Q2. Answer: C

Rationale: MALT lymphomas are associated with H. pylori infection in 80%-90% of cases. H. pylori triggers a B-cell clonal expansion leading to lymphoma. Detection of chronic H. pylori using histology is directly dependent on the number of mucosal biopsies. Negative H. pylori testing should prompt an alternative test for H. pylori (either breath or stool antigen test). Treatment of H. pylori is successful in achieving complete remission in up to 80% of cases. Surveillance after treatment of MALT lymphoma is indicated, though the exact protocol has not been established.

References

1. ASGE Standards of Practice Committee. The role of endoscopy in management of premalignant and malignant conditions of the stomach. Gastrointest Endosc. 2015 82(1):1-8.

2. Gisbert J.P., Calvet X. Review article: common misconceptions in the management of Helicobacter pylori-associated gastric MALT-lymphoma. Aliment Pharmacol Ther. 2011 Nov;34(9):1047-62.

Q2. Answer: C

Rationale: MALT lymphomas are associated with H. pylori infection in 80%-90% of cases. H. pylori triggers a B-cell clonal expansion leading to lymphoma. Detection of chronic H. pylori using histology is directly dependent on the number of mucosal biopsies. Negative H. pylori testing should prompt an alternative test for H. pylori (either breath or stool antigen test). Treatment of H. pylori is successful in achieving complete remission in up to 80% of cases. Surveillance after treatment of MALT lymphoma is indicated, though the exact protocol has not been established.

References

1. ASGE Standards of Practice Committee. The role of endoscopy in management of premalignant and malignant conditions of the stomach. Gastrointest Endosc. 2015 82(1):1-8.

2. Gisbert J.P., Calvet X. Review article: common misconceptions in the management of Helicobacter pylori-associated gastric MALT-lymphoma. Aliment Pharmacol Ther. 2011 Nov;34(9):1047-62.

Q2. Answer: C

Rationale: MALT lymphomas are associated with H. pylori infection in 80%-90% of cases. H. pylori triggers a B-cell clonal expansion leading to lymphoma. Detection of chronic H. pylori using histology is directly dependent on the number of mucosal biopsies. Negative H. pylori testing should prompt an alternative test for H. pylori (either breath or stool antigen test). Treatment of H. pylori is successful in achieving complete remission in up to 80% of cases. Surveillance after treatment of MALT lymphoma is indicated, though the exact protocol has not been established.

References

1. ASGE Standards of Practice Committee. The role of endoscopy in management of premalignant and malignant conditions of the stomach. Gastrointest Endosc. 2015 82(1):1-8.

2. Gisbert J.P., Calvet X. Review article: common misconceptions in the management of Helicobacter pylori-associated gastric MALT-lymphoma. Aliment Pharmacol Ther. 2011 Nov;34(9):1047-62.

Q1. Answer: A

While heartburn responds well to acid suppression with a proton pump inhibitor, regurgitation does not necessarily improve. It is well known that reflux persists despite acid suppression; in some patients, this manifests as troublesome postprandial regurgitation.  Transient LES relaxations (TLESRs) are the prime mechanism for persisting reflex, in patients both with and without hiatal hernias. 

Baclofen, a gamma amino butyric acid B (GABA-B) agonist, inhibits TLESRs and has potential to improve persisting regurgitation.  Metoclopramide has been demonstrated to have no adjunctive value in treating reflux disease. Hyoscyamine and sucralfate are similarly not of particular benefit in this setting. Cholesytramine is a bile salt binding resin that has value in the management of postcholecystectomy diarrhea.

References 

1. Kahrilas P.J., Jonsson A., Denison H., et al. Regurgitation is less responsive to acid suppression than heartburn in patients with gastroesophageal reflux disease. Clin Gastroenterol Hepatol. 2012;10(6):612-9. 

2. Vela M.F., Camacho-Lobato L., Srinivasan R., et al. Simultaneous intraesophageal impedance and pH measurement of acid and nonacid gastroesophageal reflux: effect of omeprazole. Gastroenterology. 2001 Jun;120(7):1599-606.

3. Vela M.F., Tutuian R, Katz PO, et al. Baclofen decreases acid and non-acid post-prandial gastro-oesophageal reflux measured by combined multichannel intraluminal impedance and pH. Aliment Pharmacol Ther. 2003 Jan;17(2):243-51.

Q1. Answer: A

While heartburn responds well to acid suppression with a proton pump inhibitor, regurgitation does not necessarily improve. It is well known that reflux persists despite acid suppression; in some patients, this manifests as troublesome postprandial regurgitation.  Transient LES relaxations (TLESRs) are the prime mechanism for persisting reflex, in patients both with and without hiatal hernias. 

Baclofen, a gamma amino butyric acid B (GABA-B) agonist, inhibits TLESRs and has potential to improve persisting regurgitation.  Metoclopramide has been demonstrated to have no adjunctive value in treating reflux disease. Hyoscyamine and sucralfate are similarly not of particular benefit in this setting. Cholesytramine is a bile salt binding resin that has value in the management of postcholecystectomy diarrhea.

References 

1. Kahrilas P.J., Jonsson A., Denison H., et al. Regurgitation is less responsive to acid suppression than heartburn in patients with gastroesophageal reflux disease. Clin Gastroenterol Hepatol. 2012;10(6):612-9. 

2. Vela M.F., Camacho-Lobato L., Srinivasan R., et al. Simultaneous intraesophageal impedance and pH measurement of acid and nonacid gastroesophageal reflux: effect of omeprazole. Gastroenterology. 2001 Jun;120(7):1599-606.

3. Vela M.F., Tutuian R, Katz PO, et al. Baclofen decreases acid and non-acid post-prandial gastro-oesophageal reflux measured by combined multichannel intraluminal impedance and pH. Aliment Pharmacol Ther. 2003 Jan;17(2):243-51.

Q1. Answer: A

While heartburn responds well to acid suppression with a proton pump inhibitor, regurgitation does not necessarily improve. It is well known that reflux persists despite acid suppression; in some patients, this manifests as troublesome postprandial regurgitation.  Transient LES relaxations (TLESRs) are the prime mechanism for persisting reflex, in patients both with and without hiatal hernias. 

Baclofen, a gamma amino butyric acid B (GABA-B) agonist, inhibits TLESRs and has potential to improve persisting regurgitation.  Metoclopramide has been demonstrated to have no adjunctive value in treating reflux disease. Hyoscyamine and sucralfate are similarly not of particular benefit in this setting. Cholesytramine is a bile salt binding resin that has value in the management of postcholecystectomy diarrhea.

References 

1. Kahrilas P.J., Jonsson A., Denison H., et al. Regurgitation is less responsive to acid suppression than heartburn in patients with gastroesophageal reflux disease. Clin Gastroenterol Hepatol. 2012;10(6):612-9. 

2. Vela M.F., Camacho-Lobato L., Srinivasan R., et al. Simultaneous intraesophageal impedance and pH measurement of acid and nonacid gastroesophageal reflux: effect of omeprazole. Gastroenterology. 2001 Jun;120(7):1599-606.

3. Vela M.F., Tutuian R, Katz PO, et al. Baclofen decreases acid and non-acid post-prandial gastro-oesophageal reflux measured by combined multichannel intraluminal impedance and pH. Aliment Pharmacol Ther. 2003 Jan;17(2):243-51.

SAN ANTONIO – Surgeons at Houston Methodist Hospital reported a 75% success rate in removing both fallopian tubes during vaginal hysterectomy in a study presented at the annual scientific meeting of the Society of Gynecologic Surgeons.

Serous ovarian carcinoma is now thought to arise from the distal fallopian tube, and it’s estimated that salpingectomy prevents diagnosis of ovarian cancer in 1 in 225 women and death from ovarian cancer in 1 in 450 women. The American Congress of Obstetricians and Gynecologists recommends that surgeons and patients “discuss the potential benefits of the removal of the fallopian tubes” during hysterectomy in women not having an oophorectomy.

* The meeting sponsor information was updated 6/9/2017.

[email protected]
 

SAN ANTONIO – Surgeons at Houston Methodist Hospital reported a 75% success rate in removing both fallopian tubes during vaginal hysterectomy in a study presented at the annual scientific meeting of the Society of Gynecologic Surgeons.

Serous ovarian carcinoma is now thought to arise from the distal fallopian tube, and it’s estimated that salpingectomy prevents diagnosis of ovarian cancer in 1 in 225 women and death from ovarian cancer in 1 in 450 women. The American Congress of Obstetricians and Gynecologists recommends that surgeons and patients “discuss the potential benefits of the removal of the fallopian tubes” during hysterectomy in women not having an oophorectomy.

* The meeting sponsor information was updated 6/9/2017.

[email protected]
 

SAN ANTONIO – Surgeons at Houston Methodist Hospital reported a 75% success rate in removing both fallopian tubes during vaginal hysterectomy in a study presented at the annual scientific meeting of the Society of Gynecologic Surgeons.

Serous ovarian carcinoma is now thought to arise from the distal fallopian tube, and it’s estimated that salpingectomy prevents diagnosis of ovarian cancer in 1 in 225 women and death from ovarian cancer in 1 in 450 women. The American Congress of Obstetricians and Gynecologists recommends that surgeons and patients “discuss the potential benefits of the removal of the fallopian tubes” during hysterectomy in women not having an oophorectomy.

