Primary Malignant Melanoma of the Lower Respiratory Tract Report of a Case and Literature Review
TIMOTHY A. JENNINGS, M.D., CONSTANTINE A. AXIOTIS, M.D., YVONNE KRESS, M.S., AND DARRYL CARTER, M.D.
MALIGNANT MELANOMA (MM) HAS been described very rarely as a primary tumor in the lower respiratory tract (LRT). Many previously reported cases are considered to represent solitary metastases of occult or regressed primary cutaneous MM. 12 Criteria to exclude an extrapulmonary origin have been developed that permit acceptance of primary MM of the LRT (PMMLRT). We document a case of PMMLRT that meets these criteria, discuss the differential diagnostic and histogenetic implications, and review the relevant literature.
Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut
lower lung field and decreased left lung volume. At examination with flexible and rigid bronchoscopes, a fleshy, yellow, focally eroded tumor was noted to occlude the left mainstem bronchus at the level of the junction of the upper and lower lobar bronchi, with no significant bleeding after biopsies. After the pathologic diagnosis of MM, scrupulous ophthalmologic and dermatologic examinations were performed. A 34-mm blue-black papule on the left posterior thigh was discovered and biopsied. This tissue showed typical morphologic characteristics of a capillary hemangioma; no melanocytic nevus cells were demonstrated. She denied prior excision or fulguration of any skin lesion. On March 12, 1987, she underwent left pneumonectomy with mediastinal lymph node dissection, with an uncomplicated postoperative course. Additional studies included chest and abdominal-pelvic computerized axial tomography scans and upper gastrointestinal series with small bowel follow through, which were negative. Abdominal pelvic ultrasonography demonstrated a right adnexal cyst, which had resolved on repeat ultrasonography. Barium enema had negative results, and colonoscopic examination showed only an 8-mm sigmoid polyp. No other therapy was given. Repeat ophthalmologic examination one year after the operation also had negative results. Follow-up in several outpatient clinics revealed no evidence of recurrent disease at 14 months after surgery. However, at 19 months she was found to have an enlarged left adrenal gland; percutaneous thinneedle aspiration was performed. No other recurrent disease was demonstrable at this time. Pathology
Report of a Case A 34-year-old Hispanic woman was admitted to the Bronx Municipal Hospital Center in February 1987 for presumed recurrent bronchitis unresponsive to oral antibiotics. History was significant only for enucleation of her right eye at age two years resulting from traumatic injury, and for cone biopsy in 1985 for cervical carcinoma in situ. She had a 35 pack-year history of cigarette smoking. Family history was noncontributory. Chest roentgenogram (Fig. 1) showed opacification of the left
Received December 21, 1989; accepted for publication January 30, 1990. Dr. Axiotis' current address is Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland 20892. Address reprint requests to Dr. Jennings: Department of Pathology and Laboratory Medicine, A-81, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208.
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. Superficial endoscopic biopsies showed an eroded bronchial mucosa with focal squamous metaplasia. Fragments of predominantly necrotic submucosal tumor were present; the neoplasm comprised nests and cords of epithelioid cells with abundant clear to eosinophilic cytoplasm with focal finely granular pigment. The nuclei varied in size, with a rare giant cell, and had small nucleoli; a rare intranuclear inclusion was evident. Mitotic figures were numerous. Abundant coarsely granular brown pigment was present in aggregates of macrophages and extracellularly. Special stains for argyrophilic (Grimelius) and argentaffin (Fontana-Masson, Fig. 2) material were strongly positive in tumor cells and macrophages; iron and mucin stains were negative.
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The authors report a case of primary bronchial malignant melanoma, occurring in a 34-year-old woman presenting with persistent cough. At bronchoscopic examination, a polypoid mass was found to occlude the left mainstem bronchus. Biopsies showed a malignant epithelioid tumor resembling an atypical carcinoid. Histochemistry, electron microscopic study, and immunohistochemistry confirmed the diagnosis of melanoma. Physical examination and additional clinical history to exclude other possible primary sites were negative. The patient underwent thoracotomy with left pneumonectomy. Nineteen months after resection she was found to have a histologically similar tumor involving her left adrenal gland. Review of the literature shows that melanoma of the lower respiratory tract has been reported only in adults and has a tendency to present as a central polypoid growth that may be responsive to surgical resection. (Key words: Melanoma; Carcinoid; Bronchus; Respiratory tract; Electron microscopy; Immunohistochemistry) Am J Clin Pathol 1990;94: 649-655
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FIG. 1 (upper, left). Posterior-anterior (PA) chest film showing opacification of left lower lung. FIG. 2 (upper, right). Granular cytoplasmic argentaffin positivity within tumor cells. Fontana-Masson (X400). FIG. 3 (lower). Gross photograph of pneumonectomy specimen with pigmented tumorfillinglingular bronchus.
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were noted within bronchial respiratory epithelium (Fig. 5), but no benign junctional melanocytes were demonstrated. Ultrastructurally the tumor cells were round to polyhedral, with rare membrane attachments. Cytoplasmic organelles included numerous mitochondria, cisternae of predominantly smooth endoplasmic reticulum, and many pigment-laden bodies, most of which appeared to be lysosomal. However, many other round and fusiform structures had heterogeneous electron-dense areas, and, in an occasional cell, some showed vaguely fibrillar or lamellar internal structure, suggestive of aberrant14 melanosomes (Fig. 6). No neurosecretory granules were demonstrated. Immunohistochemistry showed strongly positive cytoplasmic staining of tumor cells with antibodies to S100 protein (Biogenex polyclonal, undiluted, after trypsin) and HMB 45 (Enzo monoclonal, 1:4,000, without enzyme pretreatment). Grimelius and Fontana-Masson stains were also positive. Immunohistochemistry results for chromogranin (Lipshaw), neuron-specific enolase (DAKO), calcitonin (DAKO), keratin (AE1/AE3, Hybritech), and epithelial membrane antigen (DAKO) were negative, as was the Sevier-Munger stain. No staining was observed in either the antibody or tissue specificity controls. Review of her cervical punch and cone biopsy material showed cervical intraepithelial neoplasia, grade 3, without evidence of melanocytic elements. Records relating to her orbital enucleation in 1955 were not available. Aspiration biopsy material from the left adrenal mass showed a malignant epithelioid tumor with abundant intracellular argentaffin pigment. Discussion
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FlG. 4. Intraluminal growth of melanoma involving bronchial submucosa. Hematoxylin and eosin (XI6).
