FRCS: Pathology

IIB. The case in this question is of a high-grade tumour (dedifferentiated chondrosarcoma), which has invaded its natural anatomical barrier (periosteum) to become extraosseous and hence extracompartmental, in the absence of metastases, i.e. stage IIB. Stage is determined by three different subcategories: 1. Grade (histology with aid of radiographic findings and clinical correlation) G1: Low grade G2: High grade 2. Site T1: Intracompartmental T2: Extracompartmental 3. Metastasis M0: No identifiable skip lesions or distant metastases M1: Any skip lesions, regional lymph nodes or distant metastases Enneking’s and MSTS Staging System of Malignant Bone Tumours: IA Low grade, intracompartmental G1 T1 M0 IB Low grade, extracompartmental G1 T2 M0 IIA High grade, intracompartmental G2 T1 M0 IIB High grade, extracompartmental G2 T2 M0 IIIA Any grade, intracompartmental, with metastases G1/2 T1 M1 IIIB Any grade, extracompartmental, with metastases G1/2 T2 M1

Low (T1)/High (T2). MRI uses radiofrequency pulses on tissues in a magnetic field to generate images in different planes. Protons in compounds of hydrogen (e.g. water, fat, marrow, etc) are aligned in a magnetic field. The strength of this imaging modality is its sensitivity to changes in water distribution. T1 images are weighted towards fat and T2 images are weighted towards water. Water, cerebrospinal fluid and soft tissue tumours appear dark on T1 sequences and bright on T2 sequences. Fat, nerves and bone marrow appear bright on T1 sequences and grey (moderate) on T2 sequences.

Factors II, VII, IX and X. This case requires an understanding of the clotting cascade and knowledge of which factors would cause an elevation of both the PT and APTT. For both of these times to be elevated, a deficiency of clotting factors involved in both the extrinsic and intrinsic pathways is required. This narrows down the choices to either A or E. The patient in this case has Crohn’s disease. This can affect the terminal ileum resulting in malabsorption of the fat- soluble vitamins A, D, E and K. Factors II, VII, IX and X are the vitamin K-dependent clotting factors, which would be expected to be low in Crohn’s disease. Factor V would also be low if the patient had liver disease but this is not stated in the vignette. 159 Factor VIII deficiency is the cause of haemophilia A. This would give an elevated APTT but a normal PT. Factor IX deficiency is the cause of Christmas disease, which is again characterized by an elevated APTT but a normal PT. Low levels of von Willebrand factor are seen in von Willebrand disease. This causes a prolonged or normal APTT, a normal PT and a prolonged bleeding time.

Decreased chondroitin 4-sulphate concentration. Chondroitin sulphate concentration increases in osteoarthritis and this includes both chondroitin 4- and 6-sulphate. Keratin sulphate concentration decreases and hence the ratio of keratin to chondroitin sulphate decreases as well.

Urine cortisol. The opening line of this case may tempt one to consider the diagnosis of Duchenne’s muscular dystrophy for which choice B would be the correct answer. This child has features of Cushing’s syndrome, which can be caused by excess adrenocorticotrophic hormone (ACTH) production or occur independent of ACTH, due to an adrenal adenoma. Obesity, hypertension, bruising and proximal myopathy are all features of Cushing’s syndrome. The first step in establishing this diagnosis is to measure the urinary free cortisol. The cause of the Cushing’s syndrome can then be determined by performing the dexamethasone suppression test, measuring plasma ACTH and obtaining an MRI of the pituitary if appropriate.

The lacunae are characteristically empty. This patient has osteopetrosis. This bone disorder is characterized by increased sclerosis and obliteration of the medullary canals secondary to decreased osteoclast function and not number. Pathological fractures are common. It may result from a thymic defect. Histologically, osteoclasts lack their normal brush border and empty lacunae with plugged Haversian canals are seen. The autosomal recessive form can lead to death during infancy and the autosomal dominant form (Albers-Schönberg disease) tends to have a more benign course.

The causative organism is Pasteurella multocida. Cat scratch disease is caused by a wound inflicted by a cat. It causes infection of the lymphatic system by Bartonella henselae. Treatment can be supportive as the disease resolves in 2–6 months. Symptomatic treatment in the form of aspiration of painful lymph nodes is acceptable. Incision and drainage of these nodes is contraindicated. The antibiotic of choice is azithromycin. Pasteurella multocida is the causative organism in cat bite injuries.

X-linked dominant. Vitamin D-resistant rickets is also known as familial hypophosphataemic rickets. It is an X-linked dominant disorder that occurs as a result of renal phosphate wasting. It is the most common form of rickets and is treated with phosphate replacement.