* The meeting sponsor information was updated 6/9/2017.

[email protected]
 

Meridian Medical Technologies has issued a voluntary recall for 13 lots of EpiPen products, according to a press release from the U.S. Food and Drug Administration.

The voluntary recall includes EpiPen and EpiPen Jr. Auto-Injector distributed between Dec. 17, 2015, and July 1, 2016 by Mylan Specialty. Products included in the recall may contain a defective part which would prevent the device from activating.

[email protected]

Meridian Medical Technologies has issued a voluntary recall for 13 lots of EpiPen products, according to a press release from the U.S. Food and Drug Administration.

The voluntary recall includes EpiPen and EpiPen Jr. Auto-Injector distributed between Dec. 17, 2015, and July 1, 2016 by Mylan Specialty. Products included in the recall may contain a defective part which would prevent the device from activating.

[email protected]

Meridian Medical Technologies has issued a voluntary recall for 13 lots of EpiPen products, according to a press release from the U.S. Food and Drug Administration.

The voluntary recall includes EpiPen and EpiPen Jr. Auto-Injector distributed between Dec. 17, 2015, and July 1, 2016 by Mylan Specialty. Products included in the recall may contain a defective part which would prevent the device from activating.

[email protected]

ATLANTA – In the opinion of John M. Kelso, MD, assessment of immunization status in older adults should be a routine part of all visits.

“Don’t assume that your patients are getting their vaccines someplace else,” he said at the annual meeting of the American Academy of Allergy, Asthma, and Immunology. “We should be taking advantage of the fact that these patients are in our offices.”

Inactivated influenza vaccine (IIV3)

For adults aged 65 and older, the high-dose, trivalent version of the flu vaccine (60 micrograms of hemagglutinin per strain, or IIV3-HD) may be preferable to the standard dose of 15 micrograms of hemagglutinin per strain (IIV3-SD). A study of nearly 32,000 patients found that IIV3-HD induced significantly higher antibody responses and provided better protection against laboratory-confirmed influenza, compared with IIV3-SD (N Engl J Med. 2014;371:635-45). The relative efficacy of high dose vs. standard dose was 24.2%. “That means that one-quarter of all breakthrough influenza illnesses could be prevented if IIV3HD were used instead of IIV3-SD,” Dr. Kelso said.

Another approach is to use an adjuvanted influenza vaccine, which contains the standard 15 micrograms of influenza antigen but the adjuvant is MF59, a squalene-based oil-in-water emulsion. One small study of 282 patients aged 65 and older showed the adjuvanted vaccine to be more effective than the unadjuvanted vaccine (Vaccine. 2013;51:1622-8).

The Centers for Disease Control and Prevention does not express a preference for the high-dose or adjuvanted vaccine, but rather stresses the importance of influenza vaccination with whatever age-appropriate IIV formulation is available at the time of the patient’s visit.

The 13-valent pneumococcal conjugate vaccine (PCV13) and the 23-valent pneumococcal polysaccharide vaccine (PPSV23)

All adults who turn 65 years of age should receive the PCV13, followed 1 year later by the PPSV23. For those who already received the PPSV23 after age 65 years of age, they should receive the PCV13 at least 1 year later. “The real bulk of hospitalizations and fatalities from invasive pneumococcal disease are happening to people over 65 year of age,” said Dr. Kelso, who is also a clinical professor of pediatrics and internal medicine at the University of California, San Diego “So there’s a real need here for vaccination.”

Tdap

This should be administered to all adolescents and adults regardless of interval since their last tetanus-diphtheria vaccine. “This includes those age 65 years of age and older in whom the vaccine has been found to be equally safe and immunogenic,” Dr. Kelso said. “This is important not only to prevent pertussis in older adults, but also to prevent them from spreading the disease to infants where it can be fatal.”

Zoster vaccine

One in three adults will develop zoster during their lifetime, he said, and one million episodes occur in the United States each year. Common complications include postherpetic neuralgia and eye involvement that can result in loss of vision. The CDC recommends routine vaccination of all immunocompetent persons over age 60 with one dose of zoster vaccine. “Persons who report a previous episode of zoster can be vaccinated but it is not indicated to treat acute zoster, to prevent persons with acute zoster from developing postherpetic neuralgia, or to treat ongoing postherpetic neuralgia,” Dr. Kelso said.

He reported having no relevant financial disclosures.

[email protected]

ATLANTA – In the opinion of John M. Kelso, MD, assessment of immunization status in older adults should be a routine part of all visits.

“Don’t assume that your patients are getting their vaccines someplace else,” he said at the annual meeting of the American Academy of Allergy, Asthma, and Immunology. “We should be taking advantage of the fact that these patients are in our offices.”

Inactivated influenza vaccine (IIV3)

For adults aged 65 and older, the high-dose, trivalent version of the flu vaccine (60 micrograms of hemagglutinin per strain, or IIV3-HD) may be preferable to the standard dose of 15 micrograms of hemagglutinin per strain (IIV3-SD). A study of nearly 32,000 patients found that IIV3-HD induced significantly higher antibody responses and provided better protection against laboratory-confirmed influenza, compared with IIV3-SD (N Engl J Med. 2014;371:635-45). The relative efficacy of high dose vs. standard dose was 24.2%. “That means that one-quarter of all breakthrough influenza illnesses could be prevented if IIV3HD were used instead of IIV3-SD,” Dr. Kelso said.

Another approach is to use an adjuvanted influenza vaccine, which contains the standard 15 micrograms of influenza antigen but the adjuvant is MF59, a squalene-based oil-in-water emulsion. One small study of 282 patients aged 65 and older showed the adjuvanted vaccine to be more effective than the unadjuvanted vaccine (Vaccine. 2013;51:1622-8).

The Centers for Disease Control and Prevention does not express a preference for the high-dose or adjuvanted vaccine, but rather stresses the importance of influenza vaccination with whatever age-appropriate IIV formulation is available at the time of the patient’s visit.

The 13-valent pneumococcal conjugate vaccine (PCV13) and the 23-valent pneumococcal polysaccharide vaccine (PPSV23)

All adults who turn 65 years of age should receive the PCV13, followed 1 year later by the PPSV23. For those who already received the PPSV23 after age 65 years of age, they should receive the PCV13 at least 1 year later. “The real bulk of hospitalizations and fatalities from invasive pneumococcal disease are happening to people over 65 year of age,” said Dr. Kelso, who is also a clinical professor of pediatrics and internal medicine at the University of California, San Diego “So there’s a real need here for vaccination.”

Tdap

This should be administered to all adolescents and adults regardless of interval since their last tetanus-diphtheria vaccine. “This includes those age 65 years of age and older in whom the vaccine has been found to be equally safe and immunogenic,” Dr. Kelso said. “This is important not only to prevent pertussis in older adults, but also to prevent them from spreading the disease to infants where it can be fatal.”

Zoster vaccine

One in three adults will develop zoster during their lifetime, he said, and one million episodes occur in the United States each year. Common complications include postherpetic neuralgia and eye involvement that can result in loss of vision. The CDC recommends routine vaccination of all immunocompetent persons over age 60 with one dose of zoster vaccine. “Persons who report a previous episode of zoster can be vaccinated but it is not indicated to treat acute zoster, to prevent persons with acute zoster from developing postherpetic neuralgia, or to treat ongoing postherpetic neuralgia,” Dr. Kelso said.

He reported having no relevant financial disclosures.

[email protected]

ATLANTA – In the opinion of John M. Kelso, MD, assessment of immunization status in older adults should be a routine part of all visits.

“Don’t assume that your patients are getting their vaccines someplace else,” he said at the annual meeting of the American Academy of Allergy, Asthma, and Immunology. “We should be taking advantage of the fact that these patients are in our offices.”

Inactivated influenza vaccine (IIV3)

For adults aged 65 and older, the high-dose, trivalent version of the flu vaccine (60 micrograms of hemagglutinin per strain, or IIV3-HD) may be preferable to the standard dose of 15 micrograms of hemagglutinin per strain (IIV3-SD). A study of nearly 32,000 patients found that IIV3-HD induced significantly higher antibody responses and provided better protection against laboratory-confirmed influenza, compared with IIV3-SD (N Engl J Med. 2014;371:635-45). The relative efficacy of high dose vs. standard dose was 24.2%. “That means that one-quarter of all breakthrough influenza illnesses could be prevented if IIV3HD were used instead of IIV3-SD,” Dr. Kelso said.

Another approach is to use an adjuvanted influenza vaccine, which contains the standard 15 micrograms of influenza antigen but the adjuvant is MF59, a squalene-based oil-in-water emulsion. One small study of 282 patients aged 65 and older showed the adjuvanted vaccine to be more effective than the unadjuvanted vaccine (Vaccine. 2013;51:1622-8).

The Centers for Disease Control and Prevention does not express a preference for the high-dose or adjuvanted vaccine, but rather stresses the importance of influenza vaccination with whatever age-appropriate IIV formulation is available at the time of the patient’s visit.

