Granuloma Eosinófilo: Histórico

Eosinophilic granuloma

Eosinophilic Granuloma: History: In 1938, Schairer diagnosed a lesion in the skull of a child as eosionphilic myeloma or eosinophilic osteomyelitis 1 . This condition was later described as a new clinical entity by Otani and Ehrlich in 1940 under the name Solitary Granuloma of Bone 2 .

Farber and Green, in 1942, demonstrated that the lesion could occur in a localized or multiple manner in the skeleton and possibly be related to Hand-Schuller-Christian disease and Letter-Siwe disease 3 .

In 1944, Jaffe and Lichtenstein introduced the term eosinophilic granuloma of bone 4 . The relationship between this lesion and the systemic forms of the disease was confirmed by Lichtenstein in his 1953 publication, encompassing them under the name Histiocytosis X 5 .

Currently, this entity is called Langerhans Cell Histiocytosis, which has four distinct clinical forms: Eosinophilic Granuloma, a form restricted to the skeleton, which can be localized or multiple; Hand-Schuller-Christian, chronic and disseminated form; Letter-Siwe, acute or subacute disseminated form and Hashimoto-Pritzker, postnatal form with spontaneous resolution 6 .

Introduction:  Solitary eosinophilic granuloma of the bone is the most common of the four forms of presentation of Langerhans Cell Histiocytosis, representing between 60% and 80% of cases 7 .

Among benign bone lesions, it is a rare entity, accounting for less than 1% 8 . It preferentially affects children and adolescents with a male predominance 2:1 9 . Around 80% of patients are under 21 years of age and the majority of these are between five and 15 years of age 6,7,9 .

Some patients may begin with an isolated bone lesion and later develop multiple bone lesions. These cases can eventually evolve into systemic forms of the disease. When this occurs, it generally happens within the first six months of diagnosis and practically never after a year of evolution, which is a criterion for good prognosis, when no new lesions appear after this period of clinical follow-up 10 .

Hand-Schuller-Christian Syndrome is   the chronic form of Langerhans cell histiocytosis, characterized by systemic involvement with multiple bone lesions, mainly in the skull, exophthalmos and diabetes insipidus, affecting children over 3 years of age 10 .

Letter-Siwe Syndrome affects   children under three years of age, it is the acute or subacute form, also with systemic involvement. It presents with fever, otitis media, recurrent bacterial infections, anemia, hemorrhages, viceromegaly, diffuse and painful adenopathy with skin involvement similar to seborrheic eczema and generalized ostelitic lesions, with frequent progression to death 10 .

Hashimoto-Pritzker Syndrome is   a form of Langerhans cell histiocytosis that affects the skin exclusively. It affects children in the first month of life, manifesting with eczematous eruptions that resolve spontaneously 6 .

Etiology:  Unknown.

Genetics:  No significant reports regarding this.

Definition:  Eosinophilic Granuloma is a pseudotumor lesion, of unknown etiology, characterized by bone rarefaction that can be solitary or multiple. Microscopically, it presents a profile of mononuclear histiocytic cells, presenting antigens of dendritic origin, known as Langerhans cells, amidst the variable quantity of leukocytes, eosinophils, lymphocytes and giant cells.

Epidemiology:  Eosinophilic Granuloma mainly affects the axial skeleton, in this order: skull, pelvis, vertebrae, ribs, mandible, clavicle and scapula.

In the appendicular skeleton the femur, proximal region and diaphysis, humerus and tibia 9 . It most often affects the diaphysis or metadiaphyseal region, being rare in the epiphysis 7 .

The spine represents 10% of cases in the pediatric population, the majority in the lumbar region.

In adults, it occurs more frequently in the ribs and less frequently in the spine, respectively 25% and 3% 6 .

Clinical picture:  The most frequent symptom of Eosinophilic Granuloma is localized, throbbing, short-lasting pain, worsening at night associated with local heat and edema. When it affects the skull, this pain can be confused with other causes of headache.

Compromise of vertebral bodies can produce painful scoliosis. Any angular deviations are small, less than 10 0 , as the vertebral flattening is usually uniform and rarely produces neurological symptoms. 

