Case 1 -

Lymphangioleiomyomatosis (with Recurrence in the Allograft) Thomas V. Colby Mayo Clinic Scottsdale, AZ

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Clinical History There are two fragments on the slide and they come from two different patients. The piece that shows the more dramatic changes is from a 38-year-old woman with increasing dyspnea, decreased diffusing capacity, and severe obstruction functionally. Radiologic studies showed emphysema and cystic change. The patient was a never smoker. The other second tissue is from a woman who presented at age 31 with hemoptysis and cough. She developed progressive dyspnea and two years later underwent single lung transplant from a male donor. The explanted lung showed the same features as were present in the other specimen on your slide. One year after transplantation, she developed evidence of bronchiolitis obliterans and a year after that, she had refractory pneumothoraces and other complications that could not be managed and she died. This lung tissue is from the allograft taken at the autopsy. Case 1 - Figure 1 - Low power of the allograft lung shows a few small cystic spaces with focal regions of hypercellularity in their walls. Case 1 - Figure 2 - The hypercellularity seen in Figure 1 corresponds to a spindle cell proliferation. Case 1 - Figure 3 - The spindle cell proliferations seen in figure 2 is HMB 45 positive. Case 1 - Figure 4 - Classical lymphangiomyomatosis with large cystic spaces. Case 1 - Figure 5 - The wall of the cysts in figure 4 shows spindle cells resembling smooth muscle cells. Case 1 - Figure 6 - The spindle cells in Figure 5 show HMB 45 positivity with some polygonal cells more darkly staining. Histologic Findings Both pieces of tissue show cystic change with focal accumulations of spindle cells in the walls of the cyst. The more dramatic case also shows hemosiderin filled macrophages in the airspaces. The spindle cells in this case stain positively for smooth muscle actin, muscle specific actin, desmin, HMB45, estrogen receptors, and progesterone receptors. Diagnoses Lymphangioleiomyomatosis (with Recurrence in the Allograft) Comment/Discussion I. Recurrence of underlying disease in pulmonary allografts. Recurrence of the primary disease has been seen with a number entities, including: Lymphangioleiomyomatosis Pulmonary Langerhans cell histiocytosis Desquamative interstitial pneumonia Bronchioloalveolar carcinoma Hard metal pneumoconiosis/giant cell interstitial pneumonia Alveolar proteinosis Erdheim-Chester disease Diffuse Panbronchiolitis Sarcoidosis Usual interstitial pneumonia (UIP) Idiopathic pulmonary hemosiderosis Bronchiolitis obliterans (i.e. chronic rejection) In initial studies recurrent LAM was thought to be due to transformation of donor cells in the allograft, but in recent studies (including that of the case under discussion), the LAM cells in the allograft have been shown to be of recipient origin, and thus, derived from the cells that have migrated (? metastasized) to the allograft. Your case has been reported twice by Bittman, et al. In 1997, it was suggested that the recurrent LAM cells were of donor origin on the basis of Y chromosome probe analysis. There were two other reports that supported this interpretation. This case was subsequently reanalyzed in a 2003 report. Bittman, et al., proved that the cells were of recipient origin on the basis of double staining non-isotopic in situ hybridization, immunohisto chemistry, and short tandem repeat loci analysis. The authors hypothesized that the recurrent LAM cells were either metastatic LAM cells from the recipient or progenitor cells from the recipient that migrated to the lung and differentiated into LAM cells. Similar conclusions were reached by Karbowniczek, et al. in a very carefully studied case using microsatellite marker fingerprinting and TSC2 gene mutational analysis. Again, LAM cells in the allograft were proven to be recipient origin. These authors also showed that florescence in situ hybridization revealed that the cells that were immunoreactive with monoclonal antibody HMB45 (i.e., the