The 13-valent pneumococcal conjugate vaccine (PCV13) and the 23-valent pneumococcal polysaccharide vaccine (PPSV23)

All adults who turn 65 years of age should receive the PCV13, followed 1 year later by the PPSV23. For those who already received the PPSV23 after age 65 years of age, they should receive the PCV13 at least 1 year later. “The real bulk of hospitalizations and fatalities from invasive pneumococcal disease are happening to people over 65 year of age,” said Dr. Kelso, who is also a clinical professor of pediatrics and internal medicine at the University of California, San Diego “So there’s a real need here for vaccination.”

Tdap

This should be administered to all adolescents and adults regardless of interval since their last tetanus-diphtheria vaccine. “This includes those age 65 years of age and older in whom the vaccine has been found to be equally safe and immunogenic,” Dr. Kelso said. “This is important not only to prevent pertussis in older adults, but also to prevent them from spreading the disease to infants where it can be fatal.”

Zoster vaccine

One in three adults will develop zoster during their lifetime, he said, and one million episodes occur in the United States each year. Common complications include postherpetic neuralgia and eye involvement that can result in loss of vision. The CDC recommends routine vaccination of all immunocompetent persons over age 60 with one dose of zoster vaccine. “Persons who report a previous episode of zoster can be vaccinated but it is not indicated to treat acute zoster, to prevent persons with acute zoster from developing postherpetic neuralgia, or to treat ongoing postherpetic neuralgia,” Dr. Kelso said.

He reported having no relevant financial disclosures.

[email protected]

SEATTLE – When men who have sex with men were given doxycycline and told to take it after unprotected sex, the incidence of sexually transmitted infections dropped 47% over about 9 months in France.

“We were quite surprised to see” such a strong effect, especially since it was achieved with “a very low use of doxycycline, less than two pills per week” among the 232 men in the study, said lead investigator Jean-Michel Molina, MD, of St. Louis Hospital, Paris.

Alexander Otto/Frontline Medical News

[email protected]

On Twitter @IDPractitioner

SEATTLE – When men who have sex with men were given doxycycline and told to take it after unprotected sex, the incidence of sexually transmitted infections dropped 47% over about 9 months in France.

“We were quite surprised to see” such a strong effect, especially since it was achieved with “a very low use of doxycycline, less than two pills per week” among the 232 men in the study, said lead investigator Jean-Michel Molina, MD, of St. Louis Hospital, Paris.

Alexander Otto/Frontline Medical News

[email protected]

On Twitter @IDPractitioner

SEATTLE – When men who have sex with men were given doxycycline and told to take it after unprotected sex, the incidence of sexually transmitted infections dropped 47% over about 9 months in France.

“We were quite surprised to see” such a strong effect, especially since it was achieved with “a very low use of doxycycline, less than two pills per week” among the 232 men in the study, said lead investigator Jean-Michel Molina, MD, of St. Louis Hospital, Paris.

Alexander Otto/Frontline Medical News

[email protected]

On Twitter @IDPractitioner

Lymphomas constitute a very heterogeneous group of neoplasms with diverse clinical presentations, prognoses, and responses to therapy. Approximately 80,500 new cases of lymphoma are expected to be diagnosed in the United States in 2017, of which about one quarter will lead to the death of the patient.¹ Perhaps more so than any other group of neoplasms, the diagnosis of lymphoma involves the integration of a multiplicity of clinical, histologic and immunophenotypic findings and, on occasion, cytogenetic and molecular results as well. An accurate diagnosis of lymphoma, usually rendered by hematopathologists, allows hematologists/oncologists to treat patients appropriately. Herein we will describe a simplified approach to the diagnosis and classification of lymphomas (Figure 1).

Lymphoma classification

Lymphomas are clonal neoplasms characterized by the expansion of abnormal lymphoid cells that may develop in any organ but commonly involve lymph nodes. The fourth edition of the World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid tissues, published in 2008, is the official and most current guideline used for diagnosis of lymphoid neoplasms.² The WHO scheme classifies lymphomas according to the type of cell from which they are derived (mature and immature B cells, T cells, or natural killer (NK) cells, findings determined by their morphology and immunophenotype) and their clinical, cytogenetic, and/or molecular features. This official classification is currently being updated³ and is expected to be published in full in 2017, at which time it is anticipated to include definitions for more than 70 distinct neoplasms.

Lymphomas are broadly and informally classified as Hodgkin lymphomas (HLs) and non-Hodgkin lymphomas (NHLs), based on the differences these two groups show in their clinical presentation, treatment, prognosis, and proportion of neoplastic cells, among others. NHLs are by far the most common type of lymphomas, accounting for approximately 90% of all new cases of lymphoma in the United States and 70% worldwide.^1,2 NHLs are a very heterogeneous group of B-, T-, or NK-cell neoplasms that, in turn, can also be informally subclassified as low-grade (or indolent) or high-grade (or aggressive) according to their predicted clinical behavior. HLs are comparatively rare, less heterogeneous, uniformly of B-cell origin and, in the case of classical Hodgkin lymphoma, highly curable.^1,2 It is beyond the scope of this manuscript to outline the features of each of the >70 specific entities, but the reader is referred elsewhere for more detail and encouraged to become familiarized with the complexity, challenges, and beauty of lymphoma diagnosis.^2,3

Biopsy procedure

A correct diagnosis begins with an adequate biopsy procedure. It is essential that biopsy specimens for lymphoma evaluation be submitted fresh and unfixed, because some crucial analyses such as flow cytometry or conventional cytogenetics can only be performed on fresh tissue. Indeed, it is important for the hematologist/oncologist and/or surgeon and/or interventional radiologist to converse with the hematopathologist prior to and even during some procedures to ensure the correct processing of the specimen. Also, it is important to limit the compression of the specimen and the excessive use of cauterization during the biopsy procedure, both of which cause artifacts that may render impossible the interpretation of the histopathologic findings.

Given that the diagnosis of lymphoma is based not only on the cytologic details of the lymphoma cells but also on the architectural pattern with which they infiltrate an organ, the larger the biopsy specimen, the easier it will be for a hematopathologist to identify the pattern. In addition, excisional biopsies frequently contain more diagnostic tissue than needle core biopsies and this provides pathologists with the option to submit tissue fragments for ancillary tests that require unfixed tissue as noted above. Needle core biopsies of lymph nodes are increasingly being used because of their association with fewer complications and lower cost than excisional biopsies. However, needle core biopsies provide only a glimpse of the pattern of infiltration and may not be completely representative of the architecture. Therefore, excisional lymph node biopsies of lymph nodes are preferred over needle core biopsies, recognizing that in the setting of deeply seated lymph nodes, needle core biopsies may be the only or the best surgical option.

Clinical presentation

Accurate diagnosis of lymphoma cannot take place in a vacuum. The hematopathologist’s initial approach to the diagnosis of lymphoid processes in tissue biopsies should begin with a thorough review of the clinical history, although some pathology laboratories may not have immediate access to this information. The hematopathologist should evaluate factors such as age, gender, location of the tumor, symptomatology, medications, serology, and prior history of malignancy, immunosuppression or immunodeficiency in every case. Other important but frequently omitted parts of the clinical history are the patient’s occupation, history of exposure to animals, and the presence of tattoos, which may be associated with certain reactive lymphadenopathies.

Histomorphologic evaluation

Despite the plethora of new and increasingly sophisticated tools, histologic and morphologic analysis still remains the cornerstone of diagnosis in hematopathology. However, for the characterization of an increasing number of reactive and neoplastic lymphoid processes, hematopathologists may also require immunophenotypic, molecular, and cytogenetic tests for an accurate diagnosis. Upon review of the clinical information, a microscopic evaluation of the tissue submitted for processing by the histology laboratory will be performed. The results of concurrent flow cytometric evaluation (performed on fresh unfixed material) should also be available in most if not all cases before the H&E-stained slides are available for review. Upon receipt of H&E-stained slides, the hematopathologist will evaluate the quality of the submitted specimen, since many diagnostic difficulties stem from suboptimal techniques related to the biopsy procedure, fixation, processing, cutting, or staining (Figure 1). If deemed suitable for accurate diagnosis, a search for signs of preservation or disruption of the organ that was biopsied will follow. The identification of certain morphologic patterns aids the hematopathologist in answering the first question: “what organ is this and is this consistent with what is indicated on the requisition?” This is usually immediately followed by “is this sufficient and adequate material for a diagnosis?” and “is there any normal architecture?” If the architecture is not normal, “is this alteration due to a reactive or a neoplastic process?” If neoplastic, “is it lymphoma or a non-hematolymphoid neoplasm?”

