were fungating in appearance. Radiographs showed a pathologic fracture of the right body of the mandible with massive alveolar bone destruction (Fig. 6). Routine chest films showed enlargement of two nodules in the right lower lobe of the lung. Other routine laboratory studies including SMA-12, peripheral blood smears, and serum plasma electrophoresis were within normal limits. Biopsy report from the right mandible revealed histiocytin lymphoma (reticulum-cell sarcoma). The mandibular lesion was considered the primary lesion with metastatic lung involvement. Irradiation (4,400 rads) was given to the right mandible and the adjacent nodes in the
Volume Number
43 3
Fig. 6. Case 5: Pathologic destruction.
Histiocytic
fracture
in the right
body
of the mandible
right cervical chain over 31 days. The mandible appeared to be healing graphic standpoint. The patient was dismissed under the care of a physician and lost to follow-up.
lymphoma
with
alveolar
433
bone
well from a radioat a nursing home
DISCUSSION
Malignant lymphomas are classified according to histologic differentiation, transition from one cell type to another, and development into leukemic status. We categorized our casesunder Rappaport’s classification of the non-Hodgkin’s diffuse or non-Hodgkin’s nodular histiocytic type. Also, with the newer histologic classification of Lukes and Collins4 based on lymphocyte transformation, we attempted to reclassify some of our cases. Only one (case 1) could definitely be placed in one of the categories (large noncleaved). The other cases represent mixed cell type of lymphomas. Histiocytic lymphoma can affect any age group. However, soft-tissue involvement generally occurs in the elderly and primary bone involvement in the younger person.6 Symptoms are related to the site and extent of the tumor, which can obstruct or permeate adjacent structures. Patients may be asymptomatic for years until metastasesof the diseasegradually cause such systemic manifestations as anorexia, weight loss, night sweats, and pyrexia. All of our patients had swelling of the face or jawbones with a suspicion of odontogenic disease. Patient 5 presented with a fracture of the mandible and Patient 3 with a palatal ulcer. Teeth were extracted in three of the cases (Nos. 1, 2, and 4), but symptoms were still present several weeks to months later. Three patients complained of anesthesia in the facial and oral region (cases 1, 2, and 5), and all had moderate pain. Unless clinical examination showed obvious systemic or regional involvement, radiographs revealed only minor pathosis, such as thickening of the periodontal
434
Gline
and Stenger
Oral March,
Surg. 1977
ligament (case 1) and teeth abscesses(cases 2 and 4). The roentgenograms showed no special pathognomonic signs other than sometype of osteolytic activity (cases 4 and 5) and a pathologic fracture (case 5). Although malignant lymphomas are rare in the oral cavity, a tumor of any kind should be suspected when the cause of pain and swelling is uncertain. A clinical examination of the face should be made for signs of tumor involvement. Nasal obstruction (case 3) is common with maxillary sinus involvement. Because of immunosuppressive therapy, candidiasis and herpes zoster are not uncommon complications of histiocytic lymphoma.ll Leukemia may develop in the end stagesof the disease. The rarity of histiocytic lymphoma in the oral region, the variety of symptoms, the similarity of these symptoms to those of other disease,particularly inflammatory lesions, and the slow progress of the disease make establishment of the diagnosis difficult.7 Adequate specimens and biopsy are necessary for a definitive diagnosis. More extensive evaluation and repeated studies are indicated when suggested inflammatory diseaseis resistant to usual treatment (case 2). Under the classification of Lukes and Collins, both soft-tissue and bone histopathology show a cell larger than a lymphocyte, having a lobulated or indented nucleus, with one or more nucleoli. Reticulin or collagen fibers surround the individual cells or groups of cells, The fibers are well demonstrated on a reticulin stain, which is one of the definitive diagnostic criteria. Reticulin formation may be a more prominent feature of the osseouslesion. Treatment of early stages of the diseasewith irradiation followed by chemotherapy has brought total remission in several reported cases.” Two of our patients (cases2 and 3) are in remission. When systemic manifestations are present due to metastasis, palliative treatment with irradiation and chemotherapy prolong survival. However, side effects appear, and careful follow-up with the appropriate hematologic studies is essential. CONCLUSION Histiocytic lymphoma includes a variety of clinical manifestations. The most common symptom is persistent facial or oral swelling which is present for several weeks to months and often mimics an inflammatory process. The point of origin of the diseasecan be soft tissue or bone. Therefore, a thorough clinical and radiographic examination, along with appropriate laboratory studies, should be performed. Because the clinical and radiographic findings are generally not pathognomonic but only suggestive, a biopsy is necessary to establish the diagnosis. Occasionally, repeated biopsies may be needed when the initial report shows only inflammation. With continued research of the lymphomas, a more thorough understanding of this disease process is inevitable. Irradiation is the treatment of choice for early stagesof the disease,followed by chemotherapy if systemic manifestations exist. REFERENCES
1. Lukes, R. J.: Prognosis J. A. M. A. 222: 1294-1296, 2. Rubin, P.: Comment: The
and Relationship 1972. Non-Hodgkin’s
of
Histologic
Lymphomas,
Features
to
J. A. M. A. 223:
Clinical 175-178,
Stage, 1973.
