Incidental Pelvic and Para-aortic Lymph Node Lymphangioleiomyomatosis Detected During Surgical Staging of Pelvic Cancer in Women Without Symptomatic Pulmonary Lymphangioleiomyomatosis or Tuberous Sclerosis Complex.

ORIGINAL ARTICLE

Incidental Pelvic and Para-aortic Lymph Node Lymphangioleiomyomatosis Detected During Surgical Staging of Pelvic Cancer in Women Without Symptomatic Pulmonary Lymphangioleiomyomatosis or Tuberous Sclerosis Complex Joseph T. Rabban, MD, MPH,* Brandie Firetag, MD,* Ankur R. Sangoi, MD,w Miriam D. Post, MD,z and Charles J. Zaloudek, MD*

Abstract: Extrapulmonary lymphangioleiomyomatosis (LAM) is a rare neoplasm of spindle cells exhibiting melanocytic and myoid differentiation that arises as a mass in the mediastinum, retroperitoneum, uterine wall, and/or intraperitoneal lymph nodes. Many patients also have pulmonary LAM, tuberous sclerosis complex (TSC), and/or other neoplasms of the perivascular epithelioid cell tumor family. This study reports 26 patients with clinically occult LAM involving pelvic/para-aortic lymph nodes removed from women undergoing surgical staging of a uterine (17), ovarian (5), cervical (3), or urinary bladder (1) neoplasm. None of the patients exhibited symptoms of pulmonary LAM, and the median patient age (56 y) was older than what would be expected for patients presenting with pulmonary LAM. Only 2/26 patients had TSC. Four patients also had uterine LAM. One of these 4 had uterine perivascular epithelioid cell tumor, and 1 had vaginal angiomyolipoma. In all 26 patients the lymph node LAM was grossly occult, measured 3.5 mm on average (1 to 19 mm), and involved either a single lymph node (12/26) or multiple lymph nodes (14/26). HMB45 was positive in 24/25 cases, mostly in a focal or patchy distribution. Other melanocytic markers included MiTF (12/14) and MelanA (2/12). Myoid markers included smooth muscle actin (23/23) and desmin (15/16), mostly in a diffuse distribution. Estrogen receptor was positive in all cases tested, as was D240 expression in the lymphatic endothelium lining the spindle cell bundles. Concurrent findings in the involved lymph nodes included metastatic From the *Department of Pathology, University of California San Francisco, San Francisco; wDepartment of Pathology, El Camino Hospital, Mountain View, CA; and zDepartment of Pathology, University of Colorado, Denver, CO. Presented in part at the 2012 Annual Meeting of the United States and Canadian Academy of Pathology. Conflicts of Interest and Source of Funding: Support was received from the University of California San Francisco Department of Pathology Resident Teaching Research Endowment. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Joseph T. Rabban, MD, MPH, Department of Pathology, University of California San Francisco, 505 Parnassus Avenue, M552, San Francisco, CA 94143 (e-mail: [email protected]). Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.

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carcinoma (3/26), endosalpingiosis (3/26), and reactive lymphoid hyperplasia (13/26). This study demonstrates that clinically occult lymph node LAM can be detected during surgical staging of pelvic cancer and is not commonly associated with pulmonary LAM or TSC, although these patients should still be formally evaluated for both of these diseases. Key Words: lymphangioleiomyomatosis, tuberous sclerosis complex, PEComa, HMB45 (Am J Surg Pathol 2015;39:1015–1025)

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ulmonary lymphangioleiomyomatosis (LAM) is a rare cystic lung disease leading to progressive respiratory failure that mostly affects premenopausal women and that can be associated with tuberous sclerosis complex (TSC).1 The LAM cells are cytologically bland spindle cells with a myoid appearance and a unique immunophenotype of melanocytic, myoid, and estrogen receptor expression. Extrapulmonary LAM is rare but may involve the mediastinum, retroperitoneum, uterine wall, and/or intraperitoneal lymph nodes. However, the clinical presentation, behavior, and architectural morphology are different from those of pulmonary LAM, despite the similar immunophenotype of the LAM cells.2 Extrapulmonary LAM presents as nodules or masses of LAM cells growing in interdigitating bundles set within a network of compressed lymphatic channels. Extrapulmonary LAM can be associated with neoplasms of the perivascular epithelioid cell tumor (PEComa) family (eg, angiomyolipoma [AML]) and/or with any of the myriad manifestations of TSC. It remains unclear whether all patients with extrapulmonary LAM have pulmonary LAM or are at risk for developing it. The potential relationship with pulmonary LAM and/or TSC is of particular concern in a unique subset of women found to have clinically occult LAM in pelvic and paraaortic lymph nodes removed during surgical staging of uterine or ovarian cancer; 4 such cases of isolated lymph node LAM have been reported.3,4 Most cases of lymph