Both reactive and neoplastic processes have variably unique morphologic features that if properly recognized, guide the subsequent testing. However, some reactive and neoplastic processes can present with overlapping features, and even after extensive immunophenotypic evaluation and the performance of ancillary studies, it may not be possible to conclusively determine its nature. If the lymph node architecture is altered or effaced, the predominant pattern of infiltration (eg, nodular, diffuse, interfollicular, intrasinusoidal) and the degree of alteration of the normal architecture is evaluated, usually at low magnification. When the presence of an infiltrate is recognized, its components must be characterized. If the infiltrate is composed of a homogeneous expansion of lymphoid cells that disrupts or replaces the normal lymphoid architecture, a lymphoma will be suspected or diagnosed. The pattern of distribution of the cells along with their individual morphologic characteristics (ie, size, nuclear shape, chromatin configuration, nucleoli, amount and hue of cytoplasm) are key factors for the diagnosis and classification of the lymphoma that will guide subsequent testing. The immunophenotypic analysis (by immunohistochemistry, flow cytometry or a combination of both) may confirm the reactive or neoplastic nature of the process, and its subclassification. B-cell lymphomas, in particular have variable and distinctive histologic features: as a diffuse infiltrate of large mature lymphoid cells (eg, diffuse large B-cell lymphoma), an expansion of immature lymphoid cells (lymphoblastic lymphoma), and a nodular infiltrate of small, intermediate and/or mature large B cells (eg, follicular lymphoma).

Immunophenotypic evaluation

Immunophenotypic evaluation is essential because the lineage of lymphoma cells cannot be determined by morphology alone. The immunophenotype is the combination of proteins/markers (eg, CD20, CD3, TdT) expressed by cells. Usually, it is evaluated by immunohistochemistry and/or flow cytometry, which help determine the proportion of lymphoid cells that express a certain marker and its location and intensity within the cells. While immunohistochemistry is normally performed on formalin-fixed and paraffin-embedded tissue, flow cytometry can be evaluated only on fresh unfixed tissue. Flow cytometry has the advantage over immunohistochemistry of being faster and better at simultaneously identifying coexpression of multiple markers on multiple cell populations. However, certain markers can only be evaluated by immunohistochemistry.

The immunophenotypic analysis will in most cases reveal whether the lymphomas is of B-, T- or NK-cell origin, and whether a lymphoma subtype associated immunophenotype is present. Typical pan B-cell antigens include PAX5, CD19, and CD79a (CD20 is less broadly expressed throughout B-cell differentiation, although it is usually evident in most mature B-cell lymphomas), and typical pan T-cell antigens include CD2, CD5, and CD7. The immature or mature nature of a lymphoma can also be confirmed by evaluation of the immunophenotype. Immature lymphomas commonly express one or more of TdT, CD10, or CD34; T-lymphoblastic lymphoma cells may also coexpress CD1a. The majority of NHLs and all HLs are derived from (or reflect) B cells at different stages of maturation. Mature B-cell lymphomas are the most common type of lymphoma and typically, but not always, express pan B-cell markers as well as surface membrane immunoglobulin, with the latter also most useful in assessing clonality via a determination of light chain restriction. Some mature B-cell lymphomas tend to acquire markers that are either never physiologically expressed by normal mature B cells (eg, cyclin D1 in mantle cell lymphoma, or BCL2 in germinal center B cells in follicular lymphoma) or only expressed in a minor fraction (eg, CD5 that is characteristically expressed in small lymphocytic and mantle cell lymphoma). The most common mature B-cell lymphomas include diffuse large B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma, mantle cell lymphoma, marginal zone lymphoma, Burkitt lymphoma, and lymphoplasmacytic lymphoma (Figures 2 and 3). Classical HLs are also lymphomas of B-cell origin that demonstrate diminished preservation of their B-cell immunophenotype (as evidenced by the dim expression of PAX5 but absence of most other pan B-cell antigens), expression of CD30, variable expression of CD15, and loss of CD45 (Figure 1). In contrast, nodular lymphocyte predominant HL shows a preserved B-cell immunophenotypic program and expression of CD45, typically without CD30 and CD15. Of note, the evaluation of the immunophenotype of the neoplastic cells in HL is routinely assessed by immunohistochemistry because most flow cytometry laboratories cannot reliably detect and characterize the low numbers of these cells.

Mature T-cell lymphomas generally express one or more T-cell markers, and tend to display a T-helper (CD4-positive) or cytotoxic (CD8-positive) immunophenotype and may show loss of markers expressed by most normal T-cells (eg, CD5, CD7; Figure 4). However, a subset of them may express markers not commonly detected in normal T cells, such as ALK. NK-cell lymphomas lack surface CD3 (expressing only cytoplasmic CD3) and CD5 but express some pan T-cell antigens (such as CD2 and CD7) as well as CD16 and/or CD56.

Patients with primary or acquired immune dysfunction are at risk for development of lymphoma and other less clearly defined lymphoproliferative disorders, the majority of which are associated with infection of the lymphoid cells with Epstein-Barr virus (EBV). Therefore, evaluation with chromogenic in situ hybridization for an EBV-encoded early RNA (EBER1) is routinely performed in these cases; it is thus essential that the hematopathologist be informed of the altered immune system of the patient. If lymphoma develops, they may be morphologically similar to those that appear in immunocompetent patients, which specifically in the post-transplant setting are known as monomorphic post-transplant lymphoproliferative disorders (PTLD). If the PTLD does not meet the criteria for any of the recognized types of lymphoma, it may be best characterized as a polymorphic PTLD.

Once the lineage (B-, T-, or NK-cell) of the mature lymphoma has been established, the sum (and on occasion the gestalt) of the clinical, morphologic, immunophenotypic and other findings will be considered for the subclassification of the neoplasm.

Cytogenetic and molecular evaluation

If the morphologic and immunophenotypic analysis is inconclusive or nondiagnostic, then molecular and/or cytogenetic testing may further aid in the characterization of the process. Some of available molecular tests include analyses for the rearrangements of the variable region of the immunoglobulin (IG) or T-cell receptor (TCR) genes and for mutations on specific genes. The identification of specific mutations not only confirms the clonal nature of the process but, on occasion, it may also help subclassify the lymphoma, whereas IG or TCR rearrangement studies are used to establish whether a lymphoid expansion is polyclonal or monoclonal. The molecular findings should not be evaluated in isolation, because not all monoclonal rearrangements are diagnostic of lymphoma, and not all lymphomas will show a monoclonal rearrangement. Other methodologies that can aid in the identification of a clonal process or specific genetic abnormalities include metaphase cytogenetics (karyotyping) and fluorescence in situ hybridization (FISH). If any cytogenetic abnormalities are found in sufficient numbers (and constitutional abnormalities are excluded), their identification indicates the presence of a clonal process. Also, some cytogenetic abnormalities are characteristic of certain lymphomas. However, they may be neither 100% diagnostically sensitive nor diagnostically specific, for example, the hallmark t(14;18)/IGH-BCL2 is not present in all follicular lymphomas and not all lymphomas with this translocation are follicular lymphomas. Whereas FISH is generally performed on a minimum of 200 cells, compared with typically 20 metaphase by “conventional” karyotyping, and is therefore considered to have higher analytical sensitivity, it evaluates only for the presence or absence of the abnormality being investigated with a given set of probes, and therefore other abnormalities, if present, will not be identified. The value of FISH cytogenetic studies is perhaps best illustrated in the need to diagnose double hit lymphomas, amongst other scenarios. The detection of certain mutations can aid in the diagnosis of certain lymphomas, such as MYD88 in lymphoplasmacytic lymphoma, prognosis of others, such as in follicular lymphoma and identify pathways that may be precisely therapeutically targeted.

Final remarks

The diagnosis of lymphoma can be complex and usually requires the hematopathologist to integrate multiple parameters. The classification of lymphomas is not static, and new entities or variants are continuously described, and the facets of well-known ones refined. While such changes are often to the chagrin of hematologists/oncologists and hematopathologists alike, we should embrace the incorporation of nascent and typically cool data into our practice, as more therapeutically relevant entities are molded.

Lymphomas constitute a very heterogeneous group of neoplasms with diverse clinical presentations, prognoses, and responses to therapy. Approximately 80,500 new cases of lymphoma are expected to be diagnosed in the United States in 2017, of which about one quarter will lead to the death of the patient.¹ Perhaps more so than any other group of neoplasms, the diagnosis of lymphoma involves the integration of a multiplicity of clinical, histologic and immunophenotypic findings and, on occasion, cytogenetic and molecular results as well. An accurate diagnosis of lymphoma, usually rendered by hematopathologists, allows hematologists/oncologists to treat patients appropriately. Herein we will describe a simplified approach to the diagnosis and classification of lymphomas (Figure 1).

Lymphoma classification

Lymphomas are clonal neoplasms characterized by the expansion of abnormal lymphoid cells that may develop in any organ but commonly involve lymph nodes. The fourth edition of the World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid tissues, published in 2008, is the official and most current guideline used for diagnosis of lymphoid neoplasms.² The WHO scheme classifies lymphomas according to the type of cell from which they are derived (mature and immature B cells, T cells, or natural killer (NK) cells, findings determined by their morphology and immunophenotype) and their clinical, cytogenetic, and/or molecular features. This official classification is currently being updated³ and is expected to be published in full in 2017, at which time it is anticipated to include definitions for more than 70 distinct neoplasms.