Wide surgical resection and limb salvage. This patient has an adamantinoma. This is an extremely rare, low-grade, malignant tumour of long bones. It is almost always found on the anterior cortex of the tibia. It must be differentiated from osteofibrous dysplasia which also occurs on the anterior cortex of the 160 tibia, but tends to occur in children and is a benign condition. Adamantinoma is treated with wide surgical excision. It is not sensitive to radiotherapy, and chemotherapy is not used.

HLA B27 positivity. Modified New York Criteria for diagnosing ankylosing spondylitis:
Clinical criteria: Low back pain; present for more than 3 months; improved by exercise but not relieved by rest. Limitation of lumbar spine motion in both the sagittal and frontal planes. Limitation of chest expansion relative to normal values for age and sex.
Radiological criterion: Sacroiliitis on X-ray.
Diagnose: Definite ankylosing spondylitis if the radiological criterion is present plus at least one clinical criterion. Probable ankylosing spondylitis if three clinical criteria are present alone, or if the radiological criterion is present but no clinical criteria are present.

Langerhans’ cell histiocytosis. Langerhans’ cell histiocytosis or eosinophilic granuloma is usually seen in the vertebral bodies of children and adolescents. The vertebral body tends to collapse producing the classical radiographic appearance of ‘vertebra plana’. Rarely do these tumours lead to paraparesis and typically heal spontaneously.

The tumour should be approached through normal tissue before entering the reactive zone. When performing a biopsy of a suspected bone tumour the following principles must be followed (in addition to A, B, C, E):
avoid contamination of normal compartments
enter the tumour through the reactive zone
place the biopsy tract in line with incision to allow excision when performing a longitudinal extensile incision
avoid contamination of intermuscular planes
avoid contamination of neurovascular bundles

B and C. In 1994, the WHO introduced definitions for osteoporosis and osteopaenia in terms of T score thresholds of –2.5 and –1 respectively. A T score of –2.5 means that the bone mineral density in the lumbar spine (L2–L4) is at least 2.5 standard deviations below the mean of a young (age 25–35), healthy female. A T score of more than –2.5 implies it is more positive and hence could represent either osteopaenia or normal bone density.

Osteofibrous dysplasia. Most orthopaedic oncology centres would agree that there is no role for curettage and grafting in osteofibrous dysplasia. This condition often regresses by the time a child reaches 161 skeletal maturity and therefore observation is all that is required. This line of management is controversial. Osteofibrous dysplasia has been linked to progression to adamantinoma, in which case wide surgical excision is recommended.

Nora’s disease. This patient has a bizarre parosteal osteochondromatous proliferation (BPOP). This is a rare lesion that tends to occur in the hands and feet and is thought to be related to myositis ossificans. It was first described in 1983 by Dr Nora; hence the name Nora’s disease. The lesion is benign but may recur locally in up to 50% of cases. Recommended treatment is complete excision with the widest possible margin without damage to adjacent structures.

Chondroblastoma. Benign skeletal tumours rarely if ever metastasize to lung. The two exceptions to this rule are giant cell tumour (up to 10% metastasize to lung) and chondroblastoma.

Chondromyxoid fibroma. Helms has stated that 99% of epiphyseal lesions in young patients are one of the following: chondroblastoma, giant cell tumour, osteomyelitis, aneurysmal bone cyst and eosinophilic granuloma. Clear cell chondrosarcoma can also affect the epiphysis, but in an older age group. Chondromyxoid fibroma typically produces a lytic lesion in the metaphysis.

Decreased serum phosphate levels. Hypophosphatasia is an autosomal recessive disorder caused by an inborn error of the isoenzyme of alkaline phosphatase (ALP). Its features are similar to those of rickets. It is not associated with decreased serum levels of phosphate or calcium. Vitamin D and parathyroid hormone (PTH) levels are usually normal.

Cross the physis. Giant cell tumour of bone occurs in young adults aged 25–40. The physis must be closed for the radiological criteria to be met which are: 1. Epiphyseal location, 2. Abut the articular surface, 3. Eccentric, 4. Non-sclerotic margin. The most common sites in the appendicular skeleton are the distal femur and distal radius. The sacrum is the commonest site in the axial skeleton.

Albright’s hereditary osteodystrophy. Brachydactyly refers to short first, fourth and fifth metacarpals and metatarsals. This is seen in pseudohypoparathyroidism, otherwise known as Albright’s hereditary osteodystrophy. This disorder occurs due to a parathyroid hormone (PTH) receptor abnormality. In addition to the brachydactyly, patients are obese, have reduced intelligence and can present with exostoses.