In other forms of Langerhans Cell Histiocytosis, systemic symptoms may be present such as fever, skin rush and diabetes insipidus. Hepatosplenomegaly can occur in Letter-Siwe syndrome, which is the most severe form of the disease 6

Classification:  Eosinophilic granuloma can   manifest itself in two clinical forms:  Solitary  or  Multiple .

Laboratory tests:  Laboratory changes that can be found are an increase in ESR and CRP, and mild eosinophilia may occasionally occur on the blood count.

Imaging tests:  The radiographic image is of bone rarefaction, rounded or oval, which begins in the medullary bone and progresses with erosion of the cortical bone.

In the initial phase, the edges are irregular and poorly defined.

In the late phase, slight sclerosis may occur around the lesion. In long bones, there is an evident periosteal reaction that appears as multiple thick lamellar layers, which characterizes slow-evolving benign lesions or the reaction of osteomyelitis.

This type of solid periosteal reaction differentiates Eosinophilic Granuloma from Ewing’s Sarcoma, where the periosteal reaction is thin lamellar, due to the rapid evolution of the malignant tumor.

Another radiographic difference between these two lesions is that Ewing’s tumor early presents extra-cortical tumor tissue, with a large volume, which does not occur in Eosinophilic Granuloma.

In flat bones, such as the skull or pelvis, erosion affects both cortices in an irregular and asymmetrical manner, producing the visual impression of a hole within another hole, called a double contour lesion.

In the mandible, destruction of the alveolar bone produces the radiographic impression of floating teeth.

In the spine, the disease affects the vertebral body, with flattening occurring in 15% of cases, producing the so-called flat vertebra of Calvè 6 . The posterior elements and intervertebral discs are preserved, even when the injury occurs in more than one vertebra.

Pathologic anatomy:

Macroscopic appearance:  it has a soft, gelatinous consistency, yellowish in color, necrotic liquefaction is common.

Microscopic appearance:  They appear as clusters of large histiocytic cells, with a slightly basophilic cytoplasm, globose, lobulated or indented nucleoli, in these cases similar to a bean seed, which correspond to Langerhans cells.

These clusters are interspersed with giant cells, lymphocytes, numerous eosinophils and areas of necrosis, simulating an abscess. Electron microscopy shows typical cytoplasmic granules called Birbeck bodies 11,12 .

Immunohistochemistry shows positivity for S-100 protein, vimentin and CD1a 11,13 .

Diagnosis:

Differential diagnosis:  The main radiological differential diagnoses of Eosinophilic Granuloma are Osteomyelitis and Ewing Tumor.

When the lesion occurs in the skull, it must be differentiated from an epidermoid cyst or metastasis. The main histological differential diagnoses are Osteomyelitis and Lymphoma.

Staging:

Treatment:  The literature presents reports that expectant treatment or biopsy alone can be indicated as an effective therapeutic strategy for isolated skeletal injuries 7,14 .

Eosionophilic granuloma can resolve spontaneously, especially in children. The capacity for the affected bone to rebuild itself exists, as most patients are affected before skeletal maturity, therefore with great potential for remodeling by the growth physes, which are normally not affected 15,16 .

In our experience, there was resolution in five cases, which regressed only with percutaneous biopsy. The same happens after vertebral collapse in spinal injuries, probably due to the leakage of the contents of the lesion, resembling the drainage of an abscess, with surgical indication in the spine being extremely rare. Cases have been reported where there was complete restitution of the vertebral body height 15 . In our series we had two cases that presented this evolution.

Although there may be spontaneous resolution, the time required is unpredictable, and there may be significant morbidity secondary to intense pain and functional limitation.

Currently, the best therapeutic approach for Eosionophilic Granuloma is to perform a percutaneous biopsy, if possible with immediate diagnosis by frozen section, followed by intralesional corticosteroid infusion (methylpredinisolone – 40mg to 120mg depending on the size of the lesion) 7 . The anatomopathological result must be subsequently confirmed by histology in paraffin blocks.

Eosionophilic Granuloma can take up to three months to regress, and it may be necessary to repeat the infusion 6 . In our experience, we had only one case, of an isolated injury to the humerus, which required complementation of the initial treatment in which we performed oral corticosteroid therapy, prednisolone 5mg/24h, for four months. In polyostotic Eosinophilic Granuloma, systemic corticosteroid therapy is used.

