TEMPI syndrome
(Telangiectasias, Erythrocytosis with elevated Erythropoietin, Monoclonal gammopathy, Perinephric fluid collections, Intrapulmonary shunting)

Article written and reviewed by Dr Luca Moretti

TEMPI syndrome is an ultra-rare plasma cell dyscrasia identified and described only in recent years, characterized by the distinctive association of cutaneous telangiectasias, erythrocytosis with elevated erythropoietin levels, monoclonal gammopathy, perinephric fluid collections and intrapulmonary shunting.

The name itself derives from the English acronym summarizing these clinical manifestations: Telangiectasias, Erythrocytosis with elevated erythropoietin, Monoclonal gammopathy, Perinephric fluid collections, Intrapulmonary shunting.

It is an exceptionally rare syndrome: to date only a few dozen cases have been described in the international literature, with no clear geographic, sex or age predilection, although most diagnosed patients have been adults between the fourth and sixth decades of life.

TEMPI differs from all other plasma cell dyscrasias because of the association among the plasma cell clone, erythropoietin dysregulation and vascular abnormalities, whose causal relationships remain undefined, resulting in a multisystem presentation that is often subtle and progressive.

The rarity of the disorder, the absence of universally shared diagnostic criteria and its clinical overlap with other hematologic or vascular diseases make it one of the most challenging diagnostic entities, but growing scientific attention and publication of new case series are improving understanding of its pathogenetic mechanisms and therapeutic strategies.

The clinical course is highly variable: some patients may remain stable for years, whereas others progressively develop potentially serious complications, particularly involving the respiratory and renal systems.

Etiology, pathogenesis and pathophysiology

TEMPI syndrome represents a unique model among rare plasma cell dyscrasias because of the extreme complexity and originality of its pathogenetic mechanisms. The monoclonal component is often IgG, although other isotypes, including IgM, have also been described; clonal burden is generally low.

Unlike other plasma cell dyscrasias, TEMPI is characterized by a modest neoplastic burden, without massive marrow infiltration or the classic signs of multiple myeloma. No specific environmental, genetic or infectious risk factors have been identified to date: reported cases appear sporadic and without a family history. The syndrome can affect both men and women, mainly middle-aged adults, without a particular predilection.

From a pathogenetic standpoint, erythropoietin (EPO) production is one of the central physiologic abnormalities: patients typically show erythrocytosis, meaning increased red cell mass, associated with unusually high EPO levels after common secondary causes of erythrocytosis have been excluded; EPO elevation may precede development of shunts and hypoxemia.
The mechanism underlying elevated EPO is undefined. Paracrine and cytokine-mediated hypotheses have been proposed, but it has not been demonstrated that mediators produced by the clone cause neoangiogenesis, vasodilation or hypererythropoietinemia.

A characteristic feature of TEMPI is the presence of cutaneous telangiectasias, generally distributed over the trunk and upper extremities. The microvascular mechanism is undefined; the lesions are often asymptomatic and only rarely bleed.

Another distinctive feature is the development of perinephric fluid collections: these collections, generally serous and without evidence of infection, are located in the perinephric space and may be unilateral or bilateral. Their precise origin has not been definitively established, but dysregulation of vascular permeability, mediated by angiogenic factors and endothelial abnormalities, is thought to play an important role. These collections are not uncommonly found incidentally during imaging performed for other reasons.

Finally, one of the most enigmatic and clinically important features of TEMPI is intrapulmonary shunting, documented by functional imaging techniques or contrast echocardiography. These shunts impair normal blood oxygenation and, in advanced cases, may lead to progressive hypoxemia and dyspnea in the absence of obvious structural lung abnormalities.
The pathophysiology of intrapulmonary shunting appears to involve a combination of aberrant neoangiogenesis, altered pulmonary capillary architecture and vascular endothelial dysfunction, possibly promoted by cytokines secreted by the plasma cell clone.

Overall, TEMPI is a syndrome in which an apparently indolent plasma cell dyscrasia can induce profound abnormalities in erythropoietin metabolism, vascular regulation and capillary permeability, giving rise to a unique multisystem clinical picture recognizable only when a high index of clinical suspicion is maintained.

Clinical manifestations

The clinical picture of TEMPI syndrome is distinguished by a constellation of characteristic signs and symptoms whose association allows the disorder to be recognized as distinct from other plasma cell dyscrasias. Progression is generally slow, but heterogeneity of the manifestations may make diagnosis difficult in the early stages.

One of the most consistent and early signs is cutaneous telangiectasias. These are small dilatations of superficial capillary vessels, generally located on the trunk, neck and upper extremities, appearing as sharply demarcated red or violaceous lesions readily visible on physical examination. Telangiectasias may be asymptomatic or associated with a mild tendency to cutaneous bleeding, especially after minor trauma.