Primary malignant melanoma of the lower respiratory tract is extremely rare, with only 19 previously reported cases fulfilling minimal criteria to exclude a more likely primary site. Specific criteria include the following: (1) no previously removed skin lesion, particularly pigmented; (2) no ocular tumors removed and no enucleation; (3) solitary tumor; (4) tumor morphologic characteristics compatible with a primary tumor (thus, considerable polymorphism favors a metastasis); (5) no demonstrable melanoma in other organs at the time of operation; and (6) autopsy without primary melanoma being demonstrated elsewhere, more particularly in the skin or eyes.21 Although these criteria are entirely appropriate, it is clear that there are instances in which they may not or cannot all be satisfied. The current case is such an example, having fulfilled these criteria with the exception of postmortem examination and of prior enucleation,
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The resection specimen consisted of a left lung showing incomplete lobation and weighing 248 g. The pleural surface in the hilar area was black and indurated, corresponding to the dimensions of the underlying tumor. No pleural involvement by tumor was evident grossly. Initial bronchial dissection disclosed a brown-black, focally eroded endobronchial mass occupying the left mainstem bronchus approximately 1 cm from the margin of resection; both lobar bronchi were obstructed but easily probed. Further dissection showed the tumor to fill the lingular bronchus (Fig. 3), to extend into and superficially through the bronchial wall in this area, and to measure up to 7.9 X 4.2 cm. Changes of organizing postobstructive pneumonia were seen in the lingula and lower lobe. Multiple peribronchial and mediastinal lymph nodes were enlarged and brown-black in color, without gross tumor involvement. Histologically, the tumor was predominantly submucosal and endobronchial (Fig. 4), but it destroyed bronchial cartilage and extended in a circumscribed fashion into superficial peribronchial soft tissues multifocally. Other microscopic features of the tumor were similar to those in biopsy tissue, with an exclusively epithelioid growth and prominent pigmentation. Focally tumor cells
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FlG. 5 (upper). Intramuscosal melanoma cells with intact basement membrane. Hematoxylin and eosin (X400). FIG. 6 (lower). Aberrant melanosomes within cytoplasm of tumor cell (X90,000).
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The adrenal tumor in the current case is considered to represent a metastasis from the lung, inasmuch as the adrenal is the most common site of extranodal metastasis from pulmonary primary malignancies. Primary adrenal melanoma has been reported but is even less common and more controversial than those of the LRT. 9 The gross and microscopic features of the tumor provide additional evidence supporting primary origin in the LRT. The malignancy should be solitary, and most are polypoid, intraluminal growths. If metastases are present, they must be in a pattern consistent with spread from the presumed primary. Histologic criteria3 involve those used to establish a melanoma as primary in any location: (1) junctional change with "dropping ofF' of melanoma cells;
(2) invasion of (bronchial) epithelium by the melanoma cells in an area that is not eroded; and (3) an obvious melanoma underlying these intraepithelial changes. Intramucosal tumor cells were demonstrable in the current case, although no benign melanocyte element (melanosis) was seen. Generally, however, these tumors show vertical, nodular growth that may obscure these features. We found only 19 prior cases'.2.4-7.9.13..5.25-28.32.33.37.39 reported as PMMLRT acceptable. Other reports are problematic or unlikely because of either a history of antecedent cutaneous melanoma, 29 prior intraoral melanoma, 3 subsequent ocular melanoma,41 lack of histologic examination of clinically documented pigmented skin lesions,20 or inadequate8'21'23'38 or absent34 clinical and pathologic information. The case reported by Walter and associates40 is considered doubtful because of the presence of multiple peripheral pulmonary nodules. Rare cases of melanotic tumors with exclusively spindle cell growth include a case reported as malignant melanotic schwannoma, 31 which may rather be an example of primary bronchial melanoma but that is not included in our summary. Analysis of these 20 cases (Table 1) shows that the tumor occurred only in adults, ranging in age from 29 to 80 years, with 11 being male and 9 female. Only one black patient has been reported. The origin was tracheal or carinal in four patients, and the remaining 16 bronchial primary melanomas were distributed in all lobes. Of the 17 cases with adequate description, 11 lesions arose centrally. Ten of 19 had intraluminal growth, and an additional 2 tracheal primary melanomas were flat lesions.
Table 1. Data from Reported Cases of PMMLRT Case (reference)
Sex
Age
Race
Site
IL
1(1) 2(2) 3(4) 4(5) 5(6) 6(7) 7(9) 8(13) 9(15) 10(25) 11 (26) 12(27) 13(27) 14(28) 15(32) 16(33) 17(37) 18(37) 19(39) 20 (current)
F F F F M M F M M F M F M F M M M M M F
55 42 40 41 62 80 29 56 47 47 71 60 35 70 45 58 56 40 46 34
B W W ?
RUL LLL RLL RML LUL RML RUL RUL LMSB Trach LLL RLL Trach Carina LLL RLL LLL LUL Trach, bronch LMSB
+ +
Pn, CT Lb Lb
?
9
9 9
+ +
Lb WR, RT Lb, IT CT Pn, Ct None Sgmnt Lb Pn Sgmnt RT Pn Lb Lb Pn CT, IT Pn
DWD 2 mo DWD 5.5 mo DWD 1 mo DWD 1 mo Autopsy Dx AWD 1 y NED 10 y NED 11 y Postoperative death DWD 2 mo DWD 6.5 mo NED 1.5 y DWD 14 mo NED3y DWD 2 mo AWD 19 mo
w w w9 w w w9 w9 9
?
w w9 H
IL = intraluminal; MSB = mainstem bronchus; Pn = pneumonectomy; Lb = lobectomy; Sgmnt = segmental resection; WR = wedge resection; CT = chemotherapy; RT = radiotherapy; IT = immunotherapy; NED = no evidence of disease; A/DWD = alive/dead with disease;
Flat
+ + + + + -
Flat
+
Central
?
+ + + + + + + + ?
