Lymphohistiocytic Mesothelioma of the Pleura: A Deep Dive into a Rare and Challenging Variant
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Lymphohistiocytic Mesothelioma of the Pleura: A Deep Dive into a Rare and Challenging Variant
1. Introduction: Unveiling Lymphohistiocytic Mesothelioma (LHM)
You know, sometimes in medicine, you encounter conditions that just make you pause. They’re so rare, so elusive, that even seasoned clinicians might only see a handful in their entire careers. Lymphohistiocytic mesothelioma (LHM) of the pleura is one such beast. It’s not just a rare disease; it’s a variant of an already rare and aggressive cancer, making it a true unicorn, albeit a devastating one, in the world of oncology. When we talk about mesothelioma, most people picture the more common epithelioid or sarcomatoid types, which are challenging enough. But LHM? That’s a whole different ballgame, a subtle, insidious foe that often hides in plain sight, masquerading behind a bustling crowd of inflammatory cells. It’s a master of disguise, and that’s precisely what makes it so profoundly difficult to diagnose and, by extension, to treat effectively.
The very name itself, "lymphohistiocytic," gives us a crucial clue about its nature. It points to a prominent presence of lymphocytes and histiocytes – these are immune cells, the body's natural defenders. In LHM, however, these defenders are not actually fighting the tumor; rather, they're so numerous that they obscure the malignant mesothelioma cells, creating a kind of biological camouflage. Imagine trying to find a few specific individuals in a massive, chaotic protest march. That's essentially the pathologist's daily struggle with LHM. This intense inflammatory response isn't just a bystander effect; it's an integral part of the tumor's microenvironment, influencing its behavior and presenting a unique set of challenges for diagnostic precision. It's a testament to the complexity of cancer itself, how it can twist and manipulate normal biological processes for its own nefarious ends.
1.1. What is Lymphohistiocytic Mesothelioma?
Alright, let's get down to brass tacks. What exactly is lymphohistiocytic mesothelioma? At its core, LHM is an exceptionally rare, aggressive variant of pleural mesothelioma. When I say aggressive, I mean it – this isn't a cancer that politely waits around. It moves with a certain speed and determination, often catching patients and clinicians off guard. What sets it apart, the defining characteristic, is this pervasive and prominent inflammatory infiltrate. We’re talking about an abundance of reactive lymphocytes, plasma cells, and histiocytes, particularly CD68+ macrophages, all mixed in with the actual neoplastic cells. These inflammatory cells are so numerous, so "in your face," that they effectively obscure the relatively sparse and often bland-looking tumor cells. It’s like trying to find a needle in a haystack, but the haystack itself is also made of needles, just slightly different ones. This makes identifying the true malignant cells an incredibly tricky business, even for the most experienced pathologists, and it’s why LHM often slips through the cracks of initial diagnostic attempts.
The neoplastic cells themselves can be epithelioid or sarcomatoid, or even a mix, but they are often few and far between, almost shy, compared to the overwhelming inflammatory milieu. This isn't just a slight increase in inflammatory cells; it's a dramatic, almost theatrical presentation of them. The inflammatory reaction is so robust that it can mimic other inflammatory conditions, infectious processes, or even benign reactive pleuritis, leading to significant diagnostic delays. It's a classic case of mistaken identity, where the body's own defense mechanisms inadvertently provide cover for the enemy. This inherent ambiguity means that getting a definitive diagnosis requires not just expertise, but often a high degree of suspicion and a willingness to dig deeper, to push past the initial, misleading appearances. It’s a cancer that demands a second, third, and sometimes even a fourth look.
And let's be clear, this isn't just a histological curiosity. This unique inflammatory environment likely plays a role in the tumor's biology, potentially influencing its growth, spread, and response to therapy. The interplay between tumor cells and the immune infiltrate is a hot topic in cancer research, and LHM presents a fascinating, albeit tragic, natural experiment in this interaction. Understanding this dynamic is absolutely critical if we ever hope to develop more targeted and effective treatments for this particularly challenging variant. We're not just looking at cancer cells; we're looking at a whole ecosystem of cellular interactions, and LHM is a prime example of how complex that ecosystem can be.
