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Advances in Anatomic Pathology:
doi: 10.1097/PAP.0b013e3181f896dc
AMR Series

Selected Case From The Arkadi M. Rywlin International Pathology Slide Seminar: Sporadic Lymphangioleiomyomatosis

Bisceglia, Michele MD*; D'Alessandro, Vito MD; Simeone, Annalisa MD; Ben-Dor, David MD§; Pasquinelli, Gianandrea MD

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*Department of Pathology, Unit of Anatomic Pathology

Department of Medical Sciences, Unit of Internal Medicine

Department of Radiological Sciences and Imaging, Unit of Radiology, IRCCS- “Casa Sollievo della Sofferenza” Hospital, V.le Cappuccini, San Giovanni Rotondo, Italy

§Department of Pathology, The Barzilai Medical Center, Ashkelon, Israel

Department of Clinical, Radiological and Cytohistopathological Sciences, Unit of Clinical Pathology, University of Bologna, Bologna, Italy and Istituto Nazionale Biostrutture e Biosistemi–INBB

All figures can be viewed online in color at http://www.anatomicpathology.com.

Reprints: Michele Bisceglia, MD, Department of Pathology, Unit of Anatomic Pathology, IRCCS — “Casa Sollievo della Sofferenza” Hospital, V.le Cappuccini, I-71013 San Giovanni Rotondo), Italy (e-mail: bismi@libero.it).

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Abstract

Lymphangioleiomyomatosis (LAM) is a systemic, progressive, and fatal condition affecting almost exclusively women in their reproductive years. LAM most often occurs as a sporadic disease, but also occurs in women with tuberous sclerosis complex (TSC) (syndromic LAM). There are no pathologic differences between sporadic and syndromic LAM. Sporadic LAM is a rare disease with prevalence of approximately 1 to 2 cases per million women in the United States and among populations of white descent, and is even rarer among Asian and African individuals. Syndromic LAM affects 4% to 5% of women with TSC. Sporadic LAM is often found also in association with renal angiomyolipoma, the most common sign of TSC, but LAM associated with angiomyolipoma does not define TSC. Although LAM is not diagnostic for TSC either in isolation or in association with angiomyolipoma, still it is considered by some researchers as an incomplete expression (forme fruste) of TSC. LAM may involve the lungs and the axial lymphatics and lymph nodes of the thorax and retroperitoneum. In sporadic LAM, thoracic, intraabdominal, and cervical lymph nodes can be involved with or without lung involvement. The diagnosis of LAM is often delayed. A case of LAM in a young lady, which was complicated with pleural and peritoneal chylous effusions, is presented. The diagnosis was first made on a retroperitoneal lymph node biopsy. The patient had a prolonged prior history of respiratory problems owing to lung involvement, and eventually died 2 years after diagnosis. Focus on the clinicopathologic diagnosis of TSC is also made.

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OVERVIEW

Diagnosis

Sporadic lymphangioleiomyomatosis (LAM) involving the lymph node associated with pulmonary LAM.

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Referral Sources

Fourth International AMR Symposium in Anatomic Pathology, June 5th to 6th, 2010, held at Istanbul, Turkey-case no. 20 (slides labeled 85197-4), contributed by M. Bisceglia, MD, San Giovanni Rotondo, Italy.

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CLINICAL HISTORY AND PATHOLOGIC FEATURES

Intraoperative Consultation

A 38-year-old female with “ascites” and a presumptive diagnosis of non-Hodgkin's lymphoma underwent laparoscopic retroperitoneal paraaortic lymphadenectomy in June 2004. A soft tissue mass excised piecemeal and measuring 3 cm. in aggregate was submitted fresh for intraoperative consultation and tissue triage (Fig. 1). Frozen sections showed total effacement of the lymph node architecture by a bland-looking leiomyomatous-like proliferation. In places, there were slightly ecstatic lymphatic channels and scattered, small, round foci of residual lymphoid tissue. On questioning the accumulated peritoneal fluid was described as chylous. Both the histopathologic findings and clinical information suggested the possibility of LAM involving retroperitoneal lymph nodes. Most of the fragments were immersed in 10%-buffered formalin for paraffin embedding and standard processing, and the remaining small tissue fragments were fixed in Karnovski solution and processed for electron microscopy.