+ +
Treatment
Outcome NED3y NED 2.5 y
RUL = right upper lobe; RML = right middle lobe; RLL = right lower lobe; LUL = left upper lobe; LLL = left lower lobe; LMSB = left main stem bronchus.
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which she had at age two years. An interval to first metastasis in excess of 30 years, whereas very unusual, is well known for melanoma, but an ocular melanoma at two years of age would be even less likely than the proposed bronchial primary melanoma. Pulmonary metastasis as the only clinical manifestation of metastatic melanoma has been demonstrated in 7-9% of patients with cutaneous primary melanomas, 19 and the thorax appears to be the favored site for initial systemic relapse.19 Melanoma metastatic to the lung also may present as an obstructive endobronchial lesion.36 Far more commonly, however, the metastatic nature of the process is manifest clinically as multiple pulmonary nodules or concomitant extrathoracic spread." Similarly, an occult primary melanoma has been estimated to occur in as many as 15% of patients with (metastatic) melanoma 22 ; however, the vast majority of these cases present as lymph node metastases.24
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tively appears to be limited to melanocytic tumors but is not present in all melanomas. Carcinoids are almost invariably positive with chromogranin A and either keratin or epithelial membrane antigen, whereas melanomas are not. Clearly carcinoid tumors and melanomas share many biologic and pathologic features.1730 Definitive distinction between the two tumors may depend on ancillary methods such as electron microscopic studies and immunohistochemistry, as were used in this case. References 1. Adebonojo SA, Grillo IA, Durodola JI. Primary malignant melanoma of the bronchus. JAMA 1979;71:579-581. 2. Alghanem AA, Mehan J, Hassan AA. Primary malignant melanoma of the lung. J Surg Oncol 1987;34:109-112. 3. Allen AC, Spitz S. Malignant melanoma: a clinicopathologic analysis of the criteria for diagnosis and prognosis. Cancer 1953;6:1-45. 4. Allen MS, Drash EC. Primary melanoma of the lung. Cancer 1968;21:154-159. 5. Angel R, Prados M. Primary bronchial melanoma. J La State Med Soc 1984;136:13-15. 6. Bagwell SP, Flynn SD, Cox PM, Davison JA. Primary malignant melanoma of the lung. Am Rev Respir Dis 1989; 139:1543-1547. 7. Cagle P, Mace ML, Judge DM, Teague RB, Wilson RK, Greenberg SD. Pulmonary melanoma: primary vs metastatic. Chest 1984;85: 125-126. 8. Carlucci GA, Schleussner RC. Primary (?) melanoma of the lung. J Thorac Surg 1942; 11:643-649. 9. Carstens PHB, Kuhns JG, Ghazi C. Primary malignant melanoma of the lung and adrenal. Hum Pathol 1984;15:910-914. 10. Cebelin MS. Melanocytic bronchial carcinoid tumor. Cancer 1980;46:1843-1848. 11. Das Gupta T, Brasfield R. Metastatic melanoma: a clinicopathologic study. Cancer 1964;17:1323-1339. 12. Das Gupta TK, Brasfield RD, Paglia MA. Primary melanomas in unusual sites. Surg Gynecol Obstet 1969;128:841-848. 13. Demeter SL, Fuenning C, Miller JB. Primary malignant melanoma of the lower respiratory tract: endoscopic identification. Cleve Clin J Med 1987;54:305-308. 14. Erlandson RA. Ultrastructural diagnosis of amelanotic malignant melanoma: aberrant melanosomes, myelin figures or lysosomes? Ultrastruct Pathol 1987; 11:191 -208. 15. Gephardt GN. Malignant melanoma of the bronchus. Hum Pathol 1981;12:671-673. 16. Goldman JL, Lawson W, Zak FG, Roffman JD. The presence of melanocytes in the human larynx. Laryngoscope 1972,82:824835. 17. Gould VE, Memoli VA, Dardi LE, Sobel HJ, Somers SC, Johannessen JV. Neuroendocrine carcinomas with multiple immunoreactive peptides and melanin production. Ultrastruct Pathol 1981;2:199-217. 18. Grazer R, Cohen SM, Jacobs JB, Lucas P. Melanin-containing peripheral carcinoid of the lung. Am J Surg Pathol 1982;6:73-78. 19. Gromet MA, Ominsky SH, Epstein WL, Blois MS. The thorax as the initial site for systemic relapse in malignant melanoma: a prospective survey of 324 patients. Cancer 1979;44:776-784. 20. Hsu C-W, Wu S-C, Ch'En C-S. Melanoma of lung. Chin Med J [Engl] 1962;81:263-266. 21. Jensen OA, Egedorf J. Primary malignant melanoma of the lung. Scand J Respir Dis 1967;48:127-135. 22. Kopf AW, Bart RS, Rodriguez-Sains RS. Malignant melanoma: a review. J Dermatol Surg Oncol 1977;3:41-125. 23. Kunkel OF, Torrey E. Report of a case of primary melanotic sarcoma of lung presenting difficulties in differentiating from tuberculosis. NY State J Med 1916;16:198-201.