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node LAM have been associated with additional sites of extrapulmonary LAM, pulmonary LAM, PEComa-family tumors, and/or TSC.2,5–9 The aim of the current study is to report the clinicopathologic features of incidentally detected pelvic/para-aortic lymph node LAM in women undergoing surgical staging of pelvic cancer. Particular emphasis is directed to the incidence of symptomatic pulmonary LAM, TSC, and other tumors of the PEComa family in these patients. Potential diagnostic pitfalls in the evaluation of lymph nodes with LAM in the setting of cancer staging are discussed, as are recommendations for referring otherwise unaffected patients for evaluation for pulmonary LAM and TSC.

METHODS The study included patients with a diagnosis of LAM involving a lymph node from any extrathoracic site. Of the 26 patients, 16 underwent surgery at University of California San Francisco, and the remainder were consultation cases or cases contributed for this study. LAM was defined as a proliferation of bland spindle cells resembling smooth muscle cells growing in a nodular, whorled, or loosely fascicular pattern within a background of branching, anastomosing, and/or compressed lymphatic channels. Although this morphologic pattern is distinct to LAM, the diagnoses were confirmed by demonstrating that the spindle cells exhibited immunohistochemical expression of 1 melanocytic marker (HMB45 [ENZO, prediluted] and/or MiTF [Dako, 1:200 dilution] and/or MelanA [Dako, 1:10 dilution]) and 1 myoid marker (smooth muscle actin [Leica, prediluted] and/or desmin [Cell Marque, 1:5 dilution]). A subset of cases were also stained for D240 (Dako, 1:50 dilution), estrogen receptor (Ventana, prediluted), and PAX8 (Cell Marque, 1:100 dilution). Cytoplasmic staining of any intensity for HMB45, MelanA, smooth muscle actin, desmin, and D240 was defined as a positive result. Nuclear staining of any intensity for MiTF, estrogen receptor, and PAX8 was defined as a positive result. The distribution of positive cells (patchy or diffuse) was also recorded. Slides were reviewed to record the size, focality, growth patterns, and distribution of LAM within the involved lymph nodes; the presence of mitoses, nuclear atypia, or necrosis; and the presence of concurrent intranodal lesions such as endosalpingiosis, endometriosis, or metastatic cancer. In addition to measuring the maximum dimension of LAM, a visual estimate of the percent of the cross-sectional area of the lymph node occupied by LAM was also made. Clinical information and outcome data were retrieved from electronic medical records. Because this was a retrospective study, not every patient had specific clinical or radiologic data available to evaluate for the presence of pulmonary LAM. At the time of the original pathologic diagnosis of lymph node LAM in these patients, the possible association with TSC was raised, and clinical evaluation was suggested in the pathology report. Therefore, we also

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obtained follow-up data from our institution’s Cancer Risk Program, which provides patients with clinical evaluation, diagnosis, and counseling for potential hereditary syndromes, including TSC, by clinical medical geneticists and genetic counselors.

RESULTS Clinical Features Twenty-six patients were identified with LAM involving a lymph node from any extrathoracic site (Table 1). All patients were female (average age, 56 y). None of the patients had a history of pulmonary LAM or respiratory failure. One of 26 patients carried a diagnosis of TSC that was established before the surgery leading to the diagnosis of lymph node LAM. The diagnosis of LAM was made in lymph nodes removed during the surgical staging of a pelvic tumor in 25/26 patients and during the surgical staging of a urinary bladder cancer in 1/26 patients. Lymph node LAM was not diagnosed in any other clinical setting. The most common gynecologic tumor was endometrial endometrioid adenocarcinoma (14/25 patients), and the remainder included a range of primary uterine, ovarian, and cervical/vaginal tumors (Table 1). Pelvic lymph nodes were dissected in all 26 patients; the median number of nodes per patient was 15. Para-aortic lymph nodes were dissected in 12/26 patients; the median number of nodes per patient was 7. Three of the 15 patients who underwent surgery at our institution and who did not already carry a diagnosis of TSC elected to undergo evaluation for TSC at our Cancer Risk Program. One patient was confirmed to have TSC on the basis of clinical criteria.10 Germline testing revealed a mutation in TSC2. Because her pedigree analysis revealed no other affected family member, the TSC2 mutation was interpreted to likely represent a de novo mutation. No evidence for TSC was found in the other 2 patients who were evaluated. Three patients who underwent surgery at our institution also followed through with formal evaluation for pulmonary LAM by pulmonary specialists, including radiologic evaluation. None of these patients was diagnosed with pulmonary LAM. Among the patients undergoing surgery at our institution, all were alive (median 18 mo follow-up; range, 3 to 156 mo), and 1 patient developed local recurrence of uterine cancer.

