Lessons for the Unwary
By Henry Y. Li, A.B.
Stanford University School of Medicine
The case report of a young man presenting with Hodgkin's disease is used to illustrate both the continued utility of a thorough physical examination in managing the diagnostic work-up of patients and the diagnostic problems that can result from not detecting physical findings.
The patient is a twenty-eight year-old Caucasian man in apparent good health who suffered a new-onset generalized tonic-clonic seizure on a bus one afternoon. He was taken to the emergency department, where he experienced on arrival a second episode of a generalized tonic-clonic seizure. Neither episode was accompanied by incontinence of bowel or bladder, though there was tongue-biting. Physical examination was apparently remarkable only for a minor laceration of the tongue. The patient was treated with phenytoin, which controlled the seizures. No neurological sequelae were apparent. A CT scan of the head did not reveal hemmorhage. A complete blood count (CBC), however, showed pancytopenia, with a white blood cell count of 2700/mm3 (64% polymorphonuclear cells), a hematocrit of 26.9%, and a platelet count of 2000/mm3. He was immediately transfused with platelets, which did not succeed in raising the platelet count. Administration of intravenous immunoglobulin (IVIG) followed by transfusion of platelets, however, resulted in elevation of the platelet count. The patient was subsequently admitted to the neurology service for observation.
While on the neurology service, the patient's seizures remained well-controlled by phenytoin. A contrast MRI scan of the head was obtained, which revealed a 2x3x4 cm zone of edema with a 8 mm focus of enhancement in the left posterior parietal lobe; the differential diagnosis for this lesion, according to the consultant neuroradiologist, included tuberculosis and mycobacteria-avian complex, with toxoplasmosis and lymphoma less likely. In light of the patient's pancytopenia, an aspirate and a biopsy of the bone marrow were both obtained by the consultant hematologists, which revealed the following: erythroid hyperplasia, elevated numbers of megakaryocytes, unremarkable myeloid cells, and absence of iron stores in the bone marrow. The reticulocyte count was elevated at 7.3% while red blood cell morphology was unremarkable. Other laboratory values included an erythrocyte sedimentation rate (ESR) of 103, lactate dehydrogenase (LDH) of 909 (reference range <600), serum complement C3 of 51 (ref. range 50-120), serum complement C4 of 13 (ref. range 10-40), a positive direct Coomb's test, a negative HIV antibody test., and a negative urinalysis. A chest radiograph revealed multiple densities in the lungs (left > right), the differential diagnosis for which included AIDS lymphoma versus mycobacteria-avian complex (per the consultant radiologist). A chest CT scan showed perihilar lymphadenopathy and multiple peripheral pulmonary nodules consistent with fungal infection (Aspergillus or coccidiodomycosis) versus Wegener's granulomatosis (per the consultant radiologist). Clinical course to date was significant for two febrile episodes, with a maximum temperature of 38.9 °C on the second day of hospitalization; blood cultures with fungal isolates were obtained following these episodes. After two days of hospitalization on the neurology service, the patient was transferred to the general medicine service on the third day.
The patient's past medical history was significant only for a fifteen-year history of headaches, each preceded by an aura consisting of "sparkling before the eyes" and paresthesias in the right upper and lower extremities. His last tuberculin purified protein derivative (PPD) test for tuberculosis was in 1986, at which time it was apparently negative. He denied the use of medications, tobacco, ethanol, and illicit drugs. Married for several years, he worked as an airport shuttle driver at the time of admission. With the exception of one unprotected encounter with a female prostitute in the mid-1980s, he reported having only condom-protected sexual intercourse with his wife and four previous female sexual partners. Prior to this hospital admission, he did not have any blood transfusions. His last episode of foreign travel was in 1986, when he was based in South Korea while in the Army. Family history was significant for alcoholism, coronary artery disease, and psoriasis in the his father and psoriasis in his brother; his mother was in good health. Review of systems was significant for the following: 1) lower extremity ecchymosis over the preceding eight months whenever he traumatized his lower extremities with suitcases; 2) tactile fever and night sweats over the past several months (less than six months), during which he had one episode of fever and sweats every two to three weeks but no chills. He denied the following: weight loss over the preceding nine years; fatigue; cough; dyspnea; bleeding tendencies; anorexia; rashes; diarrhea; nausea; changes in bowel or bladder habits.
On physical examination following transfer to the general medicine service, the patient was found to be a thin, pleasant, well-developed man with a temperature of 37.3°C, pulse of 65, respiratory rate of 16 per minute, height of 6 feet, and weight of 65 kg. The head and neck examination was significant for a minor laceration of the tongue and one palpable lymph node at the right base of the neck (anterior cervical chain). Pulmonary and cardiac examinations were within normal limits. The abdominal examination also seemed to be within normal limits, with no hepatosplenomegaly apparent on subcostal palpation; percussion of the abdomen was not performed. The lower extremities were noted to have intact pulses and bilateral ecchymoses. No neurologic deficits were found, with cranial nerves, strength, sensation, deep tendon reflexes, and cerebellar function all grossly normal.