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Treatment varied from none to pneumonectomy, with occasional ancillary therapy. Eight patients died with disease after therapy, two were alive with disease at 12 and 19 months, and six were free of disease for as long as 11 years. All of these six patients underwent lobectomy or pneumonectomy. The histogenesis of PMMLRT is uncertain. One theory involves origin in benign melanocytes, which migrate during embryogenesis with mesoderm and/or endoderm; such cells have been identified within esophageal and laryngeal mucosa, including the glottis,16 which is part of the pulmonary anlage derived from the sixth branchial arch. However, benign melanocytes have not been convincingly demonstrated in the tracheobronchial tree, to our knowledge. Another theory speculates that epithelial cells transform into melanocytes under a metaplastic stimulus; evidence for this consists of the frequent, although not invariable, presence of squamous metaplasia in the affected mucosa. "Melanogenic metaplasia" of mucous glands within the oral cavity has also been described.35 Similar transformation of neural elements into melanocytes has also been speculated. A final possibility is that a precursor (Kulchitsky's) cell of the LRT and elsewhere has the potential to show melanocytic as well as neuroendocrine differentiation. The current case, as with most reported, represented a polypoid endobronchial growth originating centrally. Thus, this has clinical and gross features of the so-called "bronchial adenoma," most of which are carcinoid tumors, a diagnosis that was favored initially in this case. The tumor grew in a lobular pattern, with delicate fibrovascular stroma, and the neoplastic cells were exclusively epithelioid in appearance, all morphologic features of a neuroendocrine tumor. Recognition of the striking degree of pigmentation and the significant cytologic atypia led to the diagnosis of melanoma, which was substantiated by the absence of neurosecretory granules and the presence of aberrant melanosomes ultrastructurally, and by immunoreactivity with antibodies to S-100 protein and HMB45. Cytochemical and immunologic studies have shown that normal and neoplastic melanocytes and endocrine polypeptide cells of the Amine Precursor Uptake and Decarboxylation System (APUD) series share many characteristics. Rare cases of peripheral18 and central 1017 carcinoids have been shown to contain melanosomes in addition to neurosecretory granules. Conversely, melanomas have been shown to produce hormonal polypeptides. Pulmonary carcinoid tumors are generally argyrophilic but may rarely be argentaffin, as are most melanomas. S-100 immunoreactivity has also been shown in some carcinoid tumors, although generally only in sustentacular and/or Langerhans' cells within these neoplasms. HMB45 posi-
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24. Milton GW, Lane Brown MM, Gilder M. Malignant melanoma with an occult primary lesion. Br J Surg 1967;54:651-658. 25. Mori K, Cho H, Som M. Primary "flat" melanoma of the trachea. J Pathol 1977;121:101-105. 26. Reed RJ, Kent EM. Solitary pulmonary melanomas: two case reports. J Thorac Cardiovasc Surg 1964;48:226-231. 27. Reid JD, Mehta VT. Melanoma of the lower respiratory tract. Cancer 1966;19:627-631. 28. Robertson AJ, Sinclair DJM, Sutton PP, Guthrie W. Primary melanocarcinoma of the lower respiratory tract. Thorax I980;35: 158-159. 29. Rosenberg LM, Polanco GB, Blank S. Multiple tracheobronchial melanomas with ten-year survival. JAMA 1965;192:717-719. 30. Rost FWD. Polak JM, Pearse AGE. The melanocyte: itscytochemical and immunological relationship to cells of the endocrine polypeptide (APUD) series. Virchows Arch [Cell Pathol] 1969;4:93101. 31. Rowlands D, Edwards C, Collins F. Malignant melanotic schwannoma of the bronchus. J Clin Pathol 1987;40:1449-1455. 32. Salm R. A primary (?) malignant melanoma of the bronchus. J Pathol Bacteriol 1963;85:121-126.
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33. Santos F, Entrenas LM, Sebastian F, et al. Primary bronchopulmonary malignant melanoma: case report. Scand J Thorac Cardiovasc Surg 1987;21:187-189. 34. Scotto J, Fraumeni JF, Lee JAH. Melanomas of the eye and other noncutaneous sites: epidemiologic aspects. JNCI 1976;56:489491. 35. Shivas AA, MacLennan WD. "Melanogenic metaplasia" of mucous glands. Br J Cancer 1963; 17:411 -414. 36. Sutton FD, Vestal RE, Creagh CE. Varied presentations of metastatic pulmonary melanoma. Chest 1974;65:415-419. 37. Taboada CF, McMurray JD, Jordan RA, Seybold WD. Primary melanoma of the lung. Chest 1972;62:629-631. 38. Todd FW. Two cases of melanotic tumours in the lung. JAMA 1888;11:53-54. 39. Verweij J, Breed WP, Jansveld CA. Primary tracheo-bronchial melanoma. Neth J Med 1982;25:163-166. 40. Walter P, Fernandez C. Florange W. Melanome malin primitif pulmonale. Ann Anat Pathol 1972;17:91-99. 41. Weshler Z, Sulkes A, Kopolovitch J, Leviatan A, Shifrin E. Bronchial malignant melanoma. J Surg Oncol 1980;15:243-248.
An Immunohistochemical, Molecular, and Cytogenetic Study of a Single Case ANDREW C. WOTHERSPOON, M.B., B . C H . , GERALDINE N. SOOSAY, M.B., B.S., TIM C. DISS, B.SC, AND PETER G. ISAACSON, D.M., F.R.C.PATH.
A case of primary low-grade pulmonary lymphoma is described. The histologic features conformed to those laid down by Saltzstcin for a diagnosis of "pseudolymphoma." However, the immunocytochemical and molecular investigations confirmed the tumor to be a low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT). Cytogenetic studies revealed an abnormal karyotype with a translocation t(l;14). This is the first reported case of an abnormal karyotype in a case of a lymphoma of MALT. (Key words: Mucosa-associated lymphoid tissue; Pseudolymphoma; Immunocytochemistry; Karyotype; Cytogenetics; Molecular biology) Am J Clin Pathol 1990;94:655-660 TOGETHER WITH REFINED immunohistochemical techniques, cytogenetics and molecular biology are now contributing significantly to the understanding of the bi-
Received November 27, 1989; received revised manuscript and accepted for publication February 13, 1990. Supported in part by the Sir Jules Thorn Charitable Trust. Address reprint requests to Professor Isaacson: Department of Histopathology. University College and Middlesex School of Medicine. University Street, London WCIE 6JJ, United Kingdom.
Departments of Histopathology, University College and Middlesex School of Medicine, and the National Heart and Lung Institute, Brompton Hospital, London, United Kingdom
ology of lymphoid malignancies. The discovery of characteristic karyotypic abnormalities specifically associated with recognized subtypes of lymphoma has led to the cytogenetic investigation of other distinct clinicopathologic groups. 7 9 1 8 1 9 One such group is the low-grade B-cell lymphomas of mucosa-associated lymphoid tissue (MALT). To our knowledge, no cytogenetic abnormality has been reported in this group of lymphomas. We describe the histologic characteristics, immunohistochemistry, molecular biologic characteristics, and cytogenetics of a case of primary pulmonary lymphoma of MALT. Report of a Case A 60-year-old woman had a routine chest x-ray taken as part of the preoperative screening tests before an elective total hip replacement. This
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Low-Grade Primary B-Cell Lymphoma of the Lung
TIMOTHY A. JENNINGS, M.D., CONSTANTINE A. AXIOTIS, M.D., YVONNE KRESS, M.S., AND DARRYL CARTER, M.D.