Figure 1
Figure 1
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Permanent Sections

H&E-stained permanent sections confirmed a spindle cell proliferation with myoid features exhibiting a distinctive pericytic-like arrangement characterized by spindle cell bundles distributed around an arborizing network of endothelium-lined slit-like lymphatic spaces. Immunohistochemically, the myoid cells were diffusely reactive for vimentin, α-smooth muscle actin and desmin. Scattered cells lying in minute clusters or singly were immunoreactive for HMB-45 and melan-A. Additional immunomarkers, such S-100 protein, EMA, cytokeratins, and CD34 all were negative. CD34 highlighted the rich capillary network of lymphatic vessels alternating with the spindle cell fascicles. On the basis of the coexpression of both smooth muscle markers and melanocytic markers, the myomelanocytic nature of the spindle cell proliferation of which the lesion was composed was determined. Nuclear immunostaining for estrogen and progesterone receptors was also positive in 40% and 60% of the myomelanocytic cells, respectively (Figs. 2–5).

Figure 2
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Figure 5
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Ultrastructural Examination

The myoid cells shared features of both smooth muscle and melanocytes. Their cytoplasm displayed a hybrid phenotype containing intracytoplasmic wisps of actin-like microfilaments in a sub-plasmalemmal localization with dense bodies, and membrane bound granules of variable electron density corresponding to stage 1 and 2 premelanosomes and stage 3 melanosomes with a variety of configurations (Fig. 6).

Figure 6
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Preliminary Diagnosis

LAM involving the lymph node—likely systemic(exclude tuberous sclerosis complex).

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Retrospective Clinical Review

The clinical charts of this patient were reviewed. The signs and symptoms of LAM that had eluded her clinicians for about 9 years became obvious in view of her newly established diagnosis. The patient had experienced shortness of breath whose onset coincided with her first pregnancy in 1995. Her dyspnea subsided after delivery. Exacerbation of difficulty in breathing became manifest 4 years later, during her second pregnancy. She then underwent pulmonary function testing, which showed significant airflow limitation. Concomitantly, allergy testing was positive for dermatophagoides pteronissymus, and dermatophagoides farinae. With a clinical diagnosis of chronic asthmatiform obstructive pulmonary disease, the patient was treated accordingly with bronchodilators, corticosteroids, and antibiotics. In January 2003 spirometry showed a reduced forced expiratory volume (FEV1) and forced vital capacity (FVC), increased total lung capacity (TLC), increased residual volume (RV), and increased RV/TLC ratio. Computed tomography (CT) scanning showed diffused bilateral cystic changes in the lung parenchyma, which were interpreted as centrilobular pulmonary emphysema (Fig. 7).

Figure 7
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In May 2004 she was hospitalized because of severe dyspnea, cough, and chest pain at our institution. Auscultation showed reduction of breath sounds. Routine chest x-ray showed hyperinflation. A right pleural effusion was evacuated by repeat thoracenteses. The pleural fluid was described as chylous (opalescent-white), which was further proven by biochemical analyses (triglyceride level 1401 mg/mL). Other chemical analyses conducted on this material were total protein (4.89 g/dL), albumin (2.98g/dL), glucose (108(mg/dL), cholesterol (91(mg/dL). Blood gas analyses documented reduction in diffusing capacity: pH 7.4; pO2=47.9 mm Hg; pCO2=37.5 mm Hg. High resolution chest CT scan (HRCT) confirmed the earlier documented findings of diffuse, homogeneous, small (<1.0cm diameter) thin-walled cysts. No significant mediastinal or hilar lymphadenopathy was identified. CT scan of the abdomen showed multiple enlarged periaortic and pelvic lymph nodes. A periaortic lymph node was biopsied in June 2004, the pathologic findings of which were those described above. No skin, heart, brain, and/or intraabdominal visceral sign or pathologic manifestation suggesting tuberous sclerosis complex was discovered.

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Definitive Diagnosis

The definitive diagnosis was “sporadic (nonsyndromic) LAM involving the lymph node, associated with pulmonary LAM and not associated with (renal or extrarenal) angiomyolipoma.”

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Follow-up

Administration of Tamoxifen and luteinizing hormone-releasing hormone analogs (LHRH) resulted in minimal transient clinical benefits. Less than 2 years after the diagnosis, the patient died while on the waiting list for lung transplantation. Autopsy was not conducted.