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lymphoma
435
3. Aisenberg, A. C.: Immunoglobulins on the Surface of Human Lymphocytes, Hum. Pathol. 4: 301, 1973. 4. Lukes, R. J., and Collins, R. D.: Immunologic Characterization of Human Malignant Lymphomas, Cancer 84: 1488-1503, 1974. 5. Aisenberg, A. C.: Malignant Lymphomag, N. Engl. J. Med. ‘228: 883-890, 1973. 6. Beeson, P. B., McDermott, W., and Cecil, L.: Textbook of Medicine, ed. 13, Philadelphia, 1971, W. B. Saunders Company, pp. 1550-1564. 7. Shafer, W. G., Hine, M. K., and Levy, B. M.: A Textbook of Oral Pathology, ed. 3, Philadelphia, 1974, W. B. Saunders Company, pp. 170-178. 8. Robbins, S. L.: Pathology, ed. 3, Philadelphia, 1967, W. B. Saunders Company, pp. 662698 9. Craver, L. F., and Miller, D. G.: Lymphosarcoma, CA 16: 10-17, 1966. 10. Coley, B. L., Higinbotham, N. L., and Groesbeck, H. A.: Primary Reticulum-Cell Sarcoma of Bone, Radiology, 55: 641-658, 1950. 11. Harvey, A. M., Johns, R. J., Owens, A. H., and Ross, R. S.: Principles and Practices of Medicine, ed. 18, New York, 1972, Appleton-Century-Crofts, pp. 609-624. 12. Chaudhry, A. P., and Vickers, R. A.: Primary Reticulum-Cell Sarcoma of the Mouth: Report of Case, J. Oral Surg. 20: 159-162, 1962. 13. Gerry, R. G., and Williams, S. F.: Primary Reticulum-Cell Sarcoma of the Mandible, ORAL Suao. 8: 568-581,1955. 14. Worth, H. M.: Principles and Practices of Oral Radiographic Interpretations, ed. 3, 3, Chicago, 1963, Year Book Medical Publishers, Inc., pp. 547-595. 15. Halperin, 5. and Williams, A. C.: Reticulum-Cell Sarcoma of the Mandible, ORAL SURG. 28: 32-35, 1969. 16. Blake, M. N., and Beck, L.: Reticulum-Cell Sarcoma: Report of Case, J. Oral Surg. 21: 165-168, 1963. 17. Willis, R. A.: Pathology of Tumours, ed. 3, Washington, 1960, Butterworth & Company, Ltd., pp. 764-787. 18. Willis, R. A.: Pathology of Tumours, ed. 3, Washington, 1960, Butterworth & Company, Ltd., pp. 671-696. 19. Parker, F., Jr., and Jackson, H., Jr.: Primary Reticulum-Cell Sarcoma of Bone, Surg. Gvnecol. Obatet. 68: 45-53. 1939. 20. Topolnicki, W., and White, R. J.: Primary Reticulum-Cell Sarcoma of the Skull, Cancer 24: 569-573, 1969. 21. Moss, W. T., Brand, W. N., and Battifora, H.: Radiation Oncology, ed. 4, St. Louis, 1973, The C. V. Mosbv Comuanv. D. 549. 22. Boston, H. C., Jr., Dihl6; D. C., Ivins, J. C., and Cupps, R. E.: Malignant Lymphoma (so-called Reticulum-Cell Sarcoma) of Bone, Cancer 34: 1131-1137, 1974. 23. Rosenburg, 8. A,: Hodgkin’s Disease and Other Malignant Lymphomas, Calif. Med. 113: 23-38. 1970. 24. Rubin, P.: Comment: The Reclassification of Hodgkin’s Disease, J. A. M. A., 222: 13031306, 1972. Reprint requests to: Dr. Thomas G. Stenger Gundersen Clinic, Ltd. 1836 South Ave. La Crosse, Wis. 54601 or Dr. Robert E. Cline 1011 North 8 St. Sheboygan, Wis. 53081
of five cases
Robert E. Cl&e, D.D.S.,” La Crosse, Wis. LA
CROSSE
LUTHERAN
HOSPITAL
and Thomas G. Stenger, AND
GUNDERSEN
D.D.S.,
M.S.,*#
CLINIC
The subject of lymphomas is discussed and five cases seen in our Oral Surgery Department are presented. Histiocytic lymphoma, especially of the oral regions, can present with a variety of clinical manifestations. The signs and symptoms, diagnostic modalities, and treatment are discussed and the most recent classification is included.
M
alignant lymphomas are tumors of lymphoreticular tissues. They frequently arise in lymph nodes or in tissues rich with lymphoreticular cells, such as the tonsils, nasopharynx, gastrointestinal tract, spleen, liver, and bone. Less frequently they arise as primary tumors in such tissues as skin, gonads, or brain, pointing to the ubiquitous distribution of these cells. Lymphomas are divided into Hodgkin’s and non-Hodgkin’s groups. There have been reported revisions of the histologic classifications under each group. This paper is based on the most common classification by Rappaport (Tables I and II) .I, 2 Lukes and Collins revised Rappaport’s classification on t.he basis of research in immunobiology in which in vitro functional studies and immunofluorescent techniques resulted in recognition of B and T lymphocytes and of differences in their origin, structure, and function.3-5 A comparison of Lukes’ classification is given in Table III.4 The histologic classification and clinical staging of the disease have provided the clinician with valuable guidelines in treatment and prognosis. It is worth noting that the Rappaport and the Lukes and Collins classifications may not be valid with respect to primary bone lymphomas.22 We report five cases of malignant, lymphoma involving the oral structures, *Formerly **Chief
422
Senior Resident; of Dental Surgery.
now
at the Sheboygan
Clinic,
Sheboygan,
Wis.