LAM cells) did not contain a Y chromosome. References Barberis M, Harari S, Tironi A, and Lampertico P. Recurrence of Primary Disease in a Single Lung Transplant Recipient. Transplant Proc 1992; 24(6):2660-2. Baz MA, Kussin P S, Van Trigt P, Davis RD, Roggli VL, Tapson VF. Recurrence of Diffuse Panbronchiolitis after Lung Transplantation. Am J Resp Crit Care Med 1995; 151:895-8. Bittmann I, MD, Dose TB, Muller C, MD, Dienemann H, MD, Vogelmeier C, MD. Lymphangioleiomyomatosis: Recurrence after Single Lung Transplantation. Human Path 1997; 26:1420-23. Bittmann I, MD, Rolf B, PhD, Amann G, PhD, Lohrs U, MD. Recurrence of Lymphangioleiomyomatosis after Single Lung Transplantation: New Insights into Pathogenesis. Human Path 2003; 34:95-8. Etienne B, Bertocchi M, Gamondes J, Thevenet F, Boudard C, Wiesendanger T, Loire R, Brune J, Mornex J. Relapsing Pulmonary Langerhans Cell Histiocytosis after Lung Transplantation. Amer J Resp Crit Care Med 1998; 157:288-291. Frost AE, Keller CA, Brown RW, Noon GP, Short HD, Abraham JL, Pacinda S, Cacle PT. Giant Cell Interstitial Pneumonitis. Amer Rev Resp Dis 1993; 148:1401-4. Garver RI, Jr., MD, Zorn GL, MD, Wu X, PhD, McGiffin DC, MD, Young KR, Jr., MD, Pinkard NB, MD. Recurrence of Bronchioloalveolar Carcinoma in Transplanted Lungs. New Engl J Med 1993; 340:1071-4. Johnson BA, Duncan SR, Ohori NP, Paradis IL, Yousem SA, Grgurich WF, Dauber JH, Griffith BP. Recurrence of Sarcoidosis in Pulmonary Allograft Recipients. Amer Rev Resp Dis 1993; 148:1373-77. Karbowniczek M, Astrnidis A, Balsara BR, Testa JR, Lium JH, Colby TV, McCormack FX, Henski EP. Recurrent Lymphangiomyomatosis after Transplantation, Genetic Analyses Reveals a Metastic Mechanism. Amer J Resp Crit Care Med 2003; 167:976-82. King MB, Jessurun J, Hertz MI. Recurrence of Desquamative Interstitial Pneumonic after Lung Transplantation. Amer J Resp Crit Care Med 1997; 156:2003-5. Martinez FJ, MD, Orens JB, MD, Deeb M, MD, Brunsting LA, MD, Flint A, MD, Lynch JP III, MD. Recurrence of Sarcoidosis Following Bilateral Allogeneic Lung Transplantation. Chest 1994; 106:1597-99. Parker LA, MD, Novotny DB, MD. Recurrent Alveolar Proteinosis Following Double Lung Transplantation. Chest, 1997; 111:1457. Verleden GM, Sels F, Van Raemdonck D, Verbeken EK, Lerut R, Demedts M. Possible Recurrence of Desquamative Interstitial Pneumonitis in a Single Lung Transplant Recipient. Euro Resp J 1998; 11:971-4. II. Cysts on HRCT Pulmonary pathologists (and chest radiologists) are want to talk about the value of HRCT and how it has changed diagnosis and management of patients with diffuse lung disease. LAM is one of the diseases that radiologists feel comfortable diagnosing on the basis of the presence of cystic change and its character and distribution in the lungs on HRCT. In a recent large study of LAM (Urban, et al), 10% of the cases were diagnosed based on radiologic findings alone without histology (in the appropriate clinical setting). However. there are many causes of cysts on HRCT:. Lymphangioleiomyomatosis Pulmonary Langerhans cell histiocytosis Emphysema/Bullae Honeycombing Metastases (many types) Sarcoidosis Recurrent respiratory papillomatosis involving the lung Pneumatoceles Bronchiectasis Mesenchymal cystic hamartoma LIP/Sjögrens Hypersensitivity pneumonitis Asthma Interstitial clear cell proliferation with cystic change And probably others! In a recent summary (Rye and Swensen) cystic diseases of the lung were divided as follows: Cystic (wall thickness < 4 mm) Bullae Blebs Pneumatoceles Congenital cystic lesions Bronchogenic cyst Congenital adenomatoid malformation Infections Coccidioidomycosis Pneumocystis carinii Hydatid disease Traumatic cysts Cavitary (wall thickness > 4 mm or surrounding infiltrate or mass) Neoplastic Bronchogenic carcinomas Metastases Lymphomas Infections Bacteria Staphylococcus aureus, gram-negative bacteria, pneumococcus, mycobacteria, melioidosis, anaerobes, actinomycosis, nocardiosis Fungi Histoplasmosis, coccidioidomycosis, blastomycosis, aspergillosis, mucormycosis, cryptococcosis, P carinii, sporotrichosis Parasites Hydatid