Lymphomas are broadly and informally classified as Hodgkin lymphomas (HLs) and non-Hodgkin lymphomas (NHLs), based on the differences these two groups show in their clinical presentation, treatment, prognosis, and proportion of neoplastic cells, among others. NHLs are by far the most common type of lymphomas, accounting for approximately 90% of all new cases of lymphoma in the United States and 70% worldwide.^1,2 NHLs are a very heterogeneous group of B-, T-, or NK-cell neoplasms that, in turn, can also be informally subclassified as low-grade (or indolent) or high-grade (or aggressive) according to their predicted clinical behavior. HLs are comparatively rare, less heterogeneous, uniformly of B-cell origin and, in the case of classical Hodgkin lymphoma, highly curable.^1,2 It is beyond the scope of this manuscript to outline the features of each of the >70 specific entities, but the reader is referred elsewhere for more detail and encouraged to become familiarized with the complexity, challenges, and beauty of lymphoma diagnosis.^2,3

Biopsy procedure

A correct diagnosis begins with an adequate biopsy procedure. It is essential that biopsy specimens for lymphoma evaluation be submitted fresh and unfixed, because some crucial analyses such as flow cytometry or conventional cytogenetics can only be performed on fresh tissue. Indeed, it is important for the hematologist/oncologist and/or surgeon and/or interventional radiologist to converse with the hematopathologist prior to and even during some procedures to ensure the correct processing of the specimen. Also, it is important to limit the compression of the specimen and the excessive use of cauterization during the biopsy procedure, both of which cause artifacts that may render impossible the interpretation of the histopathologic findings.

Given that the diagnosis of lymphoma is based not only on the cytologic details of the lymphoma cells but also on the architectural pattern with which they infiltrate an organ, the larger the biopsy specimen, the easier it will be for a hematopathologist to identify the pattern. In addition, excisional biopsies frequently contain more diagnostic tissue than needle core biopsies and this provides pathologists with the option to submit tissue fragments for ancillary tests that require unfixed tissue as noted above. Needle core biopsies of lymph nodes are increasingly being used because of their association with fewer complications and lower cost than excisional biopsies. However, needle core biopsies provide only a glimpse of the pattern of infiltration and may not be completely representative of the architecture. Therefore, excisional lymph node biopsies of lymph nodes are preferred over needle core biopsies, recognizing that in the setting of deeply seated lymph nodes, needle core biopsies may be the only or the best surgical option.

Clinical presentation

Accurate diagnosis of lymphoma cannot take place in a vacuum. The hematopathologist’s initial approach to the diagnosis of lymphoid processes in tissue biopsies should begin with a thorough review of the clinical history, although some pathology laboratories may not have immediate access to this information. The hematopathologist should evaluate factors such as age, gender, location of the tumor, symptomatology, medications, serology, and prior history of malignancy, immunosuppression or immunodeficiency in every case. Other important but frequently omitted parts of the clinical history are the patient’s occupation, history of exposure to animals, and the presence of tattoos, which may be associated with certain reactive lymphadenopathies.

Histomorphologic evaluation

Despite the plethora of new and increasingly sophisticated tools, histologic and morphologic analysis still remains the cornerstone of diagnosis in hematopathology. However, for the characterization of an increasing number of reactive and neoplastic lymphoid processes, hematopathologists may also require immunophenotypic, molecular, and cytogenetic tests for an accurate diagnosis. Upon review of the clinical information, a microscopic evaluation of the tissue submitted for processing by the histology laboratory will be performed. The results of concurrent flow cytometric evaluation (performed on fresh unfixed material) should also be available in most if not all cases before the H&E-stained slides are available for review. Upon receipt of H&E-stained slides, the hematopathologist will evaluate the quality of the submitted specimen, since many diagnostic difficulties stem from suboptimal techniques related to the biopsy procedure, fixation, processing, cutting, or staining (Figure 1). If deemed suitable for accurate diagnosis, a search for signs of preservation or disruption of the organ that was biopsied will follow. The identification of certain morphologic patterns aids the hematopathologist in answering the first question: “what organ is this and is this consistent with what is indicated on the requisition?” This is usually immediately followed by “is this sufficient and adequate material for a diagnosis?” and “is there any normal architecture?” If the architecture is not normal, “is this alteration due to a reactive or a neoplastic process?” If neoplastic, “is it lymphoma or a non-hematolymphoid neoplasm?”

Both reactive and neoplastic processes have variably unique morphologic features that if properly recognized, guide the subsequent testing. However, some reactive and neoplastic processes can present with overlapping features, and even after extensive immunophenotypic evaluation and the performance of ancillary studies, it may not be possible to conclusively determine its nature. If the lymph node architecture is altered or effaced, the predominant pattern of infiltration (eg, nodular, diffuse, interfollicular, intrasinusoidal) and the degree of alteration of the normal architecture is evaluated, usually at low magnification. When the presence of an infiltrate is recognized, its components must be characterized. If the infiltrate is composed of a homogeneous expansion of lymphoid cells that disrupts or replaces the normal lymphoid architecture, a lymphoma will be suspected or diagnosed. The pattern of distribution of the cells along with their individual morphologic characteristics (ie, size, nuclear shape, chromatin configuration, nucleoli, amount and hue of cytoplasm) are key factors for the diagnosis and classification of the lymphoma that will guide subsequent testing. The immunophenotypic analysis (by immunohistochemistry, flow cytometry or a combination of both) may confirm the reactive or neoplastic nature of the process, and its subclassification. B-cell lymphomas, in particular have variable and distinctive histologic features: as a diffuse infiltrate of large mature lymphoid cells (eg, diffuse large B-cell lymphoma), an expansion of immature lymphoid cells (lymphoblastic lymphoma), and a nodular infiltrate of small, intermediate and/or mature large B cells (eg, follicular lymphoma).

Immunophenotypic evaluation

Immunophenotypic evaluation is essential because the lineage of lymphoma cells cannot be determined by morphology alone. The immunophenotype is the combination of proteins/markers (eg, CD20, CD3, TdT) expressed by cells. Usually, it is evaluated by immunohistochemistry and/or flow cytometry, which help determine the proportion of lymphoid cells that express a certain marker and its location and intensity within the cells. While immunohistochemistry is normally performed on formalin-fixed and paraffin-embedded tissue, flow cytometry can be evaluated only on fresh unfixed tissue. Flow cytometry has the advantage over immunohistochemistry of being faster and better at simultaneously identifying coexpression of multiple markers on multiple cell populations. However, certain markers can only be evaluated by immunohistochemistry.

The immunophenotypic analysis will in most cases reveal whether the lymphomas is of B-, T- or NK-cell origin, and whether a lymphoma subtype associated immunophenotype is present. Typical pan B-cell antigens include PAX5, CD19, and CD79a (CD20 is less broadly expressed throughout B-cell differentiation, although it is usually evident in most mature B-cell lymphomas), and typical pan T-cell antigens include CD2, CD5, and CD7. The immature or mature nature of a lymphoma can also be confirmed by evaluation of the immunophenotype. Immature lymphomas commonly express one or more of TdT, CD10, or CD34; T-lymphoblastic lymphoma cells may also coexpress CD1a. The majority of NHLs and all HLs are derived from (or reflect) B cells at different stages of maturation. Mature B-cell lymphomas are the most common type of lymphoma and typically, but not always, express pan B-cell markers as well as surface membrane immunoglobulin, with the latter also most useful in assessing clonality via a determination of light chain restriction. Some mature B-cell lymphomas tend to acquire markers that are either never physiologically expressed by normal mature B cells (eg, cyclin D1 in mantle cell lymphoma, or BCL2 in germinal center B cells in follicular lymphoma) or only expressed in a minor fraction (eg, CD5 that is characteristically expressed in small lymphocytic and mantle cell lymphoma). The most common mature B-cell lymphomas include diffuse large B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma, mantle cell lymphoma, marginal zone lymphoma, Burkitt lymphoma, and lymphoplasmacytic lymphoma (Figures 2 and 3). Classical HLs are also lymphomas of B-cell origin that demonstrate diminished preservation of their B-cell immunophenotype (as evidenced by the dim expression of PAX5 but absence of most other pan B-cell antigens), expression of CD30, variable expression of CD15, and loss of CD45 (Figure 1). In contrast, nodular lymphocyte predominant HL shows a preserved B-cell immunophenotypic program and expression of CD45, typically without CD30 and CD15. Of note, the evaluation of the immunophenotype of the neoplastic cells in HL is routinely assessed by immunohistochemistry because most flow cytometry laboratories cannot reliably detect and characterize the low numbers of these cells.

Mature T-cell lymphomas generally express one or more T-cell markers, and tend to display a T-helper (CD4-positive) or cytotoxic (CD8-positive) immunophenotype and may show loss of markers expressed by most normal T-cells (eg, CD5, CD7; Figure 4). However, a subset of them may express markers not commonly detected in normal T cells, such as ALK. NK-cell lymphomas lack surface CD3 (expressing only cytoplasmic CD3) and CD5 but express some pan T-cell antigens (such as CD2 and CD7) as well as CD16 and/or CD56.