Pathologic Findings Lymph node LAM was confined to a single lymph node in 12/26 patients and involved multiple lymph nodes (range, 2 to 19 involved nodes) in 14/26 patients (Table 2). None of the involved lymph nodes had grossly visible abnormalities. The median size of lymph node LAM was 3.5 mm, ranging from under 1 mm to nearly 2 cm in diameter (Fig. 1). The median percent of the lymph node section occupied by LAM was approximately 20%, ranging from under 1% to nearly 100%. Copyright

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Incidental Lymph Node LAM

TABLE 1. Clinical Features of Patients With Lymph Node LAM

TABLE 2. Pathologic Features of Lymph Node LAM

Age, median (range) (y) 56 (31-79) Female sex 26/26 Clinical diagnosis of TSC 2/26 (ages 31, 45) Pulmonary LAM 0/26 Surgical procedure with nodal dissection TAH, BSO 20 TAH only 3 BSO only 1 Radical hysterectomy 1 Lymph node biopsy only 1 No. lymph nodes submitted, median (range) Pelvic (26/26 patients) 15 (1-50) Para-aortic (12/26 patients) 7 (1-9) Primary uterine tumor (17/26 patients) Endometrioid adenocarcinoma 14 (4 grade 1; 6 grade 2; 2 grade 3; 2 not reviewed) Atypical hyperplasia 1 Endometrial carcinosarcoma 1 Uterine PEComa 1 Primary ovarian tumor (5/26 patients) High-grade serous carcinoma 2 Clear cell carcinoma 1 Endometrioid adenocarcinoma 1 Mucinous borderline tumor 1 Primary cervical/vaginal tumor (3/26 patients) Invasive squamous cell carcinoma 3 (all poorly differentiated) Primary urinary bladder tumor (1/26 patients) Urothelial carcinoma 1 (poorly differentiated)

Laterality of nodes with LAM No. nodes with LAM (range) Single node Multiple nodes Median number of nodes with LAM No. foci of LAM Single focus Multiple foci Size of LAM (largest focus if multifocal), median (range) (mm) Percent of node replaced by LAM, median (range) (%) Topography of intranodal LAM Confined to subcapsular space Present in nodal parenchyma Present in extranodal adipose Present in extranodal lymphatic spaces Concurrent pathology in node with LAM Metastatic cancer Endosalpingiosis Reactive lymphoid hyperplasia Immunohistochemistry HMB45 MiTF MelanA Smooth muscle actin Desmin D240 Estrogen receptor

BSO indicates bilateral salpingo-oophorectomy; LAM, lymphangioleiomyoma; TAH, total abdominal hysterectomy; TSC, tuberous sclerosus complex.

*1 case with negative HMB45 was positive for MiTF, D240, actin, desmin, and ER and exhibited classical morphology of LAM.

In most patients (22/26), LAM was located within the parenchyma of the lymph node, but in 4 patients, it was confined to the subcapsular space. Separate microscopic foci of LAM were also present in the extranodal adipose tissue of 3 patients. Detached floating microscopic clusters of LAM cells were identified in extranodal lymphatic channels of 3 patients. The classical growth pattern of nodules and nests of bland myoid-appearing spindle cells within a background of lymphatic channels was discernible, at least focally, in the lymph node LAM of all patients (Fig. 2). An additional growth pattern of densely packed intersecting fascicles of the same LAM cells, without discernible lymphatic channels, was also present in 16/26 patients. This fascicular pattern merged directly with the more classical growth pattern, providing the key diagnostic clue that the fascicular proliferation was a form of LAM. Although lymphatic channels were not easily appreciated on hematoxylin and eosin staining, they became readily apparent as compressed channels in between the fascicles on D240 immunohistochemical-stained slides. There was no necrosis in any lymph node LAM. Cytologically, the LAM cells had a distinctly myoid appearance in terms of the spindle shape of the cells and of the nuclei; however, instead of the dense fibrillar eosinophilic cytoplasm that is typical of smooth muscle cells, the cytoplasm of the LAM cells ranged from eosinophilic to clear to slightly foamy. No nuclear atypia or mitotic activity was present in any case.

