Pulmonary tumor thrombotic microangiopathy (PTTM) is an uncommon cancer-related complication characterized by intimal proliferation in pulmonary small arteries and arterioles with or without tumor emboli. In the majority of cases, the causative lesion is gastric poorly differentiated adenocarcinoma. In the present study, an autopsy case of PTTM caused by lung adenocarcinoma is reported and the pathogenesis of this complication is discussed. Multiple nodular lesions in the bilateral lungs were found in a 62-year-old Japanese man. Transbronchial biopsy revealed non-small cell carcinoma. Chemotherapy was performed; however, the patient succumbed to sudden dyspnea. Autopsy revealed poorly differentiated adenocarcinoma with multiple intrapulmonary metastases and intimal proliferation of pulmonary small arteries and arterioles with or without tumor emboli, which were characteristic of PTTM. Tumor cells were immunohistochemically positive for vascular endothelial growth factor (VEGF) and osteopontin (OPN), which are endothelial proliferative factors. This case indicates the possible involvement of VEGF and OPN in the pathogenesis of PTTM caused by lung adenocarcinoma.
lung cancer; osteopontin; pulmonary tumor thrombotic microangiopathy; vascular endothelial growth factor
Pulmonary tumour thrombotic microangiopathy (PTTM) is characterised by wide spread tumour emboli along with fibrocellular intimal proliferation and thrombus formation in small pulmonary arteries and arterioles. PTTM is a rare but fatal complication of carcinoma, but the pathogenesis remains to be clarified. An autopsy case of PTTM caused by gastric adenocarcinoma is described, in which tumour cells in the PTTM lesion had positive immunoreactivity for platelet-derived growth factor (PDGF) and PDGF receptor (PDGFR), and proliferating fibromuscular intimal cells also showed expression of PDGFR. In addition, the overexpression of PGDF was detected in the alveolar macrophages. These findings suggest that PDGF derived from alveolar macrophages and from tumour cells may act together in promoting fibrocellular intimal proliferation. To the best of the authors' knowledge, the possible involvement of activated alveolar macrophages in PTTM has not been previously reported.
Pulmonary thrombotic microangiopathy; gastric cancer; immunohistochemistry; platelet-derived growth factor; macrophages; arteries; gastric cancer; immunocytochemistry; lung; molecular pathology
Pulmonary tumor thrombotic microangiopathy (PTTM) has been known as a rare and serious cancer-related pulmonary complication. However, the pathogenesis and pathophysiology of this debilitating condition still remains obscure and no effective management was recommended. The present study aims to elucidate the pathophysiology of PTTM.
Autopsy records were searched to extract cases of pulmonary tumor embolism induced by metastasis of gastric carcinoma in the Toho University Omori Medical Center from 2000 to 2006. And then, tissue sections of extracted cases were prepared for not only light microscopic observation but morphometric analysis with the use of selected PTTM cases.
Six autopsies involved PTTM and clinicopathological data of them were summarized. There was a significant negative association between pulmonary arterial diameter and stenosis rate in four cases. Although all cases showed an increase of stenosis rate to some degree, the degree of stenosis rate varied from case to case. Significant differences were found for average stenosis rate between the under 100 micrometer group or the 100 to 300 micrometer group and the 300 micrometer group in four cases. However, no significant differences were found for average stenosis rate between the under 100 micrometer group and the 100 to 300 micrometer group in all cases. Meanwhile, all cases showed positive reactivity for tissue factor (TF), five showed positive reactivity for vascular endothelial growth factor (VEGF), and three showed positive reactivity for osteopontin (OPN).
In the present study, we revealed that the degree of luminal narrowing of the pulmonary arteries varied from case to case, and our results suggested that pulmonary hypertension in PTTM occurs in selected cases which have a widespread pulmonary lesion with severe luminal narrowing in the smaller arteries. Furthermore, our immunohistochemical examination indicated that gastric carcinoma indicating PTTM shows a higher TF-positive rate than typical gastric carcinoma. However, it remains still obscuring whether gastric carcinoma indicating PTTM shows a higher VEGF or OPN-positive rate as determined by immunohistochemistry.
Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare, malignancy-related complication that causes marked pulmonary hypertension, right heart failure, and death. We report on a patient with locally advanced breast cancer whose course was complicated by fatal PTTM based on clinical and laboratory findings.
Breast neoplasms; Pulmonary hypertension; Pulmonary tumor thrombotic microangiopathy
A 41-year-old woman, who underwent breast resection for cancer of the right breast and adjuvant chemotherapy 2 years ago, was admitted to our hospital due to shortness of breath upon exertion. High-resolution computed tomography of the chest showed small nodular opacities in the peribronchiolar area in both lungs, as well as mediastinal and hilar lymphadenopathy. A transbronchial lung biopsy revealed breast cancer metastasis and pulmonary tumor thrombotic microangiopathy (PTTM). Treatment of PTTM is rarely reported due to the difficulty of antemortem diagnosis; however, the patient was effectively treated with chemotherapy and oxygen and anticoagulation therapies for 3 months.
Pulmonary tumor thrombotic microangiopathy is a rare complication of malignant diseases. The diagnosis is extremely difficult and is most often performed after death. Invariably, patients develop acute pulmonary hypertension causing right heart failure, shortness of breath and death in a few days. We describe the clinical and radiological findings of a patient who presented with this complication.
A 28-year-old Caucasian woman with a previous history of pelvic tumor resection two months previously, suggestive of metastatic adenocarcinoma, presented with intense shortness of breath. A computed tomography scan showed signs of acute cor pulmonale and diffuse nodular opacities associated with a tree-in-bud pattern disseminated through her lungs, suggestive of bronchiolitis. Our patient's condition worsened and she underwent a surgical biopsy. Pathologic analysis of the biopsied specimens revealed pulmonary tumor thrombotic microangiopathy. Our patient's tumor evolved from a gastric origin (Krukenberg tumor). She underwent progressive clinical deterioration and died less than 24 hours after the biopsy. None of the cases described previously in the literature had diffuse centrilobular nodular opacities associated with a tree-in-bud pattern disseminated through the lungs, as in our case.
Pulmonary tumor thrombotic microangiopathy should be considered in cancer patients with rapidly progressing dyspnea, chest computed tomography findings compatible with pulmonary hypertension and typical findings of inflammatory bronchiolitis.
Thrombotic thrombocytopenia purpura (TTP) caused by a deficiency in ADAMTS-13 activity is considered to involve a subset of thrombotic microangiopathy (TMA). Although concept of TTP is included under the umbrella of TMA, discrimination of TTP from TMA is occasionally difficult in an autoimmune disorder. Herein, we report a case with TTP associated with systemic lupus erythematosus (SLE). In this case, it was difficult to discriminate TTP from TMA and the measurement of ADAMTS-13 activity was useful for obtaining an accurate diagnosis. SLE patients having thrombocytopenia in complication with anemia should be considered a monitoring of ADAMTS-13 activity even though the patients lacked symptoms of TTP related to the microvascular coagulation.
Inflammatory myofibroblastic tumors (IMTs) are benign neoplasms that can occur at different anatomic sites with nonspecific clinical symptoms. A 48-yr-old woman presented with a 2-month history of a relapsed oral ulcer, progressive dyspnea, and a thoracic pain induced by breathing. A tumorous mass was noticed in the right costodiaphragmatic recess on chest computed tomography and magnetic resonance imaging, and the patient underwent a right costotransversectomy with excision of the tumor, which originated from the 12th intercostal nerve. Histology and immunohistochemistry showed that the tumor was an IMT of the intercostal nerve. The patient's postoperative course was not favorable; dyspnea persisted after surgery, and a progressive pulmonary compromise developed. The cause of the respiratory failure was found to be bronchiolitis obliterans, which in this case proved to be a fatal complication of paraneoplastic pemphigus associated with an IMT. This case of IMT of the spinal nerve in the paravertebral region is unique in terms of its location and presentation in combination with paraneoplastic pemphigus, which is rare. A brief review of the heterogeneous theories concerning the pathogenesis, clinicopathological features, and differential diagnosis of this disease entity is presented.
Inflammatory Myofibroblastic Tumor; Intercostal Nerves; Paraneoplastic Pemphigus
Kaposi's sarcomas have been associated with different conditions of immunosuppression and are also known to be a typical complication of solid organ transplantations.