Patients with primary or acquired immune dysfunction are at risk for development of lymphoma and other less clearly defined lymphoproliferative disorders, the majority of which are associated with infection of the lymphoid cells with Epstein-Barr virus (EBV). Therefore, evaluation with chromogenic in situ hybridization for an EBV-encoded early RNA (EBER1) is routinely performed in these cases; it is thus essential that the hematopathologist be informed of the altered immune system of the patient. If lymphoma develops, they may be morphologically similar to those that appear in immunocompetent patients, which specifically in the post-transplant setting are known as monomorphic post-transplant lymphoproliferative disorders (PTLD). If the PTLD does not meet the criteria for any of the recognized types of lymphoma, it may be best characterized as a polymorphic PTLD.

Once the lineage (B-, T-, or NK-cell) of the mature lymphoma has been established, the sum (and on occasion the gestalt) of the clinical, morphologic, immunophenotypic and other findings will be considered for the subclassification of the neoplasm.

Cytogenetic and molecular evaluation

If the morphologic and immunophenotypic analysis is inconclusive or nondiagnostic, then molecular and/or cytogenetic testing may further aid in the characterization of the process. Some of available molecular tests include analyses for the rearrangements of the variable region of the immunoglobulin (IG) or T-cell receptor (TCR) genes and for mutations on specific genes. The identification of specific mutations not only confirms the clonal nature of the process but, on occasion, it may also help subclassify the lymphoma, whereas IG or TCR rearrangement studies are used to establish whether a lymphoid expansion is polyclonal or monoclonal. The molecular findings should not be evaluated in isolation, because not all monoclonal rearrangements are diagnostic of lymphoma, and not all lymphomas will show a monoclonal rearrangement. Other methodologies that can aid in the identification of a clonal process or specific genetic abnormalities include metaphase cytogenetics (karyotyping) and fluorescence in situ hybridization (FISH). If any cytogenetic abnormalities are found in sufficient numbers (and constitutional abnormalities are excluded), their identification indicates the presence of a clonal process. Also, some cytogenetic abnormalities are characteristic of certain lymphomas. However, they may be neither 100% diagnostically sensitive nor diagnostically specific, for example, the hallmark t(14;18)/IGH-BCL2 is not present in all follicular lymphomas and not all lymphomas with this translocation are follicular lymphomas. Whereas FISH is generally performed on a minimum of 200 cells, compared with typically 20 metaphase by “conventional” karyotyping, and is therefore considered to have higher analytical sensitivity, it evaluates only for the presence or absence of the abnormality being investigated with a given set of probes, and therefore other abnormalities, if present, will not be identified. The value of FISH cytogenetic studies is perhaps best illustrated in the need to diagnose double hit lymphomas, amongst other scenarios. The detection of certain mutations can aid in the diagnosis of certain lymphomas, such as MYD88 in lymphoplasmacytic lymphoma, prognosis of others, such as in follicular lymphoma and identify pathways that may be precisely therapeutically targeted.

Final remarks

The diagnosis of lymphoma can be complex and usually requires the hematopathologist to integrate multiple parameters. The classification of lymphomas is not static, and new entities or variants are continuously described, and the facets of well-known ones refined. While such changes are often to the chagrin of hematologists/oncologists and hematopathologists alike, we should embrace the incorporation of nascent and typically cool data into our practice, as more therapeutically relevant entities are molded.

Lymphomas constitute a very heterogeneous group of neoplasms with diverse clinical presentations, prognoses, and responses to therapy. Approximately 80,500 new cases of lymphoma are expected to be diagnosed in the United States in 2017, of which about one quarter will lead to the death of the patient.¹ Perhaps more so than any other group of neoplasms, the diagnosis of lymphoma involves the integration of a multiplicity of clinical, histologic and immunophenotypic findings and, on occasion, cytogenetic and molecular results as well. An accurate diagnosis of lymphoma, usually rendered by hematopathologists, allows hematologists/oncologists to treat patients appropriately. Herein we will describe a simplified approach to the diagnosis and classification of lymphomas (Figure 1).

Lymphoma classification

Lymphomas are clonal neoplasms characterized by the expansion of abnormal lymphoid cells that may develop in any organ but commonly involve lymph nodes. The fourth edition of the World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid tissues, published in 2008, is the official and most current guideline used for diagnosis of lymphoid neoplasms.² The WHO scheme classifies lymphomas according to the type of cell from which they are derived (mature and immature B cells, T cells, or natural killer (NK) cells, findings determined by their morphology and immunophenotype) and their clinical, cytogenetic, and/or molecular features. This official classification is currently being updated³ and is expected to be published in full in 2017, at which time it is anticipated to include definitions for more than 70 distinct neoplasms.

Lymphomas are broadly and informally classified as Hodgkin lymphomas (HLs) and non-Hodgkin lymphomas (NHLs), based on the differences these two groups show in their clinical presentation, treatment, prognosis, and proportion of neoplastic cells, among others. NHLs are by far the most common type of lymphomas, accounting for approximately 90% of all new cases of lymphoma in the United States and 70% worldwide.^1,2 NHLs are a very heterogeneous group of B-, T-, or NK-cell neoplasms that, in turn, can also be informally subclassified as low-grade (or indolent) or high-grade (or aggressive) according to their predicted clinical behavior. HLs are comparatively rare, less heterogeneous, uniformly of B-cell origin and, in the case of classical Hodgkin lymphoma, highly curable.^1,2 It is beyond the scope of this manuscript to outline the features of each of the >70 specific entities, but the reader is referred elsewhere for more detail and encouraged to become familiarized with the complexity, challenges, and beauty of lymphoma diagnosis.^2,3

Biopsy procedure

A correct diagnosis begins with an adequate biopsy procedure. It is essential that biopsy specimens for lymphoma evaluation be submitted fresh and unfixed, because some crucial analyses such as flow cytometry or conventional cytogenetics can only be performed on fresh tissue. Indeed, it is important for the hematologist/oncologist and/or surgeon and/or interventional radiologist to converse with the hematopathologist prior to and even during some procedures to ensure the correct processing of the specimen. Also, it is important to limit the compression of the specimen and the excessive use of cauterization during the biopsy procedure, both of which cause artifacts that may render impossible the interpretation of the histopathologic findings.

Given that the diagnosis of lymphoma is based not only on the cytologic details of the lymphoma cells but also on the architectural pattern with which they infiltrate an organ, the larger the biopsy specimen, the easier it will be for a hematopathologist to identify the pattern. In addition, excisional biopsies frequently contain more diagnostic tissue than needle core biopsies and this provides pathologists with the option to submit tissue fragments for ancillary tests that require unfixed tissue as noted above. Needle core biopsies of lymph nodes are increasingly being used because of their association with fewer complications and lower cost than excisional biopsies. However, needle core biopsies provide only a glimpse of the pattern of infiltration and may not be completely representative of the architecture. Therefore, excisional lymph node biopsies of lymph nodes are preferred over needle core biopsies, recognizing that in the setting of deeply seated lymph nodes, needle core biopsies may be the only or the best surgical option.

Clinical presentation

Accurate diagnosis of lymphoma cannot take place in a vacuum. The hematopathologist’s initial approach to the diagnosis of lymphoid processes in tissue biopsies should begin with a thorough review of the clinical history, although some pathology laboratories may not have immediate access to this information. The hematopathologist should evaluate factors such as age, gender, location of the tumor, symptomatology, medications, serology, and prior history of malignancy, immunosuppression or immunodeficiency in every case. Other important but frequently omitted parts of the clinical history are the patient’s occupation, history of exposure to animals, and the presence of tattoos, which may be associated with certain reactive lymphadenopathies.

Histomorphologic evaluation

Despite the plethora of new and increasingly sophisticated tools, histologic and morphologic analysis still remains the cornerstone of diagnosis in hematopathology. However, for the characterization of an increasing number of reactive and neoplastic lymphoid processes, hematopathologists may also require immunophenotypic, molecular, and cytogenetic tests for an accurate diagnosis. Upon review of the clinical information, a microscopic evaluation of the tissue submitted for processing by the histology laboratory will be performed. The results of concurrent flow cytometric evaluation (performed on fresh unfixed material) should also be available in most if not all cases before the H&E-stained slides are available for review. Upon receipt of H&E-stained slides, the hematopathologist will evaluate the quality of the submitted specimen, since many diagnostic difficulties stem from suboptimal techniques related to the biopsy procedure, fixation, processing, cutting, or staining (Figure 1). If deemed suitable for accurate diagnosis, a search for signs of preservation or disruption of the organ that was biopsied will follow. The identification of certain morphologic patterns aids the hematopathologist in answering the first question: “what organ is this and is this consistent with what is indicated on the requisition?” This is usually immediately followed by “is this sufficient and adequate material for a diagnosis?” and “is there any normal architecture?” If the architecture is not normal, “is this alteration due to a reactive or a neoplastic process?” If neoplastic, “is it lymphoma or a non-hematolymphoid neoplasm?”

