A 55-year-old woman with 1 year of left shoulder pain

Issue: February 2016

ByAnthony A. Romeo, MD

ByAlaa Alsadi, MD

BySteven Gitelis, MD

ByDavid M. Walton, MD

ByMatthew W. Tetreault, MD

A 55-year-old right-hand dominant chef with a history of depression and tobacco use presented to our clinic with worsening atraumatic left shoulder pain. Her symptoms began insidiously approximately 1 year prior to presentation, and had recently begun to limit her activities of daily living. She described a constant dull pain, which escalated to sharp pain with activities that required reaching away from her body. She also reported pain that awakened her at night when she rolled onto her left side and noted associated shoulder weakness.

She denied constitutional symptoms, such as fevers, weight loss or night sweats. During her initial work-up approximately 1 year prior to presentation, an outside orthopedist obtained left shoulder radiographs as well as MRI (Figure 1). At that time, she was diagnosed with osteonecrosis of the left humeral head and a total shoulder arthroplasty was recommended. She opted for nonoperative management, but her symptoms failed to improve with physical therapy or anti-inflammatories. She presented to our office for a second opinion regarding her treatment options.

Examination revealed a well-appearing female. The skin overlying the left shoulder was unremarkable and there was no observable swelling, lymphadenopathy or muscle atrophy. She was tender to palpation over the acromioclavicular joint. She was able to actively forward elevate her shoulder to 160°, abduct 120°, externally rotate with the elbow at her side to 40° and internally rotate posteriorly to the thoracolumbar junction without crepitus, but with pain at terminal ranges of motion. She also noted pain, but no significant weakness, with supraspinatus and infraspinatus testing. She was found to have a positive belly press and a positive bear-hug test with pain localized anteriorly. She was neurovascularly intact distally.

Diagnostic images of the left shoulder from 1-year prior to presentation, including anterior-posterior radiograph showing patchy osteopenia within the humeral head with questionable subchondral lucency in the superior aspect of the humeral head (arrow) (a); scapular-Y radiograph demonstrating poorly defined radiolucent regions in the humeral head (b); MRI cut of the left shoulder from 1-year prior to presentation demonstrating increased T2 signal area within the anterosuperior humeral head with surrounding marrow edema (c).

Imaging results

Updated shoulder radiographs and MRI were obtained (Figure 2). These revealed an expansile lytic lesion of the humeral head. After referral to an orthopedic oncologic surgeon, biopsy of the lesion was performed. The permanent histology specimen (Figure 3) demonstrated moderately differentiated islands of large polygonal malignant cells containing keratin and intercellular bridges. All cultures were negative.

Diagnostic images of the left shoulder from the time of presentation, include Grashey (a) and scapular-Y (b) radiographs demonstrating a large lytic lesion in the humeral head with overlying cortical destruction, MRI cuts demonstrating a large, lobulated lesion with high-T2 (c) and low-T1 (d) signal occupying much of the anterior and superior humeral head with associated cortical destruction.

Pathology specimens of the proximal humerus biopsy including a photomicrograph of the biopsy showing infiltrative nests of hyperchromatic cells with a significant fibrotic reaction (hematoxylin and eosin; 4X magnification) (a); higher magnification image revealing irregular proliferation of large cells with eosinophilic cytoplasm and malignant nuclear features of high nuclear-cytoplasmic ratio and prominent nucleoli (hematoxylin and eosin; 40X magnification) (b); and immunohistochemical staining positive for cytokeratin 8/18 in a cytoplasmic pattern supporting epithelial differentiation (40X magnification) (c).

What is your diagnosis?

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Metastatic squamous cell carcinoma

Based on the history, physical examination and imaging studies, the differential diagnosis for this patient included a neoplastic vs. infectious process; specifically: metastatic lesion, chondrosarcoma, myeloma, lymphoma, osteomyelitis and osteosarcoma.

Pain at rest that is unrelated to activity and pain that awakens the patient from sleep warrants a detailed evaluation for a neoplastic process. A thorough patient history is important. The pain from bone tumors is typically deep-seated, and may initially be intermittent and related to activity, a work injury or a sporting injury, but progress in intensity and becomes constant. NSAIDs and low-dose narcotics often fail to relieve the pain. A large, rapidly growing mass or recent changes in a previously stable lesion are suggestive of an aggressive process.

Skeletal metastases account for 70% of all malignant bone tumors with lung cancer, breast cancer, renal cell carcinoma and prostate cancer responsible for about 80% of all skeletal metastases. Metastases are particularly common in older patients (aged 40 years to 80 years). Risk factors, such as smoking, a family history and constitutional symptoms, may be tip-offs. As with other bone lesions, skeletal metastases can be difficult to identify on plain films because extensive bone mineral loss (30% to 50%) is required before the density loss is visible. Destruction of cortex or the presence of sclerosis can be the first visible signs on plain radiograph. It is important to note that unlike primary bone tumors, metastases generally incite no or only limited periosteal reaction. Occasional exceptions to this rule include prostate cancer, some gastrointestinal malignancies, retinoblastoma and neuroblastoma. Cytokeratin-positive staining on immunohistochemistry supports an epithelial origin.