At this point in the patient's course, the differential diagnosis for the patient's disparate symptoms was broad, including AIDS (despite a negative HIV-antibody test), rheumatologic conditions including systemic lupus erythematosis and vasculitides, and neoplastic diseases, especially lymphoma. Because the radiologic and hematologic evidence strongly suggested the possibility of an immunocompromised state, the Western blot and polymerase chain reaction (PCR) tests for HIV were obtained, as was a T-cell analysis. The HIV tests remained negative, while the T-cell analysis showed an absolute CD4 T-cell count of 370/mm3. Other laboratory tests were obtained to evaluate both the radiologic findings and the likelihood of a rheumatologic etiology for the patient's condition; these tests included a hepatitis panel, anti-cytomegalovirus (CMV) antibody, coccidiodes antigen, cryptosporidium antigen, anti-nuclear cytoplasm antibody (ANCA), fluorescent anti-nuclear antibody (FANA), anti-Epstein-Barr virus serology, and stool ova and parasite tests. All were eventually negative.
On the fourth day of hospitalization, the patient underwent a lumbar puncture, which revealed benign cerebral spinal fluid (CSF), with no malignant cells, no acid-fast bacilli, no organisms, and 11 lymphocytes/ml (no neutrophils). On hospital day six, a contrast CT scan of the chest, abdomen, and pelvis was obtained. It demonstrated marked splenomegaly extending into the pelvis, extensive upper abdominal and retroperitoneal lymphadenopathy, an enlarged left inguinal lymph node, and multiple pulmonary opacities of nonspecific etiology. Splenomegaly was confirmed by physical examination (palpation and percussion) of the lower abdomen and pelvis. On hospital day seven, fine needle aspiration of the enlarged left inguinal lymph node and bronchoscopy with Wang and transbronchial biopsies were performed. According to the consultant pathologists, the subcarinal lymph nodes were suspicious for, but not diagnostic of, small cell lymphoma, while the aspirate and the other biopsies and bronchoalveolar lavage were negative or non-specific for lymphoma.
Throughout the course of hospitalization, the patient remained asymptomatic except for some night sweats and recurrent late afternoon and early evening fevers; the maximum temperature recorded was 39.5°C on hospital day seven. All blood and urine cultures were negative. His platelet count rose steadily until hospital day seven, reaching a peak of 147000/mm3 without transfusions other than that given initially in the emergency department. By hospital day ten, the platelet count had fallen to 80000/mm3, and the patient was given an additional dose of intravenous immunoglobulins. Hematocrit at this point was 23.1% while the white cell count was 2300/mm3. The patient was discharged on hospital day ten, with outpatient follow-up in pulmonology, oncology, neurology, and surgery.
One and a half months after discharge, the patient was readmitted to the hospital for exploratory laparotomy to stage possible lymphoma. The laparotomy revealed Hodgkin's disease in the spleen and liver (Stage IV-B), and a splenectomy was performed. After the splenectomy, the patient's platelet count rose dramatically, reaching 548000/mm3. One month after the surgery, the patient underwent a head MRI scan, which revealed that the left posterior parietal lobe lesion seen during the initial presentation to the emergency department had resolved. Soon afterwards, he received the first cycle of chemotherapy (doxorubicin, bleomycin, vinblastine, dacarbazine) for his disease and continued with outpatient treatment.
The hospital course of this patient demonstrates the continued potential value of the physical examination in guiding the diagnostic evaluation of a patient. Because no member (student, resident, attending physician) of the examining teams in the emergency department, neurology service, and medical service detected the marked splenomegaly exhibited by this patient and all felt the physical examination to be unremarkable (other than ecchymoses), the patient was subjected to ten days of hospitalization and a large battery of diagnostic tests and procedures and ten days of hospitalization, at no small cost to the patient's comfort, to the hospital (the patient was covered by a capitated health plan), and to society at large. This battery of tests was further enlarged as a given test revealed potential abnormalities that necessitated confirmatory tests. For instance, the suggestion of a rheumatologic or opportunistic infectious etiology for the patient's pulmonary findings on a chest CT scan resulted in the ordering of a rheumatologic battery (e.g. ANCA, FANA) and a panel of tests for opportunistic organisms (e.g. cryptosporidium antigen, coccidiodes antigen, anti-CMV antibody, stool ova and parasites) and HIV (e.g. Western blot, PCR), despite an earlier negative HIV antibody test.