Histiocytic
Volume 43 Number 3
lymphoma
423
Table I. Classification of Hodgkin’s lymphomas Nodular Sclerosing Locyte predominance Lvmohocvte deoletion
Table II. Classification of non-Hodgkin’s lymphomas Nodular Lymphocytic Poorly differentiated Well differentiated H$stztic Nodular sclerosing Diffuse Lymphocytic (lymphosarcoma) Poorly differenttated Well djfferentiated l$$cyt~ (rettculum-cell sarcoma) Stem
Table Ill. Comparison of classifications 1
Nodular Undifferentiated-
Rappuporr
1
Lukes and Collins
T\ICC..--Undefined cell
*Large noncleaved -1mmunoblastic sarcoma (B-cell) .Histiocvtic Unclassifiable ‘Lymphocytic
and histiocytic.
nose, and paranasal sinuses. The histologic diagnosis according to Rappaport’s classiflcation was “malignant lymphoma, histiocytic type: diffuse.” All showed intermediate degrees of differentiation (Fig. 1). HISTIOCYTIC LYMPHOMA Histiocytes are primitive cells that normally differentiate into other cell types, including hemocytoblasts, myeloblasts, and lymphocytes. Histiocytes are found in small numbers in normal persons, where they line the sinusoids of lymph nodes and are also found in bone marrow. When a neoplasm of histiocytes develops, they proliferate and no longer differentiate into other cell types. Histiocytic lymphoma is less common than other lymphomas. It occurs pre-
424
Cline
and Stenger
Oral March,
Surg. 1977
dominantly in men, with a ratio of 2 :l.“. 7 The diseasemay involve soft tissue or bone. Primary histiocytic lymphoma of soft tissues appears mainly in the elderly, whereas primary bone involvement is seen more commonly in the younger patient (30 to 50 years of age) .O Early signs of primary soft-tissue involvement include regional enlargement of lymph nodes or prominent extranodal tumors. Later a generalized involvement of many organ systems develops. Common sites of lymphatic origin are the tonsillar, cervical, mediastinal, retroperitoneal, gastrointestinal, or inguinal nodes. At surgery these nodes arc generally found to be discrete, white nodules up to 5 cm. in diameter. The tumor can permeate the capsule of the involved node to destroy the surrounding tissue.8 The disease tends to metastasize to regional lymph nodes rather than have multicentric primaries. Generally, the patient dies of a disseminated disease. Histiocytic lymphoma of soft tissue in the head and neck area usually originates in cervical lymph nodes or Waldeyer’s ring. Occasionally, it is seenin extranodal sites. Histiocytic lymphoma of the pharynx without cervical lymph node or bone involvement is a potentially curable tumor. Primary histiocytic lymphoma of bone has a more favorable prognosis because there is less tendency for the diseaseto metastasize.g Bones frequently involved are the vertebrae, pelvis, femur, ribs, and skull, with only occasional involvement of the maxilla and mandible. Clinical
features
The patient may initially present with malaise, fever, weight loss, hyperhydrosis, and pruritus. Enlarged lymph nodes are firm, fixed, and discrete.” They are generally not painful, unless there is overlying inflammation. Mediastinal or retroperitoneal nodal involvement may cause back pain or abdominal discomfort. Progressive bone involvement is painful and disability can develop. A systems review will reveal signs and symptoms associated with localized organ involvement. Mediastinal nodal involvement may produce coughing, substernal pain, dysphagia, and paralysis of the recurrent laryngeal nerve.6 Splenomegaly is not as common in histiocytic lymphoma as in the other lymphomas.” Retroperitoneal nodes may become enlarged and produce partial obstruction of the inferior vena cava with edema of the lower extremities.6 Hematologic disorders are uncommon during early stages of histiocytic lymphoma. As the diseaseinvolves ttie peripheral blood and bone marrow, however, associated leukemic disorders develop. 2 Also normochromic anemia may appear with progressive bone marrow failure. lo Viral infections, notably herpes zoster, and fungal infections occur occasionally. Such hematologic factors and infections, combined with systemic manifestations of fever, toxemia, and multiple lesion sites, lead to a poor prognosis. Enlargement of the involved bone is the most constant feature of histiocytic lymphoma of bone. Pain and disability are common and a pathologic fracture can occur with increasing bone destruction. Bone tumors usually remain localized initially without adjacent nodal involvement or early hematologic dissemination 1%21
Histiocytic
Fig. 2. Microscopic (Rematoxylin
Oral
and eosin
appearance of a diffuse stain. Magnification, x40.)
histiocytic
type
of
Zymphoma
malignant
425
lymphoma.