Pathognomonic radiographic findings for osteonecrosis of the shoulder in a different patient (right shoulder), including anterior-posterior radiograph demonstrating the crescent sign (arrow), indicative of subchondral collapse (a), and T2-weighted coronal MRI demonstrating the double line sign (arrow), consisting of a bright T2 line representing granulation tissue and a dark line representing sclerotic bone (b).

Our patient was initially diagnosed with osteonecrosis of the humeral head. As with neoplasms and degenerative rotator cuff tears, patients with osteonecrosis can present with insidious onset and progressive shoulder pain. Loss of motion and weakness are common. Although the patient had no known risk factors for osteonecrosis (steroid and alcohol use being the most common), up to 25% of osteonecrosis is idiopathic. Shoulder radiographs in the early stages may be normal (Cruess stage I) for months or show a mottled appearance of patchy sclerosis and osteopenia (stage II), akin to our patient’s initial radiographs (Figure 1a). The pathognomonic crescent sign signifying subchondral collapse (stage III, Figure 4a) does not develop until later, making MRI without contrast the preferred imaging modality for early detection, with up to 100% sensitivity. Focal osteonecrosis lesions are well-demarcated and inhomogenous on T1-weighted images, the earliest finding being a single low-intensity line that represents the separation of normal and ischemic bone. A second high-intensity line appears on T2-weighted images, representing hypervascular granulation tissue; this is the pathognomonic double-line sign (Figure 4b).

In this case, the first MRI revealed a poorly defined area of low T1 and high T2 intensity with surrounding edema (Figure 1b) but lacked the pathognomonic osteonecrosis findings. The presence of early osteonecrosis was a reasonable differential diagnosis. However, this case emphasizes the importance of scheduled follow-up for repeat clinical and radiographic examination.

Treatment

A biopsy of the destructive lesion was performed using a biopsy tract adjacent to, but not through, the deltopectoral interval so it could easily be resected along with a tumor should the lesion prove to be a primary bone sarcoma amenable to limb-sparing surgery. Although obtaining a bone scan early in the evaluation would have helped to differentiate monostotic vs. polyostotic disease, many now pursue early biopsy since an experienced pathologist can often determine the primary diagnosis with the use of immunohistochemistry. This approach has largely replaced a work-up for a primary source prior to the biopsy. Biopsies should be performed at the center where definitive treatment will take place.

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After confirmation of a metastatic bone lesion, the next step in treatment was enlisting a medical oncology team to coordinate care. The patient underwent a CT scan of the chest, abdomen and pelvis with IV contrast for primary tumor identification and staging. This revealed a large, right lower lobe, lung mass with associated hilar and subcarinal lymphadenopathy, consistent with primary lung cancer. A whole-body positron emission tomography (PET)-CT scan was used to further stage the cancer. PET-CT scan is an integrated modality that is superior to CT alone, PET alone or visually correlated PET and CT in the staging of non-small cell lung cancer. The scan demonstrated a hypermetabolic, large, partially necrotic, right lung mass, hypermetabolic right hilar and subcarinal lymph nodes, a subcentimeter, hypermetabolic left axillary lymph node, and lytic metastases to the left humeral head and anterior seventh rib. An MRI of the brain was negative for intracranial metastases.

Follow-up

With an established diagnosis of stage IV squamous cell carcinoma of the lung, targeted irradiation therapy to the painful left humeral lesion and systemic treatment with chemotherapy were initiated. A bisphosphonate regimen was initiated to minimize bone loss, and the patient quit smoking upon diagnosis. Her left shoulder pain greatly improved with irradiation therapy and her biopsy site healed without issue. At most recent follow-up, she complained only of mild stiffness and fatigue with use of her shoulder, and was undergoing physical therapy for strengthening. Under the direction of the medical oncologists, she is receiving a four- to six-cycle course of carboplatin/gemcitabine with plans for maintenance with a targeted chemotherapy agent (erlotinib). A re-staging CT scan will be performed after every even cycle of chemotherapy, although it should be noted her overall prognosis is guarded, given the metastatic state of her disease.

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Frassica FJ, et al. Orthopaedic pathology. In: Miller MD, Thompson SR, Hart JA, editors. Review of Orthopaedics. 6th ed. Philadelphia, PA: Elsevier Saunders; 2012;623-674.
Greenspan A, et al. Differential diagnosis in orthopaedic oncology. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2007.
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For more information:
Matthew W. Tetreault, MD; David M. Walton, MD; Steven Gitelis, MD; and Anthony A. Romeo, MD, can be reached at 1611 W. Harrison St., Suite 300, Chicago, IL 60612. Tetreault can be reached at matthew.w.tetreault@gmail.com. Walton can be reached at walton.davidm@gmail.com. Gitelis can be reached at steven_gitelis@rush.edu. Romeo can be reached at orthopedics@healio.com.
Alaa Alsadi, MD, can be reached at Rush University Medical Center, Department of Pathology, 1750 W. Harrison St., Suite 570, Chicago, IL 60612; email: alaa_alsadi@rush.edu.

Disclosures: Romeo reports he receives royalties, is on the speakers bureau and a consultant for Arthrex Inc.; does contracted research for Arthrex Inc. and DJO Surgical; receives institutional grants from AANA and MLB; and receives institutional research support from Arthrex Inc., Ossur, Smith & Nephew, ConMed Linvatec, Athletico and Miomed. Alsadi, Gitelis, Tetreault and Walton report no relevant financial disclosures.