College of American Pathologists
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  Q and A





December 2008

Question Q. I recently noted an increase in LGL/NK reactive lymphocytes; on some smears they may account for 10 to 20 percent of the lymphocytes. It is my policy to describe “reactive lymphocytes” when that many are present. Please discuss large granular lymphocytes and natural killer cells.

A. Large granular lymphocyte, or LGL, is a morphologic observation. Natural killer, or NK, cell is a functional designation. LGLs are normally present in blood smears. They are medium to large cells with round nuclei, dense chromatin, and no visible nucleoli. The cytoplasm is moderate to abundant, clear, or lightly basophilic, and it contains several coarse unevenly distributed azurophilic granules. Cell surface markers show that these LGLs are suppressor/cytotoxic cells (CD3+ and CD8+) or NK cells (CD3- and CD56+). Ten to 15 percent of normal circulating lymphocytes have an LGL morphology. LGLs are not reactive lymphocytes. Reactive lymphocytes have a more abundant cytoplasm that frequently contains vacuoles, a lower nuclear-to-cytoplasmic ratio, irregular nuclear outlines, and more open chromatin, often with a small nucleolus. The Downey type II reactive lymphocyte commonly seen in conditions such as infectious mononucleosis is most easily confused with LGLs. Granules are not commonly present; the cytoplasm shows radiating basophilia and is often amoeboid in appearance, surrounding adjacent red blood cells. A full discussion of this topic is in the CAP Hematology, Clinical Microscopy, and Body Fluids Glossary, which is online for Surveys participants at manual_glossary.pdf.

Robert Novak, MD
Department of Pathology
Children’s Hospital
Medical Center of Akron

Akron, Ohio
Chair, CAP Hematology/Clinical
Microscopy Resource Committee

Question Q. What are the best chemical tests to diagnose or follow patients with osteopenia/ osteoporosis: those that indicate primarily bone collagen formation (for example, osteocalcin, procollagen amino, and/or carboxy-terminal extension peptide) or those that indicate bone resorption (for example, N or Ctelopeptide, pyridinoline, deoxypyridinoline), or both? How frequently should these tests be performed? Since vitamin D is important in bone matrix formation, are patients who take Coumadin at greater risk for osteopenia? Is it true that only PTH analog stimulates bone formation, and that calcium, vitamin D, bisphosphonates, calcitonin, estrogen, and estrogen receptor modulators only reduce bone resorption (reduce osteoclast activity)? Are other tests of importance: serum calcium, alkaline phosphatase, PTH, thyroid function tests, urinary calcium excretion?

A. Biochemical markers of bone turnover cannot be used as diagnostic tests. The easiest way to understand this is to appreciate that total and bone alkaline phosphatase are elevated in Paget’s disease, primary and secondary hyperparathyroidism, osteomalacia and rickets, metastatic disease, and osteoporosis. I make constant use of turnover markers in managing patients with osteoporosis. Anti-resorptive therapy (for example, bisphosphonates) causes a rapid (less than three months) decrease in markers of bone resorption (CTX or NTX, serum assays preferred) and formation markers (P1NP, bone alkaline phosphatase, P1CP, osteocalcin) within six months. The markers stay down as long as therapy is continued. For my patients, if bone density is stable for two years, I check that the markers are low and discontinue therapy. I re-check them every three to four months to see the “elution” of bisphosphonate off the skeleton with a progressive increase in markers. As they begin to rise to the top half of the reference interval, I restart therapy. In response to teriparatide (Forteo), the formation markers increase earlier than the resorption markers, and a three-months-on-therapy measurement is an indication that therapy is working. Which markers do I prefer? The laboratory I work with (Warde) offers serum CTX and P1NP. I don’t know that they are better than others, but they are helpful to me.

Patients on Coumadin are at risk of bone loss, but it is through a vitamin K mechanism, not vitamin D.

PTH is the only currently available formation stimulation therapy in the United States, and it increases formation markers. In several other countries, strontium ranelate is also available as a formation stimulation agent, and the biochemical response is similar.