features
Primary histiocytic lymphoma of the soft tissues of the oral cavity is rare. Clinically, it usually manifests itself as a chronic, inflammatory process. It is often confused with periodontal disease, Vincent’s infection, or pericoronitis.12 Such confusion suggests that histiocytic lymphoma should be considered in a differential diagnosis if inflammatory lesions or surgical healing sites do not resolve. If there is paresthesia or anesthesia of the oral regions, a biopsy is definitely indicated. Oral manifestations of patients with histiocytic lymphoma may include herpes zoster, with the pain persisting for weeks or months. Since the nervous system is involved in 10 to 14 per cent of histiocytic lymphomas, cranial nerve palsies, especially with ocular, facial, and trigeminal nerve involvement, may occur.g Oral petechiae and bleeding from mucous membranes occur as a result of thrombocytopenia present in terminal stages of histiocytic lymphoma.s Primary facial bone involvement is also rare. Localized pain and bony destruction in an otherwise healthy patient are the most significant features.lO Gerry and Williams13 reported some cases in which they found pain to be the most prominent finding. Tooth mobility is common, but ulceration of the mucosa over the involved bone is rare. In addition to pathologic fractures of the mandible, local extension leads to involvement of the submandibular and cervical tissues. Extension beyond the maxilla leads to involvement of the maxillary sinuses and nasal cavity. Radiographic
features
Radiographic findings are not pathognomonic for histiocytic lymphoma, but a destructive radiolucency may suggest a malignant process. It is often as long as 3 years before oral radiographs show evidence of the disease.14A mandibular osteolytic lesion may be a direct extension of a primary lesion in soft tissue.
426
Cline and Xtenger
Oral March,
Surg. 1977
Roentgenographic examination of long bones in patients with histiocytic lymphoma is a more valuable adjunct to diagnosis than roentgenographs of the jaw bones.14 Radiographic examination of primary histiocytic lymphoma of the mandible often reveals periosteal elevation, an increased radiolucency of the bone, and some soft tissue en1argement.15 Pathologic fracture and fragmentation of the cortex due to expansion of bone can result. Worth14 described the mandibular lesion as similar to a myxoma without the definitive margins of a benign tumor. When there is little osteoblastic reaction and lack of well-delineated boundaries, a mottled appearance can be present. Sinus tumors may show dense opacity, although their bony walls may show little or no destruction. Histopathology
Microscopically, there is a diffuse growth of histiocytes with obliteration of normal structures. The cells vary in shape and are pleomorphic with oddly shaped, elongated pseudopods of the nucleus and cytoplasm.* The cells are larger than lymphocytes with abundant and faintly acidophilic cytoplasm and large nucleoli that are somewhat vacuolated. I6 The nucleus is often twice the size of that of a lymphocyte and is frequently kidney shaped.16The rate of mitotic activity is great and numerous mitotic figures can be seen permeating the capsules of lymph nodes and invading the surrounding tissues, including walls of veins. Multinucleated cells are common and on occasion resemble the Reed-Sternberg ce11.7 Histiocytic lymphoma may stimulate fibroblastic production of reticulin, which can be detected by special silver impregnation.* Reticulin is abundantly laid down between individual-and clusters of-histiocytes. When bone is involved, the tumor is almost always of the nodular type, and reticulin formation is a prominent feature. This latter fact may be lacking in histiocytic lymphoma of the soft tissues. An increase in reticulin is not found in lymphoblastomas and carcinomas. The histopathology of primary histiocytic lymphoma of bone is very similar to that of soft tissue, except for the reticulin formation. Many times the tissues overlying the involved bone can be confused with an inflammatory lesion,7,I7 which adds to the difficulty in diagnosis. Microscopically, Hodgkin’s disease, plasmacytoma, and Ewing’s sarcoma have also been mistaken for histiocytic lymphoma.i, 9, I8 Because the identification of the histiocyte is difficult, Lukes and Collins revised Rappaport’s classification. Their classification of malignant lymphomas is based on the B- and T-cell systems and changes in lymphocytic transformation (B cell-bursal equivalent-thymic independent or humoral immunity ; T cellthymic dependent-or cellular immunity) .4 According to their classification most of the histiocytes (reticulum cells) cannot be differentiated from transformed lymphocytes. Retrospective studies have shown this to be true. As noted from the classification (Table III), the majority of lymphomas (nodular and diffuse non-Hodgkin’s) have the cytologic features of the follicular center cell (FCC).”