We report the case of a 65-year-old Turkish man with a history of heart transplantation 10 months ago who presented for clarification of his dyspnea. The patient had a known history of chronic obstructive pulmonary disease and a smoking history of 40 pack years. Radiologically, three progressively growing intra-pulmonary nodules were detected. The histology was diagnostic for a Kaposi's sarcoma. Visceral and especially primary intra-pulmonary Kaposi's sarcomas are very rare and have been described to have a rather unfavorable prognosis.
Even with a history suggestive for conventional lung cancer, Kaposi's sarcomas should be considered in patients after transplantation of solid organs. It should be noted that in a minority of cases this tumor exists in the absence of the typical cutaneous lesions.
The term Pulmonary–renal syndrome refers to the combination of diffuse alveolar haemorrhage and rapidly progressive glomerulonephritis. A variety of mechanisms such as those involving antiglomerular basement membrane antibodies, antineutrophil cytoplasm antibodies or immunocomplexes and thrombotic microangiopathy are implicated in the pathogenesis of this syndrome. The underlying pulmonary pathology is small-vessel vasculitis involving arterioles, venules and, frequently, alveolar capillaries. The underlying renal pathology is a form of focal proliferative glomerulonephritis. Immunofluorescence helps to distinguish between antiglomerular basement membrane disease (linear deposition of IgG), lupus and postinfectious glomerulonephritis (granular deposition of immunoglobulin and complement) and necrotizing vasculitis (pauci-immune glomerulonephritis). Patients may present with severe respiratory and/or renal failure and require admission to the intensive care unit. Since the syndrome is characterized by a fulminant course if left untreated, early diagnosis, exclusion of infection, close monitoring of the patient and timely initiation of treatment are crucial for the patient's outcome. Treatment consists of corticosteroids in high doses, and cytotoxic agents coupled with plasma exchange in certain cases. Renal transplantation is the only alternative in end-stage renal disease. Newer immunomodulatory agents such as those causing TNF blockade, B-cell depletion and mycophenolate mofetil could be used in patients with refractory disease.
Thrombotic thrombocytopenic purpura (TTP) is characterised by a thrombotic, haemolytic microangiopathy leading to microvascular occlusion, haemolysis and ischaemic dysfunction of various organs including the brain. TTP may present with a variety of neurological symptoms, including headache, focal deficits, seizures and coma. The authors describe a 55-year-old man presenting with abdominal pain and rapidly progressive deterioration into coma without focal neurological deficits or seizures. A concomitant, transient, rapid increase in blood pressure raised the suspicion of a hypertensive crisis. Yet, our patient did not improve after vigorous treatment with antihypertensives. Brain imaging excluded a hypertensive leucoencephalopathy. Despite the absence of a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13 (ADAMTS13) deficiency, the diagnosis idiopathic TTP was made after excluding secondary causes of TTP. Upon treatment with plasma exchange, corticosteroids and vincristin our patient gradually improved. On discharge to a rehabilitation centre he was awake and alert, had minor cognitive deficits and a mild proximal tetraparesis consistent with a critical illness poly(neuro)myopathy.
Kidney disease frequently complicates malignancy and its treatment. The spectrum of renal disease in cancers includes acute kidney injury, chronic kidney disease and tubular disorders. Thrombotic microangiopathy (TMA) is an uncommon initial clinical presentation of malignancies. Renal failure is an extremely rare feature of cancer-associated TMA syndromes in the absence of chemotherapy. Here, we report a patient who presented to the hospital for the first time with TMA and severe renal failure requiring hemodialysis and was diagnosed with gastric adenocarcinoma.
Gastric adenocarcinoma; thrombotic microangiopathy
Lymphangitic carcinomatosis as a manifestation of gastric carcinoma is rare. The presenting symptoms are misleading and nonspecific, often resulting in delayed diagnosis.
We present a case of a 24 year old male with progressive dyspnea. Initial radiologic assessment suggested interstitial lung disease, which was subsequently treated with antibiotics and corticosteroids. However, endoscopy and whole body diffusion-weighted magnetic resonance imaging revealed a metastatic gastric cancer with the presence of lymphangitic carcinomatosis.