MALIGNANT MELANOMA (MM) HAS been described very rarely as a primary tumor in the lower respiratory tract (LRT). Many previously reported cases are considered to represent solitary metastases of occult or regressed primary cutaneous MM. 12 Criteria to exclude an extrapulmonary origin have been developed that permit acceptance of primary MM of the LRT (PMMLRT). We document a case of PMMLRT that meets these criteria, discuss the differential diagnostic and histogenetic implications, and review the relevant literature.
Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut
lower lung field and decreased left lung volume. At examination with flexible and rigid bronchoscopes, a fleshy, yellow, focally eroded tumor was noted to occlude the left mainstem bronchus at the level of the junction of the upper and lower lobar bronchi, with no significant bleeding after biopsies. After the pathologic diagnosis of MM, scrupulous ophthalmologic and dermatologic examinations were performed. A 34-mm blue-black papule on the left posterior thigh was discovered and biopsied. This tissue showed typical morphologic characteristics of a capillary hemangioma; no melanocytic nevus cells were demonstrated. She denied prior excision or fulguration of any skin lesion. On March 12, 1987, she underwent left pneumonectomy with mediastinal lymph node dissection, with an uncomplicated postoperative course. Additional studies included chest and abdominal-pelvic computerized axial tomography scans and upper gastrointestinal series with small bowel follow through, which were negative. Abdominal pelvic ultrasonography demonstrated a right adnexal cyst, which had resolved on repeat ultrasonography. Barium enema had negative results, and colonoscopic examination showed only an 8-mm sigmoid polyp. No other therapy was given. Repeat ophthalmologic examination one year after the operation also had negative results. Follow-up in several outpatient clinics revealed no evidence of recurrent disease at 14 months after surgery. However, at 19 months she was found to have an enlarged left adrenal gland; percutaneous thinneedle aspiration was performed. No other recurrent disease was demonstrable at this time. Pathology
Report of a Case A 34-year-old Hispanic woman was admitted to the Bronx Municipal Hospital Center in February 1987 for presumed recurrent bronchitis unresponsive to oral antibiotics. History was significant only for enucleation of her right eye at age two years resulting from traumatic injury, and for cone biopsy in 1985 for cervical carcinoma in situ. She had a 35 pack-year history of cigarette smoking. Family history was noncontributory. Chest roentgenogram (Fig. 1) showed opacification of the left
Received December 21, 1989; accepted for publication January 30, 1990. Dr. Axiotis' current address is Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland 20892. Address reprint requests to Dr. Jennings: Department of Pathology and Laboratory Medicine, A-81, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208.
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. Superficial endoscopic biopsies showed an eroded bronchial mucosa with focal squamous metaplasia. Fragments of predominantly necrotic submucosal tumor were present; the neoplasm comprised nests and cords of epithelioid cells with abundant clear to eosinophilic cytoplasm with focal finely granular pigment. The nuclei varied in size, with a rare giant cell, and had small nucleoli; a rare intranuclear inclusion was evident. Mitotic figures were numerous. Abundant coarsely granular brown pigment was present in aggregates of macrophages and extracellularly. Special stains for argyrophilic (Grimelius) and argentaffin (Fontana-Masson, Fig. 2) material were strongly positive in tumor cells and macrophages; iron and mucin stains were negative.
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The authors report a case of primary bronchial malignant melanoma, occurring in a 34-year-old woman presenting with persistent cough. At bronchoscopic examination, a polypoid mass was found to occlude the left mainstem bronchus. Biopsies showed a malignant epithelioid tumor resembling an atypical carcinoid. Histochemistry, electron microscopic study, and immunohistochemistry confirmed the diagnosis of melanoma. Physical examination and additional clinical history to exclude other possible primary sites were negative. The patient underwent thoracotomy with left pneumonectomy. Nineteen months after resection she was found to have a histologically similar tumor involving her left adrenal gland. Review of the literature shows that melanoma of the lower respiratory tract has been reported only in adults and has a tendency to present as a central polypoid growth that may be responsive to surgical resection. (Key words: Melanoma; Carcinoid; Bronchus; Respiratory tract; Electron microscopy; Immunohistochemistry) Am J Clin Pathol 1990;94: 649-655
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FIG. 1 (upper, left). Posterior-anterior (PA) chest film showing opacification of left lower lung. FIG. 2 (upper, right). Granular cytoplasmic argentaffin positivity within tumor cells. Fontana-Masson (X400). FIG. 3 (lower). Gross photograph of pneumonectomy specimen with pigmented tumorfillinglingular bronchus.
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were noted within bronchial respiratory epithelium (Fig. 5), but no benign junctional melanocytes were demonstrated. Ultrastructurally the tumor cells were round to polyhedral, with rare membrane attachments. Cytoplasmic organelles included numerous mitochondria, cisternae of predominantly smooth endoplasmic reticulum, and many pigment-laden bodies, most of which appeared to be lysosomal. However, many other round and fusiform structures had heterogeneous electron-dense areas, and, in an occasional cell, some showed vaguely fibrillar or lamellar internal structure, suggestive of aberrant14 melanosomes (Fig. 6). No neurosecretory granules were demonstrated. Immunohistochemistry showed strongly positive cytoplasmic staining of tumor cells with antibodies to S100 protein (Biogenex polyclonal, undiluted, after trypsin) and HMB 45 (Enzo monoclonal, 1:4,000, without enzyme pretreatment). Grimelius and Fontana-Masson stains were also positive. Immunohistochemistry results for chromogranin (Lipshaw), neuron-specific enolase (DAKO), calcitonin (DAKO), keratin (AE1/AE3, Hybritech), and epithelial membrane antigen (DAKO) were negative, as was the Sevier-Munger stain. No staining was observed in either the antibody or tissue specificity controls. Review of her cervical punch and cone biopsy material showed cervical intraepithelial neoplasia, grade 3, without evidence of melanocytic elements. Records relating to her orbital enucleation in 1955 were not available. Aspiration biopsy material from the left adrenal mass showed a malignant epithelioid tumor with abundant intracellular argentaffin pigment. Discussion
• • : • * *
• ;} \ .