HMB45 was positive in 24/25 cases. The staining distribution was focal and patchy (< 25% of the LAM cells) in 21/24 cases and was diffuse (> 50% of the LAM cells) in 3 cases (Fig. 3). The staining intensity was weak overall in all cases. Positive staining LAM cells exhibited a granular, punctate, or perinuclear pattern in the cytoplasm. A minority of LAM cells exhibited moderate intensity cytoplasmic staining. In the 1 HMB45-negative case, the morphology was classical for LAM, and the cells were positive for MiTF, estrogen receptor, smooth muscle actin, and desmin, whereas D240 highlighted the characteristic lymphatic channels. One case of lymph node LAM was not tested immunohistochemically, because the similar-appearing concurrent LAM in the uterine wall was shown to be positive for HMB45, smooth muscle actin, desmin, and D240. Tissue blocks of the lymph node LAM in that case were not available for testing for this study. MiTF was positive in 12/14 cases and exhibited a diffuse staining pattern of moderate to strong intensity in all positive cases. MelanA was positive in 2/12 cases in a focal distribution with weak to moderate intensity. D240 staining highlighted the lymphatic endothelium lining the edges of the nests of spindle cells in areas of classical growth. D240 was positive in 15/15 cases and exhibited strong intensity staining of the endothelial lining of lymphatic channels. D240 was particularly useful to highlight compressed lymphatic channels within areas of more solid-appearing, fascicular growth patterns of LAM. Estrogen receptor was positive in 15/15

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20/26 unilateral 6/26 bilateral 12/26 14/26 (2-19) 2 11/26 15/26 3.5 (< 1 to >19) 20 (< 1 to >95) 4/26 22/26 3/26 3/26 3/26 3/26 13/26 24/25* 12/14 2/12 23/23 15/16 15/15 15/15

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FIGURE 1. A, The median size of LAM within a lymph node was 3.5 mm, occupying approximately 20% of the node. In some cases, LAM nearly replaced the entire lymph node, spanning up to 2 cm (B) whereas in other cases only a microscopic deposit of LAM was present in the subcapsular sinus (C) or within the parenchyma of the node (D). The microscopic deposits were confirmed to be LAM by immunohistochemistry.

cases, showing a diffuse pattern of moderate to strong intensity. Smooth muscle actin (23/23) and desmin (15/16) exhibited diffuse staining patterns of moderate to strong intensity. PAX8 was negative in 6/6 cases. Concurrent pathology in the involved nodes included metastatic cancer (3 patients), endosalpingiosis (3 patients), and reactive lymphoid hyperplasia (13 patients) (Fig. 4). Conventional uterine leiomyomas were present in 17/26 patients. Adenomyosis was observed in 11/26 patients and pelvic endometriosis in 3 patients.

Concurrent PEComa-family Pathologic Findings Uterine LAM was present in 4/26 patients with lymph node LAM (Table 3). In 2 patients, that was the only additional PEComa-related pathology. Both of these patients (ages 47 and 79 y) were being staged for endometrial endometrioid adenocarcinoma and had multiple lymph nodes that contained LAM. Neither of them carried a diagnosis of TSC. The third patient with concurrent lymph node and uterine LAM also had a uterine

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PEComa. This patient had a history of TSC-associated manifestations and was eventually shown to carry a TSC2 mutation. The fourth patient with concurrent lymph node and uterine LAM was known to have TSC before her staging surgery for endometrial endometrioid adenocarcinoma, during which she was also found to have an AML of the vagina.

DISCUSSION This study demonstrates that extrapulmonary LAM may present as an incidental finding in lymph nodes removed during surgical staging of pelvic cancer in patients. The majority (24/26) of the patients in our study lacked overt manifestations of TSC. None of the patients had respiratory symptoms to suggest pulmonary LAM. Morphologically, all cases exhibited the distinct, classical growth pattern of LAM; however, several variations were observed, including (1) a fascicular pattern mimicking leiomyoma, (2) coexistence with metastatic carcinoma, and (3) coexistence with endosalpingiosis. There are 3 Copyright

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FIGURE 2. The classical appearance of LAM consists of bundles of bland spindle cells (A and C) set within anastomosing lymphatic channels. E, The lymphatic endothelium lining the bundles is D240 positive. However, some cases of LAM also exhibited a solid fascicular growth pattern (B and D) resembling a leiomyoma, and the lymphatic channels were so compressed that they were challenging to recognize (D) without D240 staining (F). In both growth patterns (G and H), the spindle cells are HMB45 positive.