Another central manifestation is persistent erythrocytosis, detected on a complete blood count and associated with elevated serum erythropoietin levels. In TEMPI, common secondary causes of erythrocytosis must be excluded; hypoxemia may develop with intrapulmonary shunting and does not necessarily explain the initial EPO elevation. Erythrocytosis may be accompanied by clinical manifestations of hyperviscosity, such as headache, dizziness, visual disturbances and, rarely, venous or arterial thrombosis.

The monoclonal gammopathy is usually IgG, sometimes associated with either lambda or kappa light chains. The monoclonal component is often quantitatively small and may be detected only by sensitive serum or urine immunofixation techniques. In general, classic signs of multiple myeloma, such as lytic lesions, hypercalcemia and renal failure, are absent, and marrow plasma cell burden remains modest.

Perinephric fluid collections are a distinctive feature: they appear as fluid collections within the perinephric spaces and are detectable by ultrasound or abdominal CT. They are usually asymptomatic, but larger collections may cause a sensation of lumbar heaviness, dull pain or signs of compression of adjacent organs. In most cases they are not associated with signs of infection or inflammation.

Finally, intrapulmonary shunting is the major cause of morbidity in TEMPI syndrome. Clinically, these shunts cause dyspnea, reduced exercise tolerance and, in more advanced cases, hypoxemia documented by arterial blood gas analysis. Pulmonary examination is often normal, but arterial oxygenation is impaired by abnormal vascular channels that allow deoxygenated blood to enter the systemic circulation. Shunts can be demonstrated by contrast echocardiography or lung scintigraphy.

Other less consistent manifestations reported in the literature include mild hypertension, atypical peripheral vascular phenomena and, in isolated cases, signs of volume overload or renal dysfunction secondary to compression from perinephric fluid collections.
Overall, TEMPI syndrome presents with a suggestive but not pathognomonic clinical picture that requires careful assessment of the clinical history and active investigation of the key manifestations to achieve timely diagnosis.

Investigations and diagnosis

Diagnosis of TEMPI syndrome requires correlation of clinical, laboratory and instrumental findings. The manifestations do not necessarily appear at the same time: telangiectasias, erythrocytosis with elevated erythropoietin and monoclonal gammopathy are considered major features, whereas perinephric fluid collections and intrapulmonary shunting may emerge later. Suspicion should be high in an adult with unexplained erythrocytosis, markedly increased erythropoietin and a monoclonal component.

Laboratory tests have a key role in the initial assessment. The complete blood count documents erythrocytosis; when marked, symptoms related to increased blood viscosity may occur. Serum erythropoietin measurement shows values clearly above the normal range in the absence of common secondary causes of erythrocytosis.
The monoclonal gammopathy is identified by serum and urine immunofixation, whereas the M component is often quantitatively small and may be missed by standard electrophoretic techniques. Routine biochemical testing, including liver function, renal function and electrolytes, is generally preserved unless secondary abnormalities develop in advanced disease.

Instrumental investigations are essential to confirm the key manifestations of the syndrome. Abdominal ultrasound and CT, or MRI, demonstrate perinephric fluid collections, which appear as fluid collections without evidence of infection or solid organization.
Agitated saline contrast echocardiography can document intrapulmonary shunting by delayed passage of microbubbles into the left-sided circulation; very early passage instead suggests an intracardiac shunt. Arterial blood gas analysis documents variable hypoxemia, often disproportionate to pulmonary radiologic findings.

Bone marrow biopsy allows characterization of the plasma cell clone. Sampling of perinephric collections does not confirm the marrow clone and is reserved for selected cases when alternative diagnoses must be excluded.

An important, although not exclusive, diagnostic element is the exclusion of other causes of erythrocytosis, including polycythemia vera, chronic respiratory disease, congenital heart disease and renal neoplasms; perinephric collections, including trauma, infection and infiltrative diseases; and primary vascular or pulmonary abnormalities.

The proposed diagnostic features include:

• major criteria: telangiectasias, erythrocytosis with elevated erythropoietin and monoclonal gammopathy;
• minor criteria: perinephric fluid collections and intrapulmonary shunting;
• exclusion of the main alternative causes of erythrocytosis, hypererythropoietinemia, gammopathy and vascular shunting.

There is not yet a universally validated diagnostic system with rigid thresholds. Initial absence of one of the minor criteria does not exclude the syndrome, especially in early stages, and calls for multidisciplinary clinical and instrumental follow-up.