Would earlier detection of the marked splenomegaly (the principal finding) by physical examination, confirmed by a CT scan of the abdomen and pelvis, have altered the hospital course and diagnostic evaluation of this patient? At this point, this query invites only a speculative answer, but the limited differential diagnosis of moderate and great enlargement of the spleen suggests that a more limited and cost-effective work-up could have been planned and executed. On the basis of Adams' classification of the etiology of splenomegaly according to splenic size, the differential diagnosis of moderate splenic enlargement includes hepatitis, hepatic cirrhosis, lymphoma, anemia (pernicious, hemolytic), amyloidosis, infectious mononucleosis, abscesses, splenic infarct, and schistosomiasis. The etiologies of great splenic enlargement include chronic myelocytic leukemia (CML), myelofibrosis, thalassemia major, chronic malaria, congenital syphilis, leishmaniasis, and portal vein obstruction (1). Most of these potential causes of splenomegaly could have been excluded on the basis of the routine admission CBC and comprehensive survey panel performed on this patient. The bone marrow biopsy and aspirate (obtained to evaluate pancytopenia) would have excluded CML and myelofibrosis. Of the remaining possibilities, lymphoma would have been most prominent, especially in light of the "B symptoms" (e.g. night sweats, fever) exhibited by this patient (2,3). Splenomegaly was not detected until day six of a ten-day hospitalization. Had the enlarged spleen been noticed on the first or second day, the extent of hospitalization could perhaps have been reduced, resulting in a better quality of life for the patient (he disliked the hospital environment and food) and lower costs for the hospital.
It is not certain, however, that this patient's spleen could necessarily have been detected on routine physical examination. The bimanual splenic examination described in standard textbooks calls for the examiner's right hand to be placed below the left costal margin and for the left hand to reach around the patient and push forward the left lower thoracic cage during deep inspiration by the patient (1,4). Furthermore, the textbooks note that an enlarged spleen should be palpable approximately two centimeters below the costal margin when the patient inspires deeply (4). Such an examination was performed on this patient by several physicians, who could not detect a splenic tip since the tip was much further caudal than expected. The splenic tip was only found when the examination started from the pelvis and lower abdomen, using information from a CT scan.
The use of percussion in addition to palpation, however, could perhaps have resulted in a suspicion of splenomegaly. Because the spleen enlarges in the anterior, caudal, and medial directions, splenic enlargement replaces the tympanic tone of the normal left upper abdomen with the dullness of a solid (4). Continued percussion in a caudal direction could perhaps have alerted the examiners to the size of the mass, prompting a more in-depth examination than would otherwise have been warranted. To be sure, anecdotal evidence and personal observations suggest that splenic percussion is not as commonly performed as hepatic percussion. Perhaps more widespread use of this examination technique during routine physical examination would be of benefit.
This would especially be true for patients who present with Hodgkin's disease, in whom signs and symptoms are frequently vague and nonspecific (2,3). An estimated 60-75% of patients presenting with Hodgkin's disease have few to no symptoms. Among the remainder who do have some constitutional symptoms, the most frequent symptom is a persistent low-grade fever, associated with night sweats, that can last for weeks, followed by afebrile periods. This is especially seen in elderly patients and in those with advanced-stage disease. Other relatively common symptoms include unexplained weight loss exceeding 10% in six months, weakness, malaise, and fatigue. Even if symptoms are present, some patients may not think anything is amiss; the patient under discussion, for instance, thought that his tactile fevers and night sweats resulted from using too many blankets in bed. The most common presenting sign is asymptomatic peripheral lymphadenopathy, especially in the cervical, supraclavicular, and mediastinal regions, with splenomegaly as another finding. Since the lymphadenopathy is often painless, patients frequently do not detect the nodes until they are significantly enlarged (2,3).
This case report illustrates both the continued utility of a thorough physical examination in guiding the diagnosis of illness, even in today's realm of technology- and laboratory-driven medicine, and the diagnostic problems that can result from not detecting physical findings. While the physical examination might not suffice for a complete diagnosis to be made, it may help narrow the differential diagnosis generated from a patient's presenting symptoms. In this manner, laboratory tests and other diagnostic modalities can be chosen in a more closely tailored fashion to yield the desired information at less discomfort to the patient and less cost to society.
1. DeGowin, R.L. DeGowin and DeGowin's Bedside Diagnostic Examination, 5th edition. New York: Macmillan, 1987, pp. 506-511.
2. Weinshel, E.L. and Peterson, B.A. Hodgkin's disease. CA Cancer J Clin 1993; 43:327-346.
3. Freedman, A.S. and Nadler, L.M. Malignant lymphomas. In: Isselbacher K.J. et al., ed., Harrison's Principles of Internal Medicine, 13th edition. New York: McGraw-Hill, 1994, pp. 1774-1788.
4. Bates, B. A Guide to Physical Examination and History Taking, 4th edition. Philadelphia: J.B. Lippincott, 1987, pp. 338-344.
Reprinted from the Stanford Medical Student Clinical Journal, Spring 1996 Edition.