practical implications of the findings in this study. First, patients found to have lymph node LAM in this clinical setting should be considered for formal evaluation for Copyright

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TSC, although it is of low likelihood that they are affected by TSC. Second, lymph nodes in this clinical setting that contain a fascicular spindle cell proliferation resembling



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FIGURE 3. A, HMB45 staining was typically in a focal or patchy distribution. B, Cytoplasmic staining for HMB45 was generally punctate or granular. C, MiTF nuclear staining was usually diffuse and moderate or strong intensity. D, MelanA cytoplasmic staining was focal and weak. Smooth muscle actin (E) and desmin (F) staining was generally diffuse and moderate or strong intensity.

leiomyoma merit further evaluation for more classical features of LAM to prevent missing the opportunity to evaluate for TSC. Third, pathologists should be aware that the diagnosis of lymph node LAM does not preclude

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the possibility that the same node may contain microscopic deposits of metastatic cancer. Controversy exists in the literature regarding the relationship between lymph node LAM, pulmonary LAM, Copyright

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FIGURE 4. Unusual variations of lymph node LAM included coexisting metastatic carcinoma (A–E) and coexisting endosalpingiosis (F). A and B, Deposits of metastatic urinary bladder carcinoma are admixed with the bundles of LAM. Keratin staining highlights the carcinoma (C), and HMB45 highlights the LAM (D). E, Microscopic deposits of metastatic endometrial adenocarcinoma within lymph node LAM could be potentially easily overlooked. F, The combination of the glandular architecture of endosalpingiosis and the spindle cell appearance of LAM could be misinterpreted as carcinosarcoma; however, there is no atypia in either component.

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TABLE 3. Additional PEComa-related Pathology in Patients With Lymph Node LAM Clinical Diagnosis of TSC

Age (y)

Nodes With LAM (n)

1

Yes

31

1

2

Yes

45

19

3 4

No No

47 79

10 2

Patient

PEComa-related Pathology in Concurrent Specimen Uterine PEComa Uterine LAM Uterine LAM Vaginal AML Uterine LAM Uterine LAM

Primary Indication for Surgery Uterine PEComa Uterine endometrioid cancer Uterine endometrioid cancer Uterine endometrioid cancer

None of the remaining 22/26 patients had extranodal LAM, PEComa, or AML.

and TSC. Several studies, ranging from single-case reports to a series of 8 patients, have reported lymph node LAM in TSC patients, many of whom also had pulmonary LAM.2,5–9 Most of those patients also had uterine LAM and/or uterine PEComa. In contrast, there were 4 cases reported of lymph node LAM detected incidentally during pelvic cancer staging in patients without pulmonary LAM, uterine LAM, or TSC.3,4 Our study adds another 24 patients to the latter category of patients, although we cannot fully exclude TSC in the subset of patients who did not elect to follow our recommendation for evaluation by a clinician with expertise in TSC diagnosis. Diagnostic criteria for TSC have been set by the International TSC Consensus Group, which issued the most recent evidence-based update in 2012.10–12 Although detection of a germline mutation in TSC1 or TSC2 is sufficient to diagnose TSC, a negative result is noninformative, because up to 20% of TSC patients do not carry a germline mutation that can be detected using conventional genetic testing. Therefore the diagnosis is largely based on clinical criteria that are separated into 11 major features and 6 minor features involving a broad spectrum of organ systems. A definite diagnosis of TSC requires 2 major features or 1 major feature with 2 or more minor features. The criteria reflect that TSC is a multiorgan genetic disease of variable penetrance and expressivity. Most TSC lesions are either benign neoplasms, hamartomas, or benign anatomic alterations that most commonly involve the skin, oral cavity, eyes, central nervous system, heart, lungs, and/or kidney. The histopathology of TSC lesions is diverse, and a subset includes some of the tumors that are considered part of the PEComa tumor family. The relationship between TSC and the PEComa tumor family is not straightforward. A subset of patients with pulmonary LAM and multiple AMLs may have TSC, but these diseases can also arise in non-TSC patients. Therefore pulmonary LAM and multiple AMLs must be accompanied by 1 other major feature to meet diagnostic criteria for TSC. Conversely, PEComa of gynecologic or soft tissue origin, clear cell tumor of the lung, and other members of the PEComa tumor family are not considered to be criteria for TSC. Notably, extrapulmonary LAM is not included either. It is unclear whether it was deliberately excluded from being a diagnostic criterion on the basis of specific evidence or whether extrapulmonary LAM is so rare that it simply has not been evaluated as a possible major or minor diagnostic criterion.