When an incisional biopsy is necessary, corticosteroids can be applied locally after curettage of the lesion, which facilitates the resolution of the process. This curettage must be careful, carried out by opening in the form of a narrow slit, longitudinal to the bone, trying not to add greater local fragility. Eventually, the cavity can be filled with a bone graft, but this is generally unnecessary due to the great potential for regeneration that exists.

Radiofrequency was proposed as a percutaneous treatment for Eosionophilic Granuloma, being applied in a second stage, two to four weeks after the biopsy 17 . The author restricts the technique to small injuries that are at least one centimeter away from the neural or visceral structures, warning of the risk of fractures in the load-bearing limbs. This approach, in addition to increasing costs and causing local morbidity, does not add any advantage to the treatment. The biopsy itself may have been curative, and the infusion of corticosteroids has greater justification, as this is indicated both in isolated cases and in multiple lesions. To date, there are no studies comparing percutaneous techniques with corticosteroid infusion in relation to the use of radiofrequency that justify their use. 

Historically, radiotherapy was used in low and fractionated doses for the treatment of Langerhans Cell Histiocytosis. Currently, the indication of radiotherapy for benign lesions is controversial.

In cases of eosinophilic granuloma with more than one skeletal lesion, without visceral involvement, systemic treatment may be indicated for a period of approximately six weeks with corticosteroid therapy (2 mg/kg) and Vinblastine (6 mg/kg).

Prognosis:  Solitary lesions of eosinophilic granuloma evolve well in 97% of cases, with biopsy alone or in addition to corticosteroid infusion or surgical treatment 6 .

Bibliography:

1 SCHAIRER, E. Ueber eine eigenartige Erkrankung des kindlichen Schädels.  Zentralbl Allg Patho Pathol. Anat.,  71:113, 1938.

2 Otani S, Ehrlich JC; Solitary granuloma of bone simulating primary neoplasm. Am J Pathol 16:479–90. 1940

3 Green WT, Faber S; “eosinophilic or solitary granuloma” of bone. J Bone Joint Surg (Am) 24:499-526. 1942

4 Jaffe HL, Lichtenstein L; Eosinophilic granuloma of bone. Arch Pathol 37: 99-118. 1944.

5 Lichtenstein L.: Histiocytosis Pathol. 56:84, 1953

6 Schwartz HS.  Orthopedic Knowledge Update: Musculoskeletal Tumors 2. American Academy of orthopedic Surgeons, Rosemont, Illinois. Chapter 12 (128-32), 2007

7 Mavrogenis AF, Abati CN, Bosco G, Ruggieri P. Intralesional Methylprednisolone for Painful Solitary Eosinophilic Granuloma of the Appendicular Skeleton in Children. J PediatrOrthop 2012;32:416–422

8 Chadha M, Agarwal A, Agarwal N, et al. Solitary eosinophilic granuloma of the radius. An unusual differential diagnosis. Acta Orthop Belg. 2007; 73:413–417.

9 Campanacci, M. Bone and Soft Tissue Tumors; Springer-Verlag Wien New York. Second Edition, (54); 857-75. 1999.

10 SCHAJOWICZ, F. Buenos Aires: Osseous Tumors; Talleres de editorial Médica Panamericana SA (9); 464-80. 1981.                  

11 CHRISTIAN, HA Defects in membranous bones, exosphthalmos and diabetes insipidus: in a usual syndrome of dyspituitarism: a clinical study.  Med.Clin. North. Am.,  3:849, 1920.

12 ARCECI, RJ; BRENNER, M.K.; PRITCHARD, J. Controversies and new approaches to the treatment of Langerhans cell histiocytosis.  Hemtol. Oncol. Clinic. North. Am., 12:339, 1998

13 ALBRIGHT, F.; REIFNSTEIN, EC  The parathyroid glands and metabolic disease.  Baltmore, Williams & Wilkins, 1948.

14 Plasschaert F, Craig C, Bell R, et al. Eosinophilic granuloma. A different behavior in children than in adults. J Bone Joint Surg Br 2002;84:870–872.

15 Greenlee JD, Fenoy AJ, Donovan KA, et al. Eosinophilic granuloma in the pediatric spine. Pediatr Neurosurg. 2007; 43:285–292.

16 Sessa S, Sommelet D, Lascombes P, et al. Treatment of Langerhans cell histiocytosis in children. Experience at the Children’s Hospital of Nancy. J Bone Joint Surg Am. 1994; 76:1513–1525.