Waldenström macroglobulinaemia. This question really requires you to read the vignette carefully. There are a number of clues that should prevent you from going straight for multiple myeloma (MM) as the answer. Firstly, the age of the patient. Peak incidence for Waldenström macroglobulinaemia (WM) 162 is 60–70 whereas for MM it is 50–60. The M spike in WM is IgM whereas in MM it is usually IgG. The intensely eosinophilic plasma cells are classic for WM. The multiple lesions rule out a solitary plasmacytoma. Patients with a monoclonal gammopathy of undetermined significance are asymptomatic. Patients with POEMS have symmetrical neurology and skin lesions.

Sarcomatous degeneration occurs in 30% of patients. Ollier’s disease is a non-inherited disease characterized by multiple enchondromas. Onset is usually in childhood and results in bony deformity and shortening. The lesions continue to progress until skeletal maturity. The risk of conversion to chondrosarcoma is 25–30% in Ollier’s disease and up to 100% in Mafucci’s syndrome.

Mutation of the Gi alpha subunit of a membrane G protein. McCune–Albright syndrome is a condition defined by the presence of café-au-lait patches, precocious puberty and polyostotic fibrous dysplasia. Fibrous dysplasia has a ground glass appearance on plain radiographs and histologically features woven bone which lacks osteoblastic rimming. It arises due to a genetic mutation in the Gs alpha subunit (not the Gi subunit, which may have the opposite effect!) of a membrane G protein involved in cell signalling via the cAMP second messenger pathway.

Syringomyelia. A Charcot’s arthropathy is an extreme form of osteoarthritis caused by disturbed sensory innervation. Syringomyelia is the most common cause for an upper limb Charcot joint. Tabes dorsalis used to be the most common cause for a lower limb Charcot joint, but now diabetes is the most common cause.

Homogentisic acid oxidase. This patient has degenerative arthritis resulting from alkaptonuria. This condition is also known as ochronosis. The deficient enzyme is homogentisic acid oxidase. Homogentisic acid is deposited in joints and turns black. It is also responsible for the black urine.

Third and fourth pharyngeal pouches. This child has DiGeorge syndrome. The third pharyngeal pouch gives rise to the thymus and inferior parathyroid glands. The fourth pharyngeal pouch gives rise to the superior parathyroid glands. These patients therefore develop symptoms and signs of hypocalcaemia due to hypoparathyroidism and recurrent infections due to a T-cell deficiency which arises from inadequate development of the thymus. Other associations include tetralogy of Fallot, abnormal facies and cleft palate.

Symmetrical muscle weakness. Rheumatoid arthritis is defined by the presence of four or more of the following criteria according to the American Rheumatism Association: 1. Morning stiffness in and around joints lasting at least 1 hour before maximal improvement, present for at least 6 weeks 2. Soft tissue swelling (arthritis) of three or more joint areas observed by a physician, present for at least 6 weeks 163 3. Swelling (arthritis) of the proximal interphalangeal, metacarpophalangeal or wrist joints for at least 6 weeks 4. Symmetric swelling (arthritis) for at least 6 weeks 5. Rheumatoid nodules 6. The presence of rheumatoid factor 7. Radiographic erosions and/or periarticular osteopaenia in hand and/or wrist joints 164 1. Which of the following is the most sensitive clinical sign for detection of developmental dysplasia of the hip (DDH) in a baby aged 6 months? a. Galeazzi test. b. Asymmetric skin folds in the thighs. c. Limited hip abduction in flexion. d. Ortolani’s test. e. Barlow’s test. 2. On an anteroposterior (AP) radiograph, which of the following defines a B/C border hip according to Herring’s modified classification of Perthes disease? a. A very narrow lateral pillar which is <50% of the original height. b. A lateral pillar with very little ossification with at least 50% of the original height. c. A lateral pillar with increased ossification with at least 50% of the original height. d. A lateral pillar with exactly 50% of the original height that is higher than the central pillar. e. Gage’s sign. 3. When treating slipped upper femoral epiphysis (SUFE), which of the following might be the sole indication for subcapital osteotomy? a. Metaphyseal blanch sign. b. Southwick angle >60
. c. Avascular necrosis (AVN). d. Femoral retroversion. e. Endocrinopathy. 4. When investigating for the presence of femoroacetabular impingement (FAI), which of the following radiographic views is most likely to identify a cam lesion? a. Cross table lateral. b. False profile. c. Frog lateral. d. Billings lateral. e. Dunn lateral. # Cambridge University Press 2012. 172