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Further complicating the question of whether extrapulmonary LAM is an independent diagnostic criterion for TSC is the uncertain relationship between pulmonary LAM and extrapulmonary LAM. The incidence of symptomatic or clinically detectable extrapulmonary LAM among patients with pulmonary LAM was 11% in 1 study of 188 patients. The lesions presented as a mass (average size of 5.3 cm, maximal size of 20 cm) in the mediastinum, retroperitoneum, or pelvis.2 The incidence may be even higher for asymptomatic, clinically occult extrapulmonary LAM, as was suggested by a study that performed exhaustive histopathologic examination of the gynecologic organs in 10 pulmonary LAM patients at autopsy or at the time of gynecologic surgery.6 All but 1 patient had multifocal LAM, ranging from a few millimeters in size to 3 cm, involving the uterine wall, ovary, and/or broad ligament. Lymph node LAM was also observed in most of the patients. Conversely, the incidence of pulmonary LAM among patients with extrapulmonary LAM is difficult to determine for several reasons. First, pulmonary LAM typically presents with symptoms at an early age (on average in the third decade), and extrapulmonary LAM is often diagnosed during the workup of the patient’s pulmonary LAM.13–17 Therefore, much of the literature on extrapulmonary LAM is based on patients already known to have pulmonary LAM.2 Second, not all cases of pulmonary LAM are initially symptomatic when the characteristic pulmonary cysts are clinically detectable.16,18–20 Open lung biopsy is considered the gold standard for diagnosis of pulmonary LAM, but this is only performed for symptomatic patients. A presumptive diagnosis can be made by the clinicoradiologic constellation of bilaterally diffuse, small, thin-walled cysts on high-resolution chest computed tomography plus a history of TSC, AML, extrapulmonary LAM, and/or chylothorax.21 This means that high-resolution chest computed tomography should be performed in a study to truly evaluate the incidence of pulmonary LAM in patients with extrapulmonary LAM, but none of the studies to date has done so. However, as an alternative approach, patient age can be used as a surrogate to predict the likelihood of pulmonary LAM. Because the natural history of this disease is to progress to respiratory failure within 10 years of diagnosis,22,23 and because most patients are diagnosed around the age of 35 years, it is Copyright

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unlikely that patients in their fifth decade or older without respiratory failure have pulmonary LAM or will develop it. Only rare cases of late-onset pulmonary LAM have been reported.24 In our study, the average patient age was 56 years, and none had symptomatic respiratory disease. This makes it unlikely that these patients with incidental lymph node LAM had pulmonary LAM. Similarly, the patients in the 4 other case reports of incidental lymph node LAM were of ages 47 to 71 years, and none had respiratory symptoms.3,4 We conclude that a subset of extrapulmonary LAM, specifically incidentally detected lymph node LAM, can be found in patients who do not have pulmonary LAM. From a practical perspective, we propose that pathologists document the possibility, albeit low, of TSC when lymph node LAM is diagnosed in pelvic cancer staging specimens. Doing so will enable the clinician to determine whether formal evaluation for TSC is appropriate.10 A multidisciplinary approach to evaluating a patient for TSC is advised, given the multisystem involvement and variable expression of the syndrome.10 As patients with TSC may potentially develop diseases in nearly every organ over the course of their lifetime, early diagnosis of TSC will maximize the benefits of surveillance, management, and early intervention. Organ-specific recommendations for surveillance and management have been proposed.25 Furthermore, there are promising results in pulmonary LAM and AML patients with the use of targeted pharmacologic inhibitors of the mammalian target of rapamycin pathway, which is dysregulated in these diseases.26–31 This is another justification for formally pursuing a possible diagnosis of TSC even if the evidence, albeit limited, suggests that incidental lymph node LAM is likely not associated with TSC. In our study, only a minority of patients sought evaluation for TSC by our clinical medical genetics service or evaluation for pulmonary LAM. Low patient uptake of genetic counseling recommendations has been reported in other settings in which diagnostic pathology findings are suspicious for an inherited or syndromic disease. This has recently been described by several institutions among colorectal and endometrial cancer patients with abnormal Lynch syndrome screening tests.32–34 A variety of psychological and/or insurancerelated issues may explain part of the low uptake, but the adequacy of patient education by clinicians may also be a factor. We propose that a clearly worded and referenced surgical pathology report can contribute to increasing the likelihood that a patient seek appropriate counseling. The pathologic diagnosis of lymph node LAM is generally straightforward in cases exhibiting classical morphology. However, we observed that over half of our cases also exhibited a notable component of a fascicular growth pattern that resembled a smooth muscle proliferation. In these cases the lymphatic channels in between the fascicles of spindle cells were compressed to the point that they were difficult to discern in routine stained slides, although D240 immunohistochemistry clearly highlighted their presence. The differential diagnosis inCopyright