Volume Number
Histiocytic
43 3
Zymphoma
427
The lymphomas of FCC are divided according to the cell size type: (1) small cleaved, (2) small noncleaved, (3) large cleaved, (4) large noncleaved. DIAGNOSIS
Microscopic examination is required to establish the diagnosis of histiocytic lymphoma. However, early in the course of the disease histologic changes may not be distinctive. Radiographs, thorough history, clinical examination, and lymphangiography are valuable adjuncts to determine the extent of the disease and the subsequent treatment. ** Hematologic studies, including complete blood count (CBC) and platelet count, along with bone marrow smears, can help determine the extent of the disease, especially if a leukemic transformation is suspected. Histiocytic lymphoma has also been reported to develop in renal transplant patients on long-term immunosuppressives and in patients on immunocytotoxic agents from rheumatoid arthritis and lupus erythematosus.” Although similar histologically to soft-tissue lesions, there are primary lesions of bone as pointed out and differentiated from Ewing’s sarcoma in 1939 by Parker and Jackson.ls When the tumor is of bony origin, the patient can remain in good health even though the tumor has reached a fairly good size. The long bones, especially the femur, are more commonly affected, but there can be involvement of ribs, scapula, mandible, maxilla, and parts of the vertebral co1umn.2o An SMA-12 is routinely obtained, which generally shows an increase in enzymes such as alkaline phosphatase and a hypercalcemia. Bone scanning with radioisotopes can be a helpful adjunct. Coley, Higinbotham, and Groesbeck’Ooutlined a clinical and roentgenographic differential diagnosis for histiocytic lymphoma of bone that includes: osteogenic sarcoma, Ewing’s sarcoma, secondary bone involvement by lymphosarcoma, chronic osteomyelitis, metastatic carcinoma, eosinophilic granuloma, metastatic neuroblastoma, malignant giant-cell tumor, myeloma, and Paget’s diseaseof bone. Soft-tissue biopsy of oral lesions can be confused with inflammatory lesions such as periodontitis, Vincent’s infections, and ulcer formation. Further investigation, including repeated biopsies, is necessary if an extraction site does not heal. Anesthesia or paresthesia of the lips or gingiva along with intra- or extraoral swelling may be the only clinical manifestations present. Treatment
and
prognosis
Treatment for early stages of the diseaseis best managed by irradiation. Because there is good local control rate with megavoltage radiotherapy, surgical treatment is unnecessary in the majority of cases.2oA dosage of 4,500 to 5,000 rads over 4 to 5 weeks should bring resolution of the tumor.ll The more curable lesions are those of the tonsils, nasopharynx, or bone.6y21If the white blood count falls below 2,000 or platelets below 50,000, treatment should be temporarily interrupted.O Radiographs of irradiated bone show new bone forming, but the trabecular pattern is altered from that of normal bone.14 Chemotherapy is used when systemic manifestations are severe and the disease widespread. Treatment generally involves radiation therapy to destroy the obvious lesions followed by chemotherapy to maintain remission. Alkylating
420
Fig. extracted widening
Cline
and Stenger
8. Case 1: Arrows point to the left canine several weeks prior to biopsy in the same of the periodontal ligament.
Oral March,
tooth (Panorex radiograph) area for histiocytic lymphoma;
Surg. 1977
which note
was the
agents, vincristine and cyclophosphamide (Cytoxan), can be used with fairly good results, although response rates are lower than in Hodgkin’s diseaseor lymphosarcoma.I* Chemotherapy usually brings remission in 6 to 8 weeks.‘l Cyclophosphamide. has several toxic manifestations, including hair loss, nausea, vomiting, and hematuria. Vincristine is useful for remission and is used when other alkylating agents have lost their effectiveness.G There can be side effects such as toxic neuropathy and paresthesia of t,he deep tendon reflexes.G As with other lymphomas, adrenal corticosteroids (prednisone) have a lympholytic effect and also are used to alleviate autoimmune hemolytic anemias and thrombocytopenia. One possible chemotherapeutic regimen is cyclophosphamide (15 mg. per kilogram per week), vincristine (0.025 mg. per kilogram intravenously per week), and prednisone (0.6 mg. per kilogram orally per day) administered over 6 weeks.” Prognosis depends on the stage of the diseaseand whether there is soft tissue or bone involvement. Histiocytic lymphoma of bone doeshave a higher curability rate than that of soft tissue. In all stages, the prognosis for women is better than for men.ll Histiocytic lvmphoma, as with other non-Hodgkin’s lymphomas, can be staged under the sa& classifications as Hodgkin’s disease.But unlike Hodgkin’s disease, prognosis can be correlated better according to the histopathologic subtype rather than clinical staging.2” The Ann Arbor reclassification for Hodgkin’s is as follows :24 Stage I: Disease limited to one anatomic region or a localized extralymphatic organ or site. Stage ZZ: Disease in two or more anatomic regions on the same side of the diaphragm or solitary involvement of an extralymphatic organ or site of
Histiocytic Table IV. Clinical data of five patients sarcoma) of the head and neck region Pr. 1 Anesthesia Swelling
Radiolucency
Abscessed teeth or periodontitis Pain Fever Trismus Ulceration Inflammation
with histiocytic
Pt. 2
Yes (area of No. Ill Yes r
lymphoma
lymphoma
Pt. 3
429
(reticulum-cell
Pt. 4
Pt. 5
Yes
No
No
No
Yes (Right cheek)
Yes (lumps on both sides of neck and swelling of nose) No thickening 0 r sinus lining)
Yes (left side of face)
Yes (right side of face)
Yes
Yes (pathologic fracture; alveolar bone destruction)
Yes
No
Yes
No; edentulous
No
Yes
Yes No No Yes (ulcer-like lesion on midline of palate) Yes
Yes
E No
Yes No Yes No
Yes No Yes Yes (fungating lesion of left alveolar ridge) Yes
No-except widening /?eg$$al cloudy Yes Yes
for of
No
sinus
ii: No Yes
one or more lymph node regions on the same side of the diaphragm. Spleen may be involved in case of localization below diaphragm. Stage III: Disease in anatomic regions on both sides of the diaphragm, may be accompanied by involvement of spleen or by localized involvement of an extralymphatic organ or site or both. Stage IV: Diffuse or disseminated involvement of one or more extralymphatic organs or tissues with or without associated lymph node involvement. CASE REPORTS CASE
1
A 66-year-old man presented with mobility of the left maxillary canine, anesthesia, and localized swelling in the anterior maxillary mucobuccal fold. Periapical and Panorex films were unremarkable except for some widening of the periodontal membrane around the canine (Fig. 2). The tooth was extracted because of its extreme mobility. Biopsy was not considered necessary at this time (see Table IV). The patient returned in 4 weeks with persistent swelling in the area and was evaluated in the otolaryngology department for possible chronic sinusitis. Straw-colored fluid was aspirated from the left antrum. A culture and sensitivity tests were done. Alpha-streptococcus and Neiaseria were cultured, and the patient was placed on appropriate antibiotics. Two weeks later the swelling remained, and a firm left parotid mass was noted. Biopsy of the left maxillary antrum revealed histiocytic lymphoma (reticulum-cell sarcoma). Additional investigation showed that the lymphoma involved the left ethmoid labyrinth, left parotid and submaxillary glands, and cervical nodes. Radiation therapy was started, but during this time the patient continued to deteriorate. One month after the therapy, a low-grade fever, mucositis, bilateral levator veli paralysis, fatty stools, and bloody emesis developed. Anemia developed (hemoglobin 7.1; hematocrit 21 per cent), and esophagoseopy and gastroscopy revealed infiltrative histocytic lymphoma (reticulum-cell sarcoma). Because of the systemic nature of the disease, only supportive measures were taken. The
430
Cline and Stenger
Fig. 8. Case 2: Panorex biopsy
was taken
patient adrenal CASE
for
died 4 months glands, kidneys,
histiocytic
Oral March,
radiograph, lymphoma.
