Symptom-Based Diagnosis in Pediatrics (CHOP Morning Report) 1st Ed.

CASE 4-1

Sixteen-Year-Old Girl

DEBRA BOYER

TREGONY SIMONEAU

HISTORY OF PRESENT ILLNESS

The patient is a 16-year-old black female with a 2-week history of a dry cough. She described shortness of breath, which worsened while lying down. She had been sleeping on three pillows since her cough began. Her cough and shortness of breath were waking her at night and symptoms were somewhat relieved by sitting up. She had chest tightness with deep inspiration as well as pain when lying on her left side. She had intermittent fevers (38.0°C) during the last few weeks as well as drenching night sweats.

She was initially treated with albuterol for her cough without significant relief. One week into her illness she was seen by an allergist who noted decreased breath sounds on the left side. A chest roentgenogram was obtained and the patient admitted for further evaluation.

Review of systems revealed decreased appetite with early satiety. She had some weight loss during the last 12 months. She denied headaches, sore throat, or changes in her voice. She reported an episode of diffuse pruritis 2 months prior to admission.

MEDICAL HISTORY

The patient’s history was remarkable for no prior significant illness and no hospitalizations. She had a fibroadenoma excised from her right breast 3 months prior to this admission. Her family history was significant for a maternal grandmother with uterine cancer, an aunt with breast cancer, and a maternal great-grandmother with thyroid cancer.

PHYSICAL EXAMINATION

T 38.1°C; P 127 bpm; RR 20/min; BP 139/73 mmHg

Weight 50th percentile; Height 95th percentile

Initial examination revealed an alert young woman, sitting forward, with noticeable shortness of breath and cough. Physical examination was remarkable for decreased breath sounds on the left, most significantly at the base. She had two small subcutaneous nodules on her left superior chest wall. The remainder of her physical examination was normal.

DIAGNOSTIC STUDIES

Laboratory analysis revealed a peripheral blood count with 21 200 WBC/mm3 with 94% segmented neutrophils, 3% lymphocytes, and 3% monocytes. Hemoglobin was 8.4 g/dL with an MCV of 63 fL. Platelets were 386 000/mm3. Electrolytes, blood urea nitrogen, creatinine, and liver function tests were normal. Erythrocyte sedimentation rate (ESR) was elevated at 60 mm/h.

COURSE OF ILLNESS

A chest computed tomography (CT) scan was obtained to further assess abnormalities on chest radiograph (Figure 4-1). The patient was admitted to the intensive care unit with concerns of impending respiratory failure.

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FIGURE 4-1. Chest computed tomogram.

DISCUSSION CASE 4-1

DIFFERENTIAL DIAGNOSIS

The most common causes of cough in adolescents include infections and asthma. While viral infections are certainly the most common, other agents may include Mycoplasma pneumoniaeBordetella pertussis, and bacterial infections. Less common infectious causes include HIV and related infections, measles, tuberculosis, and fungal infections. Patients with asthma would be most likely to have had a prior history of mild wheezing and possibly atopy. Other diagnoses that should be considered in an adolescent with a chronic cough include but are not limited to allergic rhinitis, sinusitis, gastroesophageal reflux, and smoking. Rare causes would include primary ciliary dyskinesia, interstitial pneumonitis, granulomatous disorders, and malignancies.

The concerning features of this case involve the patient’s significant shortness of breath and orthopnea. These are not common complaints with simple viral infections or asthma exacerbations. Her persistent fevers and night sweats suggest a systemic disorder, such as tuberculosis or oncologic disease, and definitely warrant further investigation.

DIAGNOSIS

A chest roentgenogram revealed a large anterior mediastinal mass with rightward tracheal deviation. Chest CT revealed a large, bulky infiltrating anterior mediastinal mass that extended from above the level of the clavicle to near the level of the diaphragm (Figure 4-1).

It also extended posteriorly to involve the middle mediastinum. There was also bilateral axillary lymphadenopathy and a left pleural effusion. Chest tube placement yielded 1200 cc of pleural fluid with 3900 red blood cells/mm3, 772 white blood cells/mm3 (22% segmented neutrophils and 78% lymphocytes), pH 7.44, glucose 100 mg/dL, LDH 386 U/L, and amylase <30 U/L. A lymph node biopsy performed in the operating room revealed nodular sclerosing Hodgkin lymphoma. Bone marrow biopsy did not reveal hematologic involvement. With a negative abdominal CT scan, her lymphoma was considered Stage IIB and she commenced a course of chemotherapy.

INCIDENCE AND EPIDEMIOLOGY

Hodgkin disease is a malignancy of mature B cells. It has a bimodal age distribution in industrialized countries, with an early peak in 15-35 years old and a second peak after 50 years of age. There seem to be three separate forms of the disease: childhood (<14 years of age), young adults (15-34 years), and older adults (55-74 years). It is the most commonly diagnosed cancer for adolescents (15-19 years of age) and is rare among children less than 5 years of age. The incidence is slightly higher in males.

Hodgkin disease develops when a single transformed B cell is clonally expanded.

The malignant cells consist of Reed-Sternberg cells, lymphocytic and histiocytic cells. Interestingly, only 1% of the tumor consists of malignant cells. The greatest proportions of cells are inflammatory cells resulting from a significant cytokine release. Based on histology, there are four subtypes of Hodgkin disease: lymphocytic predominance, mixed cellularity, lymphocytic depletion, and nodular sclerosing. Nodular sclerosing is the most common type in adolescents, whereas mixed cellularity is more common in children with Hodgkin Lymphoma. Epstein-Barr virus (EBV) has been associated with some cases of Hodgkin disease with virus reactivation as a possible causative factor. This appears to be more common in younger children. Current 10-year survival rates are greater than 90% in patients diagnosed prior to the age of 45 years.