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cludes a variety of rare smooth muscle neoplasms that may involve intra-abdominal lymph nodes, including intranodal leiomyoma and lymph node involvement in the setting of disseminated peritoneal leiomyomatosis or intravascular leiomyomatosis of the uterus. Angiomyomatous hamartoma of lymph node may also contain a fascicular proliferation of myoid cells.35–40 Examination of the tissue adjacent to the fascicular spindle cell proliferation and thorough examination of the rest of the lymph node, including deeper level sections, may reveal the classical nested and nodular architecture of LAM. Because all of the entities in this differential diagnosis are uncommon, immunohistochemistry to exclude LAM may be prudent. It is possible that cases previously classified as intranodal leiomyoma may actually represent lymph node LAM. We note that the figures in at least 1 case report of intranodal leiomyoma exhibit morphologic features that are compatible with LAM; the case was reported before the use of contemporary immunohistochemical markers.38 The key stain for lymph node LAM is HMB45, and it is important to be aware of its usual staining pattern. Unlike the smooth muscle markers in LAM, which exhibit strong and diffuse staining, HMB45 is usually focal and weak, to the degree that medium to high magnification should be used to evaluate this stain. Using low magnification to interpret HMB45 will likely result in a false-negative interpretation. Other authors also draw attention to this issue with HMB45 not only in LAM but in other tumors of the PEComa as well, such as AML and gynecologic PEComa.3,41–44 Additional melanocytic markers can be used to assist in cases of equivocal stain results for HMB45. In our study, MiTF reliably marked lymph node LAM with moderate to strong intensity in the vast majority of the spindle cells. The nuclear pattern of expression makes MiTF an excellent choice to accompany HMB45. In the rare setting of a lesion that exhibits classical morphology of lymph node LAM but is HMB45 negative, MiTF appears to be an acceptable substitute as long as the remainder of the immunophenotype (myoid markers, estrogen receptor, and D240) also shows classical results. Other authors report that MelanA is useful in the tumors of the PEComa family.43 In our study, the sensitivity of MelanA for lymph node LAM was low. Although LAM cells express estrogen receptors, a positive result does not distinguish LAM from leiomyoma, as the latter can express estrogen receptors as well. Two additional potential diagnostic pitfalls merit attention when evaluating lymph node LAM in patients undergoing surgical staging for cancer. First, a lymph node may harbor both LAM and metastatic cancer. The 2 lesions may be present in different parts of the same lymph node, or the metastasis may be embedded within the LAM itself. Thus, although attention is being directed to the intranodal spindle cell proliferation, the lymph node should still be carefully evaluated for the original reason it was dissected. In 1 of our cases of coexisting LAM and metastatic cancer, the metastatic tumor cells were so scant that it is easily conceivable that they could