Pulmonary lymphangitic carcinomatosis is a rare manifestation of metastatic gastric cancer. Patients present with severe but non-specific respiratory complaints. Definitive diagnosis can be achieved by transbronchial biopsy. Prognosis is poor and optimal treatment is not defined. Whole body diffusion-weighted magnetic resonance imaging is a promising imaging tool for the diagnosis of metastatic gastric cancer.
Lymphangitic carcinomatosis; Gastric cancer; Whole body MRI
We describe the case of a never-smoker who received second-line erlotinib as a treatment for his non-small cell lung cancer. Within one month, acute hepatic failure developed as well as a thrombotic-thrombocytopenic microangiopathy, with fatal outcome. In patients with non-small cell lung cancer, hepatic toxicity of erlotinib is a rare but severe complication; so far three fatal cases have been reported. Patients’ liver function should be assessed before starting erlotinib and special care is recommended if pretreatment bilirubin is elevated.
Erlotinib; Non-small cell lung cancer; NSCLC; Liver toxicity; Hepatopathy
Haemolytic-uraemic syndrome is characterized by thrombotic microangiopathy of the glomeruli and smaller arterial vessels of the kidney. Extrarenal thrombotic microangiopathy occurs, but ocular involvement is rarely demonstrated microscopically. We describe a 33 year old woman with a 3 week febrile episode and seropositivity for cytomegalovirus infection who developed acute renal failure, blindness and severe encephalopathy which was the cause of death. Thrombotic microangiopathy of retinal vessels may be more common than is expected from the literature. The exclusion of ocular structures in postmortem examinations explains the lack of anatomoclinical correlation.
Acute pancreatitis as a cause of thrombotic microangiopathy is very rare. We report a case of 40-year-old woman with idiopathic recurrent pancreatitis, who presented with acute pancreatitis complicated by thrombotic microangiopathy. Although thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) has been reported as causing acute pancreatitis, the induction of TTP/HUS by pancreatitis is rare. As far as we are aware this is the first reported case of TTP/HUS in association with pancreatitis in India. Our patient had a complete recovery of her thrombotic microangiopathy following plasma exchange therapy.
Pancreatitis; plasma exchange therapy; thrombotic microangiopathy
Gastrointestinal system involvement is one of the principal complications seen in the recipients of hematopoietic stem cell transplantation (HSCT), and it is also a major cause of morbidity and death in these patients. The major gastrointestinal complications include typhlitis (neutropenic enterocolitis), pseudomembranous enterocolitis, viral enteritis, graft-versus-host disease, benign pneumatosis intestinalis, intestinal thrombotic microangiopathy, and post-transplantation lymphoproliferative disease. As these patients present with nonspecific abdominal symptoms, evaluation with using such imaging modalities as ultrasonography and CT is essential in order to assess the extent of gastrointestinal involvement and to diagnose these complications. We present here a pictorial review of the imaging features and other factors involved in the diagnosis of these gastrointestinal complications in pediatric HSCT recipients.
Hematopoietic stem cell transplantation; Pediatric; Complications; Gastrointestinal tract
Gastric cancer patients with acute disseminated intravascular coagulation experiences a rare but severe complication resulting in a dismal prognosis. We report a case of advanced gastric cancer complicated with disseminated intravascular coagulation with intractable tumor bleeding which was successfully treated with chemotherapy consisting of 5-fluorouracil and oxaliplatin. The patient was a 63-year-old man who complained of abdominal pain, melena, and dyspnea on 24 November 2010. We diagnosed stage IV gastric cancer complicated by disseminated intravascular coagulation. Gastric tumor bleeding was not controlled after procedures were repeated three times using gastrofiberscopy. With the patient's consent, we selected the 5-fluorouracil and oxaliplatin combination chemotherapy for treatment. After one cycle of 5-fluorouracil and oxaliplatin therapy, symptoms of bleeding improved and the disseminated intravascular coagulation process was successfully controlled. The primary tumor and multiple metastatic bone lesions were remarkably shrunken and metabolically remitted after eight cycles of chemotherapy. In spite of progression, systemic chemotherapy is effective in disease control; further, the patient gained the longest survival time among cases of gastric cancer with disseminated intravascular coagulation.