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AUTHORS' COMMENT

LAM (OMIM ♯ 606690) is a systemic condition, affecting almost exclusively women in their reproductive years. It is characterized by an abnormal proliferation of myoid cells (so-called LAM cells) in the lungs and in the axial lymphatics and lymph nodes of the thorax and retroperitoneum.1 The disorderly growth of cells with smooth muscle phenotype results in progressive obstruction of the airways and lymphatics. LAM most often occurs as a sporadic disease, but also occurs in women with tuberous sclerosis complex (TSC) (syndromic or TSC-related LAM). There are no pathologic differences between sporadic and syndromic (TSC-related) LAM.

Sporadic LAM is a rare disease with an estimated prevalence of approximately 1 to 2 cases per million women in the United States and among populations of White descent,2,3 and is even rarer among Asian and African individuals. Syndromic LAM affects 4% to 5% of women with TSC,4 but subclinical involvement is much more frequent than thought (up to 50%5). TSC, which occurs up to 1 in 6000 live births,6 is an autosomal dominantly inherited systemic malformation syndrome, linked to the TSC1 and TSC2 tumor suppressor genes, mapping on chromosome 9q (9q34) and chromosome 16p (16p13.3), respectively, with the former encoding hamartin and the latter---which accounts for the two thirds of mutations-encoding tuberin.

The diagnosis of TSC is primarily clinical (OMIM ♯ 191100), based on the presence of major clinical features (facial angiofibromas, ungual or periungual fibromas, hypomelanotic macules, shagreen patches, retinal hamartomas and astrocytomas, cortical tubers, subependymal nodules and subependymal giant cell astrocytomas, cardiac rhabdomyomas, LAM, and renal angiomyolipomas) and minor clinical features (enamel dental pits, hamartomatous rectal polyps, bone cysts, cerebral white matter migration lines, gingival fibromas, retinal achromic patches, confetti skin lesions, multiple renal cysts, and “nonrenal hamartomas.”7,8 The category of “nonrenal hamartomas” includes extrarenal angiomyolipomas, pulmonary, and extrapulmonary clear cell sugar tumors of visceral organs and somatic soft tissue, and multifocal micronodular pneumocyte hyperplasia9.

Histogenesis from the perivascular epithelioid cell10 has been proposed for renal and extrarenal angiomyolipomas, pulmonary and extrapulmonary LAM, pulmonary and extrapulmonary clear cell sugar tumors, which are collectively called PEC-omas.11–13

With regards to the diagnosis of TSC and LAM, we would like to emphasize the following: (i) a definitive clinical diagnosis of TSC now requires 2 or more distinct types of lesions; (ii) multiple lesions of the same type (eg, multiple angiomyolipomas) in the same organ system are counted as one6,7; (iii) in this context and from the clinical point of view, LAM and renal (and extrarenal) angiomyolipoma have to be considered as the same lesion (as they are all tumors of PEC cells) and when concomitantly present to be counted as one; (iv) foci of LAM have been reported in renal angiomyolipoma14,15; (v) visceral involvement other than lung (eg, uterus) has been described in TSC-related LAM16; (vi) visceral circumscribed TSC-related LAM (or nodular variant of LAM) has also been observed (eg, in the kidney concomitantly with classic angiomyolipoma)15; (vii) renal angiomyolipoma is the most frequent sign of TSC and is often (50% to 60%) found also in association with sporadic LAM2,17–19; (viii) LAM associated with angiomyolipoma does not define TSC; (ix) microscopic foci of LAM(PEComa) in visceral organs other than lung and kidney,although extraordinarily rare, may also occur.20

Although—according to the diagnostic criteria outlined above-LAM is not diagnostic on its own for TSC, it is considered per se by some researchers to be an incomplete expression (forme fruste) of this condition.18 From the genetic standpoint, syndromic LAM patients harbor germline mutations, but (according to the Knudson theory) the disease is usually caused by a second somatic cellular hit, which inactivates the remaining normal allele (“loss of heterozygosity” resulting in “two hit” TSC−/− cells). The second hit is not only new in each of several tumors occurring in TSC but may involve the TSC1 or TSC2 gene, independently from the germline TSC1−/+ or TSC2−/+ mutant allele (mechanism of trans-heterozygosity). Analogously, in sporadic LAM patients, who by definition do not have either TSC1 or TSC2 germline mutations, molecular analyses have also found somatic mutations of the TSC2 gene in the lung and kidney (TSC2+/+/ TSC2+/− mosaicism) and loss of heterozygosity in TSC2−/− LAM cells.21,22 TSC1 and TSC2 are tumor suppressor genes and their encoded proteins downregulate cell growth and proliferation by inhibiting mTOR (mammalian target of rapamycin), a ubiquitous serine-threonine kinase.23 Inactivating genetic mutations of TSC1 and/or TSC2 intimately involve the regulation of protein synthesis, cell growth, and cell proliferation.23