Treatment and prognosis

Although TEMPI syndrome was only recently described and the number of reported cases remains extremely limited, several therapeutic strategies have emerged in recent years, based on analogy with other plasma cell dyscrasias and on responses observed in published cases.

The primary objective of treatment is control of monoclonal plasma cell proliferation, because the association with the clone and the response to clone-directed therapy support a pathogenetic role, even though the mechanism remains undefined. No observation-only strategy has been validated as a standard: the available literature considers therapy directed at the plasma cell clone the cornerstone of treatment, with intensity and timing individualized according to clinical severity and comorbidities.

Systemic anti-plasma-cell treatment is therefore the central strategy, particularly in the presence of respiratory symptoms, progression of perinephric fluid collections, clinically significant erythrocytosis or a risk of thrombotic complications.

The most frequently used regimens are also used for multiple myeloma, particularly:

• Daratumumab, or regimens with lenalidomide and dexamethasone, sometimes combined with bortezomib, according to the clinical situation;
  
• Immunomodulatory or proteasome inhibitor-based regimens adapted to the patient's general condition.

High-dose chemotherapy with autologous stem cell transplantation has been described in selected cases, with remission of the main manifestations and improvement of intrapulmonary shunting and erythrocytosis.
Response to plasma cell-directed treatment is often accompanied by a progressive reduction in erythrocytosis, regression of telangiectasias and, in many cases, reduction of perinephric fluid collections and improvement in respiratory function.

Symptomatic treatment is crucial in daily disease management: monitoring and correction of hypoxemia, individualized assessment of thrombotic risk with antithrombotic measures only when clinically indicated, management of perinephric collections with drainage when compressive symptoms occur, and treatment of cutaneous telangiectasias in the event of bleeding.
Particularly large or symptomatic perinephric collections may be managed with temporary percutaneous drainage or, rarely, surgery, always with consideration of the risk of recurrence.

The prognosis of TEMPI syndrome is highly variable and depends on several factors: early diagnosis, prompt initiation of treatment, response of the plasma cell clone and control of systemic complications. In many cases, remission of the major manifestations can be maintained long term with systemic therapies; however, advanced intrapulmonary shunting or severe respiratory complications may significantly worsen outcome.
The rarity of the syndrome and the relatively short follow-up currently available make it difficult to define average survival; nevertheless, quality of life can be very good in effectively treated cases, whereas patients with uncontrolled disease progression face a substantial risk of respiratory failure, thrombosis and secondary complications.

Growing understanding of TEMPI pathophysiology and consolidation of anti-plasma-cell therapeutic strategies represent the most promising prospects for the future, paving the way for increasingly personalized and targeted therapies.

Complications

Because of the complexity of its manifestations and the association among the plasma cell clone, vascular dysregulation and erythrocytosis, TEMPI syndrome may cause numerous complications, some of which are major sources of morbidity and mortality.

One of the most frequent and feared complications is chronic hypoxemia related to intrapulmonary shunting. Abnormal pulmonary vascular channels significantly reduce blood oxygenation, causing progressive dyspnea, fatigue, reduced exercise tolerance and, in advanced cases, chronic respiratory failure. In untreated patients or those refractory to therapy, this condition may progress to a need for long-term oxygen therapy or acute respiratory failure during additional physiologic stress.

Although often asymptomatic, perinephric fluid collections may enlarge enough to compress adjacent renal and abdominal structures, causing lumbar pain, reduced renal function from mass effect and, rarely, compressive or hemorrhagic complications.

Persistent erythrocytosis exposes patients to an increased risk of venous and arterial thrombosis, including deep-vein thrombosis of the lower extremities, pulmonary embolism, ischemic stroke and, more rarely, myocardial infarction. Increased blood viscosity, stasis and endothelial dysfunction contribute to a prothrombotic milieu, particularly in the presence of other risk factors or prolonged immobility.

Cutaneous telangiectasias may, in rare cases, bleed spontaneously or for prolonged periods after trauma, especially in patients with coagulation abnormalities or receiving anticoagulant therapy.

Infectious complications have also been described during the course of TEMPI syndrome, related to drainage procedures for perinephric collections or to therapy-induced immunosuppression, as well as isolated cases of renal impairment from mass effect.

Finally, the psychological impact of the disease, chronic respiratory symptoms and the risk of disability secondary to progressive complications represent an additional source of vulnerability that is often underestimated but highly relevant to overall quality of life.
Prompt recognition of complications, adoption of preventive strategies, including individualized thrombosis prevention according to risk, oxygenation monitoring and surveillance of perinephric collections, and multidisciplinary management are fundamental to optimizing prognosis in TEMPI syndrome.

References
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