Stomach neoplasms; Disseminated intravascular coagulation; Fluorouracil; Oxaliplatin
Calcineurin inhibitor induced thrombotic microangiopathy is a rare but well recognized complication of a renal transplantation that occurs in 1% of the patients who are on tacrolimus immunosuppression. Among the other aetiological factors of the “de-novo” Thrombotic Microangiopathy (TMA), the condition especially has to be differentiated from an antibody mediated rejection, as both have different pathogenesis, therapeutic connotations and outcomes.
We report a case of a middle aged female renal transplant recipient treated with tacrolimus, who developed localised thrombotic microangiopathy in the early post transplantation period. Despite the normal trough levels of tacrolimus, a diagnosis of “Tacrolimus induced TMA” was rendered after excluding other causes of the “de-novo” TMA, which included an antibody mediated rejection, a meticulous clinico-pathological correlation and serological studies. The treatment included the substitution of tacrolimus by rapamycin, with the subsequent normalization of the renal function.
Calcineurin inhibitors; Renal transplantation; Tacrolimus; Thrombotic microangiopathy
Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening complication of gemcitabine treatment. Since the approval of this nucleoside analog for the treatment of pancreatic cancer by the FDA in 1996, reported incidence varies from 0.015 to 1.4%. The classic ‘pentad’ describing the disease process (fever, hemolytic anemia, thrombocytopenia, neurological complications and renal impairment) is not always present to the same extent in every patient. Here, we present a rare case of TTP associated specifically with gemcitabine treatment, and further, we briefly discuss the manifestations, treatment options and outcomes related to the complication. In our opinion, it is important to realize that as the indications for the use of gemcitabine increase and its use becomes more widespread, TTP and other disorders on the spectrum of thrombotic microangiopathies are important considerations to remember in patients with worsening anemia and thrombocytopenia. New onset or exacerbation of underlying hypertension may provide a clue to diagnose the disease entity earlier in this subgroup of patients.
Thrombotic thrombocytopenic purpura; Gemcitabine Non-small cell lung cancer
Postpneumonectomy syndrome is a rare condition that is characterized by dyspnea resulting from an extreme mediastinal shift and bronchial compression of the residual lung following surgical pneumonectomy. It is even rarer for this syndrome to present in patients without a history of prior lung surgery but induced by autopneumonectomy due to parenchymal disease, an entity termed ‘postpneumonectomy-like syndrome’.
We present a rare case of a 91-year-old Puerto Rican man presenting with progressively worsening dyspnea with a history of pulmonary tuberculosis diagnosed 40 years earlier who developed severe unilateral lung fibrosis. Plain X-ray and computed tomography scans confirmed the presence of postpneumonectomy-like syndrome secondary to his parenchymal lung destruction. The patient developed cor pulmonale due to his extensive lung disease and as a consequence was not a suitable candidate for surgical intervention. The patient was otherwise stable until he developed acute respiratory distress from an acute upper gastrointestinal bleed and died four days into his hospital course.
We present a rare case of postpneumonectomy-like syndrome as sequelae of severe pulmonary parenchymal tuberculosis infection along with a review of literature, in the hopes of aiding clinicians to include the differential of postpneumonectomy-like syndrome in patients presenting with worsening dyspnea without a history of surgical lung resection.
Cor pulmonale; Dyspnea; Pneumonectomy; Postpneumonectomy-like syndrome; Postpneumonectomy syndrome; Pulmonary fibrosis; Tuberculosis
The importance of a good clinical history has been emphasized by reviewing the most common diagnostic criteria in cardiac patients. Dyspnea of cardiac origin should be differentiated from respiratory disturbances, neuroses, unfitness, etc. Orthopnea, paroxysmal nocturnal dyspnea, cardiac asthma and acute pulmonary edema are manifestations of left ventricular failure. Peripheral edema is most frequently due to circulatory disturbances of the lower extremities. Edema of cardiac origin is bilateral, related to postural changes and associated with cardiomegaly. Hepatic and renal problems are also common causes of edema. Chest pain due to myocardial ischemia (angina pectoris) is characteristic in its location, radiation, onset and relief. It should be differentiated from the many other causes of chest pain (neurosis, pericarditis, myalgia, etc.) by a carefully taken history. Palpitations and syncope are common symptoms of severe cardiac disease. Patients with these complaints should be thoroughly investigated. Syncope of cardiac origin (Stokes-Adams attack) should be differentiated from epileptic seizures.