Some other studies have showed that pulmonary LAM cells are the same cells as lymph nodal LAM and renal angiomyolipoma, thus suggesting the possibility that LAM cells are capable of migrating through the lymphatics,3 and pulmonary LAM is thought to represent “metastatic” disease from other sites (renal angiomyolipomas, and lymph node and lymphatics LAM3). This hypothesis has been supported by demonstrating that LAM patients with lung involvement have circulating LAM cells in the peripheral blood3 and that recurrent pulmonary LAM after lung transplantation derive from native LAM.24,25

In descending order of frequency, in sporadic LAM, thoracic (mediastinal and hilar pulmonary), intraabdominal, and cervical lymph nodes can be affected with or without lung involvement.26 Lymph node involvement is called extrapulmonary LAM, and extrapulmonary LAM often precedes lung involvement,27 another point in favor of the capacity of LAM cells to migrate from the periphery to lung. When a lymph node is involved in isolation, then the term lymphangioleiomyoma is used.26

The clinical diagnosis of pulmonary LAM, in both sporadic and syndromic (TSC-related) forms, is based on HRCT that documents diffuse bilateral lung cystic changes. Lung cysts in conjunction with renal angiomyolipoma are considered diagnostic of LAM, and lung biopsy is not needed in these circumstances.3 In cases where the CT findings are suggestive of LAM, but renal angiomyolipomas are not detected, lung biopsy is recommended to establish the diagnosis: open biopsy is preferable in order to obtain a sufficient amount of tissue, but transbronchial lung biopsy also can yield diagnostic tissue.28 Pulmonary LAM, in both sporadic and syndromic forms, is a chronic relentless progressive and fatal disease, sometimes spanning decades, although occasionally it is rapidly progressing.3 Pulmonary LAM is the 3rd cause of death in the TSC-related form, after renal disease and brain tumors.2 It is a disease of women in childbearing age, although occasional premenarchal and postmenopausal cases (with hormonal manipulation), and extraordinary cases in males with TSC are also on record. Estrogens play a central role in disease progression.3,29 It is widely accepted that the disease is exacerbated by estrogen administration, while antiestrogens and progestins slow its progression, a fact which has been also noted in analogous experimental models.30 The main clinical presentation of pulmonary LAM is shortness of breath in a patient with cystic airspaces on HRCT (honeycomb changes in full blown disease), usually misinterpreted as emphysema, and quantitative HRCT can give appropriate indices to assess disease severity in these subjects.31 The diagnosis of pulmonary (systemic) LAM should be strongly suspected in any woman of childbearing age, who presents with emphysema, recurrent pneumothorax, and chylous effusions. Cyst formation in the lung is likely owing to a combination of mechanisms, such as air entrapment owing to interstitial nodular LAM cell proliferations, or elastase and α-1-antitrypsin imbalance leading to elastic fiber degradation. The disease course is associated with several complications, such as spontaneous pneumothorax (50%), chylothorax (30%), chyloperitoneum (10%), chyluria (2%), and hemoptysis. Chylous effusions and spillage are owing to structurally abnormal lymphatics, involved by LAM cell proliferation, and LAM cell proliferation is known to elicit abundant lymphangiogenesis.32 Meningiomas have been seen in around 3% of LAM cases in both sporadic and syndromic forms, some in patients who had received progestins.33