after the and lungs.
diagnosis
essentially
was
unremarkable,
made
with
showing
metastatic
the
involvement
area
Burg. 1977
where
of
the
2
A 72-year-old woman presented to the clinic 5 weeks after the mandibular right premolar was extracted by her local dentist. Her initial complaint was numbness and pain in the mandibular right extraction site. Other than some minor protuberances of buccal bone around the extraction site, results of the intraoral examination were normal. At her next visit, she complained of persistent discomfort in the extraction area. There was extreme tenderness of the alveolar crest distal to the site with protrusion of a small mass of yellowish tissue. A biopsy was performed under local anesthesia, and the report showed chronic inflammation and fibrosis. Three succeeding visits followed within the next 4 months, and the last one revealed a diffuse swelling involving the right submandibular and right buccal space. A Panorex film was essentially unremarkable except for several remaining periodontally involved teeth (Fig. 3). A diagnosis of cellulitis subsequent to periapical pathology was made, and the patient was placed on penicillin. An intraoral incision and drainage (I & D) was done with only a minimal amount of purulent discharge. The culture and sensitivity report revealed alpha-streptococcus sensitive to penicillin. Throughout the next month, the numbness of the right lower lip persisted, and a firm swelling remained on the lateral border of the right mandible. A developing osteomyelitis was considered at this time. Radiographs demonstrated no osteolytic activity. Seven months .after her initial presentation to the clinic and 3 weeks after her last visit, she again presented with persistent swelling and numbness. Radiographs showed possible elevation of periosteum at the inferior border of the right mandible. No evidence of fluctuance was noted. The white blood count at this time was 5,100. The patient WBS subsequently taken to the operating room where a through-and-through drainage was done. Culture and sensitivity revealed alpha-hemolytic streptococcus, and the patient was maintained on antibiotics. Soft tissue and bone biopsy in the right mandibular region revealed inflammatory granulation tissue and sclerotic bone consistent with healed osteomyelitis. Her course continued to improve for the next 2 months with decreasing trismus and anesthesia of the right lower lip. On her return visit, swelling was noted in the right mandibular area. An I & D was performed at this time under local anesthesia, and a considerable amount of necrotic tissue was biopsied. The findings revealed histiocytic lymphoma (reticulum-cell sarcoma).
Histiocytic
Fig. the right
4. Case maxillary
Treatment cyclophosphamide of 3% years. CASE
3: Water’s view sinus region.
was
irradiation and prednisone.
of
sinus
revealing
increased
(5,000 rads over 5 weeks) She has had no recurrence
cloudiness
followed by and is well
lymphoma
and
radiopacity
431
in
chemotherapy of with a remission
3
A 72-year-old woman came to the clinic with complaints of lumps on both sides of her neck and difficulty in breathing through the right nostril of approximately 6 weeks’ duration. The patient had a weight loss of 2.6 kilograms over this period, and a local physician had diagnosed her condition as mumps. The nose appeared swollen and erythematous. Removal of her upper denture disclosed a necrotic, ulcerlike lesion on the midline of the palate. Panorex films and tomograms revealed a thickened lining and two pedunculated masses of the right maxillary sinus along with cloudiness of the right ethmoid sinus (Fig. 4). There was no evidence of bone destruction. Differential diagnosis at this time included midline lethal granuloma, Wegner’s granuloma, histiocytic lymphoma, lymphoepithelioma, and squamous-cell carcinoma. A biopsy of the maxillary sinus showed histiocytic lymphoma (reticulum-cell sarcoma). The patient was placed on radiation therapy for histiocytic lymphoma of the nasopharynx, right antrum, hard and soft palates, and lymph nodes of the anterior cervical chain bilaterally. Because of metastases to the breast and parts of the maxilla, chemotherapy consisting of vincristine, cyclophosphamide, and prednisone was instituted. The patient has been in remission for 3% years. CASE
4
An do-year-old man came to the clinic in January, 1970, with swelling of the left side of the face of several weeks’ duration. One week earlier, his physician had placed him on tetracycline because of the purulent material draining from the sinuses. Panographic films and oral examination revealed a horizontally impacted left maxillary
432
Oral March,
Chine and Stenger
Fig. 5. Case 4: Horizontally impacted graph. Note the radiolucency around the root
left maxillary of the canine
canine tooth.