17 Corby RR, Stacy GS, Peabody TD, et al. Radiofrequency ablation of solitary eosinophilic granuloma of bone. Am J Roentgenol.2008;190:1492–1494.

Diagnosis of tumors

2. Parameters:

We must analyze the following aspects of the injury:

1) Identify the compromised bone or bones;

2) Regarding the number of injuries:  

          2.1) Located in a bone: monotopic;

          2.2) A lesion in several bones: monotopic and polyostotic;

          2.3) Multiple lesions in one bone: polytopic and monostotic;

          2.4) Multiple lesions in different bones: polytopic and polyostotic.

3) Regarding location in the bone:

          3.1) Epiphysis, metaphysis or diaphysis;

          3.2) Cortical, spongy, subperiosteal, paraosteal or juxta-cortical region;

          3.3) Central or eccentric.

4) Limits of bone injury:

          4.1) Precise, imprecise, infiltrative or permeative, surrounded or not by reactional sclerosis;

          4.2) It goes beyond the cortex with an extra-osseous lesion;

          4.3) It reaches the soft tissues (yes/no) (displaces/infiltrates);

          4.4) Exceeds the growth line.

5) Regarding other aspects of the injury:

          5.1) Destructive (osteolytic)

          5.2) Condensing or osteogenic

          5.3) Multiloculated, “in soap bubbles”

          5.4) Calcifications: focal, diffuse, striated

6) Type of periosteal reaction:

          6.1) In thin slices – “in onion skins”

          6.2) In thick sheets

          6.3) Spiculates – “in sunbeams” or “in a comb”

          6.4) Periosteal survey interrupted by the tumor – Codman’s Triangle

 

3. Diagnosis:

 Study methods for pathological anatomical examination:

 Cytology:

It is the study of desquamated cells obtained from secretions, excretions or obtained with needles and making “imprints” (printing tissue fragments on slides). It should rarely be used to diagnose bone neoplasia. Its importance lies mainly in the cytohistological correlation.

Punch-biopsy:

Collection of material with trephines for inclusion in paraffin and microscopic examination. Although the material obtained by this method is small, when it is collected from a significant area of ​​the neoplasia and by an orthopedist with experience in handling these lesions, it makes a definitive diagnosis possible. The location for obtaining this material must be planned by the surgeon, in order to prevent disruption of the tumor’s balance in neighboring tissues, preventing its spread.

Incisional biopsy:

It is the most used method for diagnosing bone tumors. The biopsy site must be planned, not only in terms of the area that will enable a better histological diagnosis but also to predict future resection of the tumor, which should include the skin of the biopsied region. The biopsy should not be performed in inappropriate locations of the tumor, such as areas of necrosis, hemorrhage, Codman’s triangle or in areas that only present peritumoral reactional bone sclerosis.

Frozen biopsy

It is performed during the surgical procedure. This method is not recommended when there is bone tissue. The possibility of a diagnostic error is high in this situation. Diagnostic errors in numerous bone lesions with multinucleated giant cells, in the various tumors of undifferentiated cells, small cells and round cells, the impossibility of a histological differential diagnosis when there is neoformed bone tissue in the fracture callus, osteosarcoma and myositis ossificans, are some examples that contraindicate the method. Frozen examination may be useful in cases of metastatic lesions and even so, the speed of the method will not alter the operative approach.

Microscopic study:

Fragments obtained by puncture or incisional biopsy must be embedded in paraffin and subsequently stained with hematoxylin-eosin. Special methods such as PAS (Periodic Acid Schiff) and silver impregnation to study reticulin are usually used for differential diagnosis, for example, between Ewing Sarcoma, Lymphomas and PNET (Primitive Neuroectodermal Tumor). PAS, demonstrating glycogen and a scarce amount of reticulin, are common for diagnosing Ewing’s sarcoma. In Lymphomas, reticulin is abundant and PAS is negative. Immunohistochemistry techniques with immunoperoxidase are entering the routine of anatomopathological examinations. They are mainly indicated in the search for the diagnosis of the organ of origin of metastatic neoplasms in the bones. The use of markers that allow identifying the origin of the neoplastic cell is increasingly used in daily practice. Examples are PSA, to identify neoplasia originating from the prostate, CK7 for primitive lung neoplasia, CK20 for primitive digestive tract neoplasia and estrogen and progesterone receptors for breast neoplasia.