I measure 24-hour urine calcium, sodium, and creatinine in almost all of my patients with osteoporosis. If the urine calcium is high (>4 mg/kg body weight) and urine sodium normal, the therapy is with thiazides. If both the calcium and sodium are elevated, the therapy is a low-sodium diet. Using thiazides and following a low-sodium diet are effective and inexpensive.

It is more cost-effective to recommend vitamin D3 10 units per day at five cents per day than to measure 25 hydroxyvitamin D at a cost of $10 to $16 and a charge of $60 per test.

I do check thyroid function in most patients, and in men I also check gonadal function. Serum calcium is almost always normal in osteoporosis as is PTH unless there is hypercalciuria—again a less expensive test.

Michael Kleerekoper, MD
Department of Internal Medicine
St. Joseph Mercy Reichert
Health Center
Ypsilanti, Mich.

Question Q. An orthopedic surgeon at my institution is of the opinion that it’s unnecessary to send knee and hip bones from patients with osteoarthritis to pathology for examination. He asks why, if he does not agree with sending the bone to pathology but is told by pathology he must do so, he has to be the ordering physician, rather than the pathologist. Can you help me answer this surgeon’s question?

A. The submission of specimens for microscopic examination is a quality-of-patient-care issue and not determined by the pathologists or an orthopedic surgeon but by the surgical facility’s medical staff. The orthopedic surgeon is required by the facility (hospital or surgery center) to submit the specimens for microscopic examination as part of the facility’s quality assurance plan and maybe as part of the ­surgeons’ quality assurance plan. The key question for the facility’s medical executive committee, risk management department, legal counsel, orthopedic surgeons, and laboratory is whether they are willing to expose their patients and themselves to the additional risk of not having the specimens submitted for microscopic examination. The orthopedic surgeon’s patients to date may have been a fortunate sample to not have any conditions identified other than osteoarthritis, but this does not provide any assurance that all of her or his future patients, and those of other orthopedic surgeons, will be as fortunate.

Additionally, the orthopedic surgeon may want to consult with her or his professional liability insurance provider to see if the provider wants to forego having independent documentation of what the surgeon removed from the patient.

These types of specimens are costly for the laboratory and pathologists to process and examine and provide limited revenue. However, only a few institutions exempt these specimens from submission and a minor percentage of institutions specify a “gross only” examination—with the expectation that a pathologist will use her or his professional judgment to determine if a microscopic examination should be performed.1

Any specimens not submitted to the pathology laboratory for examination must be documented in the medical record, and a log should be kept indicating the specimens’ dispositions in accordance with hospital policy. Institutions opting to not submit these types of specimens for microscopic examination should give consideration to special circumstances. Specimens from patients with a known history of malignancy or of selected systemic diseases (for example, rheumatoid arthritis, gout, sarcoid) should be required to be examined microscopically.

To the benefit of patients, standards for patient care are not set by individual physicians but by a diverse group of health care providers working cooperatively to develop them, with each bringing the knowledge and wisdom of their training and experience and, when available, providing scientific evidence from multiple scientific studies to support their decisions.

Reference and Additional Reading

  1. Zarbo RJ, Nakleh RE. Surgical pathology specimens for gross examination only and exempt from submission: a College of American Pathologists Q-Probes study of current policies in 413 institutions. Arch Pathol Lab Med. 1999;123:133–139.
  2. References cited with CAP’s Laboratory Accreditation Program’s 2007 Anatomic Pathology Checklist questions ANP.10016 and ANP.10032 (, CAP Accreditation and Laboratory Improvement, Laboratory Accreditation Program Checklists, Anatomic Pathology).
  3. College of American Pathologists. Surgical Specimens to be Submitted to Pathology for Examination, Revised November 2007 (, CAP Reference Resources and Publications, CAP Public Policy Compendium).

Edward W. Catalano, MD
Chief of Staff, Palmetto Health
Richland Memorial Hospital
Columbia, SC

Chair, CAP Practice
Management Committee