Both reactive and neoplastic processes have variably unique morphologic features that if properly recognized, guide the subsequent testing. However, some reactive and neoplastic processes can present with overlapping features, and even after extensive immunophenotypic evaluation and the performance of ancillary studies, it may not be possible to conclusively determine its nature. If the lymph node architecture is altered or effaced, the predominant pattern of infiltration (eg, nodular, diffuse, interfollicular, intrasinusoidal) and the degree of alteration of the normal architecture is evaluated, usually at low magnification. When the presence of an infiltrate is recognized, its components must be characterized. If the infiltrate is composed of a homogeneous expansion of lymphoid cells that disrupts or replaces the normal lymphoid architecture, a lymphoma will be suspected or diagnosed. The pattern of distribution of the cells along with their individual morphologic characteristics (ie, size, nuclear shape, chromatin configuration, nucleoli, amount and hue of cytoplasm) are key factors for the diagnosis and classification of the lymphoma that will guide subsequent testing. The immunophenotypic analysis (by immunohistochemistry, flow cytometry or a combination of both) may confirm the reactive or neoplastic nature of the process, and its subclassification. B-cell lymphomas, in particular have variable and distinctive histologic features: as a diffuse infiltrate of large mature lymphoid cells (eg, diffuse large B-cell lymphoma), an expansion of immature lymphoid cells (lymphoblastic lymphoma), and a nodular infiltrate of small, intermediate and/or mature large B cells (eg, follicular lymphoma).

Immunophenotypic evaluation

Immunophenotypic evaluation is essential because the lineage of lymphoma cells cannot be determined by morphology alone. The immunophenotype is the combination of proteins/markers (eg, CD20, CD3, TdT) expressed by cells. Usually, it is evaluated by immunohistochemistry and/or flow cytometry, which help determine the proportion of lymphoid cells that express a certain marker and its location and intensity within the cells. While immunohistochemistry is normally performed on formalin-fixed and paraffin-embedded tissue, flow cytometry can be evaluated only on fresh unfixed tissue. Flow cytometry has the advantage over immunohistochemistry of being faster and better at simultaneously identifying coexpression of multiple markers on multiple cell populations. However, certain markers can only be evaluated by immunohistochemistry.

The immunophenotypic analysis will in most cases reveal whether the lymphomas is of B-, T- or NK-cell origin, and whether a lymphoma subtype associated immunophenotype is present. Typical pan B-cell antigens include PAX5, CD19, and CD79a (CD20 is less broadly expressed throughout B-cell differentiation, although it is usually evident in most mature B-cell lymphomas), and typical pan T-cell antigens include CD2, CD5, and CD7. The immature or mature nature of a lymphoma can also be confirmed by evaluation of the immunophenotype. Immature lymphomas commonly express one or more of TdT, CD10, or CD34; T-lymphoblastic lymphoma cells may also coexpress CD1a. The majority of NHLs and all HLs are derived from (or reflect) B cells at different stages of maturation. Mature B-cell lymphomas are the most common type of lymphoma and typically, but not always, express pan B-cell markers as well as surface membrane immunoglobulin, with the latter also most useful in assessing clonality via a determination of light chain restriction. Some mature B-cell lymphomas tend to acquire markers that are either never physiologically expressed by normal mature B cells (eg, cyclin D1 in mantle cell lymphoma, or BCL2 in germinal center B cells in follicular lymphoma) or only expressed in a minor fraction (eg, CD5 that is characteristically expressed in small lymphocytic and mantle cell lymphoma). The most common mature B-cell lymphomas include diffuse large B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma, mantle cell lymphoma, marginal zone lymphoma, Burkitt lymphoma, and lymphoplasmacytic lymphoma (Figures 2 and 3). Classical HLs are also lymphomas of B-cell origin that demonstrate diminished preservation of their B-cell immunophenotype (as evidenced by the dim expression of PAX5 but absence of most other pan B-cell antigens), expression of CD30, variable expression of CD15, and loss of CD45 (Figure 1). In contrast, nodular lymphocyte predominant HL shows a preserved B-cell immunophenotypic program and expression of CD45, typically without CD30 and CD15. Of note, the evaluation of the immunophenotype of the neoplastic cells in HL is routinely assessed by immunohistochemistry because most flow cytometry laboratories cannot reliably detect and characterize the low numbers of these cells.

Mature T-cell lymphomas generally express one or more T-cell markers, and tend to display a T-helper (CD4-positive) or cytotoxic (CD8-positive) immunophenotype and may show loss of markers expressed by most normal T-cells (eg, CD5, CD7; Figure 4). However, a subset of them may express markers not commonly detected in normal T cells, such as ALK. NK-cell lymphomas lack surface CD3 (expressing only cytoplasmic CD3) and CD5 but express some pan T-cell antigens (such as CD2 and CD7) as well as CD16 and/or CD56.

Patients with primary or acquired immune dysfunction are at risk for development of lymphoma and other less clearly defined lymphoproliferative disorders, the majority of which are associated with infection of the lymphoid cells with Epstein-Barr virus (EBV). Therefore, evaluation with chromogenic in situ hybridization for an EBV-encoded early RNA (EBER1) is routinely performed in these cases; it is thus essential that the hematopathologist be informed of the altered immune system of the patient. If lymphoma develops, they may be morphologically similar to those that appear in immunocompetent patients, which specifically in the post-transplant setting are known as monomorphic post-transplant lymphoproliferative disorders (PTLD). If the PTLD does not meet the criteria for any of the recognized types of lymphoma, it may be best characterized as a polymorphic PTLD.

Once the lineage (B-, T-, or NK-cell) of the mature lymphoma has been established, the sum (and on occasion the gestalt) of the clinical, morphologic, immunophenotypic and other findings will be considered for the subclassification of the neoplasm.

Cytogenetic and molecular evaluation

If the morphologic and immunophenotypic analysis is inconclusive or nondiagnostic, then molecular and/or cytogenetic testing may further aid in the characterization of the process. Some of available molecular tests include analyses for the rearrangements of the variable region of the immunoglobulin (IG) or T-cell receptor (TCR) genes and for mutations on specific genes. The identification of specific mutations not only confirms the clonal nature of the process but, on occasion, it may also help subclassify the lymphoma, whereas IG or TCR rearrangement studies are used to establish whether a lymphoid expansion is polyclonal or monoclonal. The molecular findings should not be evaluated in isolation, because not all monoclonal rearrangements are diagnostic of lymphoma, and not all lymphomas will show a monoclonal rearrangement. Other methodologies that can aid in the identification of a clonal process or specific genetic abnormalities include metaphase cytogenetics (karyotyping) and fluorescence in situ hybridization (FISH). If any cytogenetic abnormalities are found in sufficient numbers (and constitutional abnormalities are excluded), their identification indicates the presence of a clonal process. Also, some cytogenetic abnormalities are characteristic of certain lymphomas. However, they may be neither 100% diagnostically sensitive nor diagnostically specific, for example, the hallmark t(14;18)/IGH-BCL2 is not present in all follicular lymphomas and not all lymphomas with this translocation are follicular lymphomas. Whereas FISH is generally performed on a minimum of 200 cells, compared with typically 20 metaphase by “conventional” karyotyping, and is therefore considered to have higher analytical sensitivity, it evaluates only for the presence or absence of the abnormality being investigated with a given set of probes, and therefore other abnormalities, if present, will not be identified. The value of FISH cytogenetic studies is perhaps best illustrated in the need to diagnose double hit lymphomas, amongst other scenarios. The detection of certain mutations can aid in the diagnosis of certain lymphomas, such as MYD88 in lymphoplasmacytic lymphoma, prognosis of others, such as in follicular lymphoma and identify pathways that may be precisely therapeutically targeted.

Final remarks

The diagnosis of lymphoma can be complex and usually requires the hematopathologist to integrate multiple parameters. The classification of lymphomas is not static, and new entities or variants are continuously described, and the facets of well-known ones refined. While such changes are often to the chagrin of hematologists/oncologists and hematopathologists alike, we should embrace the incorporation of nascent and typically cool data into our practice, as more therapeutically relevant entities are molded.

ORLANDO – The quality of life of someone with treated hypothyroidism is worse than that of the general population and requires endocrinologists to think “outside the pill box,” said Anna M. Sawka, MD, PhD, of the University of Toronto, at a spring symposium presented by the American Thyroid Association.

While issues such as whether monotherapy with T4 is the treatment of choice or whether there is a subset of patients who might benefit from treatment with either T4/T3 in combination or even with extract of dessicated thyroid, many patients with treated hypothyroidism continue to feel bad, judging from discussion during the symposium.

[email protected]

ORLANDO – The quality of life of someone with treated hypothyroidism is worse than that of the general population and requires endocrinologists to think “outside the pill box,” said Anna M. Sawka, MD, PhD, of the University of Toronto, at a spring symposium presented by the American Thyroid Association.

While issues such as whether monotherapy with T4 is the treatment of choice or whether there is a subset of patients who might benefit from treatment with either T4/T3 in combination or even with extract of dessicated thyroid, many patients with treated hypothyroidism continue to feel bad, judging from discussion during the symposium.

[email protected]

ORLANDO – The quality of life of someone with treated hypothyroidism is worse than that of the general population and requires endocrinologists to think “outside the pill box,” said Anna M. Sawka, MD, PhD, of the University of Toronto, at a spring symposium presented by the American Thyroid Association.

While issues such as whether monotherapy with T4 is the treatment of choice or whether there is a subset of patients who might benefit from treatment with either T4/T3 in combination or even with extract of dessicated thyroid, many patients with treated hypothyroidism continue to feel bad, judging from discussion during the symposium.