Surgical parts:

Routinely a surgical specimen must be examined externally and at the cuts. Externally for analysis of surgical margins in order to verify whether the neoplasm was completely extirpated. In the sections, we verified the involvement of the bone, extension and dimensions of the neoplasm and its main macroscopic characters for adequate microscopic study. (Figure 1) 

When the study of a surgical resection is of a patient undergoing preoperative chemotherapy, particularly in osteosarcoma and Ewing’s sarcoma, the study of the specimen must follow a systematized examination, as the purpose is to analyze the response of the neoplasm to therapy. The study stages will be as follows:

A) Slices will be made of the surgical piece along its entire length with a maximum thickness of 0.5 cm,

B) One or more slices must be reproduced on a computer “scanner” or photographed and x-rayed,

C) This reproduction must be gridded from the proximal to the distal end,

D) The fragments from each checkered area must be thoroughly examined under a microscope in order to quantify the necrosis of the neoplasm and the persistence of histologically viable tumor cells,

E) The final report of the study of the entire specimen must be graded according to the response to preoperative chemotherapy according to the Huvos criteria.

Huvos Criteria:

Grade I: Up to 50% tumor necrosis;

Grade II: 50 to 90% tumor necrosis;

Grade III: Above 90% necrosis;

Grade IV: 100% tumor necrosis – Absence of histologically viable neoplastic cells.

With this degree, the oncologist will be able to guide post-operative treatment taking into account the worst statistical prognosis in cases of cranes I and II and better in those of III and IV.

Diagnóstico dos tumores

2. Parâmetros:

Devemos analisar os seguintes aspectos da lesão:

1) Identificar o osso ou ossos comprometidos;

2) Quanto ao número de lesões:  

          2.1) Localizada em um osso: monotópica;

          2.2) Uma lesão em diversos ossos: monotópica e poliostótica;

          2.3) Múltiplas lesões em um osso: politópica e monostótica;

          2.4) Múltiplas lesões em diversos ossos: politópica e poliostótica.

3) Quanto à localização no osso:

          3.1) Epífise, metáfise ou diáfisa;

          3.2) Região cortical, esponjosa, subperiostal, paraosteal ou justa-cortical;

          3.3) Central ou excêntrica.

4) Limites da lesão no osso:

          4.1) Precisos, imprecisos, infiltrativo ou permeativo, circundado ou não por esclerose reacional;

          4.2) Ultrapassa a cortical com lesão extra-óssea;

          4.3) Atinge as partes moles (sim/não) (desloca/infiltra);

          4,4) Ultrapassa a linha de crescimento.

5) Quanto ais aspectos da lesão:

          5.1) Destrutiva (osteolítica)

          5.2) Condensante ou osteogênica

          5.3) Multiloculada, “em bolhas de sabão”

          5.4) Calcificações: focais, difusas, estriadas

6) Tipo de reação periostal:

          6.1) Em lâminas finas – “em casca de cebola”

          6.2) Em lâminas grossas

          6.3) Espiculadas – “em raios de sol” ou “em pente”

          6.4) Levantamento periostal interrompido pelo tumor – Triângulo de Codman

 

3. Diagnóstico:

 Métodos de estudo para exame anátomo patológico:

 Citologia:

É o estudo de células descamadas obtidas em secreções, excreções ou obtidas com agulhas e realizando-se “imprints” (impressão de fragmentos de tecidos em lâminas). Raramente devera ser utilizado para diagnóstico de uma neoplasia óssea. Sua importância reside principalmente, na correlação cito-histológica.

Punção-biópsia:

Coleta de material com trefinas para inclusão em parafina e exame microscópico. Embora o material obtido por este método seja pequeno, quando é colhido em área significativa da neoplasia e por ortopedista com experiências no manuseio destas lesões, possibilita o diagnóstico definitivo. O local de obtenção deste material deve ser planejado pelo cirurgião, a fim de impedir ruptura do equilíbrio do tumor nos tecidos vizinhos, evitando sua disseminação.