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FlG. 4. Intraluminal growth of melanoma involving bronchial submucosa. Hematoxylin and eosin (XI6).
Primary malignant melanoma of the lower respiratory tract is extremely rare, with only 19 previously reported cases fulfilling minimal criteria to exclude a more likely primary site. Specific criteria include the following: (1) no previously removed skin lesion, particularly pigmented; (2) no ocular tumors removed and no enucleation; (3) solitary tumor; (4) tumor morphologic characteristics compatible with a primary tumor (thus, considerable polymorphism favors a metastasis); (5) no demonstrable melanoma in other organs at the time of operation; and (6) autopsy without primary melanoma being demonstrated elsewhere, more particularly in the skin or eyes.21 Although these criteria are entirely appropriate, it is clear that there are instances in which they may not or cannot all be satisfied. The current case is such an example, having fulfilled these criteria with the exception of postmortem examination and of prior enucleation,
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The resection specimen consisted of a left lung showing incomplete lobation and weighing 248 g. The pleural surface in the hilar area was black and indurated, corresponding to the dimensions of the underlying tumor. No pleural involvement by tumor was evident grossly. Initial bronchial dissection disclosed a brown-black, focally eroded endobronchial mass occupying the left mainstem bronchus approximately 1 cm from the margin of resection; both lobar bronchi were obstructed but easily probed. Further dissection showed the tumor to fill the lingular bronchus (Fig. 3), to extend into and superficially through the bronchial wall in this area, and to measure up to 7.9 X 4.2 cm. Changes of organizing postobstructive pneumonia were seen in the lingula and lower lobe. Multiple peribronchial and mediastinal lymph nodes were enlarged and brown-black in color, without gross tumor involvement. Histologically, the tumor was predominantly submucosal and endobronchial (Fig. 4), but it destroyed bronchial cartilage and extended in a circumscribed fashion into superficial peribronchial soft tissues multifocally. Other microscopic features of the tumor were similar to those in biopsy tissue, with an exclusively epithelioid growth and prominent pigmentation. Focally tumor cells
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FlG. 5 (upper). Intramuscosal melanoma cells with intact basement membrane. Hematoxylin and eosin (X400). FIG. 6 (lower). Aberrant melanosomes within cytoplasm of tumor cell (X90,000).
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The adrenal tumor in the current case is considered to represent a metastasis from the lung, inasmuch as the adrenal is the most common site of extranodal metastasis from pulmonary primary malignancies. Primary adrenal melanoma has been reported but is even less common and more controversial than those of the LRT. 9 The gross and microscopic features of the tumor provide additional evidence supporting primary origin in the LRT. The malignancy should be solitary, and most are polypoid, intraluminal growths. If metastases are present, they must be in a pattern consistent with spread from the presumed primary. Histologic criteria3 involve those used to establish a melanoma as primary in any location: (1) junctional change with "dropping ofF' of melanoma cells;
(2) invasion of (bronchial) epithelium by the melanoma cells in an area that is not eroded; and (3) an obvious melanoma underlying these intraepithelial changes. Intramucosal tumor cells were demonstrable in the current case, although no benign melanocyte element (melanosis) was seen. Generally, however, these tumors show vertical, nodular growth that may obscure these features. We found only 19 prior cases'.2.4-7.9.13..5.25-28.32.33.37.39 reported as PMMLRT acceptable. Other reports are problematic or unlikely because of either a history of antecedent cutaneous melanoma, 29 prior intraoral melanoma, 3 subsequent ocular melanoma,41 lack of histologic examination of clinically documented pigmented skin lesions,20 or inadequate8'21'23'38 or absent34 clinical and pathologic information. The case reported by Walter and associates40 is considered doubtful because of the presence of multiple peripheral pulmonary nodules. Rare cases of melanotic tumors with exclusively spindle cell growth include a case reported as malignant melanotic schwannoma, 31 which may rather be an example of primary bronchial melanoma but that is not included in our summary. Analysis of these 20 cases (Table 1) shows that the tumor occurred only in adults, ranging in age from 29 to 80 years, with 11 being male and 9 female. Only one black patient has been reported. The origin was tracheal or carinal in four patients, and the remaining 16 bronchial primary melanomas were distributed in all lobes. Of the 17 cases with adequate description, 11 lesions arose centrally. Ten of 19 had intraluminal growth, and an additional 2 tracheal primary melanomas were flat lesions.
Table 1. Data from Reported Cases of PMMLRT Case (reference)
Sex
Age
Race
Site
IL
1(1) 2(2) 3(4) 4(5) 5(6) 6(7) 7(9) 8(13) 9(15) 10(25) 11 (26) 12(27) 13(27) 14(28) 15(32) 16(33) 17(37) 18(37) 19(39) 20 (current)
F F F F M M F M M F M F M F M M M M M F
55 42 40 41 62 80 29 56 47 47 71 60 35 70 45 58 56 40 46 34
B W W ?
RUL LLL RLL RML LUL RML RUL RUL LMSB Trach LLL RLL Trach Carina LLL RLL LLL LUL Trach, bronch LMSB
+ +
Pn, CT Lb Lb
?
9
9 9
+ +
Lb WR, RT Lb, IT CT Pn, Ct None Sgmnt Lb Pn Sgmnt RT Pn Lb Lb Pn CT, IT Pn
DWD 2 mo DWD 5.5 mo DWD 1 mo DWD 1 mo Autopsy Dx AWD 1 y NED 10 y NED 11 y Postoperative death DWD 2 mo DWD 6.5 mo NED 1.5 y DWD 14 mo NED3y DWD 2 mo AWD 19 mo
w w w9 w w w9 w9 9
?
w w9 H
IL = intraluminal; MSB = mainstem bronchus; Pn = pneumonectomy; Lb = lobectomy; Sgmnt = segmental resection; WR = wedge resection; CT = chemotherapy; RT = radiotherapy; IT = immunotherapy; NED = no evidence of disease; A/DWD = alive/dead with disease;
Flat
+ + + + + -
Flat
+
Central
?
+ + + + + + + + ?