disease, paragonimiasis, amebiasis Immunologic Wegener granulomatosis Rheumatoid nodule Thromboembolism or septic embolism Progressive massive fibrosis (pneumoconiosis) Bronchiectasis, localized Congenital lesions Sequestration Congenital adenomatoid malformation Pulmonary lymphangioleiomyomatosis Pulmonary Langerhans cell histiocytosis Honeycomb lung Idiopathic pulmonary fibrosis Connective tissue disease-related pulmonary fibrosis Asbestosis Chronic hypersensitivity pneumonitis Advanced sarcoidosis Bronchiectasis, diffuse Metastatic disease In a radiologic study, Koyama, et al., did a radiologic study of chronic cystic lung disease in 92 patients. Despite the general confidence that experienced radiologists express in making a definitive diagnosis of LAM by HRCT, among 18 cases of LAM compared with other cystic diseases a correct diagnosis was made only 72% of the time. Even when the radiologist had a high confidence of the diagnosis of LAM, they were correct only 88% of the time. Thus radiologists are not as accurate as they think they are! There is no question that HRCT has led to increased recognition of LAM and has probably shifted the survival curve to the left, since minimally symptomatic cases that might not have previously been recognized are now being identified. In that regard, up to 40% of women with TSC have been found to have cystic disease radiologically that has been interpreted as LAM. References Costello LC, MD, PhD, Hartman TE, MD, Ryu JH, MD. High Frequency of Pulmonary Lymphangioleiomyomatosis in Women with Tuberous Sclerosis Complex. Mayo Clin Proc, 2000: 75:591-4. Franquet T, Hansell DH, Senbanjo T, Remy-Jardin M, Muller NL. Lung Cysts in Subacute Hypersensitivity Pneumonitis. J of Comp Assist Tomo, 2003: 27(4):475-8. Franz DN, Brody A, Meyer C, Leonard J, Chuck G, Dabora S, Sethuraman G, Colby TV, Kwiatkowski DJ, McCormack FX. Mutational and Radiographic Analysis of Pulmonary Disease Consistent with Lymphangioleiomyomatosis and Micronodular Pneumocyte Hyperplasia in Women with Tuberous Sclerosis. Amer J Resp Crit Care Med, 2001; 164:661-8. Hironaka M, MD, and Fukayama M, MD. Regional Proliferation of HMB-45 Positive Clear Cells of the Lung with Lymphangioleiomyomatosislike Distribution, Replacing the Lobs with Multiple Cysts and A Nodule. Amer J Surg Path, 1999: 23(10): 1288-93. Koyama M, Johkoh T, Honda O, Tsubamoto M, Kozuka T, Tomiyama N, Hamada S, Nakamura H, Akira M, Ichikado K, Fujimoto K, Rikimaru T, Tateishi U, Muller NK. Chronic Cystic Lung Disease: Diagnostic Accuracy of High-Resolution CT in 92 Patients. AJR, 2003; 180:827-35. McCormack F, MD, Brody A, MD, Meyer C, MD, Leonard J, RN, Chuck G, BS, Dabora S, PhD, Sethuraman G, PhD, Colby TV, MD, FCCP, Kwiatkowski DJ, MD PhD, Franz DN, MD. Pulmonary Cysts Consistent with Lymphangioleiomyomatosis Are Common in Women with Tuberous Sclerosis, Genetic and Radiographic Analysis. Chest, 2002; 121:61S. Moss J,, Avila NA, Barnes PM, Litzenberger RA, Bechtle JM, Brooks PG, Hedin CJ, Hunsberger S, Kristof AS. Prevalence and Clinical Characteristics of Lymphangioleiomyomatosis (LAM) in Patients with Tuberous Sclerosis Complex. Amer J Resp Crit Care Med, 2001; 163:669-71. Ryu JH, MD, Swensen SJ, MD. Cystic and Cavitary Lung Diseases: Focal and Diffuse. Mayo Clin Proc, 2003; 78:744-52. Urban T, Lazor R, Lacronique J, Murris M, Labrune S, Valeyre D, Cordier J, for the Groupe d'Etudes Et De Recherche, Sur Les Maladies "Orphelines" Pulmonaires (Germ "O"P). Pulmonary Lymphangioleiomyomatosis, A study of 99 Patients. Med 1999; 78:321-37. III. Update on LAM A. Prognosis and Histology Prognosis in LAM correlates with the extent of cysts, more than the extent of muscle proliferation. A pathologic scoring system has been devised: the LAM histologic score (LHS). Briefly the percentage of lung tissue that is affected by cystic lesions, abnormal smooth muscle, or both is quantified as 1-25%, 26-50%, > 50% ,and these are designated LHS1, LHS2, LHS3. The five and ten year survivals for these three grades are as follows: 100%, 100%; 81%, 74%; 63%, 52%. B. Pathogenesis of the cysts The cysts of LAM are not