[email protected]

SAN DIEGO – The way the president of the American Board of Internal Medicine, Richard J. Baron, MD, sees it, maintenance of certification is more important than ever, because trust in the medical profession “is under assault right now in all kinds of ways.”

So, to help “bring clarity to uncertainty,” ABIM is continuing its makeover of the maintenance of certification (MOC) process. Beginning in 2018, an open-book option to test every 2 years will be available for physicians who are certified in internal medicine and for those in the subspecialty of nephrology.

Doug Brunk

Linking MOC and trust

Speaking at the annual meeting of the American College of Physicians, Dr. Baron said that false and misleading information circulated widely on Facebook and other social media channels runs the gamut of health issues, from falsified studies about purported links between vaccines and autism and public health scares on impostor websites, to stories of miracle cures for any number of ailments.

“It’s not just vaccines people are questioning,” said Dr. Baron, ABIM’s president and CEO. “There are erosions of trust in government, and there’s the tenacity and power of wildly inaccurate information. You will be dealing with patients who tenaciously believe things that you know not to be true. You will need to find ways to build trust, credibility, and relationships based on their trusting that what you’re saying is really in their interest.”

U.S. physicians aren’t secure in the shaky trust landscape. In fact, globally, the United States ranks 24th in public trust level of physicians by country (N. Eng. J. Med. 2014 Oct 23;371[17]:1570-2).

“The confidence in the medical system today is lower than the confidence in police or in small business,” Dr. Baron said. “That’s [the view] people are bringing into your offices every day. I don’t think we can assume that deference and trust are given to doctors, that the privileged role that society affords us is something that we’re going to have forever. We all have to think how trust is built in the new world.”

Will patients value MOC?

During a question and answer session at the ACP session, Anne Cummings, MD, an internist who practices in Greenbrae, Calif., asked the ABIM for support in educating the general public about what it means to be treated by a board-certified physician.

“I had a naturopath tell me the other day that she had the same training as I had,” Dr. Cummings said. “I was floored, but I think that patients don’t know the difference [between board-certified and not board-certified].”

Dr. Baron agreed ABIM needs to do more to promote the value of certification among patients. But he also called on board-certified physicians to deliver the value message directly to their own patients.

Other attendees recommended that ABIM expand the number of ways physicians can earn MOC points, and they expressed concern about the time MOC takes away from their daily practice.

For regular updates on the MOC process, physicians can subscribe to the ABIM’s blog at transforming.abim.org.

[email protected]

SAN DIEGO – The way the president of the American Board of Internal Medicine, Richard J. Baron, MD, sees it, maintenance of certification is more important than ever, because trust in the medical profession “is under assault right now in all kinds of ways.”

So, to help “bring clarity to uncertainty,” ABIM is continuing its makeover of the maintenance of certification (MOC) process. Beginning in 2018, an open-book option to test every 2 years will be available for physicians who are certified in internal medicine and for those in the subspecialty of nephrology.

Doug Brunk

Linking MOC and trust

Speaking at the annual meeting of the American College of Physicians, Dr. Baron said that false and misleading information circulated widely on Facebook and other social media channels runs the gamut of health issues, from falsified studies about purported links between vaccines and autism and public health scares on impostor websites, to stories of miracle cures for any number of ailments.

“It’s not just vaccines people are questioning,” said Dr. Baron, ABIM’s president and CEO. “There are erosions of trust in government, and there’s the tenacity and power of wildly inaccurate information. You will be dealing with patients who tenaciously believe things that you know not to be true. You will need to find ways to build trust, credibility, and relationships based on their trusting that what you’re saying is really in their interest.”

U.S. physicians aren’t secure in the shaky trust landscape. In fact, globally, the United States ranks 24th in public trust level of physicians by country (N. Eng. J. Med. 2014 Oct 23;371[17]:1570-2).

“The confidence in the medical system today is lower than the confidence in police or in small business,” Dr. Baron said. “That’s [the view] people are bringing into your offices every day. I don’t think we can assume that deference and trust are given to doctors, that the privileged role that society affords us is something that we’re going to have forever. We all have to think how trust is built in the new world.”

Will patients value MOC?

During a question and answer session at the ACP session, Anne Cummings, MD, an internist who practices in Greenbrae, Calif., asked the ABIM for support in educating the general public about what it means to be treated by a board-certified physician.

“I had a naturopath tell me the other day that she had the same training as I had,” Dr. Cummings said. “I was floored, but I think that patients don’t know the difference [between board-certified and not board-certified].”

Dr. Baron agreed ABIM needs to do more to promote the value of certification among patients. But he also called on board-certified physicians to deliver the value message directly to their own patients.

Other attendees recommended that ABIM expand the number of ways physicians can earn MOC points, and they expressed concern about the time MOC takes away from their daily practice.

For regular updates on the MOC process, physicians can subscribe to the ABIM’s blog at transforming.abim.org.

[email protected]

SAN DIEGO – The way the president of the American Board of Internal Medicine, Richard J. Baron, MD, sees it, maintenance of certification is more important than ever, because trust in the medical profession “is under assault right now in all kinds of ways.”

So, to help “bring clarity to uncertainty,” ABIM is continuing its makeover of the maintenance of certification (MOC) process. Beginning in 2018, an open-book option to test every 2 years will be available for physicians who are certified in internal medicine and for those in the subspecialty of nephrology.

Doug Brunk

Linking MOC and trust

Speaking at the annual meeting of the American College of Physicians, Dr. Baron said that false and misleading information circulated widely on Facebook and other social media channels runs the gamut of health issues, from falsified studies about purported links between vaccines and autism and public health scares on impostor websites, to stories of miracle cures for any number of ailments.

“It’s not just vaccines people are questioning,” said Dr. Baron, ABIM’s president and CEO. “There are erosions of trust in government, and there’s the tenacity and power of wildly inaccurate information. You will be dealing with patients who tenaciously believe things that you know not to be true. You will need to find ways to build trust, credibility, and relationships based on their trusting that what you’re saying is really in their interest.”

U.S. physicians aren’t secure in the shaky trust landscape. In fact, globally, the United States ranks 24th in public trust level of physicians by country (N. Eng. J. Med. 2014 Oct 23;371[17]:1570-2).

“The confidence in the medical system today is lower than the confidence in police or in small business,” Dr. Baron said. “That’s [the view] people are bringing into your offices every day. I don’t think we can assume that deference and trust are given to doctors, that the privileged role that society affords us is something that we’re going to have forever. We all have to think how trust is built in the new world.”

Will patients value MOC?

During a question and answer session at the ACP session, Anne Cummings, MD, an internist who practices in Greenbrae, Calif., asked the ABIM for support in educating the general public about what it means to be treated by a board-certified physician.

“I had a naturopath tell me the other day that she had the same training as I had,” Dr. Cummings said. “I was floored, but I think that patients don’t know the difference [between board-certified and not board-certified].”

Dr. Baron agreed ABIM needs to do more to promote the value of certification among patients. But he also called on board-certified physicians to deliver the value message directly to their own patients.

Other attendees recommended that ABIM expand the number of ways physicians can earn MOC points, and they expressed concern about the time MOC takes away from their daily practice.

For regular updates on the MOC process, physicians can subscribe to the ABIM’s blog at transforming.abim.org.

[email protected]

Click here to access the April 2017 Digital Edition.

Table of Contents

• Write for Us, Right for You
• A Heart Failure Management Program Using Shared Medical Appointments
• Suspected Clozapine-Induced Cardiomyopathy and Heart Failure With Reduced Ejection Fraction
• Military Sexual Trauma and Sexual Health: Practice and Future Research for Mental Health Professionals
• Veterans as Caregivers: Those Who Continue to Serve
• Conjoint Sessions With Clinical Pharmacy and Health Psychology for Chronic Pain
• Hypoperfusion Retinopathy
• William Beaumont: A Pioneer of Physiology

 

Click here to access the April 2017 Digital Edition.

Table of Contents

• Write for Us, Right for You
• A Heart Failure Management Program Using Shared Medical Appointments
• Suspected Clozapine-Induced Cardiomyopathy and Heart Failure With Reduced Ejection Fraction
• Military Sexual Trauma and Sexual Health: Practice and Future Research for Mental Health Professionals
• Veterans as Caregivers: Those Who Continue to Serve
• Conjoint Sessions With Clinical Pharmacy and Health Psychology for Chronic Pain
• Hypoperfusion Retinopathy
• William Beaumont: A Pioneer of Physiology

 

Click here to access the April 2017 Digital Edition.

Table of Contents

• Write for Us, Right for You
• A Heart Failure Management Program Using Shared Medical Appointments
• Suspected Clozapine-Induced Cardiomyopathy and Heart Failure With Reduced Ejection Fraction
• Military Sexual Trauma and Sexual Health: Practice and Future Research for Mental Health Professionals
• Veterans as Caregivers: Those Who Continue to Serve
• Conjoint Sessions With Clinical Pharmacy and Health Psychology for Chronic Pain
• Hypoperfusion Retinopathy
• William Beaumont: A Pioneer of Physiology