+ +
Treatment
Outcome NED3y NED 2.5 y
RUL = right upper lobe; RML = right middle lobe; RLL = right lower lobe; LUL = left upper lobe; LLL = left lower lobe; LMSB = left main stem bronchus.
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which she had at age two years. An interval to first metastasis in excess of 30 years, whereas very unusual, is well known for melanoma, but an ocular melanoma at two years of age would be even less likely than the proposed bronchial primary melanoma. Pulmonary metastasis as the only clinical manifestation of metastatic melanoma has been demonstrated in 7-9% of patients with cutaneous primary melanomas, 19 and the thorax appears to be the favored site for initial systemic relapse.19 Melanoma metastatic to the lung also may present as an obstructive endobronchial lesion.36 Far more commonly, however, the metastatic nature of the process is manifest clinically as multiple pulmonary nodules or concomitant extrathoracic spread." Similarly, an occult primary melanoma has been estimated to occur in as many as 15% of patients with (metastatic) melanoma 22 ; however, the vast majority of these cases present as lymph node metastases.24
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tively appears to be limited to melanocytic tumors but is not present in all melanomas. Carcinoids are almost invariably positive with chromogranin A and either keratin or epithelial membrane antigen, whereas melanomas are not. Clearly carcinoid tumors and melanomas share many biologic and pathologic features.1730 Definitive distinction between the two tumors may depend on ancillary methods such as electron microscopic studies and immunohistochemistry, as were used in this case. References 1. Adebonojo SA, Grillo IA, Durodola JI. Primary malignant melanoma of the bronchus. JAMA 1979;71:579-581. 2. Alghanem AA, Mehan J, Hassan AA. Primary malignant melanoma of the lung. J Surg Oncol 1987;34:109-112. 3. Allen AC, Spitz S. Malignant melanoma: a clinicopathologic analysis of the criteria for diagnosis and prognosis. Cancer 1953;6:1-45. 4. Allen MS, Drash EC. Primary melanoma of the lung. Cancer 1968;21:154-159. 5. Angel R, Prados M. Primary bronchial melanoma. J La State Med Soc 1984;136:13-15. 6. Bagwell SP, Flynn SD, Cox PM, Davison JA. Primary malignant melanoma of the lung. Am Rev Respir Dis 1989; 139:1543-1547. 7. Cagle P, Mace ML, Judge DM, Teague RB, Wilson RK, Greenberg SD. Pulmonary melanoma: primary vs metastatic. Chest 1984;85: 125-126. 8. Carlucci GA, Schleussner RC. Primary (?) melanoma of the lung. J Thorac Surg 1942; 11:643-649. 9. Carstens PHB, Kuhns JG, Ghazi C. Primary malignant melanoma of the lung and adrenal. Hum Pathol 1984;15:910-914. 10. Cebelin MS. Melanocytic bronchial carcinoid tumor. Cancer 1980;46:1843-1848. 11. Das Gupta T, Brasfield R. Metastatic melanoma: a clinicopathologic study. Cancer 1964;17:1323-1339. 12. Das Gupta TK, Brasfield RD, Paglia MA. Primary melanomas in unusual sites. Surg Gynecol Obstet 1969;128:841-848. 13. Demeter SL, Fuenning C, Miller JB. Primary malignant melanoma of the lower respiratory tract: endoscopic identification. Cleve Clin J Med 1987;54:305-308. 14. Erlandson RA. Ultrastructural diagnosis of amelanotic malignant melanoma: aberrant melanosomes, myelin figures or lysosomes? Ultrastruct Pathol 1987; 11:191 -208. 15. Gephardt GN. Malignant melanoma of the bronchus. Hum Pathol 1981;12:671-673. 16. Goldman JL, Lawson W, Zak FG, Roffman JD. The presence of melanocytes in the human larynx. Laryngoscope 1972,82:824835. 17. Gould VE, Memoli VA, Dardi LE, Sobel HJ, Somers SC, Johannessen JV. Neuroendocrine carcinomas with multiple immunoreactive peptides and melanin production. Ultrastruct Pathol 1981;2:199-217. 18. Grazer R, Cohen SM, Jacobs JB, Lucas P. Melanin-containing peripheral carcinoid of the lung. Am J Surg Pathol 1982;6:73-78. 19. Gromet MA, Ominsky SH, Epstein WL, Blois MS. The thorax as the initial site for systemic relapse in malignant melanoma: a prospective survey of 324 patients. Cancer 1979;44:776-784. 20. Hsu C-W, Wu S-C, Ch'En C-S. Melanoma of lung. Chin Med J [Engl] 1962;81:263-266. 21. Jensen OA, Egedorf J. Primary malignant melanoma of the lung. Scand J Respir Dis 1967;48:127-135. 22. Kopf AW, Bart RS, Rodriguez-Sains RS. Malignant melanoma: a review. J Dermatol Surg Oncol 1977;3:41-125. 23. Kunkel OF, Torrey E. Report of a case of primary melanotic sarcoma of lung presenting difficulties in differentiating from tuberculosis. NY State J Med 1916;16:198-201.