simply emphysema. That is apparent both histologically and radiologically by HRCT. At one point it was thought that they related to obstruction in small airways by LAM cells, but recent studies have suggested that there is degradation of the elastic tissue and that this may be important in the pathogeneses of the cysts, although it does not explain why they differ morphologically from emphysema. Recent studies have suggested that loss of tissue inhibitor of metalloproteinase (TIMP) activity may result in subsequent tissue destruction. It has been shown that LAM cells in the lung are not homogeneous. Some cells are more spindled and these have a higher proliferative activity and may be more important in the pathogenesis of the disease and elastic tissue degradation. They tend to have weaker staining with HMB45. There is a smaller population of larger and somewhat more epithelioid cells (more similar to the cells seen angiomyolipomas) that are more strongly positive with HMB45 but have a lower proliferative activity and may be less significant in the pathogenesis of the disease. C. Genetics and molecular pathology Although the relationship between tuberous sclerosis complex (TSC) and sporadic LAM remains to be fully clarified,. it is now thought that LAM is due to a mutation in the TSC2 gene. This is thought to be a somatic mutation and it has been identified in angiomyolipomas, in patients with sporadic LAM and in the abnormal pulmonary cells in sporadic LAM. In cases in which both angiomyolipomas and lung LAM cells have been available for study, the same TSC gene mutation has been found. This finding has led investigators to suggest that the cells have migrated from one site to the other. The molecular biology has yet to be worked out, but a TSC2 gene mutation may lead to loss of tumor suppressor activity and subsequent proliferation of LAM cells. The TSC1 gene encodes for protein hamartin and the TSC2 gene encodes for tuberin and hamartin and tuberin may be linked in intracellular signaling pathways involved in cellular proliferation. D. LAM is found (rarely) in men with TSC References Astrinidis A, Cash TP, Hunter DS, Walker CL, Chernoff J, Henske CP. Tuberin, the tuberous sclerosis complex 2 tumor suppressor gene product, regulates Rho activation, cell adhesion and migration. Oncogene, 2002; 21:8470-76. Aubry M.C., Myers, J.L., Ryu J. H., et al. Pulmonary lymphangioleiomyomatosis in a man. Amer J Resp Crit Care Med, 2000; 162:749-52. Carsillo T, Astrinidis A, Henske AP. Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. PNAS, 2000; 97(11):6085-90. Kim NR, Chung MP, Park C, Lee KS, Han J. Pulmonary lymphangioleiomyomatosis and multiple hepatic angiomyolipomas in a man. Path Intl, 2003; 53:231-235. Kyrmskaya VP. Tumour suppresors hamartin and tuberin: intracellular signalling. Cell Sign, 2003; 15:729-739. Matsui K, MD, PhD, Beasley MB, MD, Nelson WK, B.S., Barnes PM, RN, Bechtle J, C.R.N.P-A, Falk F, M.S., Ferrans VJ, MD, PhD, Moss J, MD, and Travis WD, MD. Prognostic Significance of Pulmonary Lymphangioleiomyomatosis Histologic Score. Amer J of Surg Path, 2001; 25(4): 479-484. Matsumoto Y, Horiba K, Usuki J, Chu SC, Ferrans VJ, Moss J. Markers of Cell Proliferation and Expression of Melanosomal Antigen in Lymphangioleiomyomatosis. Amer J Resp Cell Mol. Biol, 1999; 21:327-336. Pacheco-Ridriquez G, PhD, Kristof AS, MD, Stevens LA, Zhang Y, PhD, Crooks D, PhD, Moss J, MD PhD. Genetics and Gene Expression in Lymphangioleiomyomatosis. Giles F. Filley Lecture. Chest, 2002; 121:56S-60S. Sampson JR. TSCI and TSC2: genes that are mutated in the human genetic disorder tuberous sclerosis. Biochem Soc Transactions, 2003; 31:part 3. Yu J, Astrinidis A, Henske WP. Chromosome 16 Loss of Heterozygosity in Tuberous Sclerosis and Sporadic Lymphangiomyomatosis. Amer J Resp Crit Care Med, 2001; 164:1537-40. Zhe S, Yang Y, Jakkaraju S, Schuger L. Tissue Inhibitor of Metalloproteinase-3 Downregulation in Lymphangioleiomyomatosis, Potential Consequence of Abnormal Serum Response Factor Expression. Amer J Resp Cell. Mol. 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