CLINICAL PRESENTATION

Often, a patient will present with firm but painless lymphadenopathy. Approximately 60% of patients may have mediastinal involvement as part of their initial presentation. It is rare to have primary disease present in subdiaphragmatic locations. Constitutional symptoms are common and include fatigue, weight loss, anorexia, fevers, and night sweats. Interestingly, as seen in this patient, pruritis is often a complaint of patients with Hodgkin disease.

Abnormal laboratory findings may include leukocytosis, lymphopenia, eosinophilia, monocytosis, anemia, and thrombocytopenia. In contrast to many adults, most children have normal lymphocyte counts at diagnosis. Autoimmune disorders that can accompany Hodgkindisease include nephrotic syndrome and autoimmune hemolytic anemia, neutropenia, and thrombocytopenia. Nonspecific markers of inflammation such as the erythrocyte sedimentation rate and ferritin levels may be elevated.

DIAGNOSTIC APPROACH

A large pleural effusion and anterior mediastinal mass are concerning findings in this adolescent patient. Initial evaluation included a chest roent-genogram as well as aspiration of the pleural fluid.

Chest roentgenogram. Discovery of a large pleural effusion requires further diagnostic studies. Initially, lateral decubitus chest roentgenograms may be used to determine whether the fluid is free-flowing or loculated. Loculated pleural fluid suggests infection while free-flowing pleural fluid may be seen in many conditions. As in this patient, mediastinal masses, hilar lymphadenopathy, and pleural effusions may be noted in cases of malignancy.

Ultrasound. Chest ultrasound can facilitate management decisions by rapidly determining whether a pleural effusion is loculated or free-flowing.

Chest CT with intravenous contrast. CT of the chest may also be useful to analyze a pleural effusion for loculations. Chest CT is very useful to view the lung parenchyma in depth, revealing subtle lung disease not apparent on chest roentgenogram. Furthermore, a chest CT is able to further delineate masses, including mediastinal lesions and lymphadenopathy that may have been suggested on chest roentgenogram. With Hodgkin disease specifically, the most common extranodal disease sites include the lung parenchyma, chest wall, pleura, and pericardium.

Aspiration of pleural fluid. Ultimately, with a significant pleural effusion the pleural fluid should be aspirated. This is important from a diagnostic, and in many cases, therapeutic, standpoint. Pleural fluid should be sent for pH, culture, gram stain, cell count with differential, glucose, protein, and LDH. These studies can help to divide pleural effusions into exudates and transudates (Table 4-5). Exudates are most common in parapneumonic effusions, neoplasms, and connective tissue disease, whereas transudates are more common in congestive heart failure, nephrotic syndrome, and cirrhosis. If the pleural fluid pH is greater than 7.4, it is unlikely to be an exudative process. Malignant pleural effusions, such as those from Hodgkin lymphoma, are exudative in nature and most often have quite reduced glucose levels. On occasions, malignant cells themselves are noted in the pleural fluid.

TABLE 4-5. Pleural fluid analysis.

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Tissue biopsy. The key to diagnosis of Hodgkin disease is pathologic confirmation of disease. This can be obtained from mass lesions as well as affected lymph nodes.

CT of neck/chest/abdomen and pelvis. Once the diagnosis of Hodgkin disease is established, these studies are performed in addition to a chest CT to stage the degree of disease.

MRI. In selected cases, MRI may be helpful in further delineating lymph node involvement and thus with staging of the disease.

Bone marrow biopsy. Useful for staging.

18-Fluorodeoxyglucose positron emission tomography (FDG-PET). PET scans are used to supplement initial staging and to monitor response to therapy. FGD-PET seems to be more sensitive than gallium scans in the detection of Hodgkin lymphoma.

TREATMENT

Determination of staging is essential in choosing the course of therapy for Hodgkin disease. Stages are based on the Ann Arbor staging classification and include:

• Stage I—Involvement of a single lymph node region or of a single extralymphatic organ or site.

• Stage II—Involvement of two or more lymph node regions on the same side of the diaphragm or localized involvement of an extralymphatic organ or site and one of more lymph node regions on the same side of the diaphragm.

• Stage III—Involvement of lymph node regions on both sides of the diaphragm.

• Stage IV—Diffuse or disseminated involvement of one or more extralymphatic organs or tissues with or without associated lymph node involvement.

Patients are stratified into low, intermediate, and high-risk categories on the basis of distribution of disease, bulk, and presence of B symptoms. Standard therapy for Hodgkin disease includes risk-adapted chemotherapy and involved-field radiation. Patients with favorable presentations (localized nodal involvement with no constitutional symptoms and without bulky disease) have been treated with fewer cycles of chemotherapy and lower radiation doses. In contrast, those patients with unfavorable presentations (constitutional symptoms, bulky mediastinal, or peripheral lymphadenopathy, and advanced Stage IIIB/IV disease) receive much more intense protocols.

SUGGESTED READINGS

1. Hudson MM, Onciu M, Donaldson SS. Hodgkin lymphoma. In: Pizzo PA, Poplack DG, eds. Principles and Practice of Pediatric Oncology. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2006:695-721.

2. Montgomery M. Air and liquid in the pleural space. In: Chernick V, Boat TF, eds. Kendig’s Disorders of the Respiratory Tract in Children. 6th ed. Philadelphia: W.B. Saunders Company; 1998:389-411.

3. Punnet A, Tsang RW, Hodgson DC. Hodgkin lymphoma across the age spectrum: epidemiology, therapy, and late effects. Semin Radiat Oncol. 2010;20:30-44.