as seen on Panorex
Surg. 1977
radio-
canme and massive swelling in the maxillary left labial sulcus (Fig. 5). The tooth was removed along with extensive amounts of heavy fibrous-type scar tissue. The biopsy of the surrouzfding tissue revealed histiocytic lymphoma (reticulum-cell sarcoma). Further radiographs, including Water’s sinus, lateral skull, and periapical films, showed destruction of bone in the floor of the left maxillary antrum and a large tissue mass on the medial wall of the sinus. Tomograms revealed destruction on the lower rim of the left orbit. The patient received cobalt therapy (4,440 to 5,370 rads over 35 days) to the left cheek, left nares, and left ethmoid labyrinth.After completion of the radiotherapy, no further treatment was indicated. Follow-up was maintained, and in March, 1971, the patient returned with a lesion of softball size in the pectoralis region of the left axilla. Supraclavicular nodes were also noted to be enlarged. Chemotherapy was initiated with vincristine, cyclophosphamide, and Allopurinol. The patient did not maintain his follow-up visits. When the patient returned, his maintenance dose of cyclophosphamide was increased. The patient died in September, 1972, with generalized metastasis. CASE
5
A
79-year-old woman was brought from a nursing home for evaluation of right facial and mandibular swelling. Her oral appearance showed a nonfluctuant swelling of the right midface, extending from the infraorbital area to the inferior border of the mandible. Intraorally, the patient was edentulous and a large mass was noted on the right side of the mandible along the crest of the ridge, obliterating the vestibule. The lesion was covered with mucosa except for two small round areas on top of the ridge that were fungating in appearance. Radiographs showed a pathologic fracture of the right body of the mandible with massive alveolar bone destruction (Fig. 6). Routine chest films showed enlargement of two nodules in the right lower lobe of the lung. Other routine laboratory studies including SMA-12, peripheral blood smears, and serum plasma electrophoresis were within normal limits. Biopsy report from the right mandible revealed histiocytin lymphoma (reticulum-cell sarcoma). The mandibular lesion was considered the primary lesion with metastatic lung involvement. Irradiation (4,400 rads) was given to the right mandible and the adjacent nodes in the
Volume Number
43 3
Fig. 6. Case 5: Pathologic destruction.
Histiocytic
fracture
in the right
body
of the mandible
right cervical chain over 31 days. The mandible appeared to be healing graphic standpoint. The patient was dismissed under the care of a physician and lost to follow-up.
lymphoma
with
alveolar
433
bone
well from a radioat a nursing home
DISCUSSION
Malignant lymphomas are classified according to histologic differentiation, transition from one cell type to another, and development into leukemic status. We categorized our casesunder Rappaport’s classification of the non-Hodgkin’s diffuse or non-Hodgkin’s nodular histiocytic type. Also, with the newer histologic classification of Lukes and Collins4 based on lymphocyte transformation, we attempted to reclassify some of our cases. Only one (case 1) could definitely be placed in one of the categories (large noncleaved). The other cases represent mixed cell type of lymphomas. Histiocytic lymphoma can affect any age group. However, soft-tissue involvement generally occurs in the elderly and primary bone involvement in the younger person.6 Symptoms are related to the site and extent of the tumor, which can obstruct or permeate adjacent structures. Patients may be asymptomatic for years until metastasesof the diseasegradually cause such systemic manifestations as anorexia, weight loss, night sweats, and pyrexia. All of our patients had swelling of the face or jawbones with a suspicion of odontogenic disease. Patient 5 presented with a fracture of the mandible and Patient 3 with a palatal ulcer. Teeth were extracted in three of the cases (Nos. 1, 2, and 4), but symptoms were still present several weeks to months later. Three patients complained of anesthesia in the facial and oral region (cases 1, 2, and 5), and all had moderate pain. Unless clinical examination showed obvious systemic or regional involvement, radiographs revealed only minor pathosis, such as thickening of the periodontal
434
Gline
and Stenger
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Surg. 1977