Thrombotic microangiopathy, which includes thrombotic thrombocytopenic purpura (TTP), shiga-toxin associated hemolytic uremic syndrome (Stx-HUS) and atypical HUS, is characterized pathologically by the development of hyaline thrombi in the microvasculature and clinically by the manifestations of thrombocytopenia, microangiopathic hemolysis, and organ dysfunction. Renal failure is a predominant complication of both Stx-HUS and atypical HUS, while neurological complications are more prominent in TTP. Other disorders such as lupus or bone marrow transplantations may occasionally present with features of thrombotic microangiopathy. Recent studies have found autoimmune inhibitors or genetic mutations of a von Willebrand factor cleaving metalloprotease ADAMTS13 in patients with TTP. In approximately 30% – 50% of patients with atypical HUS, mutations have been detected complement factor H, membrane cofactor protein (CD46), or factor I. All three proteins are involved in the regulation of complement activation. Additionally autoantibodies of factor H have been described in patients without genetic mutations. These advances illustrate that dysregulation of VWF homeostasis or complement activation due to genetic or autoimmune mechanisms may lead to syndrome of thrombotic microangiopathy.
ADAMTS13; Hemolytic uremic syndrome; Shear stress; Thrombotic microangiopathy; Thrombotic thrombocytopenic purpura; Regulators of complement activation; von Willebrand factor
Sarcoidosis is a multisystem inflammatory disease of unknown etiology, characterized by noncaseating epithelioid cell granulomas. In sarcoidosis, the most common radiological findings are mediastinal and bilateral hilar lymph node enlargement. We present a case of sarcoidosis with a rare radiological aspect of pulmonary hilar tumor mass.
A 54-year-old female patient, active smoker (40 packs/year), with a history of cutaneous lupus, was admitted in our institute for progressive dyspnea and dry cough. At admission physical examination and laboratory tests were normal. Pulmonary function tests diagnosed an obstructive syndrome. Chest X-ray showed a tumor mass of the right pulmonary hilum. Transbronchial biopsy was nondiagnostic. HRCT-scan showed a tumor mass in the right hilum, which raised the suspicion of a lung cancer. PET-CT scan revealed a high metabolic activity of the tumor mass and of a paratracheal right lymphadenopathy. Lymph node biopsy by mediastinoscopy showed noncaseating epithelioid-cell granulomas, sustaining the diagnosis of sarcoidosis. The outcome was favorable, with spontaneous remission without treatment, but with a relapse that responded after systemic corticotherapy.
In conclusion, even if a tumor mass in the pulmonary hilum is highly suggestive of lung cancer, a positive diagnosis should be made only after histological examination, because other benign conditions, like sarcoidosis, could have such an aspect.
sarcoidosis; lung cancer; tumor mass
Microangiopathic hemolytic anemia (MAHA) occurs occasionally as a paraneoplastic syndrome in some solid tumors, but MAHA accompanied by signet ring cell carcinoma of an unknown origin is very rare. In this study, we present the case of an 80-yr-old man who was admitted to the hospital because of a 1-month history of lower back pain and dyspnea. He was diagnosed with MAHA on the basis of the laboratory findings that revealed anemia with schistocytes, decreased haptoglobin levels, and a negative direct Coombs' test. Bone marrow examination, which was performed because of the progression of anemia, revealed bone marrow metastases of signet ring cell carcinoma with extensive bone marrow necrosis. However, the primary origin of this signet ring cell carcinoma was not found. When the cause of progressive MAHA is unknown, the possibility of cancer-associated MAHA must be excluded by performing additional tumor workup, including the detection of tumor markers, gastric and colorectal endoscopic examinations, bone marrow examinations, and positron emission tomography-computed tomography or bone scans.
Bone marrow metastasis; Microangiopathic hemolytic anemia; Signet ring cell carcinoma