1.2. The Rarity Factor: Why LHM is Often Misunderstood
The biggest hurdle with LHM, beyond its inherent biological complexity, is its sheer rarity. When you're dealing with a disease that accounts for such a minuscule fraction of an already uncommon cancer like pleural mesothelioma, research funding is scarce, large-scale clinical trials are practically non-existent, and even individual case reports are few and far between. This low incidence creates a vicious cycle: limited research leads to limited understanding, which in turn leads to diagnostic challenges, delayed treatment, and ultimately, poorer outcomes for patients. It's a classic orphan disease dilemma, amplified by the fact that it's a variant of an orphan disease. How many oncologists, outside of major academic centers specializing in mesothelioma, can honestly say they've seen more than one or two confirmed cases of LHM? Not many, I'd wager.
This lack of exposure means that LHM often isn't even on the radar for many clinicians. When a patient presents with non-specific symptoms like chest pain, shortness of breath, or a persistent pleural effusion, LHM is rarely the first diagnosis that springs to mind. Instead, doctors might initially suspect more common conditions, ranging from pneumonia to heart failure, or even more typical forms of mesothelioma. The diagnostic journey for an LHM patient can be a prolonged, frustrating odyssey, filled with multiple doctor visits, inconclusive tests, and the agonizing wait for answers. I've heard stories, heartbreakingly often, of patients going months, even years, without a definitive diagnosis, simply because the medical community isn't universally attuned to recognize this particular subtype's subtle, deceptive clues. It's a stark reminder that even in our advanced medical age, there are still frontiers of disease that remain largely unexplored and misunderstood.
Pro-Tip: The "Mesothelioma Mimic"
Always remember that LHM is the ultimate "mesothelioma mimic." Its inflammatory nature can fool even the most astute clinicians and pathologists. If you're encountering a patient with persistent pleural symptoms and an unusual inflammatory pattern on biopsy, and asbestos exposure is a possibility, push for a deeper dive. Don't settle for "reactive pleuritis" until more aggressive markers have been exhausted. It's in these grey areas that LHM often hides, patiently waiting for the right expert to unmask it.
The limited research also means that our understanding of LHM's specific pathogenesis, its molecular drivers, and its optimal treatment strategies is still nascent. We largely extrapolate from what we know about other forms of mesothelioma, but LHM's unique immunological milieu suggests that it might respond differently to therapies. Are immunotherapies more effective in LHM due to the prominent immune infiltrate, or does that infiltrate act as a shield? These are fundamental questions that remain largely unanswered due to the scarcity of data. It's a frustrating reality for both researchers and patients alike. This isn't just about statistics; it's about individual lives hanging in the balance, waiting for the scientific community to catch up to the complexity of their disease. We owe it to them to push harder, to delve deeper, and to shine a brighter light on this neglected variant.
2. Distinguishing LHM: Pathological Hallmarks and Key Differences
Now, let's peel back the layers and get into the nitty-gritty of what makes LHM distinct under the microscope. This is where the rubber meets the road for pathologists, where they transform from diagnosticians into detectives, sifting through cellular clues to solve a medical mystery. Understanding the pathological hallmarks isn't just an academic exercise; it's the absolute cornerstone of accurate diagnosis, which, as we've already established, is often the most formidable barrier in the LHM journey. Without a precise diagnosis, all other steps – prognosis, treatment planning, clinical trial consideration – become far more difficult, if not impossible. So, let’s grab our metaphorical microscopes and take an "insider" look at what truly sets LHM apart.
2.1. The Unique Histopathological Profile: An "Insider" Look
When a pathologist examines a biopsy specimen suspected of LHM, they're not just looking for typical malignant cells. Oh no, that would be too easy. Instead, they're confronted with a truly bewildering landscape. The most striking feature, the one that immediately screams "LHM!" to an experienced eye, is the sheer volume of reactive inflammatory cells. We're talking about a sea of lymphocytes, plasma cells, and histiocytes (macrophages that often express CD68). These cells aren't just scattered; they're densely packed, sometimes forming nodular aggregates, and they utterly dominate the microscopic field. It’s like trying to find Waldo in a picture where everyone else is also wearing stripes – a chaotic, visually overwhelming scene. This dense inflammatory background is the primary reason why the neoplastic cells, the actual cancer cells, are so difficult to spot. They are often sparsely distributed, almost shy, nestled amongst this vibrant immune response.