Biópsia incisional:

É o método mais utilizado para diagnóstico de tumores ósseos. O local da biópsia deve ser planejado, não só quanto à área que possibilitará melhor diagnóstico histológico como para prever a futura ressecção do tumor, na qual deverá ser incluída a pele da região biopsiada. A biópsia não deverá ser realizada em locais inadequados do tumor como áreas de necrose,  hemorragia, no triângulo de Codman ou em áreas que apresentam apenas esclerose óssea reacional peritumoral.

Biópsia de congelação

É realizada durante o ato cirúrgico.  Este método não é indicado quando existir tecido ósseo. A possibilidade de erro diagnóstico é grande, nesta situação. Os erros de diagnóstico nas numerosas lesões ósseas com células gigantes multinucleadas, nos diversos tumores de células indiferenciadas, de células pequenas e redondas, a impossibilidade de diagnóstico diferencial histológico quando há tecido ósseo neoformado no calo de fratura, osteossarcoma e miosite ossificante, são alguns exemplos que contra-indicam o método. O exame em congelação poderá ser útil em casos de lesões metastáticas e mesmo assim, a rapidez do método não alterará a conduta operatória.

Estudo microscópico:

Os fragmentos obtidos por punção ou biópsia incisional devem ser incluídos em parafina e posteriormente faz-se a coloração com hematoxilina-eosina. Métodos especiais como PAS (Acido periódico de Schiff) e impregnação pela prata para estudo da reticulina são usualmente utilizados para diagnóstico diferencial, por exemplo, entre Sarcoma de Ewing, Linfomas e PNET (Tumor neuroectodérmico primitivo). O PAS, demostrando glicogênio e a escassa quantidade de reticulina, são usuais para diagnóstico de  sarcoma de Ewing. Nos Linfomas a reticulina é abundante e o PAS é negativo. Técnicas de imuno-histoquímica com imunoperoxidase estão entrando na rotina dos exames anatomopatológicos. São principalmente indicadas na procura do diagnóstico do órgão de origem de neoplasias metastáticas nos ossos. O uso de marcadores que permitem identificar a origem da célula neoplásica é cada vez mais usado na prática diária. Exemplos são o PSA, para identificar neoplasia originária da próstata, CK7 para neoplasia primitiva do pulmão, CK20 para neoplasia primitiva do tudo digestivo e receptores de estrógeno e progesterona para neoplasia da mama.

Peças cirúrgicas:

Rotineiramente uma peça cirúrgica deve ser examinada externamente e aos cortes. Externamente para análise das margens cirúrgicas com a finalidade de se verificar se a neoplasia foi completamente extirpada. Aos cortes verificamos o comprometimento do osso, extensão e  dimensões da neoplasia e seus caracteres macroscópicos principais para adequado estudo microscópico. (Figura 1) 

Quando o estudo de uma ressecção cirúrgica for de paciente submetido a quimioterapia pré-operatória, particularmente no osteossarcoma e no sarcoma de Ewing,  o estudo da  peça deverá obedecer uma sistematização de exame, pois a finalidade é analisar a resposta da neoplasia à terapêutica. As etapas do estudo serão as seguintes:

A) Serão feitas fatias da peça cirúrgica em toda sua extensão com espessura máxima de 0,5 cm,

B) Uma ou mais fatias deverão ser reproduzidas em “scanner” de computador ou fotografadas e radiografadas,

C) Esta reprodução deverá ser quadriculada da extremidade proximal até a distal,

D) Os fragmentos de cada área quadriculada deverão ser minuciosamente examinados ao microscópico com a finalidade de quantificar a necrose da neoplasia e a persistência de células tumorais histológicamente viáveis,

E) O relatório final do estudo de toda a peça deverá ser graduado quanto à resposta de quimioterapia pré-operatória nos critérios de Huvos.

Critérios de Huvos:

Grau I: Até 50% de necrose tumoral;

Grau II: de 50 a 90/% de necrose tumoral;

Grau III: Acima de 90% de necrose;

Grau IV: 100% de necrose tumoral – Ausência de células neoplásicas histológicamente viáveis.

Com esta graduação o oncologista poderá orientar o tratamento pós-operatório tendo em vista o pior prognóstico estatístico nos casos de gruas I e II e melhor nos de III e IV.

Author: Prof. Dr. Pedro Péricles Ribeiro Baptista

 Orthopedic Oncosurgery at the Dr. Arnaldo Vieira de Carvalho Cancer Institute

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