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Treatment varied from none to pneumonectomy, with occasional ancillary therapy. Eight patients died with disease after therapy, two were alive with disease at 12 and 19 months, and six were free of disease for as long as 11 years. All of these six patients underwent lobectomy or pneumonectomy. The histogenesis of PMMLRT is uncertain. One theory involves origin in benign melanocytes, which migrate during embryogenesis with mesoderm and/or endoderm; such cells have been identified within esophageal and laryngeal mucosa, including the glottis,16 which is part of the pulmonary anlage derived from the sixth branchial arch. However, benign melanocytes have not been convincingly demonstrated in the tracheobronchial tree, to our knowledge. Another theory speculates that epithelial cells transform into melanocytes under a metaplastic stimulus; evidence for this consists of the frequent, although not invariable, presence of squamous metaplasia in the affected mucosa. "Melanogenic metaplasia" of mucous glands within the oral cavity has also been described.35 Similar transformation of neural elements into melanocytes has also been speculated. A final possibility is that a precursor (Kulchitsky's) cell of the LRT and elsewhere has the potential to show melanocytic as well as neuroendocrine differentiation. The current case, as with most reported, represented a polypoid endobronchial growth originating centrally. Thus, this has clinical and gross features of the so-called "bronchial adenoma," most of which are carcinoid tumors, a diagnosis that was favored initially in this case. The tumor grew in a lobular pattern, with delicate fibrovascular stroma, and the neoplastic cells were exclusively epithelioid in appearance, all morphologic features of a neuroendocrine tumor. Recognition of the striking degree of pigmentation and the significant cytologic atypia led to the diagnosis of melanoma, which was substantiated by the absence of neurosecretory granules and the presence of aberrant melanosomes ultrastructurally, and by immunoreactivity with antibodies to S-100 protein and HMB45. Cytochemical and immunologic studies have shown that normal and neoplastic melanocytes and endocrine polypeptide cells of the Amine Precursor Uptake and Decarboxylation System (APUD) series share many characteristics. Rare cases of peripheral18 and central 1017 carcinoids have been shown to contain melanosomes in addition to neurosecretory granules. Conversely, melanomas have been shown to produce hormonal polypeptides. Pulmonary carcinoid tumors are generally argyrophilic but may rarely be argentaffin, as are most melanomas. S-100 immunoreactivity has also been shown in some carcinoid tumors, although generally only in sustentacular and/or Langerhans' cells within these neoplasms. HMB45 posi-
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24. Milton GW, Lane Brown MM, Gilder M. Malignant melanoma with an occult primary lesion. Br J Surg 1967;54:651-658. 25. Mori K, Cho H, Som M. Primary "flat" melanoma of the trachea. J Pathol 1977;121:101-105. 26. Reed RJ, Kent EM. Solitary pulmonary melanomas: two case reports. J Thorac Cardiovasc Surg 1964;48:226-231. 27. Reid JD, Mehta VT. Melanoma of the lower respiratory tract. Cancer 1966;19:627-631. 28. Robertson AJ, Sinclair DJM, Sutton PP, Guthrie W. Primary melanocarcinoma of the lower respiratory tract. Thorax I980;35: 158-159. 29. Rosenberg LM, Polanco GB, Blank S. Multiple tracheobronchial melanomas with ten-year survival. JAMA 1965;192:717-719. 30. Rost FWD. Polak JM, Pearse AGE. The melanocyte: itscytochemical and immunological relationship to cells of the endocrine polypeptide (APUD) series. Virchows Arch [Cell Pathol] 1969;4:93101. 31. Rowlands D, Edwards C, Collins F. Malignant melanotic schwannoma of the bronchus. J Clin Pathol 1987;40:1449-1455. 32. Salm R. A primary (?) malignant melanoma of the bronchus. J Pathol Bacteriol 1963;85:121-126.
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33. Santos F, Entrenas LM, Sebastian F, et al. Primary bronchopulmonary malignant melanoma: case report. Scand J Thorac Cardiovasc Surg 1987;21:187-189. 34. Scotto J, Fraumeni JF, Lee JAH. Melanomas of the eye and other noncutaneous sites: epidemiologic aspects. JNCI 1976;56:489491. 35. Shivas AA, MacLennan WD. "Melanogenic metaplasia" of mucous glands. Br J Cancer 1963; 17:411 -414. 36. Sutton FD, Vestal RE, Creagh CE. Varied presentations of metastatic pulmonary melanoma. Chest 1974;65:415-419. 37. Taboada CF, McMurray JD, Jordan RA, Seybold WD. Primary melanoma of the lung. Chest 1972;62:629-631. 38. Todd FW. Two cases of melanotic tumours in the lung. JAMA 1888;11:53-54. 39. Verweij J, Breed WP, Jansveld CA. Primary tracheo-bronchial melanoma. Neth J Med 1982;25:163-166. 40. Walter P, Fernandez C. Florange W. Melanome malin primitif pulmonale. Ann Anat Pathol 1972;17:91-99. 41. Weshler Z, Sulkes A, Kopolovitch J, Leviatan A, Shifrin E. Bronchial malignant melanoma. J Surg Oncol 1980;15:243-248.
An Immunohistochemical, Molecular, and Cytogenetic Study of a Single Case ANDREW C. WOTHERSPOON, M.B., B . C H . , GERALDINE N. SOOSAY, M.B., B.S., TIM C. DISS, B.SC, AND PETER G. ISAACSON, D.M., F.R.C.PATH.
A case of primary low-grade pulmonary lymphoma is described. The histologic features conformed to those laid down by Saltzstcin for a diagnosis of "pseudolymphoma." However, the immunocytochemical and molecular investigations confirmed the tumor to be a low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT). Cytogenetic studies revealed an abnormal karyotype with a translocation t(l;14). This is the first reported case of an abnormal karyotype in a case of a lymphoma of MALT. (Key words: Mucosa-associated lymphoid tissue; Pseudolymphoma; Immunocytochemistry; Karyotype; Cytogenetics; Molecular biology) Am J Clin Pathol 1990;94:655-660 TOGETHER WITH REFINED immunohistochemical techniques, cytogenetics and molecular biology are now contributing significantly to the understanding of the bi-
Received November 27, 1989; received revised manuscript and accepted for publication February 13, 1990. Supported in part by the Sir Jules Thorn Charitable Trust. Address reprint requests to Professor Isaacson: Department of Histopathology. University College and Middlesex School of Medicine. University Street, London WCIE 6JJ, United Kingdom.
Departments of Histopathology, University College and Middlesex School of Medicine, and the National Heart and Lung Institute, Brompton Hospital, London, United Kingdom
ology of lymphoid malignancies. The discovery of characteristic karyotypic abnormalities specifically associated with recognized subtypes of lymphoma has led to the cytogenetic investigation of other distinct clinicopathologic groups. 7 9 1 8 1 9 One such group is the low-grade B-cell lymphomas of mucosa-associated lymphoid tissue (MALT). To our knowledge, no cytogenetic abnormality has been reported in this group of lymphomas. We describe the histologic characteristics, immunohistochemistry, molecular biologic characteristics, and cytogenetics of a case of primary pulmonary lymphoma of MALT. Report of a Case A 60-year-old woman had a routine chest x-ray taken as part of the preoperative screening tests before an elective total hip replacement. This
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Low-Grade Primary B-Cell Lymphoma of the Lung