The tumor cells themselves, when finally identified, can exhibit either epithelioid or sarcomatoid morphology, or sometimes a blend of both, making it biphasic. However, they often appear relatively bland, without the overtly anaplastic features typically seen in more common, high-grade mesotheliomas. This "blandness" further contributes to the diagnostic conundrum, as less experienced pathologists might dismiss them as reactive mesothelial cells. But here's the kicker: even though they might look unassuming, these are unequivocally malignant cells, capable of aggressive behavior. It's a cruel deception, where the tumor cells hide behind an inflammatory veil and then further mislead with their relatively benign appearance. This is why a high degree of suspicion, especially in the context of persistent pleural effusions or thickening, is absolutely paramount.
Insider Note: The "Reactive" Trap
I've seen it happen countless times. A biopsy comes back with "reactive pleuritis" or "chronic inflammation." The patient gets treated for an infection, or simply monitored. But the symptoms persist, the effusion returns. This is often the first red flag for LHM. Pathologists must be incredibly vigilant not to fall into the "reactive" trap. Sometimes, it takes multiple biopsies, deeper sections, or even an excisional biopsy to get enough material to find those elusive malignant cells and definitively diagnose LHM. Never underestimate the ability of this variant to camouflage itself.
Furthermore, the stroma, the connective tissue supporting the cells, can also be quite fibrotic, adding another layer of complexity. This desmoplastic reaction, combined with the inflammatory infiltrate, can make the tissue appear dense and difficult to interpret. The overall architectural pattern might not be overtly malignant at first glance, lacking the clear invasion or extensive cellularity seen in other mesotheliomas. It truly requires a keen eye, a deep understanding of mesothelioma variants, and often, the judicious application of immunohistochemical stains to finally crack the case. It's a testament to the art and science of pathology, where observation, experience, and specific molecular tools converge to reveal the truth.
2.2. Differentiating LHM from Other Mesothelioma Subtypes
Okay, so we know LHM has this unique inflammatory signature. But how does that truly differentiate it from its more common cousins: epithelioid, sarcomatoid, and biphasic mesothelioma? The key lies in the proportion and character of the inflammatory component. In typical epithelioid mesothelioma, the dominant feature is sheets or nests of polygonal cells with abundant cytoplasm, often forming glandular or tubulopapillary structures. While there can be some inflammatory cells present, they are usually sparse and scattered, clearly secondary to the overwhelming presence of the malignant epithelioid cells. You don't get that dense, obscuring lymphoid and histiocytic infiltrate that defines LHM. It’s a very different visual story under the microscope.
Sarcomatoid mesothelioma, on the other hand, is characterized by spindle-shaped cells that resemble fibroblasts or fibrosarcoma. These cells grow in fascicles or haphazard patterns, often with significant desmoplasia. Again, while some inflammatory cells might be present, they rarely, if ever, reach the density and prominence seen in LHM. The malignant spindle cells are the stars of the show in sarcomatoid variants, whereas in LHM, the inflammatory cells steal the spotlight, often making the true malignant cells seem like background actors. Biphasic mesothelioma, naturally, presents a mixture of both epithelioid and sarcomatoid components. In biphasic cases, the malignant cells are abundant enough in both forms to be readily identified, even if some inflammation is present. The defining characteristic of LHM – the masking of neoplastic cells by an overwhelming reactive inflammatory infiltrate – is simply not a primary feature of these other subtypes.
It's a crucial distinction because misdiagnosing LHM as a more common subtype, or worse, as a benign inflammatory process, can have catastrophic consequences for patient care. The subtle nature of the malignant cells in LHM means that if a pathologist isn't specifically looking for this variant, or isn't aware of its existence, they might easily miss the diagnosis. This is why specialized expertise in mesothelioma pathology is so vital. A general pathologist might understandably struggle with LHM, whereas a subspecialist who has seen a few cases will immediately recognize the pattern and know to pursue further specific stains and potentially deeper tissue sampling. It’s a nuanced area, one that highlights the immense value of subspecialization in modern medicine. The devil, as they say, is truly in the details when it comes to LHM.