ligament (case 1) and teeth abscesses(cases 2 and 4). The roentgenograms showed no special pathognomonic signs other than sometype of osteolytic activity (cases 4 and 5) and a pathologic fracture (case 5). Although malignant lymphomas are rare in the oral cavity, a tumor of any kind should be suspected when the cause of pain and swelling is uncertain. A clinical examination of the face should be made for signs of tumor involvement. Nasal obstruction (case 3) is common with maxillary sinus involvement. Because of immunosuppressive therapy, candidiasis and herpes zoster are not uncommon complications of histiocytic lymphoma.ll Leukemia may develop in the end stagesof the disease. The rarity of histiocytic lymphoma in the oral region, the variety of symptoms, the similarity of these symptoms to those of other disease,particularly inflammatory lesions, and the slow progress of the disease make establishment of the diagnosis difficult.7 Adequate specimens and biopsy are necessary for a definitive diagnosis. More extensive evaluation and repeated studies are indicated when suggested inflammatory diseaseis resistant to usual treatment (case 2). Under the classification of Lukes and Collins, both soft-tissue and bone histopathology show a cell larger than a lymphocyte, having a lobulated or indented nucleus, with one or more nucleoli. Reticulin or collagen fibers surround the individual cells or groups of cells, The fibers are well demonstrated on a reticulin stain, which is one of the definitive diagnostic criteria. Reticulin formation may be a more prominent feature of the osseouslesion. Treatment of early stages of the diseasewith irradiation followed by chemotherapy has brought total remission in several reported cases.” Two of our patients (cases2 and 3) are in remission. When systemic manifestations are present due to metastasis, palliative treatment with irradiation and chemotherapy prolong survival. However, side effects appear, and careful follow-up with the appropriate hematologic studies is essential. CONCLUSION Histiocytic lymphoma includes a variety of clinical manifestations. The most common symptom is persistent facial or oral swelling which is present for several weeks to months and often mimics an inflammatory process. The point of origin of the diseasecan be soft tissue or bone. Therefore, a thorough clinical and radiographic examination, along with appropriate laboratory studies, should be performed. Because the clinical and radiographic findings are generally not pathognomonic but only suggestive, a biopsy is necessary to establish the diagnosis. Occasionally, repeated biopsies may be needed when the initial report shows only inflammation. With continued research of the lymphomas, a more thorough understanding of this disease process is inevitable. Irradiation is the treatment of choice for early stagesof the disease,followed by chemotherapy if systemic manifestations exist. REFERENCES
1. Lukes, R. J.: Prognosis J. A. M. A. 222: 1294-1296, 2. Rubin, P.: Comment: The
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3. Aisenberg, A. C.: Immunoglobulins on the Surface of Human Lymphocytes, Hum. Pathol. 4: 301, 1973. 4. Lukes, R. J., and Collins, R. D.: Immunologic Characterization of Human Malignant Lymphomas, Cancer 84: 1488-1503, 1974. 5. Aisenberg, A. C.: Malignant Lymphomag, N. Engl. J. Med. ‘228: 883-890, 1973. 6. Beeson, P. B., McDermott, W., and Cecil, L.: Textbook of Medicine, ed. 13, Philadelphia, 1971, W. B. Saunders Company, pp. 1550-1564. 7. Shafer, W. G., Hine, M. K., and Levy, B. M.: A Textbook of Oral Pathology, ed. 3, Philadelphia, 1974, W. B. Saunders Company, pp. 170-178. 8. Robbins, S. L.: Pathology, ed. 3, Philadelphia, 1967, W. B. Saunders Company, pp. 662698 9. Craver, L. F., and Miller, D. G.: Lymphosarcoma, CA 16: 10-17, 1966. 10. Coley, B. L., Higinbotham, N. L., and Groesbeck, H. A.: Primary Reticulum-Cell Sarcoma of Bone, Radiology, 55: 641-658, 1950. 11. Harvey, A. M., Johns, R. J., Owens, A. H., and Ross, R. S.: Principles and Practices of Medicine, ed. 18, New York, 1972, Appleton-Century-Crofts, pp. 609-624. 12. Chaudhry, A. P., and Vickers, R. A.: Primary Reticulum-Cell Sarcoma of the Mouth: Report of Case, J. Oral Surg. 20: 159-162, 1962. 13. Gerry, R. G., and Williams, S. F.: Primary Reticulum-Cell Sarcoma of the Mandible, ORAL Suao. 8: 568-581,1955. 14. Worth, H. M.: Principles and Practices of Oral Radiographic Interpretations, ed. 3, 3, Chicago, 1963, Year Book Medical Publishers, Inc., pp. 547-595. 15. Halperin, 5. and Williams, A. C.: Reticulum-Cell Sarcoma of the Mandible, ORAL SURG. 28: 32-35, 1969. 16. Blake, M. N., and Beck, L.: Reticulum-Cell Sarcoma: Report of Case, J. Oral Surg. 21: 165-168, 1963. 17. Willis, R. A.: Pathology of Tumours, ed. 3, Washington, 1960, Butterworth & Company, Ltd., pp. 764-787. 18. Willis, R. A.: Pathology of Tumours, ed. 3, Washington, 1960, Butterworth & Company, Ltd., pp. 671-696. 19. Parker, F., Jr., and Jackson, H., Jr.: Primary Reticulum-Cell Sarcoma of Bone, Surg. Gvnecol. Obatet. 68: 45-53. 1939. 20. Topolnicki, W., and White, R. J.: Primary Reticulum-Cell Sarcoma of the Skull, Cancer 24: 569-573, 1969. 21. Moss, W. T., Brand, W. N., and Battifora, H.: Radiation Oncology, ed. 4, St. Louis, 1973, The C. V. Mosbv Comuanv. D. 549. 22. Boston, H. C., Jr., Dihl6; D. C., Ivins, J. C., and Cupps, R. E.: Malignant Lymphoma (so-called Reticulum-Cell Sarcoma) of Bone, Cancer 34: 1131-1137, 1974. 23. Rosenburg, 8. A,: Hodgkin’s Disease and Other Malignant Lymphomas, Calif. Med. 113: 23-38. 1970. 24. Rubin, P.: Comment: The Reclassification of Hodgkin’s Disease, J. A. M. A., 222: 13031306, 1972. Reprint requests to: Dr. Thomas G. Stenger Gundersen Clinic, Ltd. 1836 South Ave. La Crosse, Wis. 54601 or Dr. Robert E. Cline 1011 North 8 St. Sheboygan, Wis. 53081