The histologic diagnosis relies upon documentation of LAM cell proliferations in any site of involvement. LAM cells are typically immunopositive for both smooth muscle antigens and HMB-45, one of the well-known melanoma-associated antigens. Frequent estrogen and progesterone receptor immunoreactivity is usually documented in LAM cells both in the lung and lymph node.29,30 Lymph node involvement by LAM is well illustrated by the case presented herein. Lung involvement has been the subject of many papers and is well treated in textbooks on pulmonary diseases,1,34 to which the reader is invited to refer. Lung biopsy shows cystic changes and spindle to epithelioid LAM cells infiltrates peripherally located as plaque-nodules at the borders of the cysts or protruding as polyps and papillations inside the cysts. Larger myoid nodules and polypoid LAM cell proliferations can be easily differentiated from benign metastasizing leiomyoma, owing to the absence of cystic lesions in the latter. For prognostic purposes a LAM histologic score (LHS) has been proposed, which is based on the percentage of lung tissue involvement by cystic lesions and LAM cells infiltrates. This scoring system is graded as follows: LHS1=<25%; LHS2=25% to 50%; LHS3=>50%).1,35 In addition, in the lung, multifocal micronodular pneumocyte hyperplasia is noted, which is a hamartomatous lesion seen in descending order of frequency in TSC patients with and without LAM, and in sporadic LAM,9 to be distinguished from atypical adenomatous alveolar hyperplasia. Rarely multifocal micronodular pneumocyte hyperplasia may also be seen in non-TSC/non-LAM patients as a sole manifestation.9

In conclusion LAM is a rare and often unrecognized disease, for which early diagnosis is desirable. Early therapeutic intervention may alleviate the symptomatology and slow disease progression. The mainstay of treatment is based on hormonal manipulation, such as oophorectomy, progestin therapy (medroxyprogesterone acetate), tamoxifen, LHRH analogs. Sirolimus, an immunosuppressive drug, acting as mTOR inhibitor, has recently been also proposed.36

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REFERENCES

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3. Steagall WK, Taveira-DaSilva AM, Moss J. Clinical and molecular insights into lymphangioleiomyomatosis. Sarcoidosis Vasc Diffuse Lung Dis 2005;22(Suppl 1):S49–S66

4. Castro M, Shepherd CW, Gomez MR, et al. Pulmonary tuberous sclerosis. Chest 1995;107:189–195

5. Moss J, Avila NA, Barnes PM, et al. Prevalence and clinical characteristics of lymphangioleiomyomatosis (LAM) in patients with tuberous sclerosis complex. Am J Respir Crit Care Med 2001;164:669–671

6. Morrison PJ, Shepherd CH, Stewart FJ, et al. Prevalence of tuberous sclerosis in UK. Lancet. 1998;352:318–319

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20. Michael C, Gibson P, Lowell J, et al. Microscopic uterine lymphangioleiomyomatosis perivascular epithelioid cell neoplasm (LAM PEComa): a case report with the earliest manifestation of this enigmatic neoplasm. Int J Gyn Pathol. 2010 In press. (DOI:10.1097/PGP.0b013e3181efe08d).

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23. Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med 2006;355:1345–1356

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25. Karbowniczek M, Astrinidis A, Balsara BR, et al. Recurrent lymphangiomyomatosis after transplantation: genetic analyses reveal a metastatic mechanism. Am J Respir Crit Care Med 2003;167:976–982

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28. Bonetti F, Chiodera PL, Pea M, et al. Transbronchial biopsy in lymphangiomyomatosis of the lung. HMB45 for diagnosis. Am J Surg Pathol 1993;17:1092–1102

29. Logginidou H, Ao X, Russo I, Henske EP. Frequent estrogen and progesterone receptor immunoreactivity in renal angiomyolipomas from women with pulmonary lymphangioleiomyomatosis. Chest 2000;117:25–30

30. El-Hashemite N, Walker V, Kwiatkowski DJ. Estrogen enhances whereas tamoxifen retards development of Tsc mouse liver hemangioma: a tumor related to renal angiomyolipoma and pulmonary lymphangioleiomyomatosis. Cancer Res 2005;65:2474–2481

31. Crausman RS, Lynch DA, Mortenson RL, et al. Quantitative CT predicts the severity of physiologic dysfunction in patients with lymphangioleiomyomatosis. Chest 1996;109:131–137

32. Kumasaka T, Seyama K, Mitani K, et al. Lymphangiogenesis in lymphangioleiomyomatosis: its implication in the progression of lymphangioleiomyomatosis. Am J Surg Pathol 2004;28:1007–1016

33. Moss J, DeCastro R, Patronas NJ, et al. Meningiomas in lymphangioleiomyomatosis. JAMA 2001;286:1879–1881

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36. Bissler JJ, McCormack FX, Young LR, et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med. 2008;358:140–1451

lymphangioleiomyomatosis (LAM); tuberous sclerosis complex; lymphangioleiomyoma; LAM cells; chylous effusion

© 2010 Lippincott Williams & Wilkins, Inc.

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