2.3. Immunohistochemistry: The Gold Standard for LHM Identification
Given the diagnostic labyrinth presented by LHM's unique histopathology, immunohistochemistry (IHC) isn't just helpful; it's absolutely essential. It's the pathologist's secret weapon, the definitive tool that helps unmask the elusive malignant cells and confirm their mesothelial origin amidst the inflammatory chaos. Think of IHC as a cellular GPS, allowing us to pinpoint specific proteins expressed by different cell types. For LHM, this means not only confirming the presence of malignant mesothelial cells but also characterizing the inflammatory infiltrate that surrounds them. Without IHC, diagnosing LHM would be akin to navigating a dense fog without a compass – almost impossible.
The panel of IHC markers used for mesothelioma diagnosis is extensive, and for LHM, certain markers become particularly critical. We're looking for markers that are typically positive in mesothelial cells and negative in inflammatory cells, and vice-versa. Key mesothelial markers include calretinin, WT1, D2-40 (podoplanin), CK5/6, and sometimes EMA (epithelial membrane antigen), though EMA can be trickier due to its broader expression. The trick with LHM is that the malignant cells might be sparse, so you're looking for even a few scattered cells that express these mesothelial markers. This requires meticulous scanning and careful interpretation. A critical marker for mesothelioma, regardless of subtype, is BAP1 loss. BAP1 is a tumor suppressor gene, and its loss of expression in the nuclei of tumor cells (as detected by IHC) is a highly specific indicator of malignancy in mesothelial proliferations, including LHM. This marker is particularly valuable because it helps distinguish truly malignant mesothelial cells from benign reactive ones, which typically retain BAP1 expression.
Numbered List: Key IHC Markers for LHM Diagnosis
- Mesothelial Markers (Positive in tumor cells):
- Malignancy-Indicating Marker:
- Inflammatory Cell Markers (To characterize the infiltrate):
The interpretation of these stains in LHM is a nuanced art. You're not just looking for broad positivity; you're looking for discrete clusters or individual cells that light up with the mesothelial markers, amidst a sea of cells that are negative for these markers but positive for inflammatory cell markers like CD68 or CD3/CD20. The BAP1 stain, in particular, can be a game-changer. Seeing scattered mesothelial cells that are negative for nuclear BAP1, while the surrounding benign inflammatory and stromal cells show positive nuclear BAP1 staining, is a powerful piece of evidence for malignancy. It's a meticulous process, demanding patience and a deep understanding of both normal and abnormal cellular immunology. It truly is the gold standard, the definitive step in moving from suspicion to confirmed diagnosis for this challenging variant of mesothelioma.
3. Etiology and Risk Factors: The Shadow of Asbestos, and Beyond
When we talk about mesothelioma, the conversation inevitably turns to one word: asbestos. It's the elephant in the room, the undeniable culprit responsible for the vast majority of cases. And LHM, despite its unique histological presentation, is no exception to this grim rule. The shadow of asbestos looms large over every subtype of mesothelioma, a testament to the long-lasting and devastating health consequences of what was once considered a miracle mineral. But while asbestos exposure is the primary driver, it's also worth considering if there are other, perhaps lesser-known, factors that might contribute to the development of LHM, or if its unique inflammatory profile hints at a slightly different pathogenic pathway.
3.1. The Undeniable Link to Asbestos Exposure
Let's be unequivocally clear: the primary, overwhelming risk factor for lymphohistiocytic mesothelioma, just like all other forms of pleural mesothelioma, is exposure to asbestos. There's simply no getting around it. For decades, asbestos was widely used in construction, shipbuilding, automotive parts, and countless other industries due to its incredible heat resistance, insulating properties, and durability. People working in these industries – miners, insulators, pipefitters, electricians, construction workers, shipyard workers, even their family members who handled their contaminated clothing – were unknowingly inhaling microscopic asbestos fibers. These fibers, once lodged in the pleura, the lining of the lungs, can remain dormant for decades, a ticking time bomb, before initiating the complex cellular changes that lead to mesothelioma. The latency period is notoriously long, often 20 to 50 years, meaning that a diagnosis today reflects exposures that occurred decades ago.
What makes asbestos so insidious is its physical properties. The fibers are needle-like, durable, and virtually indestructible once inhaled. They cause chronic inflammation, oxidative stress, and DNA damage in the mesothelial cells lining the pleura. This persistent irritation and genetic insult eventually lead to malignant transformation. While the exact mechanisms by which asbestos triggers LHM specifically, compared to other subtypes, aren't fully understood, it's widely accepted that the initial carcinogenic trigger is the same. The chronic inflammation induced by asbestos fibers might, in some individuals, lead to a more exaggerated or specific type of immune response that culminates in the lymphohistiocytic presentation. It's a hypothesis, of course, but it makes intuitive sense given the disease's name. The body's attempt to wall off or clear these foreign fibers might inadvertently create the perfect storm for this particular variant to emerge.