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have gone unrecognized. The second potential diagnostic pitfall may occur when endosalpingiosis is present within the LAM. As other authors have also reported,45 we found instances in which a few simple glands composed of cytologically benign, tubal-type columnar epithelium, which otherwise resemble endosalpingiosis, were embedded within the lymph node LAM. This combination of intimately admixed glandular epithelium and spindle cell proliferation should not be interpreted as metastatic carcinosarcoma or metastatic adenocarcinoma. The absence of nuclear atypia and atypical mitoses in the glandular epithelium and the absence of atypia and mitotic activity in the spindle cells are the key features to recognize in order to avoid overdiagnosis as metastatic malignancy. In summary, lymph node LAM does not appear to be associated necessarily with TSC or pulmonary LAM when detected as an incidental finding during staging surgery for pelvic cancer. The association seems to be of low likelihood. Nevertheless, these patients may benefit from formal exclusion of TSC and pulmonary LAM, especially given the diagnostic complexity of both diseases and opportunities for early management. ACKNOWLEDGMENTS The authors thank Beth Crawford, MS, for assistance with data from our institution’s Cancer Risk Program. REFERENCES 1. Meraj R, Wikenheiser-Brokamp KA, Young LR, et al. Lymphangioleiomyomatosis: new concepts in pathogenesis, diagnosis, and treatment. Semin Respir Crit Care Med. 2012;33:486–497. 2. Matsui K, Tatsuguchi A, Valencia J, et al. Extrapulmonary lymphangioleiomyomatosis (LAM): clinicopathologic features in 22 cases. Hum Pathol. 2000;31:1242–1248. 3. Iwasa Y, Tachibana M, Ito H, et al. Extrapulmonary lymphangioleiomyomatosis in pelvic and paraaortic lymph nodes associated with uterine cancer: a report of 3 cases. Int J Gynecol Pathol. 2011;30:470–475. 4. Song DH, Choi IH, Ha SY, et al. Extrapulmonary lymphangioleiomyoma: clinicopathological analysis of 4 cases. Korean J Pathol. 2014;48:188–192. 5. Gyure KA, Hart WR, Kennedy AW. Lymphangiomyomatosis of the uterus associated with tuberous sclerosis and malignant neoplasia of the female genital tract: a report of two cases. Int J Gynecol Pathol. 1995;14:344–351. 6. Hayashi T, Kumasaka T, Mitani K, et al. Prevalence of uterine and adnexal involvement in pulmonary lymphangioleiomyomatosis: a clinicopathologic study of 10 patients. Am J Surg Pathol. 2011;35: 1776–1785. 7. Liang SX, Pearl M, Liu J, et al. “Malignant” uterine perivascular epithelioid cell tumor, pelvic lymph node lymphangioleiomyomatosis, and gynecological pecomatosis in a patient with tuberous sclerosis: a case report and review of the literature. Int J Gynecol Pathol. 2008;27:86–90. 8. Longacre TA, Hendrickson MR, Kapp DS, et al. Lymphangioleiomyomatosis of the uterus simulating high-stage endometrial stromal sarcoma. Gynecol Oncol. 1996;63:404–410. 9. Lim GS, Oliva E. The morphologic spectrum of uterine PEC-cell associated tumors in a patient with tuberous sclerosis. Int J Gynecol Pathol. 2011;30:121–128. 10. Northrup H, Krueger DA. International Tuberous Sclerosis Complex Consensus G. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013; 49:243–254.

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Tuberous sclerosis complex presenting as pulmonary lymphangioleiomyomatosis--a clinicoradiological diagnosis.

Pulmonary lymphangioleiomyomatosis: a "forme fruste" of tuberous sclerosis?

Tuberous sclerosis complex 2 loss increases lysophosphatidylcholine synthesis in lymphangioleiomyomatosis.

Pharmacokinetics and pharmacodynamics of everolimus in patients with renal angiomyolipoma and tuberous sclerosis complex or lymphangioleiomyomatosis.

Association of oestrogen-containing contraceptives with pulmonary lymphangioleiomyomatosis in women with tuberous sclerosis complex--findings from a survey.

Recovery of chylous pulmonary congestion in tuberous sclerosis complex-associated lymphangioleiomyomatosis.

Patterns of pelvic and paraaortic lymph node involvement in ovarian cancer.

[Pulmonary lymphangioleiomyomatosis of unusual revelation during multiple sclerosis].

Pulmonary lymphangioleiomyomatosis.

Staging laparoscopic pelvic lymph node dissection. Experience and indications.

Clinicopathological study on para-aortic lymph node metastasis without pelvic lymph node metastasis in endometrial cancer.

Everolimus for renal angiomyolipoma in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis: extension of a randomized controlled trial.

Staging laparoscopic pelvic lymph node dissection: comparison of results with open pelvic lymphadenectomy.

Pulmonary mechanics in lymphangioleiomyomatosis.

Laparoscopic radical hysterectomy with paraaortic and pelvic node dissection.

Laparoscopic pelvic lymph node dissection.

How important is the number of pelvic lymph node retrieved to locorregional staging of cervix cancer?

Pulmonary lymphangioleiomyomatosis in a male.

Two cases of pulmonary lymphangioleiomyomatosis in postmenopausal women.

Implications of para-aortic lymph node metastasis in patients with endometrial cancer without pelvic lymph node metastasis.

Extraperitoneal endoscopic pelvic lymph node dissection vs. laparoscopic lymph node dissection in the staging of prostatic and bladder carcinoma.

Prophylactic pelvic lymph node dissection in patients with penile cancer.

Salvage pelvic lymph node dissection in recurrent prostate cancer: surgical and early oncological outcome.

Lymphangioleiomyomatosis.