Pro-Tip: The Asbestos Interview
When diagnosing any form of mesothelioma, a thorough occupational and environmental history is non-negotiable. For LHM, even if the pathology report is initially ambiguous, push for that detailed asbestos exposure interview. Knowing a patient's history of working in high-risk industries (e.g., shipbuilding, construction, power plants, brake manufacturing, military service involving asbestos) can significantly increase the clinical suspicion for mesothelioma, guiding the pathologist to look harder for those elusive malignant cells and to interpret ambiguous IHC results with a higher index of suspicion. Don't underestimate the power of a good patient history in solving these diagnostic puzzles.
The legal and ethical implications of asbestos exposure are immense, leading to widespread litigation and the eventual banning or strict regulation of asbestos in many countries. However, the legacy of past exposures continues to manifest in new diagnoses of mesothelioma, including LHM, every single year. It’s a tragic reminder of industrial negligence and the long-term human cost of putting profit before health. For patients and their families, understanding this link is often a crucial part of coming to terms with the diagnosis, providing some context for a disease that otherwise feels like an arbitrary, cruel twist of fate. The shadow of asbestos is long, and for LHM patients, it's a very real and present darkness.
3.2. Other Potential Contributing Factors and Genetic Predispositions
While asbestos is the undisputed heavyweight champion of mesothelioma risk factors, the scientific community is always asking if there are other, perhaps subtler, players in the game, especially for rare variants like LHM. Are there genetic predispositions that make certain individuals more susceptible to developing mesothelioma, or specifically LHM, after asbestos exposure? And what about other environmental factors, or even viral infections, that might act as co-carcinogens or modifiers? The truth is, for LHM, much of this remains speculative due to its rarity and the lack of large-scale studies. However, some general insights from other mesothelioma types can offer clues.
One area of increasing interest is genetic susceptibility. We know, for example, about the BAP1 gene mutation. Germline mutations in BAP1 (meaning they are inherited and present in every cell of the body) significantly increase an individual's risk of developing mesothelioma, uveal melanoma, and other cancers. While BAP1 loss is a key immunohistochemical marker for sporadic mesothelioma (meaning it happens spontaneously in the tumor, not inherited), inherited BAP1 mutations are a separate phenomenon that can predispose individuals. Could an inherited BAP1 mutation, combined with asbestos exposure, somehow influence the development of the lymphohistiocytic variant? It's a fascinating question that requires more research. Similarly, other genetic polymorphisms related to immune response or DNA repair pathways might play a role in how an individual's body responds to asbestos, potentially influencing the robust inflammatory reaction seen in LHM.
Bulleted List: Potential Modifying Factors for Mesothelioma (including LHM)
- Genetic Predisposition:
- Radiation Exposure:
- Simian Virus 40 (SV40):
- Chronic Inflammation/Immunosuppression:
Beyond genetics, other factors like previous therapeutic radiation to the chest have been weakly linked to mesothelioma, but these are incredibly rare compared to asbestos. There's also the long-standing, somewhat controversial debate about Simian Virus 40 (SV40) and its potential role in mesothelioma development. While some studies have suggested a link, it's far from universally accepted as a significant causative agent. For LHM specifically, the pronounced inflammatory component does raise questions about whether chronic underlying inflammatory conditions or certain immune dysregulations could contribute to its unique presentation, but this remains an area ripe for future investigation. The reality is, for now, if you're looking for the primary cause of LHM, your gaze must inevitably return to asbestos. Any other factors, if they exist, are likely minor modifiers in a story overwhelmingly dominated by those insidious fibers.
4. Clinical Presentation and Diagnostic Journey: A Labyrinth of Symptoms
Imagine being a patient, feeling unwell, experiencing persistent symptoms that just don't make sense. You visit your doctor, hoping for clarity, for answers. For someone with lymphohistiocytic mesothelioma, that journey is often anything but straightforward. The non-specific nature of the initial symptoms, combined with the extreme rarity and diagnostic challenges of LHM, creates a veritable labyrinth. Patients often bounce between specialists, undergo numerous tests, and endure prolonged periods of uncertainty before finally arriving at a definitive diagnosis. It's an emotionally draining, physically exhausting process, and it’s a stark reminder of how complex the human body, and the diseases that afflict it, can truly be.
4.1. Common Symptoms and Initial Patient Presentation
The cruel irony of LHM, and indeed most mesotheliomas, is that its initial symptoms are infuriatingly non-specific. There’s no unique, flashing neon sign that screams "lymphohistiocytic mesothelioma!" Instead, patients typically present with complaints that could easily be attributed to a myriad of more common, less ominous conditions. The most frequent symptoms are related to the accumulation of fluid in the pleural space (pleural effusion) and the thickening of the pleural lining. This leads to classic respiratory distress. We're talking about things like persistent shortness of breath (dyspnea), which often worsens with exertion and doesn't seem to resolve; a dull, aching chest pain that might be localized or radiate; and a persistent cough that just won't quit. These are the "great mimickers" of pulmonary medicine, making early diagnosis incredibly challenging.
Beyond the respiratory symptoms, patients might experience systemic signs that further muddy the diagnostic waters. Unexplained weight loss, a hallmark of many advanced cancers, is common. Fatigue, a profound and debilitating tiredness that isn't relieved by rest, often accompanies the other symptoms. Some patients might report night sweats or a general feeling of malaise. These constitutional symptoms, while concerning, are so generalized that they rarely point directly to mesothelioma, let alone its rare lymphohistiocytic variant. I remember one patient, an elderly gentleman with a long history of working in construction, who was initially treated for recurrent pneumonia and then even cardiac issues due to his shortness of breath and fluid buildup. It took nearly a year of progressive decline and multiple hospitalizations before a persistent pleural effusion finally led to a biopsy that uncovered the true culprit. His story, sadly, is not unique.
Insider Note: The "Silent" Onset
One of the most insidious aspects of LHM is its "silent" onset. The disease often progresses significantly before symptoms become noticeable enough to prompt medical attention. By the time a patient is experiencing significant shortness of breath or chest pain, the tumor might already be quite advanced. This late presentation, coupled with the diagnostic delays inherent to LHM, means that patients are often diagnosed at a stage where treatment options are more limited and the prognosis is already grim. It underscores the urgent need for heightened awareness among clinicians, especially in regions with a history of asbestos exposure.
The insidious nature of these symptoms means that the disease is often quite advanced by the time a definitive diagnosis is made. The pleural effusion, which is present in a majority of cases, can be recurrent and refractory to drainage, a red flag that should prompt a more aggressive diagnostic workup. However, even the fluid itself can be misleading – cytology performed on pleural fluid is notoriously difficult for mesothelioma, and even more so for LHM, where the malignant cells are sparse and easily missed amidst reactive inflammatory cells. So, while the symptoms are the patient's first signal, they are often just the beginning of a long and arduous diagnostic journey, fraught with uncertainty and misdirection.
4.2. Imaging Modalities: Seeing the Unseen
Once symptoms prompt medical attention, imaging plays a pivotal role in narrowing down the possibilities and guiding further investigation. For suspected LHM, a battery of imaging modalities is typically employed, each offering a different perspective on the pleural pathology. However, just like the symptoms, the imaging findings in LHM can be non-specific, often mimicking other benign or malignant conditions. This requires a radiologist with a keen eye and, ideally, experience with mesothelioma. We're trying to "see the unseen," to find subtle clues that point towards this rare variant.
The initial imaging study is almost always a chest X-ray. It's quick, inexpensive, and can reveal the presence of pleural effusion, pleural thickening, or even diffuse pleural plaques (calcified areas often associated with prior asbestos exposure). However, an X-ray is a blunt instrument; it provides limited detail. The next step is usually a Computed Tomography (CT) scan of the chest. A CT scan offers far greater anatomical detail, allowing clinicians to better characterize the pleural effusion (loculated vs. free-flowing), identify areas of nodular pleural thickening, and assess for involvement of the mediastinum or other intrathoracic structures. In LHM, CT might show diffuse, often irregular, pleural thickening, sometimes with associated pleural effusions. However, these findings are not unique to LHM and can be
